Advances en Pediatrics 2013

ADVANCES IN
Pediatrics
CONTRIBUTORS
CAROL D. BERKOWITZ, MD, FAAP, FACEP, Executive Vice Chair, Department
of Pediatrics, Harbor-UCLA Medical Center; Professor of Clinical Pediatrics,
David Geffen School of Medicine at UCLA, Torrance, California
ARTURO BRITO, MD, MPH, Associate Clinical Professor of Population and Family
Health, Columbia University, Mailman School of Public Health, New York,
New York
PERRY M. BUTTERFIELD, MA, Retired, Senior Research Associate, Department of

Psychiatry, University of Colorado Medical School, Denver, Colorado
SILVANA CARR, MD, Division of Infectious Diseases, Department of Pediatrics,

Morsani College of Medicine, University of South Florida, Tampa, Florida
TINA Q. CHENG, DO, Fellow, Division of Pediatric Endocrinology, Cohen Children’s

Medical Center of New York, New Hyde Park, New York
ANDREW M. DAVIDOFF, MD, Chairman, Member, Department of Surgery, St. Jude

Children’s Research Hospital; Professor, Departments of Surgery, Pediatrics,
Pathology and Laboratory Medicine, University of Tennessee Health Science
Center, Memphis, Tennessee
PENELOPE H. DENNEHY, MD, Division of Pediatric Infectious Diseases, Hasbro

Children’s Hospital; Professor and Vice Chair for Academic Affairs, Department
of Pediatrics, The Alpert Medical School of Brown University, Providence,
Rhode Island
MARY E. FALLAT, MD, Hirikati S. Nagaraj Professor and Division Director of Pediatric
Surgery, Department of Surgery, University of Louisville, Surgeon-in-Chief,
Kosair Children’s Hospital, Louisville, Kentucky
ROGER GILLER, MD, Department of Pediatrics, Children’s Hospital Colorado,

University of Colorado Denver School of Medicine, Aurora, Colorado
DELANEY GRACY, MD, MPH, Chief Medical Officer, Senior Vice President for
Medical Affairs, Children’s Health Fund, New York, New York
ROY GRANT, MA, Director, Clinical Information Systems, Children’s Health Fund,
New York, New York
PAIGE HERTWECK, MD, Chief of Gynecology, Director of Pediatric and Adolescent

Gynecology, Kosair Children’s Hospital; Clinical Professor, Department of
Pediatrics, University of Louisville, Louisville, Kentucky
vii
CONTRIBUTORS continued
FRAN HICKEY, MD, Medical Director, Associate Professor, Department of Pediatrics,

Anna and John Sie Center for Down Syndrome, Children’s Hospital Colorado,
University of Colorado School of Medicine, Aurora, Colorado
ERIN HICKEY, Research Assistant, Anna and John Sie Center for Down Syndrome,
Children’s Hospital Colorado, University of Colorado School of Medicine,
Aurora, Colorado
QUYNH B. HOANG, MD, Pediatrics Sports Medicine Program; Assistant Professor,

Department of Orthopedics, Children’s Hospital Colorado, University of
Colorado Health Sciences Center, Aurora, Colorado
STEPHEN P. HUNGER, MD, Department of Pediatrics, Children’s Hospital Colorado,

MICHAEL S. KAPPY, MD, PhD, FAAP, Department of Pediatrics, Children’s Hospital

Colorado, University of Colorado Health Sciences Center, Aurora, Colorado
CHRISTINA LAM, MD, Division of Medical Genetics, Department of Pediatrics, David

Geffen School of Medicine at UCLA, Los Angeles, California
DAVID M. MAAHS, MD, PhD, Department of Pediatrics, Children’s Hospital

Colorado; Barbara Davis Center for Childhood Diabetes, University of Colorado
Denver, Anschutz Medical Campus, Aurora, Colorado
SHIDEH MAJIDI, MD, Department of Pediatrics, Children’s Hospital Colorado;

Barbara Davis Center for Childhood Diabetes, University of Colorado Denver,
Anschutz Medical Campus, Aurora, Colorado
KELLY W. MALONEY, MD, Department of Pediatrics, Children’s Hospital Colorado,

MICHAEL A. MILLER, MD, Assistant Professor of Pediatrics, Pediatric Infectious

Diseases and Immunology, University of Florida; Wolfson Children’s Hospital,
Jacksonville, Florida
AYESHA MIRZA, MD, FAAP, Assistant Professor, Department of Pediatrics, Division

of Infectious Diseases and Immunology, University of Florida, Jacksonville, Florida
MOHAMMED MORTAZAVI, MD, Pediatric Primary Care Sports Medicine Fellow,

Department of Orthopedics, Children’s Hospital Colorado, University
of Colorado Health Sciences Center, Aurora, Colorado
IAN M. PAUL, MD, MSc, Professor, Departments of Pediatrics and Public Health
Sciences, Penn State College of Medicine, Hershey, Pennsylvania
JENNIFER PRUITT, Director, Clinical Information Systems, Children’s Health Fund,

New York, New York
viii
CONTRIBUTORS continued
STEVEN J. RALSTON, MD, MPH, Instructor in Obstetrics and Gynecology, Harvard

Medical School, Boston, Massachusetts
MOBEEN H. RATHORE, MD, FAAP, CPE, Professor and Associate Chair, Department
of Pediatrics, Chief, Division of Infectious Diseases and Immunology, University
of Florida; Wolfson Children’s Hospital, Jacksonville, Florida
PHYLLIS W. SPEISER, MD, Professor of Pediatrics, Hofstra North Shore LIJ School
of Medicine, Lake Success; Division of Pediatric Endocrinology, Cohen
Children’s Medical Center of New York, New Hyde Park, New York
KAREN L. SUMMAR, MD, MS, Assistant Professor, Department of Pediatrics George

Washington University, Children’s National Medical Center, Washington, DC
ANGELA SUN, MD, Medical Genetics Institute, Cedars-Sinai Medical Center,

Los Angeles, California
JEB WEISMAN, PhD, Chief Information Officer, Children’s Health Fund, New York,
New York
DEREK A. WONG, MD, Division of Medical Genetics, Department of Pediatrics,

David Geffen School of Medicine at UCLA, Los Angeles, California
ix
C
ADVANCES IN
Pediatrics
CONTENTS VOLUME 59 2012
Associate Editors v
Contributors vii
Introduction xxi
By Michael S. Kappy
Foundations of Pediatrics: Virginia Apgar

(1909—1974)
By Perry M. Butterfield
References 7
Pediatric HIV Infection

By Ayesha Mirza and Mobeen H. Rathore
Pediatric HIV infection: 30 years and moving forward 9
Evolution of HIV-1 10
Immunopathogenesis of HIV-1 infection 10
Immune dysfunction and HIV infection 15
Pediatric HIV infection with a focus on mother-to-child transmission 16
Management of HIV disease in children and adolescents 17
Management of the HIV-exposed infant 19
HIV prevention efforts in the United States 21
Summary 23
References 24
Advances in Pediatric Pharmacology, Therapeutics,

and Toxicology
By Ian M. Paul
Symptomatic care 29
Analgesic-antipyretics 29
Cough and cold 30
Teething 31
Pulmonary and allergy 31
Asthma 31
Cystic fibrosis 33
Drug allergy 33
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CONTENTS continued
Infectious diseases 34
Otitis media 34
Urinary tract infections 34
Pneumonia 35
Methicillin-resistant Staphylococcus aureus 35
Neonatology 36
Gastroesophageal reflux 36
Transient tachypnea of the newborn 36
Herpes simplex virus 36
Retinopathy of prematurity 37
Fetal and neonatal effects of medications taken during pregnancy 37
Dermatology 38
Endocrinology 38
Type 1 diabetes mellitus 38
Obesity 39
Neurology 39
Psychiatry 39
Attention deficit hyperactivity disorder 39
Antipsychotic medications 40
Cardiology 41
References 41
Rotavirus Infection: An Update on Management

and Prevention
By Penelope H. Dennehy
Epidemiology and transmission of infection 48
Control measures to prevent infection 49
Pathophysiology of rotavirus disease 49
Clinical illness 50
Diagnosis and management of infection 52
Adjunctive therapy 53
Rotavirus structure and classification 53
Natural protection 54
Goals for a rotavirus vaccine 55
Development of rotavirus vaccines 55
Human-rhesus rotavirus reassortant vaccine 55
Currently licensed vaccines 56
Human-bovine rotavirus reassortant vaccine (RV5, RotaTeq) 56
Live, attenuated human rotavirus vaccine (RV1, Rotarix) 58
Worldwide implementation of rotavirus vaccines 59
Rotavirus vaccine use in the United States 59
Recommendations for the use of rotavirus vaccine 59
Implementation of the rotavirus vaccine program in the United States 62
Vaccine Uptake 62
Postlicensure safety-monitoring data from the United States 63
Rotavirus surveillance in the United States 63
The effectiveness of rotavirus vaccination in the prevention
of rotavirus disease 64
xii
CONTENTS continued
The impact of rotavirus vaccination on the health burden of

rotavirus disease in the United States 65
Herd immunity after rotavirus vaccination 65
Changing epidemiology and seasonality of rotavirus disease after
vaccine introduction in the United States 66
Effect of vaccination on rotavirus strain circulation and emergence 66
Summary 67
References 68
Seasonal and Pandemic Influenza: An Overview

with Pediatric Focus
By Silvana Carr
Biology of influenza 76
Structure 76
Influenza life cycle 77
Immunity to influenza infection 77
Antigenic drift and antigenic shift 78
Impact and epidemiology of influenza in children 78
Clinical manifestations 80
Diagnosis 81
Complications 82
Treatment 83
Prophylaxis 87
Influenza vaccines 87
Current recommendations for influenza vaccination 87
Influenza vaccine to egg-allergic children 89
Influenza chemoprophylaxis 89
Summary 90
Acknowledgments 90
References 90
Immunization in Special Populations

By Michael A. Miller and Mobeen H. Rathore
Preterm and low-birth weight infants 96
Hepatitis B vaccine 96
DTaP, Hib, and IPV vaccines 97
Pneumococcal conjugate vaccine 97
Influenza vaccine 98
Pregnant women 98
Tdap 98
Influenza 98
Other inactivated vaccines 99
Live vaccines 99
Other vaccines 99
Primary immune deficiencies 99
Live vaccines 100
Inactivated vaccines 100
Solid organ transplant recipients 100
xiii
CONTENTS continued
Live vaccines 101

Children with cancer 104
Live attenuated vaccines 105
Inactivated and recombinant vaccines 105
Hematopoietic stem cell transplant recipients 107
DTaP 108
Poliovirus vaccine 108
MMR 108
Hib vaccine 110
Pneumococcal vaccine 110
HIV-infected children 110
Live vaccines 117
Children on corticosteroids 118
Children with hyposplenia/asplenia 118
Hib vaccine 120
Meningococcal vaccine 120
Children with rheumatologic diseases 120
DTaP 121
Hepatitis B vaccine 121
Live vaccines 122
Internationally adopted children 122
Pediatric travelers 124
IPV 124
Measles 124
Hepatitis B 124
Hepatitis A 124
DTaP 125
Hib 125
Varicella 125
Yellow fever 125
Typhoid vaccine 126
Japanese encephalitis vaccine 126
Rabies vaccine 126
Summary 127
References 127
Medical Update for Children With Down Syndrome

for the Pediatrician and Family Practitioner
By Fran Hickey, Erin Hickey and Karen L. Summar
Epidemiology, genetics, and prenatal diagnosis of down syndrome 137
Clinical assessment 138
xiv
CONTENTS continued
The newborn period 138

Childhood 139
Comorbidities by systems 141
Cardiovascular 141
Otolaryngology 141
Hematology and oncology 143
Neurology 143
Immunology 147
Pulmonary and sleep 148
Gastrointestinal 149
Endocrinology 152
Orthopedics 153
Dental 154
Acknowledgments 154
References 155
Content Barriers to Pediatric Uptake of Electronic

Health Records
By Delaney Gracy, Jeb Weisman, Roy Grant, Jennifer Pruitt,
and Arturo Brito
Introduction 159
A brief history of EHRs 161
The status of current EHRs for use in pediatric practice 162
EHRs in practice: case studies 164
Structured data, unstructured data, and required fields 168
Structured data 168
Unstructured data 169
Required fields 169
Considerations in the development of pediatric EHR clinical content 170
Structured data: history, orders, and plans 171
Ability to document caregiver information 175
Units of measurement 175
Pediatric norms 176
Developmental screening 176
Referral tracking 176
Confidentiality, behavioral health, and sensitive health information 177
Summary 177
References 178
Sudden Infant Death Syndrome, Sudden

Unexpected Infant Death, and Apparent
Life-Threatening Events
By Carol D. Berkowitz
Definition 184
Epidemiology 184
Apnea and SIDS: a historical perspective 185
Apparent life-threatening event 186
xv
CONTENTS continued
A changing picture of SIDS 188

SUID 190
Inborn errors of metabolism 190
Gene polymorphisms 191
Child abuse 191
Channelopathies: prolonged QT syndrome 192
Triple-risk model 193
Intrinsic risk factors 193
Role of neurotransmitters 193
Environmental factors 194
Extrinsic risk factors 194
Death scene investigation 194
Unsafe sleep environments: beyond back to sleep 198
Bed-sharing risks 198
Breastfeeding and bed sharing 199
Bed sharing and cultural and socioeconomic considerations 200
The role of grandparents 200
Recommendations of the AAP to promote safe sleep 200
A quality improvement model 202
References 202
Expanded Newborn Screening for Inborn Errors of

Metabolism: Overview and Outcomes
By Angela Sun, Christina Lam, and Derek A. Wong
Introduction 209
Carbohydrate disorders galactosemia 210
Amino acid disorders 212
Phenylketonuria and hyperphenylalaninemia 212
Disorders of biopterin metabolism 213
Tyrosinemia type I (hepatorenal) 213
Tyrosinemia type II (oculocutaneous) 214
Tyrosinemia type III 214
Homocystinuria 214
Methionine adenosyltransferase and related disorders 215
Biotinidase deficiency 215
Maple syrup urine disease 216
Urea cycle disorders 217
Ornithine transcarbamylase deficiency 217
Citrullinemia 217
Argininosuccinate lyase deficiency 218
Other urea cycle disorders 218
Citrin deficiency 218
Organic acid disorders 218
Overview 218
Propionic acidemia 219
Isovaleric acidemia 220
Methylmalonic acidemia types mut0/mut- 220
Cobalamin A/B/C/D1 220
3-methylcrotonyl-CoA-carboxylase deficiency 221
xvi
CONTENTS continued
HMG-CoA-lyase deficiency 221

Holocarboxylase synthetase deficiency 221
2-methyl-3OH butyryl-CoA dehydrogenase deficiency 222
2-methylbutyrylglycinuria 222
b-ketothiolase deficiency 223
Glutaric aciduria type I 223
Isobutyrylglycinuria 223
3-methylglutaconic aciduria 224
Ethylmalonic encephalopathy 224
Malonic aciduria 224
Disorders of fatty acid oxidation 225
Overview 225
SCAD deficiency 225
MCAD deficiency 226
VLCAD deficiency 226
CPT-I deficiency 227
CPT-II deficiency 227
CACT deficiency 227
CTD deficiency 228
LCHAD and TFP deficiency 228
M/SCHAD deficiency 228
GA-II/multiple acyl-CoA dehydrogenase deficiency 229
Lysosomal storage diseases 229
Overview 229
Pompe disease 230
Krabbe disease 230
Fabry disease 230
Other lysosomal storage disorders 231
Ethical issues 231
Future developments 232
References 232
Wilms Tumor
By Andrew M. Davidoff
Introduction 247
Pathology 248
Genetics 248
Presentation 251
Evaluation 251
Staging 252
NWTS 252
Current protocols 254
AREN0532: treatment of very low-risk and standard-risk
favorable histology Wilms tumor 254
AREN0533: treatment of newly diagnosed higher risk
favorable histology Wilms tumors 256
AREN0321: treatment of high-risk renal tumors 257
AREN0534: treatment of patients with bilateral, multicentric, or
bilaterally predisposed unilateral Wilms tumor 258
xvii
CONTENTS continued
Surgery for Wilms tumor 258

Timing of surgery 258
Bilateral Wilms tumor 261
Intravascular tumor extension 262
Metastatic disease 262
Recurrent disease 263
Late effects 263
Summary 264
References 264
Treatment Outcomes in Congenital Adrenal Hyperplasia

By Tina Q. Cheng and Phyllis W. Speiser
21-Hydroxylase deficiency CAH 269
11b-Hydroxylase deficiency CAH 272
17a-Hydroxylase/17,20-lyase deficiency CAH 273
3b-Hydroxysteroid dehydrogenase deficiency CAH 273
Congenital lipoid adrenal hyperplasia 274
P450 oxidoreductase deficiency 274
Update on specific 21-hydroxylase deficiency treatment guidelines 275
Newborn screening 275
Prenatal treatment of CAH 275
Medical treatment 275
NCCAH 277
Growth and development 277
Surgical intervention 278
Psychosexual health 278
Genetic testing/counseling 279
Transition to adult care 279
Pregnancy and fertility 279
Summary 279
References 279
Surgical and Ethical Challenges in Disorders of

Sexual Development
By Mary E. Fallat, Paige Hertweck, and Steven J. Ralston
Introduction 283
DSD categories 284
Female DSD 284
Male DSD 286
Gonadal ambiguities resulting from chromosomal abnormalities
or syndromes 287
Neoplasia arising in abnormal gonads 288
Diagnostic evaluation 288
Ethical issues 289
Initial presentation 289
Informed consent and the pediatric patient 290
What should be done in the context of what is being asked for? 291
Treatment options 291
xviii
CONTENTS continued
Case 1: CAIS 292

Case 2: Müllerian agenesis 292
Case 3: Mixed gonadal dysgenesis 293
Case 4: Anatomic developmental abnormality after bladder
exstrophy repair 293
Case 5: Vaginal atresia 295
Case 8: Ovotesticular DSD 298
Case 9: CAH presenting after early reconstruction with inadequate
vagina 299
Treatment effectiveness and patient outcomes 299
CAH 299
Vaginal atresia 300
Clitoral procedures 300
Summary 300
References 301
Update on Care of Children with Type 1 Diabetes

By Shideh Majidi and David M. Maahs
Incidence and prevalence 304
Cause/pathophysiology 305
Management 306
Diagnosis 306
DKA 307
Management of outpatient insulin 311
Multidisciplinary teams 313
Comorbid conditions 313
Complications 314
Hypoglycemia 314
Macrovascular and microvascular complications 315
Current research 319
Closed-loop system 319
Prevention of T1D 320
Transplantation 321
References 322
Recent Advances in the Understanding and

Treatment of Pediatric Leukemias
By Kelly W. Maloney, Roger Giller, and Stephen P. Hunger
Introduction and overview 329
ALL 330
Overview of chemotherapy used to treat ALL 330
Recent developments in treatment of newly diagnosed childhood ALL 333
Treatment of relapsed ALL 336
New prognostic factors and potential therapeutic targets in childhood
ALL 336
AML 338
xix
CONTENTS continued
Treatment of AML 338

Special subgroups of AML 339
CML 341
Overview 341
Biology of CML 341
CML treatment and prognosis 342
Hematopoietic Stem Cell Transplantation 343
Overview 343
Details of HSCT therapy 343
Components of transplant care 345
The role of HSCT in ALL treatment 347
The role of HSCT in AML treatment 349
The role of HSCT in CML treatment 350
The role of HSCT in treatment of JMML and MDS 350
References 352
Pediatric Overuse Injuries in Sports

By Quynh B. Hoang and Mohammed Mortazavi
Introduction 359
Upper extremity injuries 360
Little league shoulder (proximal humerus epiphysitis) 360
Multidirectional shoulder instability 362
Medial epicondyle apophysitis (little league elbow) 364
Gymnast’s wrist (distal radius epiphysitis) 365
Lower extremity injuries 367
Iselin disease (fifth metatarsal apophysitis) 367
Sever disease (calcaneal apophysitis) 369
Osgood-Schlatter disease (tibial tubercle apophysitis) 370
Sinding-Larsen-Johansson disease (apophysitis of the inferior
pole of the patella) 371
Patellar tendinopathy (‘‘jumper’s knee’’) 372
Patellofemoral pain syndrome 372
Hip injuries 374
Pelvic apophysitis 374
IT band syndrome (IT band tendinitis) 376
Back injuries 377
Spondylolysis 377
Summary 379
References 379
Index 385
xx
Advances in Pediatrics 59 (2012) xxi
ADVANCES IN PEDIATRICS
Introduction
Michael S. Kappy, MD, PhD
T
he members of the Editorial Board are pleased to present volume 59 of
Advances in Pediatrics. In accordance with the title, we seek articles of
interest on a broad spectrum of topics to acquaint the reader with signif-
icant advances in the practice of pediatrics. We feature Virginia Apgar, who
was critical in establishing modern guidelines for the care of the neonate, as
our ‘‘Foundations of Pediatrics’’ tribute by Perry Butterfield. Advances in
the field of infectious diseases are presented in the articles contributed by
Drs Mirza and Rathore, Dennehy, Carr, and Miller and Rathore’s guidelines
for immunizing special populations.
Ian Paul continues to update us on pharmacology, therapeutics and toxicology
every two years, as many changes occur in these fields rapidly. Drs Hickey and
Summar and Gracy et al provide guidelines for establishing a ‘‘medical home’’
for children with Down syndrome and other special needs.
Issues relevant in early life are presented by Dr Berkowitz (SIDS, SUIDS and
ALTEs) and advances and controversies regarding screening for inherited disor-
ders of metabolism in the newborn (Sun et al). The course of children after hema-
tologic/oncologic conditions are described by Dr Davidoff (Wilm’s tumor) and
by Dr Hunger et al (leukemias), and companion articles appear on congenital
adrenal hyperplasia (Drs Cheng and Speiser) and the surgical approach to chil-
dren with disorders of sexual development (Fallat et al).
The constantly evolving approach to the treatment of children with Type 1
diabetes is given by Drs Majidi and Maahs, and we conclude this volume with
a discussion of overuse injuries in sports by Drs Hoang and Mortazavi.
As always, the editors welcome comments about each volume of Advances in
Pediatrics and suggestions for topics for future volumes. These can be sent to:
michael.kappy@childrenscolorado.org.
Michael S. Kappy, MD, PhD

Department of Pediatrics
University of Colorado Health Sciences Center
The Children’s Hospital
13123 East 16th Avenue
B-265, Aurora, CO 80045, USA
E-mail address: Michael.Kappy@childrenscolorado.org
0065-3101/12/$ – see front matter

doi:10.1016/j.yapd.2012.04.014 Ó 2012 Elsevier Inc. All rights reserved.
Advances in Pediatrics 59 (2012) 1–7
Foundations of Pediatrics
Virginia Apgar (1909–1974)
Virginia Apgar, MD (1909–1974). (Courtesy of Augustus C. Long Health Sciences Library,

Columbia University, new York, NY; with permission.)
Perry M. Butterfield, MA
2198 South Jackson Street, Denver, CO 80210, USA
V
irginia Apgar changed the path of obstetric anesthesia, opened the eyes
of the world to the need for neonatal medicine, and brought support and
understanding for the birth defective child (Fig. 1). She was a woman
of effervescent personality, boundless energy, with a brilliant and creative
mind. I am pleased to write about one of medicine’s great physicians, a remark-
able woman and dear friend.
Born in Westfield, New Jersey in June 1909, to Charles and Helen Apgar,
Virginia was the youngest of 3 children. She was raised in an intellectual envi-
ronment. Her father taught her to read before she could begin school. The
family enjoyed reading aloud together, and every member played a musical
E-mail address: perry.butterfield@gmail.com

2 BUTTERFIELD
instrument. Virginia began violin lessons at the age of 6 years, often joining in
home family concerts. Virginia’s interest in science and invention were encour-
aged by her father, who was a well-known amateur astronomer who published
in professional journals. He built a laboratory with a telescope and wireless in
their basement, where Virginia loved to spend time. After graduating from
Westfield High School, Virginia announced that she would pursue a career
in medicine [1,2].
Her undergraduate degree was from Mt Holyoke College in 1929. She sup-
ported her studies with scholarships and odd jobs, such as catching stray cats
for the zoology laboratory. Her MD was from Columbia University College of
Physicians and Surgeons, 1933. She graduated fourth in her class, a member of
Alpha Omega Alpha, and was deeply in debt.
Embarking on her career during the Great Depression meant that career
choices were often driven by financial necessity. At that time, women
comprised less than 6% of physicians in the United States. She hesitated about
continuing her training, but won a prized surgical internship at Columbia, so
she completed a residency in surgery. Her Chairman, Dr Allen Whipple,
discouraged her from trying to find a job in the practice of surgery. He sug-
gested a new specialty for doctors, that of anesthesiology, which was thought
to be more suitable for women.
Her anesthesiology training included 6 months at the University of Wisconsin,
working with Dr Ralph Waters, and 6 months at Bellevue Hospital, New York.
At Dr Whipple’s urging, she returned to Columbia University College of Physi-
cians and Surgeons in 1938 to become an attending anesthesiologist as well as
Chief of the newly formed Division of Anesthesia. She also continued her clinical
work in obstetric anesthesia at the affiliated Sloane Hospital for Women [1].
Between the years 1938 and 1945, Dr Apgar increased the number of residents
in the training program from 1 to 18. As more MDs entered anesthesiology, Vir-
ginia was a leader in promoting its acceptance and respect as a medical subspe-
cialty. At that time, physicians giving anesthesia were not allowed to charge
professional fees and, in October 1940, Dr Apgar threatened to resign because
of this inequity. The policy was soon changed at Columbia and elsewhere [1].
In 1949, Emmanuel Papper, an anesthesiologist from Bellevue, was brought
to Columbia to focus on research. The division was reclassified as a depart-
ment, and Virginia Apgar became the first female full professor at Columbia.
Freed from administrative duties, Virginia focused her attention on obstetric
anesthesia. At that time, most babies were delivered under anesthesia. Saddle
blocks, caudal blocks, and cyclopropane were used for most vaginal deliveries.
Forceps deliveries and large episiotomies kept the obstetricians occupied with
repairing the episiotomy after the birth. The newborn, often lethargic from
the anesthesia, was unattended for long periods of time waiting to be trans-
ported with the mother to a recovery room. Virginia observed these babies
and realized that many of them were in distress. She began doing resuscitations
of them in the delivery room and teaching her students to be attentive to the
newborn [1,3].
FOUNDATIONS OF PEDIATRICS 3
The story, often told at Columbia, is that a medical student on her service
asked Dr Apgar at breakfast how to evaluate a newborn. ‘‘That’s easy, you
would do it like this,’’ said Virginia. She grabbed a napkin and jotted down
5 points, then rushed off to the obstetric unit to try it out.
Dr Apgar began a systematic examination of these 5 points in a research para-
digm. The parameters of the score were (1) color, (2) pulse, (3) activity, (4) reflex
response, and (5) respiratory effort. Each category was given a weighted score: 2,
1, or 0, with 2 being the best and 0 the worst scores. These scores were assessed
at 1 minute and 5 minutes after birth, provided guidelines for resuscitative
parameters, and were regarded as prognostic indicators of the child’s outcome.
In 1952, Dr Apgar presented her results at the 27th annual Congress of Anesthe-
tists and International College of Anesthetists. It was published in Anesthesia &
Analgesia in 1953 [4]. Dr Apgar’s friend, Dr Lulu Lubchenco at the University
of Colorado Medical School, was another pioneering woman in medical
research.
Dr Lubchenco was studying the viability of a newborn according to gesta-
tional age, weight, and length. Her so-called egg chart of gestational viability
is still referred to today. My husband, Dr Joe Butterfield, was a fellow with
Dr Lubchenco in 1955 and both were asked by Dr Apgar to use the Apgar score
as a teaching tool for students. To make it easier for their students to remember
the points on the score, Joe rearranged them into a mnemonic device using the
letters in Dr Apgar’s name: A for appearance (color), P for pulse, G for grimace
(reflex response), A for activity level, and R for respiratory effort. In 1962, Joe
and a colleague, Dr Mervyn J. Covey, sent the acronym to the Journal of the
American Medical Association (JAMA) in a letter, which they published [5,6].
Dr Apgar graciously wrote:
‘‘Dear Joe: I was surprised and naturally pleased to open my JAMA this
week to find the epigram looking at me! Many thanks for your interest in
this field and for figuring out this simple teaching device.
Sincerely yours,
—Virginia Apgar MD, MPH’’
In 1962, the American Journal of Diseases of Children requested permission to

reprint the acronym [6].
The Apgar score is still used worldwide as a clinical tool for the evaluation of
the neonate. It provided a systematic way for clinicians and researchers to eval-
uate a newborn’s physiologic integrity. Its 1-minute and 5-minute requirements
focused physicians in the delivery room on the need for immediate attention to
the newborn infant and on follow-up care of the baby as a patient.
As our knowledge has advanced, the Apgar score has come under scrutiny
from time to time as being obsolete [7,8]. Dr Maureen Hack, at Case Western
Reserve University, commented to Joe, ‘‘It was never intended to predict later
outcome and is probably not intended for use with the less than 28-week gesta-
tion infant,’’ but the Apgar score still provides a standardized baseline for
neonatal resuscitation parameters [7].
4 BUTTERFIELD
Because smaller and earlier gestational newborns are now being saved
through advanced medical technologies, sophisticated evaluation scales have
been developed, such as the neonatal resuscitation program (NRP) and pedi-
atric advanced life support (PALS). It has been often said that every baby
born in a modern hospital anywhere in the world today is looked at first
through the eyes of Virginia Apgar.
In the late 1950s, there were only a handful of physicians doing research with
newborns. When Joe Butterfield finished his fellowship with Dr Lubchenco in
1958, he joined the staff at The Children’s Hospital Denver, where he initiated
an intensive care nursery with 3 beds. By 1965, Children’s could give Joe the
resources to open a regional newborn center with air and ground capabilities
for transport. He called this ‘‘Newborn Center USA.’’ He wrote to Virginia
asking whether he could come to New York and consult with her. At that time,
she urged him to contact the handful of physicians who were doing research
with neonates or sick newborns and try to bring them together to share and coor-
dinate their work. He followed through on this suggestion in the early 1960s and
invited them to a meet in Aspen, Colorado, to share their research. There were 8
doctors in attendance, including Jerold Lucey, University of Vermont; William
Tooley, San Francisco; L. Stanley James, Columbia University, NY; and Mildred
Stahlman, Vanderbilt University. A nurse at the University of Colorado
Hospital, June Reinholt, agreed to come as cook for the group. There were to
be no minutes, documentation, or publications from this meeting; only open,
free sharing of information and ideas. This original group communicated with
others and continued to meet during the next few years to set standards for treat-
ment of the newborn. They formed the nucleus for a growing group of pediatri-
cians who continued to focus their interest on the neonate and to work together as
‘‘neonatologists’’. In 1971, the Colorado chapter of the American Academy of
Pediatrics (AAP) petitioned the AAP Executive Board to establish a section on
perinatal medicine. In 1976, the first AAP District VIII Perinatal Section was
formed, and neonatology as a specialty/perinatology was born [9].
Dr Apgar teamed with a New Zealand pediatrician, L. Stanley James, to
continue critical observations of the newborn infant. Using the Apgar score as
a method of evaluation, Virginia went on to relate it to the effects of labor and
maternal anesthesia on the baby. She and a fellow anesthesiologist provided
new methods of measuring blood gases, concentrations of anesthetics, and pH.
She was the first person to realize that acidosis and hypoxia are not normal in
the newborn and should be treated promptly, and she was the first to catheterize
the umbilical artery of the newborn. Her research group investigated the effects of
maternal anesthetics on the baby and found them to be dangerous depressants.
The use of anesthesia in obstetrics subsequently declined markedly [1].
In 1952, Dr Apgar took a sabbatical and went to Johns Hopkins University
for a Masters of Public Health degree. She told friends that it was the most diffi-
cult thing she had ever done. While there, she was urged to join the reorgani-
zation of the National Foundation March of Dimes to in order to encompass all
birth defects. Her biographer, Joan Beck, wrote, ‘‘The challenge was irresistible
for Virginia, with her pioneering mind, her relentless mental and physical
energy, and her commitment to the welfare of babies’’ [9]. In 1959, on her
50th birthday, Virginia accepted the position as Director of the Division of
Congenital Malformations at the National Foundation. She became its Director
of Basic Research in 1967, Vice President for Medical Affairs in 1968, and
Senior Vice President for Medical Affairs in 1973. In this new role, Dr Apgar
supervised grants for medical research into the causes, treatment, and preven-
tion of birth defects. During her 15-year tenure at the National Foundation,
annual grants increased from $19 million to $45 million. She traveled more
than 160,00 km a year, speaking at medical conferences and to lay audiences
about birth defects and ways to give babies the best chance at a healthy start
to their lives. At her death, the National Foundation/March of Dimes gave
a grant of $900,000 to Columbia University to develop an integrated research
program in genetics, nutrition, and human development in her memory [2,10].
Dr Apgar suffered from a bleeding gastric lesion, which she rarely discussed
with friends or colleagues. She entered Columbia Presbyterian Medical Center
in July 1974, where she died in her sleep on August 6, at the age of 65 years.
Perhaps my most salient memory of Virginia is of a crisp moonlit evening in
the Colorado mountains. Bach cantatas drifted down from a balcony high
above a garden where conferees lingered over banquet coffee. Looking up
toward the sounds wafting from the lanai above, we saw the figure of an
imposing woman in red pajamas accompanied by a wisp of a child clad in
a summer nighty. Virginia with her cello, and our 10-year-old daughter, Brigid,
with her guitar, were providing an impromptu recital. Virginia had coaxed
Brigid to climb across the balconies and join her in something creative, chal-
lenging, and beautiful. Every time she came to Denver, Virginia found time
to visit with Brigid. They would play and sing duets, some expanding our
daughter’s musical literature, others disclosing Virginia’s often mischievous
and bawdy side.
Virginia was known for her wild driving habits. The common tease was that
she knew most of the New York traffic officers by first name. She was also a formi-
dable athlete, feared on the tennis court, and, at Mt Holyoke, she played on 11
class teams and 7 varsity teams. She carried the nicknames of Flash and Dyny
(for Dynamo). She loved to chop wood at her home in Tenafly, New Jersey,
and to take friends hiking near her cabin in the New Hampshire woods [2,4,10].
Virginia had a stock of slightly shocking medically oriented jokes that
peppered her teaching. She also kept a briefcase full of pelvic bones and resus-
citation equipment with her in case a teachable moment presented itself. In her
position at the March of Dimes, she was often asked to speak about birth
defects on radio and TV. According to her biographer, Joan Beck, she was
a hit on the Johnny Carson show one night by asking, ‘‘Do you know how
to tell a male chromosome from a female chromosome?’’ Her answer: ‘‘You
pull down its genes’’ [9].
Virginia Apgar was a humanitarian. She gravitated toward children, especially
birth defective children. She was interested in her patients’ lives and talents beyond
6 BUTTERFIELD
their medical problems, often befriending and collaborating with them after they
left the hospital. Such a patient was Carleen Maley Hutchins, who was an acoustical
engineer and an accomplished maker of stringed instruments. Virginia asked
Carleen to help her craft her own cello, and Carleen suggested that it should be
made of the cherry wood shelf she had noticed in the fourth floor ladies bathroom
at Columbia College of Physicians and Surgeons Hospital. Sometime later, the 2
women managed to ‘‘liberate’’ the shelf late one night, and Dr Apgar crafted a cello
backed with the seasoned wood. She enjoyed playing that cello for many years until
she switched to playing the viola, which she also crafted.
Virginia continued making instruments with Dr Hutchins. She joined the
Catgut Acoustical Society and supported the society’s efforts toward promoting
a violin octet, in which each note of the scale was acoustically toned to each
instrument. Columbia College of Physicians and Surgeons owns one of the
few violin octets in this country, and it is played in honor of Virginia Apgar
each year by the musical physicians and students who volunteer [11].
Virginia Apgar sought creative people throughout her life. Together they
would expand ideas into projects and programs within and beyond medicine.
Her diversity of interests afforded her opportunities in a time when history and
finances did not favor women. Such cross-fertilization of science and art opens
the creative mind to what Thomas Cech, Nobel Laureate at the University of
Colorado, Department of Biofrontiers, calls productive collisions.
Virginia was shaped by her position in history: the Depression, World War II,
and the novelty of women in medicine all defined her path. She was encouraged by
her family, who revered science and education for women. She was endowed with
exceptional energy and an ebullient personality, and she pushed toward obtaining
the best education, often at great financial and personal sacrifice. She gained the
respect of her superiors and benefitted from their support throughout her career.
Dr Apgar laid the foundations for modern neonatology/perinatology. She
expanded the knowledge of anesthesiology. Every day, clinicians throughout
the world use concepts developed from her research. She humanized children
with birth defects, raising public understanding and funds to support research
in this field. All of her contributions are foundational legacies for medicine today.
Dr Virginia Apgar has been recognized with honorary degrees and distin-
guished services awards for her work by every institution with which she
was associated. She received the Distinguished Service Award from the Amer-
ican Society of Anesthologists in 1961, and the Distinguished Service Medal
from Columbia University in 1973. She was elected to the National Woman’s
Hall of Fame in 1995. At her death, the National Foundation March of Dimes
established a grant in her name at Columbia University to be used to develop
integrated research facilities in genetics, nutrition, and human development.
The AAP established the Virginia Apgar Award in Perinatal Pediatrics for
outstanding contributions to perinatal medicine.
On October 24, 1994, at the annual meeting of the AAP, the US Postal
Service announced the issuance of a postage stamp in The Great Americans
Series to honor Virginia Apgar [9,11,12].
References
[1] Calmes SH. Virginia Apgar: a woman physician’s career in a developing specialty. J Am
Med Women’s Assoc 1984;39(6):184–8.
[2] Calmes SH, Virginia A. At the forefront of obstetric anesthesia. ASA Newsl
1992;56(10):Our Changing Times; Women in Anesthesiology.
[3] Roche Medical Image. 1963. Focus on Virginia Apgar, MD.
[4] Calmes SH. And what about the baby? Virginia Apgar and the Apgar score. ASA Newsl
1997;61(9).
[5] Butterfield LJ. Let’s keep the Apgar score in perspective. ACOG Clin Rev 1997;2(6).
[6] New York Times; Medical Science, Commercial Newspaper. Tuesday October 17, 1989.
Doctors debate value of test that gauges health of a newborn.
[7] Is the Apgar score outmoded? The Lancet, March 8, 1989.
[8] Butterfield LJ. The AAP Section on Perinatal Pediatrics 1994–1999, The Perinatal Section
News. 25 Anniversary edition.
[9] Beck J. Virginia Apgar, In memoriam. Beck is a Chicago Tribune reporter and Apgar
biographer.
[10] Butterfield LJ. Virginia Apgar, MD, PHD. Neonatal Network News, 1994.
[11] Laird PR. The Violin Octet; its first forty years. Catgut Acoustical Society Journal
1997;3(4 (Series II)):3–9.
[12] Perinatal Section News, American Academy of Pediatrics. Virginia Apgar, Physician,
1909–1974. Vol. 19, #1.
Pediatric HIV Infection

Ayesha Mirza, MDa, Mobeen H. Rathore, MD, CPEa,b,*
a
Department of Pediatrics, Division of Infectious Diseases & Immunology, University of Florida,
Jacksonville, FL, USA; bWolfson Children’s Hospital, Jacksonville, FL, USA
Keywords
Pediatric HIV infection Mother to child transmission of HIV
Perinatal HIV infection Adolescent HIV infection HIV testing
Key Points
Significant progress has been achieved in the reduction of mother to child
transmission (MTCT) of HIV since the start of the epidemic.
The use of highly active antiretroviral therapy has decreased the rate of MTCT
from 25% to less than 2% in resource rich countries.
Despite the success of MTCT, young people continue to be at risk for HIV
infection.
HIV prevention programs should have a multifaceted approach which should
include expanded testing particularly for high risk groups, early linkage to care
and treatment.
PEDIATRIC HIV INFECTION: 30 YEARS AND MOVING

FORWARD
Five cases of Pneumocystis carinii pneumonia were described in the Mortality and
Morbidity Weekly Report in 1981 [1]. This was the first published report of
what would come to be known as acquired immunodeficiency syndrome
(AIDS). The causative retrovirus, human immunodeficiency virus (HIV-1),
was described in May 1983 by Dr Francois Barré-Sinoussi and Dr Luc Mon-
tagnier and their colleagues from the French Pasteur Institute [2]. Little did
the world know then that this seemingly small outbreak would reach pandemic
proportions globally in a few short years. Neither was it conceivable at the time
that such tremendous progress would be made-when a diagnosis of HIV/AIDS
is no longer considered a death sentence and HIV infection has evolved into
a chronic disease for which effective treatments. Albeit no cure yet, are
available.
*Corresponding author. Department of Pediatrics, 653-1 West 8th Street, LRC 3rd Floor,
Jacksonville, FL 32209. E-mail address: mobeen.rathore@jax.ufl.edu

10 MIRZA & RATHORE
This article briefly discusses the origins of the virus, HIV immunopathogen-
esis, and pediatric infection, in particular mother-to-child transmission
(MTCT). Current issues that have an impact on the care of HIV-infected chil-
dren and adolescents, despite the availability of highly active antiretroviral
therapy (HAART), primarily in resource-rich countries, are outlined, and,
finally, this article focuses on ongoing prevention efforts by the Centers for
Disease Control and Prevention (CDC) and other organizations in an effort
to control and decrease the number of old and new HIV infections.
EVOLUTION OF HIV-1
Assessment of samples from apes and human beings with African equatorial
forest ancestry have traced the likely progenitor of HIV-1 to simian immuno-
deficiency virus (SIV) found in chimpanzees [3]. SIV is a recombinant virus
derived from lentiviruses in certain species of monkeys [4]. These lentiviruses
have been found in more than 30 species of nonhuman primates in sub-
Saharan Africa and could have crossed over to humans multiple times over
decades and led to divergence. It is now estimated that HIV-1 has been in hu-
mans since 1902–1921 (Fig. 1) [5]. On the basis of phylogenetic analysis, HIV
has been divided into 2 types—HIV-1 and HIV-2. HIV-1 is divided into groups
M (main), N (non-M, non-O), P, and O. Group M is further classified into 9
subtypes (A–D, F–H, J, and K) [6]. Group O infections are most concentrated
in Cameroon with spread restricted to surrounding central African countries;
groups N and P have also been found in small numbers of people from
Cameroon. Group M strains are the most diversified having been found world-
wide, with multiple subtypes identified, and are responsible for the majority of
HIV-1 infections [7]. By using a molecular clock, it has been estimated that
HIV-1 infections were introduced into the United States from Haiti in 1972.
Before this, HIV-1 was introduced into Haiti between 1962 and 1970, probably
from the Democratic Republic of the Congo. HIV-1 subtype B infection was
identified in a sample from 1982 or 1983 from Haitian immigrants—this was
the first known infection in the United States [8]. Shortly thereafter the first
reports of infections in children were published [9,10].
IMMUNOPATHOGENESIS OF HIV-1 INFECTION

In vivo models of SIV have given insight into the primary events after intro-
duction of HIV into the genital tract or rectal mucosa. Less than a week after
exposure, partially activated CD4þ T cells in the genital mucosa seem to be
one of the first targets of viral replication. After this, propagation of SIV in acti-
vated CD4þ T cells takes place and the virus migrates rapidly, probably via
the draining lymph nodes to the gut-associated lymphoid tissue (GALT).
Massive depletion of memory CD4þ T cells then takes place in the lamina
propria. Initial infection in humans seems to follow a similar course (Fig. 2)
[11,12]. Availability of target CD4þ T cells that express the chemokine
receptor CCR5 is crucial to the ability of HIV and related simian viruses to
establish infection [13]. The presence of certain cells, such as Langerhans cells,
PEDIATRIC HIV INFECTION
Fig. 1. Estimated time line of global evolution and spread of HIV types, groups and subtypes. Enlarged parts of map show the main disease epicenters. The
11
timeline indicates the key events in the evolution of HIV-1 groups, M, N, and O, and of HIV-2. CRF, circulating recombinant form. (From Tebit DM, Arts EJ. Tracking
a century of global expansion and evolution of HIV to drive understanding and to combat disease. Lancet Infect Dis 2011;11(1):45–56; with permission.)
12
MIRZA & RATHORE
Fig. 2. Phases of infection after exposure to HIV. Infection begins with transmission across a mucosal barrier, either by a cell-free virus, infected cell, or virion
attached to dendritic cells (DC) or Langerhans cells. Early low-level propagation probably occurs in partially activated CD4þ T cells, followed by massive propaga-
tion in activated CD4þ Tcells of the GALT lamina propria. Dissemination of HIV to other secondary lymphoid tissues and establishment of stable tissue viral reservoirs
ensue. Immune response lags behind the burst of viremia and provides only partial control of viral replication. CTL, cytotoxic T lymphocyte; PD-1, programmed death
1. (From Moir S, Chun TW, Fauci AS. Pathogenic mechanisms of HIV disease. Annu Rev Pathol Mech Dis 2011;6:223–48.)
PEDIATRIC HIV INFECTION 13
dendritic cells, and macrophages, in addition to CD4þ T cells, all facilitate

transmission. Inflammation or breach of the mucosal barrier of the genital tract,
as may happen in certain genital-ulcerative sexually transmitted infections, also
facilitates transmission. Based on studies that estimate the rates of transmission,
it has been postulated that the probability of HIV transmission ranges from
0.0001 to 0.0040 per sexual contact [14]. Circumcision offers a degree of
protection against HIV infection [15].
Two to four weeks after transmission of the virus, the majority of HIV-infected
individuals experience what is known as acute HIV or acute retroviral syndrome.
This is also often described as an acute, infectious mononucleosis-like illness with
flu-like symptoms, fever, lymphadenopathy, and rash. Other symptoms may
include myalgias, headache, anorexia, and diarrhea. During this time, HIV often
replicates aggressively in the absence of an immune response, reaching plasma
viral levels as high as 10 million copies per milliliter [16]. Given the high viral
loads achieved during this early period, individuals remain highly infectious to
other susceptible hosts. It is, therefore, imperative that clinicians maintain
a high index of suspicion for HIV infection in adolescent patients who are sexu-
ally active and who present with acute mononucleosis-like symptoms. It is appro-
priate to offer an HIV test along with other routinely administered tests, a classic
example being testing for the presence of Epstein-Barr virus. HIV testing should
become the standard of care in such instances given the increasing number of
infections in young people (discussed later).
In the absence of any treatment, plasma viral loads peak after 3 to 4 weeks
and then decline and reach a viral set point (Fig. 3). This set point may deter-
mine the rate of disease progression in those individuals not on HAART [17].
This acute phase is also characterized by a massive depletion of CD4þ T cells
usually associated with depletion of CCR5þ memory CD4þ T cells in the
GALT. After the initial infection, persistent viral replication continues, and
in the absence of HAART, plasma viremia remains detectable throughout
the course of the disease. Decline in HIV plasma viremia during the
acute phase of infection is also believed the result of early HIV-specific
CD8þ T-cell responses. Neutralizing antibody responses do not develop until
approximately 12 weeks after transmission; however, neutralization sensitive
virus is quickly replaced by neutralization-resistant variants. Several mecha-
nisms whereby the virus escapes neutralization have been proposed. This
also leads to enhanced viral persistence [18].
The early replication and dissemination of the virus to peripheral lymphoid
tissue is also followed by the development of persistent lymphoid tissue viral
reservoirs. The rapid development and persistence of such reservoirs remain
major impediments to complete eradication of the virus despite the availability
of HAART. Viral reservoirs include both lymphoid tissue that provides HIV
with an abundance of target cells and cellular reservoirs that consist mainly
of CD4þ T cells that are highly susceptible to HIV replication when activated
but can also carry latent virus. GALT, apart from being one of the major
targets for HIV infection and replication during early infection, remains a major
14 MIRZA & RATHORE
Fig. 3. Kinetics of immunologic and virologic events associated with HIV infection during
acute and early chronic phases. The schematic represents the sequence of events, including
the appearance of viral antigens, HIV-specific antibodies, and HIV-specific CD8þ T cells during
the acute and early chronic phases of infection. HIV reservoirs are established during the acute
phase of infection soon after emergence of plasma viremia. Throughout the acute phase of
infection, characterized by massive virus replication and high levels of plasma viremia, an
acute HIV syndrome develops in the majority of infected individuals, and the virus rapidly
spreads to various lymphoid organs, causing extensive depletion of CD4þ T cells. Although
anti-HIV immunity, including virus-specific CD8þ T cells and antibodies, develops during the
acute phase of infection, escape viral mutants rapidly emerge. ELISA, enzyme-linked
immunosorbent assay. (From Moir S, Chun TW, Fauci AS. Pathogenic mechanisms of HIV
disease. Annu Rev Pathol Mech Dis 2011;6:223–48.)
reservoir for HIV throughout the course of the disease even in individuals who
have been on HAART for several years. This suggests that GALT is a persis-
tent reservoir of HIV [19]. Apart from GALT, peripheral lymph nodes of clin-
ically asymptomatic HIV-infected individuals also serve as reservoirs, although
the level of persistence of HIV after several years of HAART has yet to be
determined [20,21]. The first evidence of HIV latency at the cellular level
was described in resting CD4þ T cells of infected individuals in 1995 [22].
Proof of the persistence of the virus as well as the presence of stable reservoirs
is supported by HIV-infected individuals, whose plasma viremia had been fully
suppressed by HAART for a minimum of 12 months and up to 3 years,
experiencing a rapid rebound of plasma viremia once treatment was interrup-
ted [23]. This usually occurred within 2 weeks of treatment interruption.
Although there is no consensus on the precise half-life of latently infected,
resting CD4þ T cells, several studies have projected that it would take 7 to
more than 60 years to eliminate HIV in CD4þ T cells [24,25].
IMMUNE DYSFUNCTION AND HIV INFECTION

Alterations in the normal functioning of the immune system once affected by
HIV infection are complex. A simplified version is presented to help readers
better understand the disease process and subsequent consequences. As dis-
cussed previously, massive CD4þ T-cell depletion in the GALT occurs soon
after transmission of HIV in humans. Loss of mucosal integrity has been
reported associated with translocation of microbial products from the intestinal
mucosa into the circulation, thus contributing to HIV-induced systemic
immune activation and dysregulation [26]. In addition, HIV infection has
a profoundly deleterious effect on peripheral lymphoid tissues, causing exten-
sive follicular and germinal-center hyperplasia during the clinically early stages
of infection and involution during the advanced stage of disease. These
changes start soon after initial infection and are associated with ongoing repli-
cation in untreated patients. They are due to both direct and indirect effects,
such as activation of B cells (which are not targets for HIV replication), result-
ing in hyperplasia in lymphoid tissues (discussed previously).
Perturbations in the homeostasis of different T-cell subsets during HIV infec-
tion have been linked to immune activation. Depletion of CD4þ T cells results
in increased turnover of CD4þ T cells as well [27]. Other cell populations,
such as CD8þ T cells, B cells, and natural killer cells, also exhibit increased
turnover during HIV viremia, which is decreased by the initiation of HAART.
Some of the explanations for the inverse ratio between CD4þ T cells and
CD8þ T cells include increased death rate of the former cell population as
well as ongoing viral replication in infected individuals receiving HAART,
leading to inverse ratios between the 2 cell types [28,29]. The quality of both
CD4þ and CD8þ T cells is also severely affected, which not only leads to
altered immune responses but also contributes to cytokine secretion and ulti-
mately to progression of HIV disease, particularly in untreated individuals.
The chronic phase of the infection is characterized by generalized immune
activation, including proinflammatory cytokines (eg, tumor necrosis factor a,
interleukin [IL]-1, IL-12, and IL-6) and chemokines, such as lipopolysaccharide
and type 1 interferon (IFN-a). All these changes predispose to increased suscep-
tibility to apoptosis (programmed cell death) and chronic immune activation,
which leads to the appearance of HIV-specific T cells and B cells that show
signs of senescence. All these events contribute to HIV pathogenesis.
Senescence or immune exhaustion has been described as a consequence of
the chronic immune activation caused by HIV infection. As a result of this
phenomenon, effector T cells become dysfunctional and lose not only their
function but also their proliferative capacity. In a normal host, during an adap-
tive immune response, human naive T cells are activated by antigen-presenting
cells, such as dendritic cells, through certain costimulatory molecules. This acti-
vation leads to proliferation and acquisition of effector functions. Most of the
activated T cells become differentiated into short-lived effector T cells whereas
a small portion become long-lived central memory T cells. During the course of
HIV infection, T cell functions, such as cytokine secretion, proliferation, and
16 MIRZA & RATHORE
cytotoxic potential, seem to diminish gradually. This is what has been termed,
immune exhaustion [30]. Although this concept is not new, more recently this
theory has gained renewed interest due to the identification of a molecular
signature of exhaustion [31]. What is more important is that some of these
negative regulators found in HIV infection seem reversible, increasing the
potential for the possible role of immunotherapy in the control of the infection
and maintenance of T-cell function.
PEDIATRIC HIV INFECTION WITH A FOCUS

ON MOTHER-TO-CHILD TRANSMISSION
In children under age 13 at diagnosis of AIDS, the CDC estimates that,
through 2009 in the 50 states and District of Columbia, 8640 acquired their
infection perinatally and 807 by other transmission modes, including hemo-
philia, blood transfusion, or other unreported or unidentified transmission cate-
gory [32]. These numbers may have been different had it not been for current
state-of-the-art care.
Perhaps one of the single biggest success stories in pediatric infectious
diseases, apart from vaccines, has been the prevention of MTCT of HIV
with the use of zidovudine (ZDV) treatment. In 1994, the groundbreaking
Pediatric Aids Clinical Trials Group 076 trial of antepartum, intrapartum,
and neonatal ZDV to prevent MTCT demonstrated a 67% reduction in trans-
mission [33]. Before this intervention, the number of infected infants born each
year in the United States peaked at approximately 1650, in 1991, with 25% of
infected pregnant women transmitting the virus to their babies [34]. With the
use of HAART, the risk of perinatal transmission from an infected mother
has now decreased to less than 2% in resource-rich countries [33]. Although
the number of HIV-infected infants has declined to less than 100 per year in
the United States, the number of babies born to HIV-infected mothers seems
to have increased. Implementation of programs to ensure continued access to
care and treatment remains vital to maintain the success seen, with decreasing
numbers of babies born with perinatally acquired HIV infection [35,36].
In the United States, many states have adopted a multifaceted approach to
HIV care and management. Likewise in Florida, the state has adopted a multi-
pronged approach that has resulted in a significant decline in cases of perinatal
HIV infection from a peak of 201 cases in 1992 to only 4 in 2009 [37]. This
approach includes opt-out testing for pregnant women, testing all pregnant
women for HIV infection at the beginning and again during the third trimester
of pregnancy, and rapid testing during labor and delivery if a mother’s HIV
status is unknown. Data from the Pregnancy Risk Assessment Monitoring
System indicate that Florida’s HIV testing rates for pregnant women have
increased significantly over the past few years, with 86% to 90% of women
surveyed reporting that they had discussions with their health care provider
about HIV testing [38]. Another state program that has contributed to the
increased rate of HIV testing for pregnant women is the Targeted Outreach
for Pregnant Women Act.
Additionally, all newborns have ready access to ZDV through the Baby
Rxpress program, another state-sponsored program. This program provides
ZDV to HIV-exposed newborns at no cost when a family has no means to
pay for the medication. The goal is to ensure that no mother leaves the hospital
without ZDV in hand for the baby.
Although prevention of MTCT has been a great success story, this is not the
time to be complacent. Young people continue to be one of the highest risk groups
at risk for HIV infection, although the risk of HIV infection varies with
community prevalence rates, sexual behaviors, and concurrent substance use.
HIV continues to be among the top 10 leading causes of death in the 20-year to
24-year age group. Between 2005 and 2008, the estimated number of HIV/
AIDS cases increased among 15-year-olds to 19-year-olds and 20-year-olds to
24-year-olds. The rate of new HIV diagnoses per 100,000 population increases
with age from 12.6 in the 15-year to 19-year age group to 37.2 in the 20-year to
24-year age group. In 2007, 73% of 13-year-olds to 24-year-olds diagnosed with
HIV/AIDS were male and 27% were female. As with adults, most
adolescent cases occur through sexual transmission. Among young men, at least
two-thirds of HIV transmissions occur via male-to-male sexual contact, whereas
heterosexual encounters are the primary means of transmission among female
adolescents. The greatest increase in new diagnoses has occurred among young
minority men who have sex with men (MSM).
The American Academy of Pediatrics Committee on Pediatric AIDS recently
released a position statement with guidelines for pediatricians and their role in
promoting HIV testing among adolescents [39]. The main emphasis of these
guidelines is to encourage testing at every opportunity available, particularly in
sexually active adolescents regardless of the prevalence of HIV infection in the
area where they live. High-risk youth need to be tested frequently. In addition,
emergency departments and urgent care facilities need to offer HIV testing
because this may be the only opportunity for young people who do not seek
regular primary care services. It is also essential that linkage to appropriate
services be provided if an adolescent does have a positive HIV test.
MANAGEMENT OF HIV DISEASE IN CHILDREN AND

ADOLESCENTS
Although the management of HIV/AIDS is beyond the scope of this review and
would require several more articles, suffice it to say that physicians providing
care for HIV-infected patients today have an impressive armamentarium of
drugs available to them. Management of antiretroviral medications should be
in conjunction with a pediatric infectious disease specialist with expertise in
managing HIV infection. Box 1 lists the currently available drugs for children
and adolescents.
Despite the availability of effective and generally well-tolerated medications,
the management of these individuals continues to present significant challenges.
Obstacles, such as late entry into care, retention in care, and adherence to care,
present a tremendous challenge. These issues are further fueled by social
18 MIRZA & RATHORE
Box 1: List of currently available antiretroviral medications

Nucleoside reverse transcriptase inhibitors
Abacavir (ABC)
Didanosine (ddI)
Emtricitabine (FTC)
Lamivudine (3TC)
Stavudine (d4T)
Tenofovir (TDF)b
Zidovudine (ZDV)
Non-nucleotide reverse transcriptase inhibitors
Delavirdine (DLV)
Efavirenz (EFV)
Etravirine (EVR)e
Nevirapine (NVP)
Rilpivirinea
Protease inhibitors
Atazanavir (ATV)
Darunavir (DRV)
Fosamprenavir (FPV)
Indinavir (IDV)a
Lopinavir (LPV)
Nelfinavir (NFV)
Ritonavir (RTV)
Saquinavir (SQV)c
Tipranavir (TPV)
CCR5 antagonist
Maraviroc (MVC)d
Integrase inhibitor
Raltegravir (RAL)f
Fusion inhibitor
Enfuvirtide (ENF, T-20)
a
Not approved by the Food and Drug Administration for pediatric patients.
b
Only nucleotide reverse transcriptase inhibitor. Investigational use only for children <12
years but can be used for children 12.
c
Investigational use for children 2 years.
d
Not approved for children 16 years.
e
f
issues, such as societal discrimination and stigma. These are in addition to

many of these children coming from dysfunctional homes, where often there
is no parental supervision (parents are diseased, incarcerated, or have lost
parental custody). They may be living with elderly grandparents or other rela-
tives or in foster homes, making the dynamics of the situation complex. Disclo-
sure of HIV status is another major dilemma that both providers and parents
face [40]. Lastly, transition of care from pediatric to adult providers has proved
an area where attention is needed, particularly as these young adolescents tend
to fall through the cracks [41]. They may suffer from a sense of abandonment
as they lose perhaps what may have been one of the only dependable things in
their lives, the clinic with its familiar environs and staff (clinicians, social
workers, and nursing staff).
Specific medical issues include increasingly recognized metabolic complica-
tions, particularly in perinatally HIV-infected adolescents who are now
entering their second or third decades of life [42]. These complications are
related to both long-standing disease and antiretroviral medications. Central
nervous system abnormalities, such as cognitive deficits, attention-deficit disor-
ders, and psychiatric disorders, can all impair day-to-day functioning as well as
pose a barrier to their care and compliance with medications. Due to the avail-
ability of HAART, debilitating complications, such as encephalopathy, are seen
far less frequently; however, the other seemingly benign conditions (discussed
previously) pose a major barrier to care. Metabolic abnormalities, such as lip-
ohypertrophy, lipodystrophy, dyslipidemias, and insulin resistance, are also
increasingly recognized in HIV-infected children as they age. Bone loss and
renal disease are other complications of HIV disease and treatment. Thus,
HIV disease remains a management challenge for patients and caregivers.
MANAGEMENT OF THE HIV-EXPOSED INFANT

Approximately 7000 babies are born annually to HIV-infected women in the
United States [43]. Therefore, it is important for pediatricians to be aware of
the most recent guidelines for postnatal prophylaxis and testing. Because these
guidelines are updated regularly, it is also important that physicians verify
available recommendations at www.aidsinfo.nih.gov. All HIV-exposed babies
require testing to rule out HIV infection along with routine primary care.
Testing for HIV infection by HIV DNA polymerase chain reaction (PCR) is
the standard of care. Box 2 lists the algorithm for testing and follow-up of
newborn babies with exposure to HIV that used at the authors’ institution.
This is based on the most recent 2011 perinatal guidelines [44]. Again, consul-
tation with a pediatric infectious diseases expert in the area is highly
recommended.
HIV PREVENTION EFFORTS IN THE UNITED STATES

Finally, it is prudent to discuss the most important aspect of this epidemic as it
stands today—that is, the prevention efforts that are ongoing at many different
levels: global, national, regional, state, and local.
Box 2: Neonatal care of infants born to an HIV-positive mother
Purpose: to provide guidelines for the care of an infant born to an HIV-infected
mother.
Policy: Infants born to HIV-infected mothers will be cared for in the same manner as
all other infants, with special attention given to body secretions and not breaking
the infant’s skin barrier. Breastfeeding of these infants should be avoided.
Procedure:
1. Avoid procedures that disrupt the infant’s skin barrier whenever possible (fetal
scalp monitoring/pH sampling).
2. Clean skin/bathe with chlorhexidine soap and water before invasive procedures.
3. Administer eye prophylaxis once maternal body fluids are wiped from the eyes.
4. Administer first dose of hepatitis B vaccine before discharge.
5. If infant is high risk for HIV infection due to inadequate maternal treatment
during pregnancy and intrapartum period, contact Pediatric Infectious
Diseases in the area for consultation regarding additional medications (such
as nevirapine) for the infant along with the 6 weeks of ZDV.
6. All HIV-exposed infants—start ZDV soon after birth and within 6–12 hours of
birth according to the table below (according to infant’s gestation and ability
to take po). Infant to have ZDV for a total of 6 weeks.
Gestation Dosing
>35 Weeks 4 mg/kg/dose po bid (or 1.5 mg/kg/dose IV q 6 h)
<35 to >30 Weeks 2 mg/kg/dose po q 12 h (or 1.5 mg/kg/dose IV) q 12 h, then
advanced to every 8 h at 2 weeks of age
<30 Weeks 2 mg/kg/dose po (or 1.5 mg/kg/dose IV) q 12 h, then advanced
to every 8 h at 4 weeks of age
Order laboratory tests: complete blood cell count with differential, urine cytomeg-
alovirus test, test urine for drugs of abuse, and HIV DNA PCR.
Order: Mother to have medication in hand for the baby at time of discharge (put
this as an order).
Nutrition: Infant must be formula fed. Breastfeeding should be avoided.
Consultations: pediatric infectious diseases.
After discharge from the newborn nursery, the following testing guidelines should
be followed:
1. Birth DNA PCRa (already done in the nursery before discharge)
2. Second HIV DNA PCR within 14–21 days of age
3. Third HIV DNA PCR at 1–2 months of age and the fourth and final HIV DNA
PCR at 4–6 months of age
4. HIV antibody testing at 18 month of ageb
HIV may be presumptively excluded with 2 or more negative tests, 1 at age 14 days or older and
the other at age 1 month or older. Definitive exclusion of HIV in non-breastfed infants may be
based on 2 negative virologic tests at age 1 month or older and at age 4 months or older.
Trimethoprim-sulfamethoxazole for prophylaxis of Pneumocystis carinii pneumonia need not
be given to those infants in whom HIV has been presumptively excluded.
In addition to the specific testing and care guidelines outlined above, routine primary care
and immunizations should be given to HIV-exposed newborns according to the schedule rec-
ommended by the American Academy of Pediatrics.
a,b
The birth HIV DNA PCR and antibody test at 18 months of age are not mandatory but
recommended by some experts.
Currently, there are 1.2 million individuals in the United States living with
HIV infection. One in five (20%) of those individuals are unaware of their infec-
tion and despite the stable rates, new infections continue to occur [45]. In August
2011, the CDC released new estimates of the annual number of new HIV infec-
tions in the United States (HIV incidence) using the BED HIV-1 Capture
enzyme-linked immunosorbent assays [46]. The new estimates suggest that over-
all, HIV incidence in the United States has been stable at approximately 50,000
annual infections between 2006 and 2009. The largest number of new HIV infec-
tions, have been among MSM and within this group, black MSM. The challenge
for pediatricians is that young MSM (13–29 years) are particularly affected, rep-
resenting more than one-quarter of all new HIV infections nationally [47], not
only underscoring the importance for ongoing HIV prevention programs to
continue but also stressing the urgent need for developing new programs that
specifically address the population subgroups at high risk.
One of these new programs has been the CDC’s approach to reducing new
HIV infections—the High-Impact Prevention approach. This approach is guided
by 5 major considerations: effectiveness and cost, feasibility of full-scale imple-
mentation, coverage in the target populations, interaction and targeting, and
finally prioritization. Under this plan, approaches that are most cost effective at
reducing overall HIV infections, such as HIV testing programs and condom
distribution, are prioritized. Programs that help HIV-infected individuals from
spreading the infection to others are also cost effective. The CDC has also taken
several steps to prioritize prevention efforts in certain geographic areas that could
have the highest impact on HIV infection rates and health equity. This approach
is also in line with the 2010 National HIV/AIDS Strategy [48].
The authors cannot stress enough the importance of increasing testing and
further linkage to care to reduce the number of new HIV infections. In
2006, the CDC put forward guidelines for testing in health care settings, which
strongly encouraged HIV testing to be incorporated as a part of routine annual
well-care visits [49]. These guidelines recommend testing for HIV using the
opt-out approach similar to that for testing of pregnant women (discussed
previously). Furthermore, they recommend testing for high-risk individuals
annually. In an effort to make the process easier and decrease paperwork,
the guidelines also recommend using general medical consent for HIV testing
rather than using separate consent forms. Testing for pregnant women is rec-
ommended in the first trimester with repeat testing in the third trimester for
women living in jurisdictions with high rates of HIV infection.
The availability of several Food and Drug Administration–approved point-
of-care HIV tests has facilitated the ability to provide easy-to-perform tests in
physicians’ offices, emergency departments, and acute care centers [50]. Despite
this, however, published studies show that significant differences exist in
different clinical settings regarding HIV testing and, although the overall trend
is increasing, it is far from optimal [51,52]. In a national cross-sectional survey
study of emergency departments across the United States, significant differ-
ences in HIV testing rates were seen between academic and community
22 MIRZA & RATHORE
medical centers, with academic medical centers performing more HIV tests. A
large proportion of the academic sites in the survey reported external funding
availability for HIV testing whereas costs were seen as a major barrier to
providing increased testing for the smaller community medical centers [53].
Given that academic medical centers constitute only approximately 3% of
the emergency departments across the country, this is a significant issue. Com-
pounding this problem is that many uninsured/underinsured individuals
routinely use emergency departments for routine medical care and have no
other means of obtaining an HIV test.
In 2007, the CDC launched the Expanded HIV Testing Initiative to supple-
ment existing HIV testing efforts and improve the accessibility of HIV
screening and testing services [54]. In addition, health departments funded
under this effort also had to ensure linkage to care for those individuals with
newly diagnosed HIV infection. During October 2007–September 2010, a total
of 2,786,739 HIV tests were conducted, of which 29,503 (1.1%) were positive
for HIV infection. Among persons who were HIV infected, 18,432 (62%) were
unaware of their infection. Among 17,247 persons with new HIV diagnoses for
whom some follow-up data were available, 15,737 (91%) received their test
results, 12,711 (75%) were linked to care, and 14,234 (83%) were referred to
partner services. Compared with nonclinical settings, more persons who
were tested in clinical settings received their test results (93% vs 84%) and
were linked to care (78% vs 63%). At the authors’ center, the authors have
been involved in this effort through the emergency department at their institu-
tion and have seen a steady decline in the positivity rate among the total
number of people tested since 2007. This speaks to the fact that as the testing
rates among high-risk populations increase, fewer individuals who are HIV
positive and unaware of their HIV status will be seen in the community.
Several other strategies have been used and tested to reduce not only the
number of new infections but also the transmission of infections to uninfected
individuals. In an initial pre-exposure prophylaxis clinical trial conducted in
the United States, Peru, Ecuador, Brazil, Thailand, and South Africa, HIV-
uninfected men and male-to-female transgender adults who reported sex with
a man and engaging in high-risk sexual behaviors in the preceding 6 months
were randomized to receive daily doses of tenofovir disoproxil fumarate (TDF)
and emtricitabine (FTC) or a placebo pill. There was a 44% reduction in HIV
acquisition in the pre-exposure prophylaxis group versus the placebo group as
well as a 92% reduction in the risk for HIV acquisition in those with detectable
TDF/FTC levels compared with those with no detectable drug [55].
Other studies in South Africa (eg, CAPRISA 004) have looked at the use of mi-
crobicidal gel (containing 1% TDF) compared with placebo [56]. In the CAPRISA
004 trial among women who applied the gel 80% of the time, HIV incidence was
54% lower in the TDF group than in the placebo group. In a separate trial in the
United States and South Africa, use of daily 1% TDF gel also showed 100-fold
higher tissue levels of TDF compared with daily tablet use [57]. In another inter-
national trial funded by the National Institutes of Health, which took place at
13 sites, including in the United States, and was designed to evaluate whether
antiretroviral use by an HIV-infected partner reduced HIV transmission to an
uninfected partner, 27 infections occurred out of a total of 28 in the serodiscord-
ant group where the partner did not start antiretroviral therapy immediately;
rather, the partner waited until the counts fell below 250 cells/mm3 or an
AIDS-related event occurred [58]. This trial was discontinued once the prelimi-
nary results became available. This lends credence to what the authors have sus-
pected for a long time, that treating infected individuals is another means of
preventing new infections because the sexual transmission of HIV from infected
persons to their partners is strongly correlated with concentrations of HIV in
blood and the genital tract. These studies also support the use of HAART as
a part of a public health strategy to control the spread of HIV.
This review would not be complete without any discussion about an HIV
vaccine. In addition to the other strategies discussed, there is consensus
regarding the need for a safe and effective HIV vaccine to ultimately end the
global HIV pandemic. In general, for most infections, the human body can
mount an effective immune response that can clear infection and provide
enduring protection against re-infection. This is the basic principal used in
the development of vaccines. Unlike other vaccine-preventable infectious
diseases, however, the body’s natural immune response to HIV infection is
at best inadequate. For most viral infections, the appearance of neutralizing
antibodies generally heralds the clearance of the infection and subsequent
protection from re-infection. With HIV infection, this is a challenge because
HIV does not naturally induce broadly neutralizing antibodies.
Induction of neutralizing antibodies has been one of the goals for an HIV
vaccine. This approach has been supported by the prevention of virus acquisi-
tion in nonhuman primate models of AIDS by the passive infusion of several
broadly neutralizing antibodies [59]. Researchers are currently studying the
steps involved in B-cell evolution during prolonged chronic infection that result
in the production of broadly neutralizing HIV antibodies and trying to design
novel vaccines that might accelerate this process. The major challenge rests on
overcoming the hypervariability of HIV, which would require not only the
induction of broadly protective neutralizing antibodies to prevent HIV infec-
tion but also robust cellular responses to control HIV infection [60]. Other chal-
lenges that have persistently dogged the efforts to produce a successful HIV
vaccine include the capacity of the virus to target and integrate its genome
into cells of the immune system and the lack of an ideal animal model.
SUMMARY
As this article was written, celebrating another World AIDS Day, which falls
on December 1 each year, was just days away. Not only is this a time to reflect
on all the success with the treatment and management of HIV infection, in
particular MTCT but also a time to reflect on the challenges ahead. As cham-
pions of children, pediatricians need to be more vocal in educating patients,
families, and their communities about the risks of sexually transmitted
24 MIRZA & RATHORE
infections and HIV infection and the need for testing as part of routine primary
care. This needs to be the norm rather than the exception. All persons should
be aware of their HIV status; until and unless this approach is taken, new infec-
tions will continue to be seen in young people, and even those who are aware
of their status will continue to be wary of seeking care.
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Advances in Pediatric Pharmacology,

Therapeutics, and Toxicology
Ian M. Paul, MD, MSca,b,*
a
Department of Pediatrics, Penn State College of Medicine, 500 University Drive, HS83, Hershey,
PA 17033, USA; bDepartment of Public Health Sciences, Penn State College of Medicine, 500
University Drive, HS83, Hershey, PA 17033, USA
Keywords
Pediatric pharmacology Pediatric therapeutics Pediatric toxicology
Comparative effectiveness research Drug shortages
Key Points
Drug shortages are dramatically increasing and cause major problems with re-
gards to the safety, cost, and availability of drugs used to treat a myriad of
pediatric conditions.
The number of drugs with pediatric label information has dramatically increased
due to the Best Pharmaceuticals for Children Act (BPCA) and Pediatric Research
Equity Act (PREA).
Comparative effectiveness research and advances in medical genomics continue
to inch us slowly forward to the eventuality of ‘‘personalized medicine’’.
C
omparative effectiveness research is a term that has gained increased
popularity in the past several years and is directly related to the
evolution of therapeutics for children. The Agency for Healthcare
Research and Quality has framed comparative effectiveness research as
research ‘‘designed to inform health care decisions by providing evidence on
the effectiveness, benefits, and harms of different treatment options. The
evidence is generated from research studies that compare drugs, medical
devices, tests, surgeries, or ways to deliver health care’’ [1]. This type of
research, plus advances in medical genomics, continue to inch us slowly
forward to the eventuality of ‘‘personalized medicine.’’ This article highlights
some of the steps toward this frontier and other advances that occurred
between July 2009 and December 2011, but also highlights the governmental
and industrial issues that are imminent challenges and opportunities.
An emerging concern over the past several years has been the increase in
drug shortages that have affected all patients, including children. Shortages
*Department of Pediatrics, Penn State College of Medicine, 500 University Drive, HS83,
Hershey, PA 17033. E-mail address: ipaul@psu.edu

28 PAUL
are 5 times as common as they were in 2004 (Fig. 1)[2,3], with most being
sterile injectable drugs, including dexamethasone, propofol, and methotrexate,
although commonly used oral drugs, such as stimulants for attention deficit
hyperactivity disorder (ADHD) and erythromycin ophthalmic ointment,
have also been in short supply [4]. Reasons cited for these shortages include
issues in production quality (contamination, particulates, impurities), manufac-
turer delays, drug discontinuations, raw material or component shortages, loss
of manufacturing sites, and industry consolidation. Many of the drugs are older
and off patent, making them less profitable for manufacturers [5]. The short-
ages cause major problems with regard to the safety, cost, and availability of
drugs used to treat a myriad of pediatric conditions. To address this issue, Pres-
ident Barack Obama signed an executive order in October 2011 that directed
the Food and Drug Administration (FDA) to take steps to address this problem
[6]. In this order, the FDA was directed to use all appropriate administrative
tools to require drug manufacturers to (1) provide adequate advance notice
of manufacturing discontinuations that could lead to drug shortages for life-
supporting or life-sustaining compounds, or those that prevent debilitating
diseases; (2) take step to expedite regulatory reviews when such review would
help to minimize potential drug shortages; and (3) communicate to the Depart-
ment of Justice cases involving drug hoarding or price gouging.
The second major governmental issue related to therapeutics for children is
the expiration in 2012 of the Best Pharmaceuticals for Children Act (BPCA)
and Pediatric Research Equity Act (PREA), the 2 pieces of federal legislation
that have resulted in 426 drug label changes to address pediatric dosing since
1998 [7]. The number of drugs with label changes has been increasing, with
a particularly active period having occurred since BPCA and PREA were
last reauthorized in 2007 (Fig. 2). In addition to the label changes, the pediatric
Fig. 1. Yearly drug shortages reported since 2004. (Data from GAO-12–116. Drug shortages:
FDA’s ability to respond should be strengthened. Washington, DC: U.S. Government Account-
ability Office; 2011; and Drug shortages hit record levels in 2011; 2012 may not be much better.
Available at: http://www.modernmedicine.com/modernmedicine/article/articleDetail.jsp?
id¼755523. Accessed January 27, 2012.)
ADVANCES IN PEDIATRIC PHARMACOLOGY 29
Fig. 2. Pediatric label changes as a result of federal legislation since 1998. (Data from
Pediatric labeling changes table through Wednesday, January 4, 2012. Available at:
http://www.fda.gov/downloads/ScienceResearch/SpecialTopics/PediatricTherapeutics-
Research/UCM163159.pdf. Accessed January 4, 2012.)
drug studies conducted to support the label changes have provided information
regarding drug adverse events that have often differed from those found by the
same drugs in adult studies, particularly neuropsychiatric adverse events [8].
Many organizations that advocate for the health of children, including the
American Academy of Pediatrics (AAP), will be urging the Congress to reau-
thorize BPCA and PREA during 2012.
SYMPTOMATIC CARE
As in the first decade of this century, there continue to be new developments in
some of the oldest and most commonly used drugs taken by children, those
used for symptomatic care that are typically found over the counter (OTC).
Indeed a report from the Slone Survey indicated that nearly 20% of children
younger than 12 years use either acetaminophen or ibuprofen each week, and
these drugs are the most commonly used medications taken by children [9].
Other OTC medications, including those used to treat cough and cold symptoms
(eg, pseudoephedrine, dextromethorphan, chlorpheniramine, diphenhydra-
mine, and guaifenesin), were also among the most commonly taken drugs. These
cough and cold preparations are still commonly used by children despite recent
guidance from professional organizations against such use [10–12].
Analgesic-antipyretics
In 2011, the AAP published a clinical report guiding clinicians on the use of
antipyretics in children [13]. Emphasized within the report is the notion that
improving comfort should be the therapeutic goal of use of these medications
as opposed to the attainment of normothermia. The 2 drugs that were exten-
sively discussed and recommended given evidence of both safety and efficacy
were acetaminophen and ibuprofen. The report recognized that there has been
30 PAUL
some evidence showing that combined or alternating use of these drugs may
provide a greater antipyretic effect, but did not endorse such a strategy because
of the lack of evidence showing improved comfort with such practice, as well as
potential safety concerns. Subsequent to this report being accepted for publica-
tion, one additional study examined whether combined or alternating use of
ibuprofen and acetaminophen was more effective at treating fever than
ibuprofen alone [14]. In this study by Paul and colleagues [14], children were
followed for 6 hours; all but one of the children in the combined and alter-
nating groups were afebrile at hours 4, 5, and 6. In contrast, for those receiving
ibuprofen alone, 30%, 40%, and 50% had temperatures 38.0 C or higher at
hours 4, 5, and 6, respectively. Despite data similar to these from other studies,
guidance similar to that from the AAP against the use of combined or alter-
nating antipyretic regimens has also been issued in the British and Italian liter-
ature [15,16]. One other issue discussed by the AAP report was the important
point that antipyretics do not prevent the occurrence of acute febrile seizures.
This statement was confirmed in a recently published, double-blind, placebo-
controlled study from Finland [17].
Although acetaminophen has been widely used as an OTC analgesic and
antipyretic for decades, and is believed to be generally safe in recommended
doses, several recent controversies around it have arisen. First, concerns
regarding its well-established relationship with hepatotoxicity with high doses
led to label changes [18]. Adults are advised not to take more than 4000 mg
daily and prescription products containing acetaminophen have been limited
to 325 mg per pill. Working with industry, the FDA also recommended that
a single concentration of liquid acetaminophen be available with a concentration
of 160 mg/5 mL, which would eliminate concentrated drops with 80 mg/0.8 mL
and 80 mg/1.0 mL if adopted universally by industry [19].
A second new concern regarding acetaminophen arose when data suggested
that prophylactic use of the medication before immunization administration re-
sulted in reduced antibody responses to vaccination [20]. In this study, infants
given routine childhood immunizations were randomized to receive 3 doses of
acetaminophen spaced throughout the first 24 hours after vaccination or no
antipyretic. Although the presence of fever was reduced in the active treatment
group, antibody concentrations were significantly lower to numerous antigens
including pneumococcus and tetanus.
A third emerging concern regarding acetaminophen is its relationship with
the development of asthma among young children, as well as on asthma exac-
erbations. This topic is discussed in the asthma section later in this article.
Cough and cold

With increasing questions regarding the efficacy and safety of oral OTC cough
and cold preparations over the past decade, parents and clinicians continue to
seek safe and effective treatments. One recent study attempted to provide
evidence for an old, but relatively unstudied remedy: vapor rubs [21]. One
topical vapor rub preparation containing menthol, camphor, and eucalyptus
oils in a petroleum jelly base was compared with petroleum jelly and no treat-
ment in a single-dose, single-night study. In a comparison of the 3 groups, the
vapor rub group was significantly better in treating children’s coughs and
congestion, but not rhinorrhea. Further, both the children and their parents
had improved sleep in the vapor rub group.
A second study examined the administration of probiotics twice daily for 6
months during the colder weather months on cold and influenzalike symptoms
among children 3 to 5 years of age [22]. In a 3-arm study comparing placebo
versus Lactobacillus acidophilus NCFM versus Lactobacillus acidophilus NCFM
plus Bifidobacterium animalis subspecies lactis Bi-07, the 2 active treatment groups
showed a 53% reduction in fever, 41% reduction in coughing incidence, and
28% reduction in rhinorrhea incidence. Importantly, antibiotic use and days
absent from child care were also significantly lower.
Teething
As a reminder that even the most seemingly benign products can be potentially
dangerous for children, 2 compounds used for infant teething were the subject
of FDA action in the past 2 years. A homeopathic product, Hyland’s Teething
Tablets (Hyland’s Inc., Los Angeles, CA, USA), was subject to a recall because
of the discovery that the tablets contained inconsistent amounts of belladonna
along with case reports of children taking the tablets with signs and symptoms
consistent with belladonna toxicity [23]. The second product, benzocaine, is
found in many OTC lozenges, sprays, and gels, but has been associated
with methemoglobinemia, particularly among children younger than 2 years
using the product to relieve discomfort from teething, aphthous ulcers, or
sore gums [24].
PULMONARY AND ALLERGY

Asthma
As mentioned previously, several studies over the past 2 decades have
been used to support the view that the rise in asthma prevalence over the
past 30 years is because of the increasing use of acetaminophen. This argument
was summarized in a review by McBride [25], who opined that this association
is consistent across populations studied, exhibits a dose-response relationship,
is supported by both epidemiologic and acetaminophen sales data, and is bio-
logically plausible via the mechanism of glutathione depletion in the airway
mucosa. Although the review presents the association in a compelling way,
recent studies have demonstrated mixed results. For example, Lowe and
colleagues [26] followed a birth cohort of 620 children with a family history
of atopy and found that although there was a weak association of asthma at
age 7 with acetaminophen use in the first 2 years after birth, this association
disappeared when the data were adjusted for frequency of respiratory
infections. In contrast, an Ethiopian birth cohort did demonstrate an increased
likelihood of wheeze during early life with increasing acetaminophen consump-
tion [27]. Similarly, an association between acetaminophen use during the first
32 PAUL
6 months after birth and asthma at age 10 years was found among girls, but not
boys, in a Norwegian birth cohort of more than 1000 children [28]. This same
cohort did not demonstrate any association with asthma when their mothers
consumed acetaminophen during early pregnancy, which conflicts with 2 other
studies showing positive associations between prenatal acetaminophen use and
asthma development among offspring [29,30]. The presence of mixed data
suggests that this question can be answered only by a prospective, randomized,
controlled trial that includes acetaminophen as a treatment group for pregnant
women and/or infants, something that to date has not been performed.
A second controversial area in the treatment of asthma is the use of long-acting
beta agonist (LABA) drugs such as formoterol and salmeterol. Concerns
regarding the increased incidence of severe adverse events associated with
LABA use prompted the FDA to review the medication class. The review deter-
mined that although the benefits of LABAs currently appear to outweigh the
risks, several label changes to these drugs were mandated [31]. First, LABAs
should only be used concomitantly with asthma controller medications, such
as inhaled corticosteroids (ICS). Second, LABA use should be discontinued if
asthma control is achieved and a patient can be maintained on an asthma
controller medication alone. Third, LABAs should not be used in a patient whose
asthma is adequately controlled on a low- or medium-dose of ICS. Last, if pedi-
atric and adolescent patients require LABAs, it should be administered only in
the form of a combination product that contains an ICS. These recommendations
may be particularly important for children who have been shown to suffer an
excess of serious adverse events (eg, death, hospitalization, intubation) attribut-
able to LABAs compared with adults [32].
These controversies aside, there have also been some recent positive develop-
ments in the treatment of children with asthma. Moving toward the age of person-
alized medicine was the Best Add-on Therapy Giving Effective Responses
(BADGER) trial, which sought to determine how to better manage children
aged 6 to 17 years with uncontrolled asthma despite low-dose ICS treatment
[33]. In this study, each participant received 16 weeks of ‘‘step-up’’ treatment
(increasing therapy to the next level specified by the National Asthma Education
and Prevention Program guidelines) with a medium-dose ICS, low-dose ICS plus
LABA, and low-dose ICS plus montelukast in random order to determine
whether a differential response to the 3 treatments existed. Although the low-
dose ICS plus LABA treatment was most likely to be the ‘‘preferred’’ treatment
among the 165 participants completing the trial, there were some participants
who had the best response to each of the 3 treatments, suggesting that those treat-
ing children should regularly evaluate each child’s asthma treatment and be open
to different treatment regimens for each individual child.
Another study, by Martinez and colleagues [34], examined whether an effec-
tive ‘‘step-down’’ treatment approach is available for children with mild persis-
tent asthma well controlled on low-dose ICS. This 4-arm randomized trial with
children 5 to 18 years of age compared twice daily ICS with ICS plus albuterol
as rescue therapy, twice daily ICS with placebo and albuterol as rescue, twice
daily placebo with ICS and albuterol as rescue, and twice daily placebo with
placebo and albuterol rescue. Although treatment failures were lowest among
those receiving daily ICS, rescue ICS plus albuterol emerged as an effective
approach, reducing exacerbations by more than a third while avoiding the
growth suppression known to occur with daily ICS use.
A similar question regarding the need for daily ICS therapy was asked
among children 1 to 5 years of age with a history of asthma exacerbations in
the previous year. In a study by Zeiger and colleagues [35], the children
were randomized to receive either daily inhaled budesonide (0.5 mg every
night) plus a placebo ICS with upper respiratory infections or a placebo daily
medication plus higher-dose budesonide (1.0 mg) twice daily for 7 days with
upper respiratory infections. No difference in the rate of exacerbations was de-
tected between groups, and like the Martinez and colleagues’ [34] study, a lower
cumulative dose of ICS was received by the group using them intermittently
for the predefined symptoms.
For those with more severe asthma, omalizumab, a humanized monoclonal
anti–immunoglobulin E (IgE) antibody, has drawn interest as a step-up
therapy, particularly for those with allergic sensitization. As such, it was eval-
uated among 6-year-olds to 20-year-olds from inner cities in a placebo-
controlled, 60-week trial [36]. With this population, omalizumab was effective
at reducing the number of days with asthma symptoms, as well as the propor-
tion of participants having one or more exacerbations.
Cystic fibrosis
Pseudomonas aeruginosa is a particularly dangerous organism for the airway of
children with cystic fibrosis. After more than a decade with no new inhaled anti-
biotic treatments, in 2010, the FDA approved aztreonam for inhalation solution
(Cayston) [37]. This aerosolized antibiotic given at doses of 75 mg 3 times daily
has been shown to improve symptoms and pulmonary function among
those with moderate to severe cystic fibrosis disease and Pseudomonas coloniza-
tion [38].
Although treating patients with cystic fibrosis with antibiotics has been done
for decades, a novel approach being developed is to improve the functioning of
the mutant cystic fibrosis transmembrane conductance regulator. An oral drug,
VX-770, given to adults for 28 days significantly improved lung function in
these patients and was well tolerated, suggesting that future treatments for
this devastating disease may target the genetic defect of the disease, rather
than just the clinical manifestations of it [39].
Drug allergy
In clinical practice, children frequently present with rashes while taking
a prescribed course of b-lactam antibiotics, and often they are labeled as peni-
cillin allergic without further testing. Although some have questioned this in the
past, a new study from Switzerland discovered that among 88 children who
presented with delayed-onset urticarial or maculopapular rashes while taking
a b-lactam antibiotic, only 6 (6.8%) had a reaction following an oral challenge
34 PAUL
test [40]. These patients also were very unlikely to have positive intradermal or
blood allergy tests. Further, those with positive oral challenge tests all had reac-
tions more mild than those following the initial antibiotic course. The investi-
gators argue that because so many patients are being mislabeled as penicillin
allergic, oral challenge tests should be considered for patients who develop
a rash while taking these drugs.
INFECTIOUS DISEASES
Otitis media
The benefits of antibiotic treatment for acute otitis media have been debated for
many years with differing standards of care around the world. Two simulta-
neously published articles attempted to end this debate using randomized,
double-blind, placebo-controlled trial designs to evaluate relevant outcomes.
In the first trial, Hoberman and colleagues [41] assigned 291 children ages 6 to
23 months with stringently diagnosed acute otitis media to either twice daily
amoxicillin-clavulanate or placebo for 10 days. Although the most participants
in both treatment arms had symptom resolution 4 days after randomization,
the children treated with amoxicillin-clavulanate had lower symptom scores in
the first 7 days after treatment as well as significantly less persistence of acute otitis
media on otoscopic examination at both 4 and 10 days after treatment was initi-
ated (4% vs 23% and 16% vs 51%, respectively). The second study also compared
amoxicillin-clavulanate with placebo among 6-month-old to 35-month-old chil-
dren with acute otitis media [42]. Again, antibiotic treatment was associated
with a reduced occurrence of treatment failure defined based on the child’s overall
condition and otoscopic signs of acute otitis media. Notably, however, was the
significantly increased adverse event of diarrhea found in the antibiotic arm of
both studies, with incidence rates between active and placebo group of 25%
versus 15% in the first study and 48% and 27% in the second trial.
Although most cases of acute otitis media completely resolve, for some, reso-
lution is not complete and otitis media with effusion occurs and can persist for
months. Because no medical treatments are currently accepted, a randomized
trial was conducted in which more than 200 children ages 4 to 11 years with bilat-
eral otitis media with effusion were treated with either daily mometasone furoate
nasal spray or placebo for 3 months [43]. Unfortunately, the active treatment was
not superior to placebo with 41% of those treated with mometasone showing reso-
lution at 1 month and 58% cured at 3 months compared with 45% and 52% in the
placebo group at those time points.
Urinary tract infections

Although debated in recent years, children with a history of urinary tract infec-
tions with vesicoureteral reflux are frequently treated with long-term low-dose
antibiotics as an attempt to prevent further infection and comorbid renal damage.
To assess the effectiveness of this approach, 576 children younger than 18 years
meeting these criteria were randomized to receive low-dose daily trimethoprim-
sulfamethoxazole or placebo for 12 months [44]. Although 19% of those in the
placebo group developed an infection over the 12-month period, only 13% in the
antibiotic group did, and although significant, the study was not powered to deter-
mine whether children with higher levels of reflux are more likely to benefit from
antibiotics than those with lower grades of the condition. Fortunately, data from
this study were combined with other trials over the previous decade to tease out
some key findings, as reported in the AAP clinical practice guideline for urinary
tract infections [45]. The meta-analysis performed by the investigators demon-
strated that antibiotic prophylaxis was not beneficial for those with a history of
urinary tract infection without vesicoureteral reflux and for those with grades I
to IV reflux. The AAP guideline also included a recommended 7-day to 140-
day treatment for acute urinary tract infections with either oral or intravenous
antibiotics with culture-demonstrated sensitivity guiding the antibiotic choice.
However, a recent study suggested that shorter durations of antibiotics, particu-
larly when given intravenously may be equally effective [46].
Pneumonia
In an attempt to reduce morbidity and mortality from community-acquired pneu-
monia in children ages 3 months and older, the Infectious Diseases Society of
America (IDSA) issued new guidelines for the diagnosis and management of
this common condition in 2011, guidelines that were endorsed by the AAP
[47]. Within the guideline are recommendations that preschoolers not be
routinely prescribed antibiotics given that the vast majority of pathogens in this
age group are viral. For children of all ages with signs and symptoms consistent
with Streptococcus pneumoniae pneumonia, amoxicillin is the first-line treatment of
choice with macrolide antibiotics being the principal antimicrobial class for atyp-
ical pneumonias. Additional recommendations are included in the guideline for
influenza outbreaks, the not fully immunized child, treatment in the inpatient
setting, and for less common pathogens.
Methicillin-resistant Staphylococcus aureus
The IDSA issued another practice guideline that was endorsed by the AAP in
2011, and the subject was the management of methicillin-resistant Staphylococcus
aureus (MRSA) [48]. For community-acquired skin and soft tissue infections
caused by MRSA, the society endorsed the use of clindamycin, trimethoprim-
sulfamethoxazole, doxycycline, minocycline, and linezolid, with the caveats
that the 2 tetracyclines not be used for children younger than 8 years, as well
as the recommendation that mupirocin 2% be used for minor skin infections.
Notably, one recent study did conflict with these guidelines by showing higher
rates of treatment failures and recurrences for these infections among children
when trimethoprim-sulfamethoxazole was used as treatment compared with clin-
damycin [49]. The IDSA guidelines also addressed patients suffering from recur-
rent MRSA skin and soft tissue infections by suggesting nasal decolonization with
mupirocin twice daily for 5 to 10 days and topical body decolonization regimens
with a skin antiseptic solution such as chlorhexidine for 1 to 2 weeks or dilute
bleach baths (one-fourth cup per one-fourth tub given for 15 minutes twice
weekly for 3 months) that can be considered to prevent further outbreaks. Within
36 PAUL
the guidelines are also recommendations for less common MRSA-related infec-
tions, including endocarditis, osteomyelitis, septic arthritis, and meningitis.
NEONATOLOGY
Gastroesophageal reflux
Many newborns ‘‘spit-up’’ and some are given the diagnosis of gastroesopha-
geal reflux disease (GERD) when the spit-ups are severe or associated with
other morbidities. One class of medication that has been commonly used to
treat GERD in newborns and infants is the proton-pump inhibitors. Unfortu-
nately, a recent systematic review found that these medications are not effective
at reducing GERD symptoms among children younger than 1 year [50]. At an
FDA advisory committee meeting in 2010, reasons why the drugs may not be
effective were discussed [51]. Among the reasons postulated was that unlike
adult GERD, infant GERD is often not acid-related.
One study not evaluating proton-pump inhibitors examined the treatment of
GERD among preterm infants with the primary outcome being reduction in
bradycardia episodes [52]. In a blinded, placebo-controlled trial evaluating me-
toclopramide and ranitidine, the active treatment group demonstrated signifi-
cantly more bradycardia episodes, suggesting that treatment of GERD for this
purpose may actually result in poorer outcomes.
Transient tachypnea of the newborn
Traditionally, transient tachypnea of the newborn (TTN) has been treated with
oxygen and observation, as the condition typically improves spontaneously
within a day or two. A research group from Turkey sought to capitalize on
the b-adrenergic receptors present on alveolar epithelium by treating newborns
with TTN with albuterol with the hypothesis that such stimulation would
increase alveolar epithelial sodium transport and enhance the resorption of fetal
lung fluid thought to be the source of tachypnea [53]. In a randomized trial that
used a normal saline solution as the placebo control, those who received a single
dose of nebulized albuterol (2.5 mg) given over 20 minutes saw significant
improvements in respiratory rate and oxygen requirement. Further, these
newborns had a significantly shorter stay in the neonatal intensive care unit.
Herpes simplex virus
Neonatal herpes simplex virus (HSV) infections can have devastating
morbidity, particularly affecting neurodevelopmental outcomes. Although de-
laying antiviral treatment with acyclovir by even 24 hours for those undergoing
diagnostic evaluation for neonatal HSV was recently shown to be associated
with increased in-hospital mortality [54], another study among neonates with
HSV and central nervous system involvement showed improved neurodeve-
lopmental outcomes when such infants received suppressive therapy with
oral acyclovir for 6 months [55]. After completing 14 to 21 days of parenteral
acyclovir, infants were randomized to receive either 6 months of suppressive
acyclovir therapy by mouth or placebo. Neurodevelopmental outcomes at
age 1 year measured by the Mental Development Index of the Bayley Scales
of Infant Development were significantly higher for those in the active treat-
ment group.
Retinopathy of prematurity
Although blindness attributable to retinopathy of prematurity (ROP) has
become relatively rare in the developed world because of advances in neonatal
care of premature infants, it remains a significant cause of blindness around the
world. Confluent laser therapy, a treatment in which a laser is applied through
a dilated pupil to the internal retinal surface, has been the standard of care for
more than a decade for moderately severe ROP, and this treatment is effective
at destroying the cells that produce vascular endothelial growth factor (VEGF),
which is essential for ROP progression. A new, alternative approach to treat-
ment is to use anti-VEGF drugs to slow progression of ROP. A prospective,
randomized trial was conducted with 150 neonates comparing conventional
laser therapy with intravitreal therapy for stage 3þ ROP with an anti-VEGF
drug, bevacizumab, a drug previously approved by the FDA for metastatic
colon cancer [56]. Bevacizumab demonstrated a significant benefit for those
with zone I, but not zone II, ROP compared with laser therapy. The drug
was associated with development of peripheral retinal vessels, whereas laser
therapy led to destruction of the peripheral retina. A subsequent article by
the principal investigator detailed that the timing of administration of the
drug is critical given the ongoing retinal development [57]. Therapy before
30 to 31 weeks postmenstrual age can lead to severe retinal dystrophy, whereas
therapy beginning after 44 weeks can accelerate the development of retinal
detachment.
Fetal and neonatal effects of medications taken during pregnancy
Although most women take medications during their pregnancy [58], few clin-
ical trials are performed to test the safety of medications among pregnant
women. To address this problem, a collaborative effort between the FDA
and researchers at the HMO Research Network Center for Education and
Research in Therapeutics, Kaiser Permanente and Vanderbilt University,
was developed to form a new research program, the Medication in Pregnancy
Risk Evaluation Program [59]. This development will hopefully contribute to
some of the excellent epidemiologic work that has already been occurring in
the United States and Europe with Denmark in particular contributing
numerous studies. For example, a group from Copenhagen has recently
demonstrated that proton-pump inhibitors [60], anti-HSV drugs (acyclovir, va-
lacyclovir, and famciclovir) [61], and newer-generation antiepileptic drugs (la-
motrigine, oxcarbazepine, topiramate, gabapentin, and levetiracetam) [62]
when taken during the first trimester of pregnancy were not associated with
major birth defects in offspring. Although this is very reassuring, another
Danish group demonstrated that selective serotonin reuptake inhibitor
consumption by pregnant women is associated with increased risk of preterm
birth and neonatal intensive care unit admissions [63], whereas another group
found it to be associated with an increased rate of persistent pulmonary
38 PAUL
hypertension in the newborn [64]. Among the US-based findings was the
discovery that many antibiotics commonly prescribed to pregnant women
are not associated with many birth defects including penicillins, erythromycin,
and cephalosporins [65]. Alternatively, that study showed that sulfonamides
and nitrofurantoins were associated with an increased risk of some severe,
although rare, birth defects.
DERMATOLOGY
A common infestation among school children, head lice, has become increas-
ingly difficult to treat with resistance to OTC products expanding in recent
years. To address the treatment of head lice, the AAP published a clinical
report in 2010 [66]. The guidance offered still recommended 1% permethrin
or pyrethrins plus piperonyl butoxide as first-line treatments unless there is
proven resistance in the community. Alternatives, particularly when resistance
is present, include a ‘‘petrolatum shampoo’’ (30–40 g of petroleum jelly
massaged on the entire surface of the hair and scalp and left on overnight
with a shower cap), malathion 0.5% for children 2 years and older, or a newer
product, benzyl alcohol 5%, for children 6 months or older. Benzyl alcohol
lotion 5% was the first non-neurotoxic lice treatment approved by the FDA,
and works by asphyxiating lice, a mechanism that has been shown to be effec-
tive when the hair is completely saturated once weekly for 2 weeks [67]. A
second new product for the treatment of lice, spinosad topical suspension
0.9%, was approved by the FDA for children 4 years and older after the
AAP report was published [68]. Spinosad is a naturally occurring insecticide
discovered from Caribbean soil samples that is packaged together with benzyl
alcohol for topical application to the hair and scalp [69]. It affects the function of
nicotinic acid and c-aminobutyric acid–gated ion channels in lice and nit
embryos, thereby exhibiting its mechanism of action, leading to neuronal exci-
tation, which kills the lice after a prolonged period of excitation. Although the
product is relatively expensive at $200 per dose, 1 application is typically
needed with a second application only if active lice are seen 1 week after the
first dose.
Yet a third option in this era of permethrin-resistant lice is oral ivermectin.
Ivermectin also interrupts c-aminobutyric acid–gated ion channels in inverte-
brates and therefore was tested in a multicenter, double-blind trial against
0.5% malathion among 812 children and adults older than 2 years [70]. Iver-
mectin, given at 400 lg/kg, once per week for 2 weeks was successful at elim-
inating lice in more than 95% of the participants assigned to its treatment
compared with only 85% of those assigned to malathion lotion.
ENDOCRINOLOGY
Type 1 diabetes mellitus
Insulin is not the only hormone produced by pancreatic beta cells, as another
hormone, amylin, is also produced and is responsible for helping to regulate
glycemia, gastric emptying, glucagon secretion, and satiety. Several recent
studies have been published to examine whether pramlintide, a synthetic

analog of amylin, can improve outcomes among adolescents with type 1 dia-
betes mellitus. Pramlintide is an injectable medication delivered subcutane-
ously. In one pilot trial, a dose of 15 lg or 30 lg was compared with
placebo when given before breakfast, and the active arms resulted in lower
postprandial hyperglycemia without any adverse events [71]. A second,
longer-term trial over 28 days found that pramlintide was associated with lower
hemoglobin A1c, body weight, and total insulin dose, although the control
group did not receive a placebo [72].
Obesity
With such a high percentage of children now being obese, there is interest in the
ability of medications to help children lose weight. One drug used for type 2 dia-
betes mellitus, metformin, was compared with placebo in a 48-week-long trial
involving 77 adolescents [73]. Although those receiving metformin hydrochlo-
ride XR, 2000 mg daily, had a significantly better body mass index change
compared with the placebo group (–0.9 vs þ0.2 kg/m2) after 48 weeks, the differ-
ence completely disappeared in the subsequent year when the metformin was
discontinued.
NEUROLOGY
Rectal diazepam has long been the standard home medication to stop a seizure,
but alternative methods to deliver benzodiazepines have been sought that are
simpler to administer. A research group in Utah tested the Mucosal Atomization
Device as a method to deliver intranasal midazolam in the home setting [74]. In
this study, 92 children were given either the midazolam or rectal diazepam during
a seizure at home, with those in the midazolam group having cessation of seizure
1.3 minutes earlier than those in the diazepam group, and importantly, caregivers
reported that the intranasal drug was easier to administer.
For the most common type of pediatric epilepsy, absence epilepsy, 3 drugs
are typically used as preventive treatment, ethosuximide, valproic acid, and
lamotrigine, but the comparative effectiveness and safety of these medications
has been unclear. To answer these questions, a double-blind, randomized trial
was conducted with 453 children with newly diagnosed absence epilepsy free of
seizures during a study run-in period where dose optimization occurred [75]. In
the subsequent 16 weeks, 53% of those treated with ethosuximide and 58%
treated with valproic acid were seizure free compared with only 29% in the la-
motrigine group. Although there was no difference between groups in terms of
drug discontinuation owing to adverse events, the valproic acid was associated
with significantly more attentional dysfunction than the ethosuximide.
PSYCHIATRY
Attention deficit hyperactivity disorder
Because of previous reports of an association between stimulant medications
taken for ADHD and sudden cardiac events, many clinicians feel obligated
40 PAUL
to order an electrocardiogram in addition to routine history and physical exam-

ination before dispensing these drugs. A comprehensive evaluation performed
on these medications involving nearly 400,000 person-years of medication use,
however, suggests that a cautious approach out of concern for serious cardio-
vascular events is not necessary [76]. The study, which evaluated children and
young adults between ages 2 and 24 years, found no increased risk of sudden
cardiac death, acute myocardial infarction, or stroke among current or former
users of ADHD drugs. A similar study among those between 25 and 64 years
also did not find an association [77].
Antipsychotic medications
A different kind of cardiovascular risk has been attributed to antipsychotic
medications, as age-inappropriate weight gain, obesity, hypertension, and lipid
and glucose abnormalities have been attributed to these drugs. To evaluate the
cardiometabolic effect of second-generation antipsychotic medications, weight
gain and changes in lipid and metabolic parameters were evaluated in a cohort
of children treated with aripiprazole, olanzapine, quetiapine, or risperidone for
12 weeks [78]. Each medication resulted in significant weight gain during this
period, with olanzapine having the greatest mean gain (8.5 kg) and aripiprazole
having the least (4.4 kg). A control group that received no medication gained
a mean of only 0.2 kg. There were also variable degrees of cholesterol and
triglyceride increases among those that took the antipsychotic drugs.
With appropriate concern for these adverse effects, an updated practice
parameter on the use of psychotropic medications in children and adolescents
from the American Academy of Child and Adolescent Psychiatry was well-
timed [79]. Although acknowledging the increase in use of psychotropics
over the past 2 decades, a fact that led an FDA advisory panel to question
whether the drugs were being overused [80], the committee responsible for
the publication urged practitioners to complete a full psychiatric and medical
evaluation before medication initiation, to continually evaluate patients for
medication-related adverse events, and to discuss treatment alternatives with
patients and families.
One additional use of the antipsychotics has been for behavioral problems
among autistic children. Risperidone has been approved for several years to treat
aggressive behaviors among autistic children, and a recent trial evaluated aripi-
prazole for the treatment of irritability in children and adolescents with autism
[81]. In this double-blind, placebo-controlled trial with nearly 100 autistic children
between ages 6 and 17 years, the mean improvement on the Aberrant Behavior
Checklist irritability subscale was significantly greater for those taking aripipra-
zole, although 11% had to discontinue treatment because of adverse events
compared with only 6% of the placebo-treated children. For most of the study
participants, however, the drug was well tolerated with the exception of signifi-
cantly greater weight gain over the 8-week treatment course (2.0 vs 0.8 kg).
This study was one of the trials that helped gain aripiprazole an FDA-approved
indication for the treatment of irritability in autistic children [82].
CARDIOLOGY
Perhaps the biggest development regarding therapeutics and pediatric cardiovas-
cular health came in the form of new expert guidelines that resulted from the
National Heart, Lung, and Blood Institute’s efforts to address the prevention of
cardiovascular risk factor development and effectively manage identified risk
factors when present [83]. Although the entire scope of the guidelines is broad,
several areas related to cardiovascular health therapeutics were addressed.
For pediatric hypertension, drugs in several classes are recommended:
angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers,
a-receptor and b-receptor antagonists, calcium-channel blockers, central
a-agonists, diuretics, peripheral a-antagonists, and vasodilators. For each drug,
dose regimens and monitoring requirements are listed. Changes from the prior
recommendations included the addition of losartan, amlodipine, felodipine, fosi-
nopril, lisinopril, metoprolol, and valsartan to the list of medications that are
tolerated and can reduce blood pressure in children from ages 6 to 17 years.
Also regarding management of hypertension, those with chronic kidney disease
is a subpopulation commonly affected by this condition. A recent study demon-
strated that intensified blood pressure control with an ACE inhibitor, ramipril,
slowed progression to renal failure among 385 children with chronic kidney
disease [84].
The evaluation and treatment of pediatric dyslipidemias became somewhat
controversial when the guidelines were published because of the new recommen-
dation to screen all 9-year-old to 11-year-old children for these conditions.
Although the guidelines recommended no treatment for children younger than
10 years unless they carry a diagnosis of a severe primary hyperlipidemia or
similar condition (eg, homozygous hypercholesterolemia, primary hypertrigly-
ceridemia), children and adolescents 10 years and older with persistent low-
density lipoprotein (LDL) cholesterol levels of 250 mg/dL or higher are to be
referred to a lipid specialist, who may consider therapy with a statin drug if
diet and lifestyle changes do not significantly lower these levels. Those taking sta-
tins require ongoing assessment of liver function and creatine kinase levels, and
women are advised to avoid pregnancy while taking these drugs. In addition to
statins, a bile sequestrant, colesevelam, was approved by the FDA to reduce
LDL cholesterol alone or in combination with a statin for children 10 to 17 years
of age with familial hypercholesterolemia [85].
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Rotavirus Infection
An Update on Management and Prevention
Penelope H. Dennehy, MDa,b,*

a
Division of Pediatric Infectious Diseases, Hasbro Children’s Hospital, Providence, RI, USA;
b
Department of Pediatrics, The Alpert Medical School of Brown University, Providence, RI, USA
Keywords
Rotavirus Rotavirus vaccine Rotavirus gastroenteritis
Key Points
Rotavirus vaccines have reduced the burden of rotavirus disease in the United
States.
The real-world effectiveness data for both vaccines are consistent with efficacy
data obtained from clinical trials.
Herd immunity has also been seen after vaccine introduction.
Vaccine introduction has led to no significant strain shifts or escape mutants as yet.
R
otavirus infection is the leading cause of severe acute diarrhea among
young children worldwide. An estimated 527,000 children aged less than
5 years die from rotavirus diarrhea each year, with greater than 85% of
these deaths occurring in the low-income countries of Africa and Asia [1].
Rotavirus-related deaths represent approximately 5% of all deaths in children
younger than 5 years worldwide. Each year rotavirus causes approximately
114 million episodes of gastroenteritis requiring only home care, 24 million
clinic visits, and 2.4 million hospitalizations in children less than 5 years of
age worldwide [2]. By age 5, nearly every child will have an episode of rota-
virus gastroenteritis, 1 in 5 will visit a clinic, 1 in 50 will be hospitalized, and
approximately 1 in 205 will die [2]. Recent results from the World Health
Organization (WHO) rotavirus surveillance networks indicate that approxi-
mately 36% of diarrhea hospitalizations among children aged less than 5 years
worldwide can be attributed to rotavirus infection [3]. In view of the high
burden of rotavirus disease, safe and effective rotavirus vaccines are urgently
needed, particularly in the resource poor countries of the world.
In the United States, before the introduction of rotavirus vaccine in 2006, rota-
virus caused an estimated 20 to 60 deaths, 55,000 to 70,000 hospitalizations,
*Division of Pediatric Infectious Diseases, Rhode Island Hospital, 593 Eddy Street, Providence,
RI 02903. E-mail address: pdennehy@lifespan.org

48 DENNEHY
205,000 to 272,000 emergency department visits, and 410,000 outpatient visits

annually [4]. Nearly every child in the United States was infected with rotavirus
by 5 years of age and most developed gastroenteritis [5]. One child in 7 required
a clinic or emergency room visit and 1 in 70 was hospitalized [5,6]. Rotavirus was
responsible for 22% to 54% of the acute gastroenteritis cases in the United States
and caused more severe disease than did other enteric pathogens, accounting for
30% to 50% of all hospitalizations for gastroenteritis among children less than 5
years of age and more than 70% of hospitalizations for gastroenteritis during the
seasonal peaks of rotavirus disease in the United States [7–9]. Annual direct and
indirect costs were estimated at approximately 1 billion dollars, primarily due to
the cost of time lost from work to care for an ill child [10,11]. Rotavirus activity
in the United States decreased significantly after introduction of rotavirus vaccine
in 2006.
EPIDEMIOLOGY AND TRANSMISSION OF INFECTION

Rotavirus outbreaks exhibit a seasonal pattern. In temperate climates, disease is
more prevalent during fall and winter. In the United States, before introduction
of rotavirus vaccine, annual epidemics began in the southwest during November
and December, progressing north and east and reaching the northeast by April or
May [12]. The reason for this seasonal pattern is unknown. In tropical climates,
the disease is less seasonal than in temperate areas but is more pronounced
during drier and cooler months.
The reservoir of rotavirus is the gastrointestinal tract and stool of infected hu-
mans. Although rotavirus infection occurs in many nonhuman mammals, trans-
mission of animal rotaviruses to humans is believed to be rare and probably does
not lead to clinical illness. Although immunodeficient persons may shed rota-
virus for a prolonged period, a true carrier state has not been described.
Rotavirus is highly communicable, with a small infectious dose of less
than 100 virus particles [13]. Viruses are shed in high concentration in the stool
of rotavirus-infected persons. Children shed large numbers of viruses in stool,
from 100 to 1000 viruses per milliliter, during the acute illness. Shedding may
occur beginning 2 days before the onset of diarrhea and for up to 10 days after
onset of symptoms. Rotavirus may be detected in the stool of immunodeficient
persons for more than 30 days after infection.
Transmission is by fecal-oral spread, both through close person-to-person
contact and by fomites (such as toys and other environmental surfaces contami-
nated by stool). The virus may also be transmitted by respiratory droplets [14].
Rotaviruses are also probably transmitted by other modes such as fecally contam-
inated food and water. These routes of transmission are probably uncommon as
rates of rotavirus illness among children in industrialized and resource poor coun-
tries are similar, indicating that clean water supplies and good hygiene have had
little effect on virus transmission.
Spread within families, institutions, hospitals, and childcare settings is common.
From 30% to 50% of adult contacts of infected infants become infected, although
most are asymptomatic. The virus survives well in the environment and only 10
ROTAVIRUS INFECTION 49
to 100 infectious virus particles are needed to cause infection. This amount of
virus can readily be acquired through contact with contaminated surfaces facili-
tating spread to household contacts.
Rotavirus is a major cause of acute gastroenteritis in children attending child
care. Most children in childcare will have their first infection in that setting. In child
care centers rotavirus is introduced from the community and quickly spreads to
most of the children in the center [15]. During these outbreaks toys, food prepara-
tion areas, and toilet facilities are usually heavily contaminated with rotaviruses.
Rotavirus is also a common hospital-acquired infection on pediatric wards in
the winter months [16]. These infections result in prolonged hospital stays and
increased medical costs. One in 5 children hospitalized during rotavirus season
may acquire a nosocomial rotavirus infection. The likelihood of infection
increases with duration of hospitalization.
CONTROL MEASURES TO PREVENT INFECTION

The single most important procedure to minimize transmission of rotavirus is
frequent hand hygiene measures [17]. Rotavirus can rapidly contaminate envi-
ronmental surfaces because of the large number of viruses shed in an infected
child’s stool. Rotavirus is very stable and may remain viable in the environment
for weeks or months if not disinfected [18]. Hands may be contaminated from
environmental surfaces further facilitating spread of infection. Skin disinfectants
such as chlorhexidine are ineffective against rotavirus. Studies have shown that
hand washing with soap and water removes only 75% of virus from the hands.
Agents containing alcohol are the most effective against rotavirus. To control
the spread of rotavirus hands should be cleaned of visible stool with soap and
water and then an alcohol-containing hand rub should be used. Because general
disinfectants, such as bleach, are ineffective against rotavirus, potentially contam-
inated surfaces, such as changing tables, should be cleaned of all visible stool and
then disinfected with 95% ethanol or other alcohol-containing disinfectant [17].
Although hand hygiene and cleaning of potentially contaminated surfaces are
important control measures, vaccination is the only measure likely to have
a significant impact on the incidence of severe dehydrating rotavirus disease.
PATHOPHYSIOLOGY OF ROTAVIRUS DISEASE

Rotavirus enters the body through the mouth. The virus is thought to cause diar-
rhea by at least three different mechanisms. The first is by infecting the mature
enterocytes on the tips of the absorptive intestinal villi of the small intestine [19].
Histopathology of jejunal and duodenal mucosal small intestinal biopsies in chil-
dren performed 24 to 129 hours after the onset of illness shows patchy irregular-
ities that consist of shortening and blunting of villi and increased infiltration of
the lamina propria with mononuclear cells [20]. Blunting of the villus tips causes
a loss of absorptive surface in the small intestine resulting in decreased absorp-
tion of salt and water. This net secretion of salt and water leads to the production
of voluminous watery stools. In addition, rotavirus infection of the enterocytes
destroys intestinal brush border enzymes, such as maltase, sucrase, and lactase,
50 DENNEHY
which are located on the villus tips and are involved in the digestion of carbohy-
drates. The resulting complex sugar malabsorption and osmotic diarrhea
contribute to the diarrhea seen in rotavirus infections.
The second mechanism that rotavirus uses to cause diarrhea is a viral entero-
toxin that works much like cholera toxin. Rotavirus nonstructural protein NSP4
has been shown to have direct toxic effects on the gastrointestinal mucosa [21].
Diarrhea is induced when NSP4 triggers chloride secretion via a calcium-
dependent signaling pathway.
Finally, rotavirus-induced diarrhea may also be the result of activation of the
enteric nervous system by infection. This results in net intestinal fluid and elec-
trolyte secretion and diarrhea [22].
Rotavirus infection is usually localized to the intestine; however, studies
have reported antigenemia is common in children with rotavirus diarrhea.
Rotavirus viremia is less commonly detected [23–28]. Rarely, involvement of
extraintestinal sites, including the respiratory tract, liver, kidney, lymph nodes,
and central nervous system (CNS), has been reported [29–37].
CLINICAL ILLNESS
The incubation period for rotavirus diarrhea is short, usually less than 48
hours. The clinical manifestations of infection vary and depend on whether
it is the first infection or reinfection. Rotavirus predominantly infects children,
but infection also occurs in adults. Immunosuppressed hosts, including chil-
dren, seem to develop a more severe and protracted infection.
Studies of children with rotavirus infection have shown a spectrum of disease,
ranging from asymptomatic shedding to severe dehydration, seizures, and even
death. Rotavirus gastroenteritis typically begins with acute onset of fever and
vomiting followed 24 to 48 hours later by watery diarrhea [38]. On average, there
are up to 10 to 20 bowel movements per day. Symptoms generally persist for 3 to
8 days, although protracted episodes have been noted on occasion. Fever is
usually low-grade and occurs in up to half of all infected children. Some children
may have high fevers. Rotavirus infection with fever may trigger seizures in chil-
dren with a propensity for febrile seizures. Vomiting is nonbilious and occurs in
80% to 90% of infected children. Vomiting is usually brief, lasting 24 hours or less
in most children. Dehydration and electrolyte disturbances are the major
sequelae of rotavirus infection and occur most often in the youngest children.
Studies of hospitalized children have indicated that cases of gastroenteritis asso-
ciated with rotavirus have tended to be more severe than cases in which rotavirus
was not detected, with more severe dehydration and higher incidences of vomit-
ing and fever. Respiratory symptoms may be seen in 30% to 50% of children with
rotavirus gastroenteritis.
Although infection can occur at any age, rotavirus most commonly causes clin-
ically significant disease in young infants and children. In industrialized countries
severe, dehydrating rotavirus gastroenteritis primarily occurs among infants and
children aged 3 to 24 months, although 25% of cases of severe disease occur after
2 years of age. Infants younger than 3 months of age have relatively low rates of
rotavirus infection, probably because of passive maternal antibody, and possibly

breastfeeding. In developing countries, 60% to 80% of severe rotavirus disease
occurs by 12 to 15 months of age.
Most children are infected with rotavirus more than once. First infections are
more likely to result in severe gastroenteritis than are subsequent infections.
Protective immunity develops after rotavirus infection and is strongest against
moderate to severe disease. Subsequent infections are usually milder or may
even be asymptomatic. Adults usually have asymptomatic or mild disease
because of immunity from previous exposure.
Most mothers have rotavirus antibody from previous infection that is passed
transplacentally, protecting the neonate. As a result, most infected neonates will
have asymptomatic or mild disease. An exception is the preterm infant, who is
at greater risk of severe illness than the term infant is because of the lack of
transplacental maternal antibodies [39]. Exposure of neonates (asymptomati-
cally) to rotavirus is associated with a reduced likelihood of their developing
severe rotavirus diarrhea later in infancy [40,41].
Although rotavirus gastroenteritis most commonly affects small children,
adults may also develop symptomatic infections [42]. Among adults in the
United States, rotavirus infection occurs most often in travelers returning
from developing countries, persons caring for children with rotavirus gastroen-
teritis, immunocompromised persons, and older adults [43]. The clinical mani-
festations in adults seem similar to those in children but are usually less severe.
Dehydration and severe disease have been reported in adults.
Severe and prolonged rotavirus gastroenteritis has been reported in children
with immunodeficiency, particularly those with T-cell immunodeficiencies or
severe combined immunodeficiency (SCID), and after bone marrow transplan-
tation. In these cases, rotavirus may be associated with severe disease and may
be fatal, and extraintestinal replication has been reported. Rotavirus infection
of children after solid organ transplantation is usually self-limited but more
severe than in healthy children. Rotavirus does not seem to be a common cause
of severe or persistent diarrhea in individuals with HIV infection.
Rotavirus gastroenteritis has occurred in association with multiple other clin-
ical syndromes, which may or may not be causally associated with rotavirus.
These clinical syndromes include gastrointestinal complications or CNS
complications.
The gastrointestinal syndromes that may be associated with rotavirus
include necrotizing enterocolitis, intussusception, biliary atresia, and prolonged
diarrhea. Necrotizing enterocolitis has been associated with nosocomial rota-
virus infections in neonates. Intussusception was reported in association with
rotavirus gastroenteritis shortly after recognition of this virus. However, subse-
quent studies have never established a definitive causal link with natural rota-
virus infection. Biliary atresia has also been reported in association with
rotavirus infection. Although most children recover from rotavirus gastroenter-
itis completely, some children continue to have protracted diarrhea. Carbohy-
drate intolerance or lactase intolerance may persist after resolution of diarrhea.
52 DENNEHY
Epidemiologic studies have suggested that rotavirus infection does not increase
the risk for subsequent persistent diarrhea in childhood.
Rotavirus gastroenteritis may be associated with CNS complications, particu-
larly seizures and encephalopathy. Rotavirus has been detected by polymerase
chain reaction (PCR) in cerebrospinal fluid (CSF) in some cases. However, it
is unclear whether detection of rotavirus represents actual replication in the
CNS, contamination at the time of lumbar puncture, or carriage of rotavirus
RNA in CSF lymphocytes.
DIAGNOSIS AND MANAGEMENT OF INFECTION

Enzyme immunoassays and latex agglutination assays for detection of group A
rotavirus antigen in stool are available commercially and are widely used for
diagnosing rotavirus infection. Virus also can be identified in stool by electron
microscopy and by reverse transcriptase-PCR, but these techniques are
primarily used in the research setting.
No antiviral is currently available to treat rotavirus infection. The current
mainstay of treatment of acute rotavirus gastroenteritis consists of oral rehydra-
tion and early introduction of feedings [44]. Adequate fluid and electrolyte
replacement and maintenance is the key to managing rotavirus gastroenteritis.
Oral rehydration is the preferred method unless the child has intractable vom-
iting that would require intravenous (IV) rehydration. Hydration status in chil-
dren can be assessed based on easily observed signs and symptoms. Children
who are not thirsty, have moist mucous membranes, wet diapers and tears are
not dehydrated and do not require oral rehydration solution (ORS). In the
absence of dehydration, ORS should be used to replace ongoing stool losses
only in severe cases in which the patient has already required rehydration
and still has ongoing diarrhea. Children who are mildly or moderately dehy-
drated should receive 50 to 100 mL/kg of ORS over 4 hours and should be
reevaluated often for changes in hydration status. Children who are vomiting
generally tolerate ORS. ORS is contraindicated in the child who is obtunded or
at risk for aspiration. When ORS is complete, regular feeding should be
resumed.
Children who are severely dehydrated with changes in vital signs or mental
status require emergency IV fluid resuscitation. Hypotension is a late manifesta-
tion of shock in children. Mental status, heart rate, and perfusion are better indi-
cators of severe dehydration and incipient shock. After initial treatment with IV
fluids, these children can be given ORS.
Early refeeding is recommended in managing acute rotavirus gastroenteritis
because oral feedings help facilitate mucosal repair following rotavirus infec-
tion. Introducing a regular diet within a few hours of rehydration or
continuing the diet during diarrhea without dehydration has been shown
to shorten the duration of the disease. Early refeeding has not been associated
with increased morbidity, such as electrolyte disturbances or a need for IV
fluids.
ADJUNCTIVE THERAPY
Although oral rehydration treats dehydration, it is not effective in shortening
the duration of rotavirus-induced diarrhea. There is a growing body of litera-
ture establishing the effectiveness of selected probiotics as an adjunct to rehy-
dration therapy. In developed countries, Lactobacillus rhamnosus GG given in
a daily dose of 10 billion colony-forming units per day has proven efficacy
in rotavirus gastroenteritis to reduce the duration of diarrhea, the risk of pro-
tracted diarrhea, and the duration of hospitalization [45–47]. The duration of
diarrhea may be reduced as much as 1 to 2 days with the use of probiotics.
Nitazoxanide is a thiazolidine antimicrobial with activity against anaerobic
bacteria, protozoa, and viruses. Three randomized double-blind clinical trials
have demonstrated effectiveness of nitazoxanide in treating rotavirus gastroen-
teritis in young children with significant reductions in time to resolution of
symptoms [48–50]. More data on nitazoxanide is needed before it can be
considered for routine use.
Antidiarrheal drugs are generally not recommended for treatment of rota-
virus gastroenteritis [44,51]. Over-the-counter medicines such as loperamide
and bismuth subsalicylate can help relieve gastroenteritis symptoms in adults
but are not recommended for children.
Antiemetics should not be routinely used in the management of children with
acute rotavirus gastroenteritis [52,53]. Although ondansetron use may decrease
vomiting during the first hours after presentation, decrease the need for IV fluids
in the emergency department, and decrease hospitalization rates in those patients
who require IV fluids, its use may increase diarrheal episodes. In addition, most
studies of ondansetron in children with acute gastroenteritis have been performed
only on mildly dehydrated children. Of greatest concern is the use of ondansetron
may increase risk of developing prolongation of the Q-T interval. For more informa-
tion, see http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsfor
HumanMedicalProducts/ucm272041.htm. Patients at risk for adverse outcomes
include those with underlying heart conditions, such as congenital long QT
syndrome, those who are predisposed to low levels of potassium and magnesium
in the blood, and those taking other medications that lead to QT prolongation.
ROTAVIRUS STRUCTURE AND CLASSIFICATION

Human rotaviruses are part of a large family of viruses causing neonatal diarrhea in
a variety of domestic animals and birds. Animal strains are antigenically distinct
from those causing human infection, and rarely cause infection in humans. Rota-
viruses are classified into at least seven distinct groups (A through G). Only groups
A, B, and C infect humans. Group A rotaviruses are the most important cause of
severe acute gastroenteritis in infants and young children worldwide.
Rotaviruses were first described as a causative agent of gastroenteritis in hu-
mans in 1973 when they were seen in electron micrographs of duodenal mucosal
biopsies from children with acute gastroenteritis. Rotaviruses have a distinctive
wheel-shape on electron microscopy giving rise to their name which is derived
from the Latin word ‘‘rota’’ meaning wheel.
54 DENNEHY
To understand how vaccines have been developed to prevent rotavirus

disease, one must understand the structure of the rotavirus virion. Rotavirus
is a double-stranded RNA virus composed of three concentric shells that enclose
11 gene segments. For the most part, each gene segment codes for a single pro-
tein. When mixed infection with more than one rotavirus strain occurs, the gene
segments from the parental viruses may reassort independently, producing reas-
sortants of mixed parentage, a source of viral diversity.
The outermost shell of the rotavirus virion contains two important structural
proteins, VP7, the glycoprotein (G protein), and VP4, the protease-cleaved protein
(P protein) [28]. VP7 and VP4 define the serotype of the virus and are considered
critical to vaccine development because they are targets for neutralizing antibodies
that may provide both serotype specific and, in some instances, cross-reactive
protection [54]. A typing system has been developed for each protein. Fourteen
G serotypes and 11 P serotypes have been identified in humans.
Human rotaviruses exhibit enormous diversity. The gene segments that
encode the G and P proteins can segregate independently giving rise to strains
with at least 42 different G-P serotype combinations [55]. Until recently, four rota-
virus strains (G1, G3, G4 combined with P[8], and G2 combined with P[4]) made
up 96% of the globally identified strains [56]. Recently, previously rare G sero-
types, such as G5, G6, G8, G10, and in particular G9, have emerged [55].
Predominant serotypes vary from year to year and region to region. G1P[8]
is the globally predominant strain, representing over 70% of rotavirus infec-
tions in North America, Europe, and Australia, but only about 30% of the
infections in South America and Asia, and 23% of those in Africa [57]. G9
strains now constitute the predominant strains in some parts of Asia and Africa
and G8 strains are proportionally more frequent in Africa. In South America,
G5 strains have emerged in children with diarrhea and G9 is associated with
more severe disease in Latin America [58]. Similarly, the distribution of the
P[6] antigen differs according to region. P[6] strains now constitute over 50%
of the circulating strains in Africa, whereas P[8] is associated with most rota-
virus strains from the rest of the world [59]. The development of successful
rotavirus vaccines may require inclusion of all the major G or P types causing
disease in a specific region.
NATURAL PROTECTION
Naturally acquired rotavirus infections provide the greatest protection against
reinfection causing severe disease [60]. After a first natural infection, infants
and young children are protected against subsequent symptomatic disease regard-
less of whether the first infection was symptomatic or asymptomatic. After a single
natural infection, 40% of children are protected against any subsequent infection
with rotavirus, 75% are protected against diarrhea caused by a subsequent rota-
virus infection, and 88% are protected against severe rotavirus diarrhea. Second,
third, and fourth infections confer progressively greater protection. In observa-
tion studies, no child with two previous infections has subsequently developed
severe rotavirus diarrhea.
Despite three decades of research, the components of the immune response

that protect children from rotavirus infection and disease are not completely
understood. Both serum and mucosal antibodies are probably important. Anti-
bodies to both VP4 and VP7 proteins neutralize virus infectivity. However, in
vaccine studies, correlation between these antibodies and protection has been
poor. The first infection with rotavirus elicits serum-neutralizing antibody
response to the serotype of the infecting virus. Subsequent infections elicit
a broader, cross-reactive response. Studies have suggested that antibody is
important in the resolution of infection and in protection against subsequent
infection, whereas cell-mediated immunity is most important in the resolution
of rotavirus infections [61]. Local immunity in the gut also seems to be impor-
tant for protection against subsequent infection. Total serum antirotavirus IgA,
measured shortly after infection, generally reflects intestinal IgA levels and
seems to be the best marker of protection [62]. However, gut immunity seems
to be of short duration and has been hard to measure. Because a reliable
immune correlate of protection has not been found, each new vaccine candi-
date must be tested in large field trials for efficacy.
GOALS FOR A ROTAVIRUS VACCINE

A realistic goal for a rotavirus vaccine is to duplicate the degree of protection
against disease that follows natural infection. Therefore, vaccine program
objectives include the prevention of moderate-to-severe disease but not neces-
sarily of mild disease associated with rotavirus. Effective rotavirus vaccines
should decrease the number of children admitted to the hospital with dehydra-
tion or seen in emergency departments and should decrease the burden on the
practicing primary care practitioner by reducing the number of office visits or
telephone calls due to rotavirus gastroenteritis.
Effective rotavirus vaccines are most needed in resource-poor countries
where mortality associated with rotavirus is high. The development and intro-
duction of rotavirus vaccines for children in the resource-poor countries of the
world has been given high priority by the WHO. In 2003, GAVI (Global Alli-
ance for Vaccines and Immunizations) sponsored a new public-private organi-
zation, the Rotavirus Vaccine Program at PATH (Program for Appropriate
Technology in Health), whose role was to accelerate the development and
introduction of rotavirus vaccines in developing countries.
DEVELOPMENT OF ROTAVIRUS VACCINES

Human-rhesus rotavirus reassortant vaccine
The first multivalent live oral reassortant vaccine developed was a human-rhesus
rotavirus reassortant vaccine (RotaShield; RRV-TV). This tetravalent vaccine
contained four virus strains representing the most commonly seen G types,
G1 to G4; three rhesus-human reassortant strains containing the VP7 genes of
human serotype G1, G2 and G4 strains were substituted for the VP7 gene of
the parent rhesus rotavirus (RRV), and the fourth strain comprised serotype
G3 of RRV [63]. RRV-TV was extensively evaluated in field trials in the United
56 DENNEHY
States, Finland, and Venezuela and was found to be 80% to 100% effective in pre-
venting severe diarrhea due to rotavirus in each of these settings [64–67]. Due to
the proven efficacy, the RRV-TV vaccine was licensed in August 1998 for
routine use in children in the United States at 2, 4, and 6 months of age [68].
After inclusion of this vaccine in the immunization schedule in the United
States, and immunization of over 600,000 infants in the first 9 months of the
program, several cases of vaccine-associated intussusception were reported
[69]. The period of greatest risk of intussusception was shown to be 3 to 10
days after the first of three oral doses [70–72]. Although the true overall inci-
dence of this adverse event proved difficult to assess, a group of international
experts suggested a consensus rate of 1 per 10,000 vaccinated infants [73]. The
pathogenic mechanisms involved in intussusception following vaccination are
currently unknown. As a consequence of this rare but potentially dangerous
adverse effect, the manufacturer withdrew RotaShield from the market in the
United States 14 months after its introduction.
CURRENTLY LICENSED VACCINES

There are two rotavirus vaccines currently licensed for use in the United States.
The two rotavirus vaccine products differ in composition and schedule of
administration. RV5 (RotaTeq) is a live oral vaccine manufactured by Merck
and licensed by the US Food and Drug Administration (FDA) in February
2006. RV5 is routinely recommended as a three-dose schedule at 2, 4, and 6
months of age. RV1 (Rotarix), a live oral vaccine manufactured by GlaxoS-
mithKline, was licensed by the FDA in April 2008. RV1 is routinely recom-
mended as a two-dose schedule at 2 and 4 months of age.
Human-bovine rotavirus reassortant vaccine (RV5, RotaTeq)

RV5 contains five reassortant rotaviruses developed from human and bovine
parent rotavirus strains. Initially, VP7 was thought to be the most important
antigen in inducing protection; therefore, human-animal reassortant rotavi-
ruses for use in vaccines such as RRV-TV included only human VP7 genes
to provide protective immune responses. More recently, VP4 has also been
considered important in protection; therefore, RV5 includes human VP7 or
VP4 genes to provide protective immune responses. Four reassortant rotavi-
ruses express the VP7 protein (G1, G2, G3, or G4) from the human rotavirus
parent strain and the attachment protein (P[5]) from the bovine rotavirus
parent strain WC3. The fifth reassortant virus expresses the attachment protein
(P[8]) from the human rotavirus parent strain and the outer capsid protein G6
from the bovine rotavirus parent strain.
RV5 was tested in a large phase III trial in 11 countries, with the United States
and Finland accounting for more than 80% of all enrolled subjects [74]. The trial
included more than 70,000 children and was primarily designed to evaluate vaccine
safety with respect to intussusception, but also to evaluate the immunogenicity and
efficacy of the vaccine with respect to the severity of illness and the number of hospi-
talizations or emergency department visits for rotavirus gastroenteritis.
The risk of intussusception was evaluated for 42 days after each vaccine
dose in the phase III trial. Six cases of intussusception were observed in the
RV5 group versus 5 cases of intussusception in the placebo group. The
data did not suggest an increased risk of intussusception in vaccine recipients
relative to placebo. Among vaccine recipients, there were no confirmed cases
of intussusception within the 42-day period after the first dose, which was the
period of highest risk for the previously licensed RRV-TV vaccine. In addi-
tion, no evidence of clustering of cases of intussusception was observed within
a 7-day or 14-day window after immunization for any dose. The overall rate
of intussusception is consistent with the expected background rate of
intussusception.
Pooled data from the large phase III and two smaller phase III trials showed
that in the week following the first dose of RV5 the incidence of fever and irri-
tability did not differ between vaccine and placebo recipients. Diarrhea and
vomiting occurred more frequently among vaccine versus placebo recipients
(10.4% vs 9.1% and 6.7% vs 5.4%, respectively).
The efficacy of RV5 was evaluated in two phase III trials [74,75]. In these
trials, the efficacy of a 3-dose regimen of RV5 against rotavirus gastroenteritis
of any severity was 74% and against severe rotavirus gastroenteritis was 98%.
RV5 also proved strongly efficacious in preventing rotavirus gastroenteritis of
any severity caused by the predominant G1 serotype (75% efficacy) and the G2
serotype (63% efficacy). There was a trend toward efficacy for the remaining
serotypes, but patient numbers were too small to show statistical significance
(G3 83% efficacy, G4 48% efficacy, and G9 65% efficacy).
The efficacy of RV5 in reducing the number of office visits for rotavirus
gastroenteritis and in reducing the number of emergency department visits
and hospitalizations for rotavirus gastroenteritis was evaluated in a large study
[74]. RV5 reduced the incidence of office visits by 86%, emergency department
visits by 94%, and hospitalizations for rotavirus gastroenteritis by 96%. Efficacy
against all gastroenteritis hospitalizations of any cause was 59%. The efficacy of
RV5 in the second rotavirus season after immunization was 63% against rota-
virus gastroenteritis of any severity and 88% against severe rotavirus gastroen-
teritis [74].
To assess the efficacy of RV5 between doses of a 3-dose series and with less
than 3 doses (incomplete regimen) post hoc analyses of the large study of the
efficacy of RV5 were conducted. RV5 reduced the rates of combined hospital-
izations and emergency department visits for G1 to G4 rotavirus gastroenteritis
by 100% between doses 1 and 2, and 91% between doses 2 and 3. RV5 reduced
the rates of rotavirus gastroenteritis, regardless of serotype, by 82% between
doses 1 and 2, and 84% between doses 2 and 3 [76].
Efficacy and safety trials of RV5 in Asia and Africa have been conducted.
The efficacy of an RV5 against severe rotavirus gastroenteritis in Ghana,
Kenya, and Mali was 39% [77]. Vaccine efficacy of RV5 in Vietnam and
Bangladesh was 48% against severe disease during nearly 2 years of follow-
up [78].
58 DENNEHY
Live, attenuated human rotavirus vaccine (RV1, Rotarix)

A live, attenuated human rotavirus vaccine (strain 89–12) was originally devel-
oped in Cincinnati, OH, USA, by tissue culture passage of a wild-type human
rotavirus isolate [79]. This vaccine is a G1P[8] strain and thus represents the
most common of the human rotavirus VP7 and VP4 antigens. The vaccine
was further developed by Avant Immunotherapeutics and licensed to GSK Bio-
logicals, who further modified the vaccine by cloning and tissue culture
passaging of the parent 89–12 vaccine strain. The resulting vaccine,
RIX4414 (RV1), underwent initial trials in Finland that showed safety, immu-
nogenicity, and efficacy.
A large scale, double-blind, placebo-controlled trial of more than 63,000
infants enrolled in 11 Latin American countries and Finland was done to con-
firm that the vaccine did not cause intussusception [80]. The vaccine was
administered in two oral doses at 2 and 4 months of age and was well-
tolerated with a reactogenicity profile similar to the placebo in terms of fever,
diarrhea, or vomiting. During a 31-day period after each dose, there was no
increase of intussusception among recipients of vaccine compared with placebo.
Six vaccinated patients and seven placebo recipients developed intussusception
in this period, confirming the lack of a causal association.
A subset of 20,000 infants in this large trial was followed for efficacy [80].
The results demonstrated a protection rate of 85% against severe rotaviral
gastroenteritis and 100% protection against the most severe dehydrating rota-
viral gastroenteritis episodes. The vaccine also proved strongly efficacious in
preventing rotavirus gastroenteritis of any severity caused by the predomi-
nant G1 serotype (92% efficacy) and for serotypes G3, G4, or G9 (88% effi-
cacy). Efficacy against the G2 serotype (41%) was not significant in this large
trial.
Although RV1 was not efficacious against the G2 serotype in the large phase
III trial, significant cross-protection against non-G1 and non-P[8] strains was
shown in a European trial with two seasons follow-up. In this study, efficacy
was 79% against rotavirus gastroenteritis of any severity, 90% against severe
rotavirus disease, and 96% against hospitalization due to rotavirus. For severe
rotavirus gastroenteritis the vaccine had efficacy of 96% against G1P[8] and
88% against non-G1P[8] RV strains, including G2P[4] [81].
Efficacy and safety trials of RV1 have been conducted in Asia and Africa. In
a large phase III trial (>9000 infants) in Singapore, Hong-Kong, and Taiwan
vaccine efficacy was 96% against severe rotavirus gastroenteritis, 100% against
wild-type G1P[8] and 94% against circulating non-G1 rotavirus types. No intus-
susception cases were reported within 31 days postvaccination [82]. In a phase
III trial in South Africa and Malawi, RV1 showed an overall efficacy of 61% by
1 year of age. Vaccine efficacy was lower in Malawi than in South Africa (49%
vs 77%); however, the number of episodes of severe rotavirus gastroenteritis
that were prevented was greater in Malawi than in South Africa (6.7 vs 4.2
cases prevented per 100 infants vaccinated per year) [83]. Efficacy against all-
cause severe gastroenteritis was 30%.
WORLDWIDE IMPLEMENTATION OF ROTAVIRUS VACCINES

In 2007, after RV5 and RV1 became available, the WHO recommended inclu-
sion of rotavirus vaccine in the immunization programs of Europe and the
Americas and, in 2009, expanded the recommendation to all infants over the
age of 32 weeks worldwide [84].
Currently rotavirus vaccines are licensed in over 125 countries and are avail-
able in the private sector in many countries. These vaccines are part of the national
immunization program in 29 (15%) of 193 countries worldwide. Over 50% of
these countries are in Latin America and none are the low-income countries where
rotavirus disease is most severe. With donor support, GAVI plans to introduce
rotavirus vaccine in more than 40 low-income countries by 2015.
ROTAVIRUS VACCINE USE IN THE UNITED STATES

Recommendations for the use of rotavirus vaccine
The current recommendations for the use of rotavirus vaccine in the United
States were published by the Advisory Committee on Immunization Practices
(ACIP) of the Centers for Disease Control and Prevention (CDC) in February
2009 and by the American Academy of Pediatrics (AAP) in May 2009 [7,85].
Because of similar estimates of efficacy and safety, neither the ACIP nor AAP
state a preference for one vaccine versus the other.
The AAP and ACIP recommend routine rotavirus vaccination of all infants.
The vaccine should be administered as a series of either two or three oral
doses, for RV1 and RV5, respectively, beginning at 2 months of age. Rotavirus
vaccine should be given at the same visit as other vaccines given at these ages.
The vaccination series for both vaccines may be started as early as 6 weeks of
age. The minimum interval between doses of both rotavirus vaccines is 4
weeks. The AAP and ACIP did not define a maximum interval between doses.
It is preferable to adhere to the recommended interval of 8 weeks. But if the
interval is prolonged, the infant can still receive the vaccine as long as it can
be given on or before 8-months of age. It is not necessary to restart the series
or add doses because of a prolonged interval between doses.
The maximum age for any dose of RV1 approved by the FDA is 24 weeks,
whereas the maximum FDA-approved age for any dose of RV5 is 32 weeks.
The AAP and ACIP developed age recommendations that vary from those
of the manufacturers. The AAP and ACIP recommendations state that the
maximum age for the first dose of both vaccines is 14 weeks 6 days. This is
an off-label recommendation for RV5 because the approved maximum age
for the first dose of that vaccine is 12 weeks. The maximum age for any
dose of either rotavirus vaccine is 8 months 0 days. This is an off-label recom-
mendation for both vaccines because the labeled maximum age for RV1 is 24
weeks and the labeled maximum age for RV5 is 32 weeks.
Infants for whom the first dose of rotavirus vaccine was inadvertently admin-
istered at age 15 weeks or older should receive the remaining doses of the series
at the routinely recommended intervals. Timing of the first dose should not
60 DENNEHY
affect the safety and efficacy of the remaining doses. Rotavirus vaccine should
not be given after age 8 months 0 days even if the series is incomplete.
There are currently no data on schedules that include both RV1 and RV5.
The AAP and ACIP recommend that the rotavirus vaccine series should be
completed with the same product whenever possible. However, vaccination
should not be deferred if the product used for a prior dose or doses is not avail-
able or is not known. In this situation, the provider should continue or
complete the series with the product that is available. If any dose in the series
was RV5 or the vaccine brand used for any prior dose in the series is not
known, a total of three doses of rotavirus vaccine should be administered.
The AAP and ACIP recommend that providers not repeat the dose if the
infant spits out or regurgitates the vaccine. Any remaining doses should be
administered on schedule.
Breastfeeding does not seem to diminish immune response to rotavirus
vaccine. Infants who are being breastfed should be vaccinated on schedule.
There are at least five serotypes of rotavirus that may cause diarrheal disease
in the United States. In addition, infants may experience multiple episodes of
rotavirus diarrhea because the initial infection may provide only partial immu-
nity. Infants documented to have had rotavirus gastroenteritis before receiving
the full course of rotavirus vaccinations should still begin or complete the 2-
dose or 3-dose schedule.
Rotavirus vaccine is contraindicated for infants who are known to have had
a severe allergic reaction (anaphylactic) to a vaccine component or following
a prior dose of vaccine. Latex rubber is contained in the RV1 oral applicator,
so infants with a severe allergy to latex should not receive RV1. The RV5 dosing
tube is latex free.
Chronic, wild-type rotavirus infection has been reported in infants with
SCID, with resulting prolonged diarrhea or shedding of rotavirus [86]. In
2010, in response to reported cases of vaccine-acquired rotavirus infection in
infants with SCID following rotavirus vaccine administration, the prescribing
information and patient labeling for RV5 and RV1were revised to include
SCID as a contraindication for administration of rotavirus vaccine [87–89].
The CDC updated the list of contraindications for rotavirus vaccine (RV1
and RV5) to include infants diagnosed with SCID [90].
Available data suggest that infants with a history of intussusception might be
at higher risk for a repeat episode than are other infants. In 2011, the CDC up-
dated the contraindications for rotavirus vaccine (RV1 and RV5) to include
history of intussusception [91]. Previously, the CDC had considered history
of intussusception a precaution but not a contraindication.
Precautions are those conditions that may increase the chance of a vaccine
adverse reaction or reduce the efficacy of the vaccine. In general, infants
with precautions to vaccination (see later discussion) should not receive rota-
virus vaccine until the condition improves unless the benefit of vaccination
outweighs the risk of an adverse reaction. However, clinicians may consider
use of the vaccine on a case-by-case basis.
Children who are immunocompromised because of congenital immunodefi-

ciency, or hematopoietic stem cell or solid organ transplantation sometimes expe-
rience severe, prolonged, and even fatal rotavirus gastroenteritis. However, no
safety or efficacy data are available regarding administration of rotavirus vaccine
to infants who are, or are potentially, immunocompromised due to either disease
or drugs, except for those with SCID. Consultation with an immunologist or
infectious disease specialist is advised for infants with known or suspected altered
immunocompetence before rotavirus vaccine is administered [7]. General guide-
lines on immunodeficiency and use of live virus vaccines are available in the 2009
Red Book, Table 1.14 [92].
HIV-infected infants acquire rotavirus at the same frequency as uninfected
infants but may have more severe disease if there are concurrent nutritional
deficiencies or opportunistic infections [93]. However, there are few data on
the safety and immunogenicity of rotavirus vaccines in HIV-infected infants.
In a study in South Africa, administration of three doses of RV1 were well
tolerated by a group of infants with HIV and demonstrated immunogenicity
comparable to HIV-uninfected infants living in the same country [94]. The
vaccinated cohort had no evidence of increased rate of CD4 decline, which
is relevant to the concern that vaccine administration could accelerate HIV
disease progression. The ACIP and AAP recommend that rotavirus vaccine
be administered during early infancy. In addition to the safety and immunoge-
nicity data from South Africa, two considerations support vaccination of HIV-
exposed and potentially infected infants. First, the HIV diagnosis might not be
established in infants born to HIV-infected mothers by the time they reach the
age of the first rotavirus vaccine dose and only 1.5% to 3% of HIV-exposed
infants in the United States will eventually be determined to be HIV infected.
Second, vaccine strains of rotavirus are considerably attenuated and exposure
to an attenuated rotavirus is preferable to exposure to wild-type rotavirus.
Rotavirus vaccine should generally not be administered to infants with acute,
moderate, or severe gastroenteritis, or other acute illness, until the condition
improves. However, infants with mild acute gastroenteritis or other mild acute
illness can be vaccinated, particularly if the delay in vaccination will delay the
first dose of vaccine beyond 15 weeks 0 days of age.
No data are available on the immune response to rotavirus vaccine in infants
who have recently received a blood product. In theory, infants who have
recently received an antibody-containing blood product might have a reduced
immunologic response to a dose of oral rotavirus vaccine. However, two or
three doses of vaccine are administered in the full rotavirus vaccine series
and no increased risk for adverse events is expected. ACIP now recommends
that rotavirus vaccine may be administered at any time before, concurrent
with, or after administration of any blood product.
Available data suggest that preterm infants (ie, infants born at less than 37-week
gestation) are at increased risk for hospitalization from rotavirus during the first 1
to 2 years of life. In clinical trials, rotavirus vaccines seemed to be generally well
tolerated in preterm infants, although a relatively small number of preterm
62 DENNEHY
infants have been evaluated [95,96]. The AAP and ACIP consider the benefits of
rotavirus vaccination of preterm infants to outweigh the risks of adverse events.
The AAP and ACIP support vaccination of a preterm infant according to the
same schedule and precautions as a full-term infant, provided the following condi-
tions are met: the infant’s chronologic age is at least 6 weeks, the infant is clinically
stable, and the vaccine is administered at the time of discharge or after discharge
from the neonatal intensive care unit or nursery. Although the lower level of
maternal antibody to rotavirus in very preterm infants theoretically could
increase the risk for adverse reactions from rotavirus vaccine, the AAP and
ACIP believes the benefits of vaccinating the infant when age eligible, clinically
stable, and no longer in the hospital outweigh the theoretic risks.
Vaccine strains of rotavirus are shed in the feces of vaccinated infants. So if
an infant were to be vaccinated with rotavirus vaccine while still needing care
in the hospital, a theoretic risk exists for vaccine virus being transmitted to
infants in the same unit who are acutely ill and to preterm infants who are
not age eligible for vaccine. The AAP and ACIP consider that, in usual circum-
stances, the risk from shedding outweighs the benefit of vaccinating an infant
who will remain in the hospital and recommends that these infants not be vacci-
nated until they meet the conditions described above.
Although rotavirus is shed in the feces of vaccinated infants, transmission of
vaccine virus has been documented in only a few cases [97,98]. Infants living in
households with persons who have or are suspected of having an immunode-
ficiency disorder or impaired immune status can be vaccinated. The AAP and
ACIP believe that the indirect protection of the immunocompromised house-
hold member provided by vaccinating the infant in the household, and thereby
preventing wild-type rotavirus disease, outweighs the small risk for transmit-
ting vaccine virus to the immunocompromised household member.
Infants living in households with pregnant women should be vaccinated ac-
cording to the same schedule as infants in households without pregnant women.
Because most women of childbearing age have preexisting immunity to rotavirus,
the risk for infection by the attenuated vaccine virus is considered to be very low.
Although transmission of vaccine virus has not been documented, it is prudent
for all members of the household to use measures such as good hand washing
after changing a diaper or otherwise coming in contact with the feces of the vacci-
nated infant.
IMPLEMENTATION OF THE ROTAVIRUS VACCINE PROGRAM

IN THE UNITED STATES
Vaccine uptake
The uptake of rotavirus vaccine in the United States has been rapidly increasing.
Estimates of rotavirus vaccination coverage were not available before 2009. Since
2009, rotavirus vaccine coverage has been included in the National Immunization
Survey (NIS). NIS monitors vaccination coverage among children aged 19 to 35
months using a random-digit–dialed sample of telephone numbers of households.
Coverage with a full series of rotavirus vaccine increased to 59.2% in 2010 from
43.9% in 2009 [99]. Within the 2010 sample, rotavirus vaccination coverage
increased from 51.9% among children born during January to June 2007, to
69.8% among children born during January to June 2009. Coverage varied by
race or ethnicity. Among black children, coverage with rotavirus vaccine was
lower compared with white children. Coverage among children living below
poverty level was lower than coverage among children living at or above poverty
level. In 2010, coverage with rotavirus vaccine significantly increased in 40 states
compared with 2009, and coverage ranged from 42.1% in Maine to 82.1% in
Delaware.
Postlicensure safety-monitoring data from the United States
As the rotavirus vaccination program is implemented, it is important to continue
to assess the safety profile of the vaccines to detect rare or unusual events as well
as to continue to monitor the potential for intussusception following vaccination.
Current rotavirus vaccines were not associated with intussusception in large pre-
licensure trials. However, recent postlicensure data from international settings
suggest the possibility of a low-level elevated risk, primarily in the first week after
the first vaccine dose [100,101]. Two recently reported studies have been con-
ducted to examine the risk of intussusception following RV5 in United States
infants. The first study, a cohort study that included infants 4 to 34 weeks of
age enrolled in the Vaccine Safety Datalink, found the risk of intussusception
in vaccinated infants was not increased compared with infants not receiving
the rotavirus vaccine [102]. A second study identified and followed infants
with a health insurance claim for RV5 during the first 2 years of RV5 availability.
The relative risk of intussusception in 85,000 children receiving RV5 was 0.8
compared with a control group and the general safety evaluation did not identify
any specific diagnoses or patterns of diagnoses that might suggest other safety
concerns [103]. No published data is available on the risk of intussusception
following RV1 in United States infants.
In 2010, researchers using novel laboratory techniques found that rotavirus
vaccines contain DNA or DNA fragments from porcine circovirus (PCV)
[104]. PCV is a virus that commonly infects pigs and has been detected in
5% of stool samples from United States adults, likely as a result of dietary
consumption of pork products. PCV is not believed to cause illness among hu-
mans. Based on available evidence regarding a theoretical risk of PCV infection
among humans and the observed benefits of rotavirus vaccines in preventing
severe acute gastroenteritis among infants, the FDA expressed reassurance
that the detection of DNA and DNA fragments from PCV in rotavirus vaccines
was not likely to cause harm to humans and recommended continued use of
the vaccines [105]. Subsequent investigation suggests that PCV DNA was intro-
duced into both rotavirus vaccines through porcine-derived trypsin, a reagent
used in the cell-culture growth process of vaccine production.
Rotavirus surveillance in the United States
Rotavirus gastroenteritis is not a reportable disease in the United States and
testing for rotavirus infection is not often performed when a child seeks medical
64 DENNEHY
care for acute gastroenteritis. Methods of surveillance for rotavirus disease at the
national level include review of national hospital discharge databases for
rotavirus-specific or rotavirus-compatible diagnoses, surveillance for rotavirus
disease at three sites that participate in the New Vaccine Surveillance Network,
and reports of rotavirus detection from a sentinel system of laboratories, the
CDC National Respiratory and Enteric Virus Surveillance System (NREVSS).
At the state and local levels, surveillance efforts at sentinel hospitals or by review
of hospital discharge databases are used to monitor the impact of the vaccine
program. Special studies, such as case-control studies and retrospective cohort
studies, are used to measure the effectiveness of rotavirus vaccine under routine
use in the United States. CDC has established a national strain surveillance
system of sentinel laboratories to monitor circulating rotavirus strains before
and after the introduction of rotavirus vaccine. This system is designed to detect
new or unusual strains causing gastroenteritis that might not be prevented effec-
tively by vaccination, which might affect the success of the vaccination program.
The effectiveness of rotavirus vaccination in the prevention of rotavirus

disease
The effect of vaccine on rotavirus disease and epidemiology needs to be evalu-
ated for several reasons [106]. First, routine immunization occurs in conditions
different from the ideal clinical trial setting. Monitoring postlicensure effective-
ness of rotavirus vaccine is important to assure that the expected benefits of rota-
virus vaccine programs are achieved. Second, assessing protection in infants
through the first and second years of life is crucial for the success of a rotavirus
vaccination program because infancy is when most severe disease and mortality
from rotavirus occur. Third, assessing whether vaccination results in herd immu-
nity is important because a vaccine with indirect protection could provide
substantially greater benefits than expected based on direct efficacy. Fourth,
changes in the epidemiology of rotavirus disease may occur postlicensure,
such as duration of protection, changes in age-specific and seasonal incidence
of disease, and timing of epidemics. These changes may be important in immu-
nization program planning. Fifth, surveillance is important to describe serotype
distribution to identify newly emerging strains or changes in strain distribution
because these may compromise the effectiveness of rotavirus vaccines.
Unlike efficacy studies that are done in a carefully controlled setting, studies
on vaccine effectiveness compare the risks of disease outcomes in vaccinated
or nonvaccinated populations in a real-life setting. Because the introduction of
rotavirus vaccines into the national immunization program in 2006, seven
studies have been conducted to assess vaccine effectiveness of RV5 in the United
States [107–113]. A complete series of RV5 showed effectiveness ranging from
78% to 100% in preventing severe rotavirus disease (hospitalizations and/or
emergency department visits) and 96% in preventing outpatient visits. There
have no studies to evaluate the vaccine effectiveness of RV1 in the United States.
The real-world effectiveness data for RV5 are consistent with efficacy data
obtained from clinical trials and strengthen the argument for the introduction
of rotavirus vaccination as an effective means for controlling severe childhood

diarrhea. Additionally, no indication of waning vaccine-induced immunity has
yet been observed during the rotavirus vaccine postlicensure period [108,114].
The impact of rotavirus vaccination on the health burden of rotavirus

disease in the United States
Vaccine impact studies have demonstrated that the burden of rotavirus disease
in the United States has been reduced significantly since the introduction of
rotavirus vaccines. Since 2009, eight studies have assessed the impact of vacci-
nation on use of health care resources in the United States [115–122]. These
include studies using national surveillance data as well as studies evaluating
the impact of introduction of vaccines in specific regions or hospitals. Three
studies used prospective surveillance data [117,121,122]. The remaining studies
were based on retrospective analyses of data sources that included hospital
records, data from laboratory reports, and health-insurance claims databases.
The impact of vaccination on rotavirus-related hospitalizations was the most
frequently reported outcome. Evaluation of the prevaccination and postvacci-
nation periods demonstrated that rotavirus vaccination significantly reduced
the burden of rotavirus-related hospitalizations; ranging from 60% to 93% de-
pending on vaccine coverage, age group, and rotavirus season studied.
Studies have also evaluated the impact of rotavirus vaccination on all-cause
gastroenteritis or diarrhea-related hospitalizations, emergency visits, and outpa-
tient or physician office visits. Reductions were seen in all these parameters.
All-cause gastroenteritis or diarrhea-related hospitalizations declined 16% to
50% in the United States. Three studies also found significant reductions in
emergency department and office visits after the introduction of rotavirus
vaccine [109,115,118].
Studies comparing the numbers or proportions of rotavirus-positive tests
before and after introduction of the rotavirus vaccination program are useful
in evaluating vaccine impact. Sentinel laboratory surveillance data from the
NREVSS demonstrated a decline in the numbers or proportions of rotavirus-
positive tests in the United States during the first two seasons after the introduc-
tion of RV5 when compared with the period of 1991 to 2006 [123]. These
reductions have sustained through the 2009 to 2010 rotavirus season [124].
Herd immunity after rotavirus vaccination

Herd immunity has been noted after routine rotavirus vaccination in the
United States. Herd immunity occurs as a result of decreased transmission
of rotavirus in the community and provides indirect protection to unvaccinated
individuals. The rotavirus vaccination schedule should be completed by 32
weeks of age in the United States and there have been no catch-up vaccination
programs in older children. Evidence suggestive of herd immunity after the
widespread use of rotavirus vaccines comes, therefore, from older children
who were unlikely to have been vaccinated. Postvaccination data in the early
years after introduction of rotavirus vaccines show significant reductions in
66 DENNEHY
rotavirus disease among members of age groups who were too old and/or too
young to be vaccinated [115,116,118,119,121,123,125].
Changing epidemiology and seasonality of rotavirus disease after

vaccine introduction in the United States
Surveillance and disease monitoring after vaccine introduction can supply infor-
mation on changes in age-specific incidence of disease. Rotavirus vaccines have
shown sustained efficacy for first 2 to 3 years of life in the United States and Eu-
rope with no changes in expected age-specific incidence of disease [74,81,126].
In the United States, there were alterations in the rotavirus season following
the introduction of rotavirus vaccine. The CDC compared the onset, duration,
and magnitude of the 2007 to 2008, 2008 to 2009, and 2009 to 2010 rotavirus
seasons with median values for the previous 15 years. In 2007 to 2008, onset
was delayed by 2 to 4 months, the duration was reduced by 12 weeks (14 vs 26
weeks), and the median was 11 weeks later than the median onset during 2000
to 2006. The rotavirus season was longer during 2008 to 2009 compared with
2007 to 2008 rotavirus activity [124].
Before introduction of vaccine, rotavirus had a predictable winter-spring sea-
sonality and geographic pattern in the United States, with activity beginning in
the west from December to January, extending across the country, and ending
in the northeast from May to June [12]. Studies from the United States show
a shift in the onset of the epidemic by 1 to 2 months has occurred after rota-
virus vaccination; during the 2010 rotavirus season in the United States, rota-
virus activity was below the epidemic threshold, a finding that had never
occurred in the previous 19 years of rotavirus surveillance [124]. In addition,
impressive alterations in the spatiotemporal spread of rotavirus disease in the
United States occurred after vaccination [127].
Effect of vaccination on rotavirus strain circulation and emergence

Rotavirus vaccines need to provide cross-protection against multiple rotavirus
serotypes because circulating strains vary and multiple strains can circulate
within the same region at the same time. RV1 differs from G2P[4] strains by
both G-type and P-type and genogroup. Although RV5 contains either the G
or P antigen for all common strains, serotype-specific immune responses varied
by strain with the lowest response against G3P[8] in the pivotal clinical trial
[74]. Despite the potential for decreased efficacy, both RV5 and RV1 vaccines
provided good cross-protection against the common circulating strains in trials
in Europe and the United States [74,80]. In the Latin American trial, RV1
seemed to provide less protection against the fully heterotypic G2P[4] rotavirus
strains (vaccine efficacy was 44%). However, it is important to note that the
G2P[4] strain was not circulating in Latin America during the study period;
thus the study was not powered to conclusively assess protection against this
strain [80]. However, in a 2-year efficacy study conducted in six European
countries, RV1 provided 85% protection against severe rotavirus gastroenter-
itis caused by G2P[4] strains [81]. In more recently published trials from
Asia and Africa, both vaccines had similar efficacy against a wide range of
strains circulating during the study period [77,78].
Both RV5 and RV1 vaccines provided good cross-protection against the
common circulating strains in postlicensure vaccine studies. In two vaccine
effectiveness studies from Brazil that were conducted during 2 years when
G2P[4] strain circulation predominated, RV1 effectiveness ranged from 75%
to 81% against severe rotavirus disease caused by this strain during the first
year of life [128,129]. In a similar case-control study from Australia, during
an outbreak of G2P[4]-related gastroenteritis among an indigenous population,
effectiveness of RV1 was 86% [130]. A postlicensure study from the United
States reported high effectiveness of RV5 against severe disease due to G3P
[8] strains [131]. In a case-control study from Mexico, after the emergence of
a novel G9P[4] strain, effectiveness of RV1 against severe rotavirus gastroen-
teritis was 94% [132].
Three nationwide longitudinal strain surveillance studies address the issue of
strain ecology before and after routine childhood vaccination. A nationwide
predominance of G2P[4] strains was noticed in Brazil in the first 2 years after
introduction of RV1 [133]. In the United States, a higher prevalence of G3P[8]
strains occurred in some cities after introduction of RV5 [134]. In Australia
individual states used either RV1 or RV5 exclusively. A higher prevalence
of G2P[4] strains was noted in states that were exclusively using RV1
compared with states using RV5 and the RV5 states had a higher prevalence
of G3P[8] strains than states using RV1 [135].
Both effectiveness studies and clinical trial efficacy data suggest that a natural
shift in strain, unrelated to vaccination, is the most plausible explanation for the
observed short-term changes postvaccination. However, the studies showing
shifts in strain predominance highlight the need for robust longitudinal surveil-
lance and epidemiologic studies to better assess the long-term effect of rotavirus
vaccination on strain ecology. These longer term studies could help assess
whether the continued high level of immunity to vaccine serotypes eventually
leads to evolution of strains that evade vaccine immunity.
SUMMARY
Rotavirus infection is the most common cause of severe diarrhea disease in
infants and young children worldwide and continues to have a major global
impact on childhood morbidity and mortality. Vaccination is the only control
measure likely to have a significant impact on the incidence of severe dehydrat-
ing rotavirus disease.
Rotavirus vaccines have reduced the burden of rotavirus disease in the
United States. Long-term monitoring will need to continue to assess the effects
of rotavirus immunization programs and epidemiologic strain surveillance is
necessary to determine whether changes in strain ecology will affect the rota-
virus vaccine effectiveness and whether rotaviruses with the ability to evade
vaccine immunity emerge.
68 DENNEHY
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Seasonal and Pandemic Influenza

An Overview with Pediatric Focus
Silvana Carr, MD
Division of Infectious Diseases, Department of Pediatrics, Morsani College of Medicine, University
of South Florida, 17 Davis Boulevard, Tampa, FL 33606, USA
Keywords
Influenza Children Antiviral Vaccination
Key Points
Influenza viruses are constantly changing their antigenic structure. These
changes allow the influenza viruses to escape from the host immunity and are
responsible for the ability of these viruses to cause annual epidemics.
Influenza viruses can cause disease among persons in any age group, but rates
of illness are highest among children and those with underlying chronic medical
conditions.
The clinical presentation of influenza is variable in children at different age
groups and may be atypical in infants.
Annual influenza vaccination is the most effective strategy for the prevention and
control of influenza and is recommended for all individuals 6 months of age or
older.
Influenza antiviral therapy is effective for the prevention of influenza, and, when
used for treatment, can reduce the duration and severity of illness.
I
nfluenza is a globally important respiratory pathogen, which causes nearly
annual epidemics and occasional pandemics. Although influenza viruses
can cause disease among persons in any age group, rates of illness are high-
est among children and those with conditions that increase their risk for devel-
oping influenza-related complications [1]. Annual influenza vaccination is the
most effective strategy for the prevention and control of influenza and its
complications, and is recommended for all individuals aged 6 months or older
[2]. Antiviral therapy is effective for the prevention of influenza, and, when
used for treatment, can reduce the duration and severity of illness [3–5]. This
article reviews the biologic, epidemiologic, and clinical aspects of seasonal and
pandemic influenza A (H1N1) infection in pediatric patients, and discusses anti-
viral therapy and disease prevention.
E-mail address: scarr1@health.usf.edu

76 CARR
BIOLOGY OF INFLUENZA
Structure
Influenza viruses belong to the family Orthomyxoviridae (from the Greek myxa,
meaning mucus). They are enveloped negative-stranded, segmented RNA
viruses with an average diameter of 120 nm. Currently, 3 types of influenza
viruses are described (A, B, and C), which are distinguished by antigenic differ-
ences in 2 of their internal proteins, nucleoprotein (NP) and matrix protein
1 (M1). Influenza A (Fig. 1) and B viruses each contain 8 viral RNA segments,
whereas influenza C has 7 viral RNA segments. In influenza A viruses, these
segments encode for the 11 viral genes: hemagglutinin (HA), M1, matrix protein
2 (M2), NP, nonstructural protein 1 (NSP 1), nonstructural protein 2 (NS2), poly-
merase acidic protein (PA), polymerase basic protein 1 (PB1), and polymerase
basic protein 2* (PB2). The viral envelope is made up of a lipid bilayer derived
from the plasma membrane of the host and contains 3 of the viral transmem-
brane proteins: HA, NA, and M2 [6]. Sitting just underneath the viral lipid
membrane is M1, which forms a matrix holding the viral ribonucleoproteins
(vRNPs). These vRNPs are the core of the virus and are made up of the viral
negative-stranded RNAs, which are wrapped around NP. At one end of the
vRNPs are the 3 polymerase proteins (PB1, PB2, and PA) that make up the viral
RNA polymerase complex [6].
Aquatic birds are the natural reservoir for type A influenza viruses, which
are also found in a wide variety of other warm-blooded animals, including
pigs, horses, whales, and humans. Types B and C influenza are predominantly
Fig. 1. Influenza virus structure. Eight segments of viral RNA are contained within the enve-
lope and matrix (M1) shell. Each codes for 1 or 2 proteins that form the virus or regulate its
intracellular replication. (From Hayden FG. Influenza. In: Goldman L, Schafer AI, eds. Cecil
Medicine, 24th edition. Philadelphia: Saunders, 2011. Courtesy of Robert G. Webster, MD,
Memphis, TN; with permission.)
SEASONAL AND PANDEMIC INFLUENZA 77
human pathogens. Influenza A viruses are subdivided further into subtypes

based on the surface antigens, HA and neuraminidase (NA). Fifteen subtypes
of HA (H1–H15) and 9 subtypes of NA (N1–N9) have been described in influ-
enza A viruses [6].
Influenza life cycle

The influenza virus binds to the cell surface by fixing the outer top of the HA
to the sialic acid, the receptor for HA found on the surface of the membrane of
the host cell. The sialic acid linkage to the penultimate galactose, either a2, 3
(in birds) or a2, 6 (in humans), determines host specificity. Influenza viruses
from swine recognize both bird and human receptors, which explains why
swine are a good mixing vessel for avian and human influenza viruses. After
attachment, the virus enters the host cell in an endosome. The endosome has
a low pH (around 5–6), which triggers the fusion of the viral and endosomal
membranes. The acidic environment inside the endosome also opens up the
M2 ion channel that acts as a proton-selective ion channel. Opening the M2
ion channels acidifies the viral core, allowing release of the vRNPs into the
cytoplasm of the host cell. The vRNPs are subsequently transported to the
nucleus, where transcription and replication of the viral genome take place.
The newly formed RNPs leave the nucleus, then viral particles are formed,
which subsequently leave the cell. Because influenza is an enveloped virus,
it uses the plasma membrane of the host cell to form the virions that leave
the cell and go on to infect neighboring cells. The viral NA facilitates virus
release from infected cells by removing sialic acid from the viral HA protein
[6,7].
IMMUNITY TO INFLUENZA INFECTION

Immunity to influenza infection is mediated by systemic and local antibodies, as
well as cytotoxic T-cell responses. The first line of defense is mediated by the
innate immune system. Infiltration of neutrophils and monocytes/macrophages
into the lungs occurs during the initial stages of infection, followed by the recruit-
ment of influenza-specific B and T cells [8].
Immune B cells secrete antibodies to neutralize the virus. Secretory immuno-
globulin A is a major factor in resistance to natural infection in the upper respira-
tory tract [9,10]. Serum antibody production against HA is critical for viral
neutralization, whereas antibodies against the viral NA are responsible for inhib-
iting virus release from the cell, thus preventing spread of the infection [11,12].
Influenza-specific CD8þ cytotoxic T lymphocytes (CTL) are believed to
promote the elimination of the virus and host recovery via the production of
proinflammatory cytokines, including interferon c, and the direct killing of
virus-infected cells. Once infectious virus is cleared, the CTL population
contracts, leaving a pool of long-lived, antigen-specific memory CD8þ T cells
capable of rapid recall to perform as effectors. This enhanced secondary response
forms the basis for vaccination strategies based on priming CD8þ T-cell memory
to promote early virus clearance [13].
78 CARR
ANTIGENIC DRIFT AND ANTIGENIC SHIFT

Influenza is continuously undergoing antigenic changes in the viral HA and, to
a lesser extent, in the viral NA. These changes allow the influenza viruses to
escape from the acquired immunity of the host and are responsible for the
ability of these viruses to cause annual epidemics.
Antigenic drift results from point mutations that lead to a minor change in the
HA or NA antigens, without resulting in a change in the viral subtype. It is
responsible for the annual influenza epidemics. Antigenic shift occurs when
there is a major change in the HA or NA antigens, resulting in the generation
of a new influenza viral subtype. It occurs at infrequent and unpredictable inter-
vals and occurs only with influenza A, because antigenically distinct subtypes of
HA and NA occur only among influenza A viruses. Antigenic shifts have the
potential to cause pandemics if the new virus subtype can be transmitted effi-
ciently from person to person in a population with little or no preexisting immu-
nity [14].
The 2009 pandemic H1N1 virus (2009 H1N1) has a unique combination of
genes from both North American and Eurasian swine lineages that has not
been identified previously in either swine or human populations [15]. The
HA gene of the 2009 H1N1 belongs to the classic swine lineage and is antigen-
ically and genetically distinct from HAs of contemporary human seasonal influ-
enza H1N1 viruses. Because the H1 seasonal influenza subtype is currently
circulating in humans, swine-origin influenza virus H1 is not a subtype new
to humans; it is a virus that jumped species (from a nonhuman animal host
to humans) and did not arise from previously circulating human viruses by
mutation (ie, by antigenic drift) [16]. However, because most humans had no
preexisting antibody to key pandemic influenza A (H1N1) virus HA epitopes,
widespread transmission was possible [17].
IMPACT AND EPIDEMIOLOGY OF INFLUENZA IN CHILDREN

Annual influenza epidemics usually occur in the winter months in temperate
zones. Influenza peak activity can occur any time from November to May,
but most often it occurs during January or February [18]. Within a given
community, an influenza epidemic may last 4 to 8 weeks or longer. Influenza
A (H1N1, H3N2) usually causes annual epidemics, whereas influenza B circu-
lates every 3 to 4 years, but both viruses can circulate during a single season.
The severity of each influenza season varies and the level of mortality is highest
when influenza A (H3N2) viruses predominate [19].
The most common mode of natural influenza transmission is from person to
person through close contact, during which large respiratory droplets are
produced during coughing or sneezing. Indirect contact transmission via
hand transfer of influenza virus from contaminated surfaces or objects to
mucosal surfaces of the face (eg, nose and mouth) or airborne transmission
can also occur [20]. However, the relative contribution of the different modes
of influenza transmission is unclear [21]. In 1 reported case, aerosol transmis-
sion is believed to have been a possible source of nosocomial transmission
from a patient receiving noninvasive ventilation to other patients on a medical

ward [22].
The incubation period ranges from 1 to 4 days (average: 2 days) [23]. Influ-
enza viral shedding in the respiratory mucosa occurs 1 day before the first
symptoms and after resolution of the symptoms. In adults, the virus shedding
lasts 5 to 10 days after the illness onset. In young children, viral shedding may
last more than 10 days after resolution of symptoms. The peak level of virus in
the respiratory secretions occurs 1 to 3 days after inoculation and correlates
with the degree of fever [23,24].
Influenza infection affects 5% to 10% of the US population every year.
Annual peaks of pediatric and adult acute respiratory disease (including ambu-
latory cases and hospital admissions) coincide with the peak activity of influ-
enza in the community [1,25–28]. In addition, antibiotic prescriptions for
children are estimated to increase by 10% to 30% during the winter months
because of influenza and its complications [26].
During community-based outbreaks of influenza, the highest attack rates of
infection occur in school-age children (5–18 years old), with rates reaching
70% (range 15%–70%) in some communities [29]. Children have the highest
attack rates, and for this reason play a significant role in introducing and
spreading influenza virus into households and throughout the community. Cases
among school-age children and school absenteeism peak in the early stage of an
epidemic. As the epidemic progresses, the proportions of infected adults and
preschool children increase, whereas the proportion of infected school-age chil-
dren decreases [30].
Young children have the highest risk of hospitalization [26,28]. Hospitaliza-
tion rates among children 2 years of age or younger are similar to hospitaliza-
tion rates among other groups considered at higher risk for influenza-related
complications, including persons aged 65 years and older [31]. Annual hospital-
ization rates for laboratory-confirmed influenza decrease with increasing age,
ranging from 240 to 720/100,000 children aged less than 6 months to approx-
imately 20/100,000 children aged 2 to 5 years. Hospitalization rates for children
less than 5 years of age with high-risk medical conditions are approximately
250 to 500/100,000 children [32].
Although children have the highest rates of influenza infection; older adults
have the highest mortality. Previous studies report an estimated annual average
of 92 influenza-associated deaths (0.4 deaths/100,000 persons) among children
less than 5 years of age during the 1990s versus 32,651 deaths (98.3 deaths/
100,000 persons) among adults aged 65 years or older [32]. However, half of
all influenza-related deaths occur in groups with other risk factors for
influenza-related complications (see later discussion) [33].
Most illnesses caused by the 2009 H1N1 influenza virus were acute and self-
limited, with the highest attack rates reported among children and young adults.
Also, hospitalization rates were highest among the youngest group, especially
those 4 years of age or younger, and 90% of the deaths occurred in those 65 years
of age or older [17]. Deaths among persons aged 65 years or older traditionally
80 CARR
have accounted for 90% or more of seasonal influenza-related deaths [34]. The
relative sparing of adults older than 60 years of age is presumably because of
the exposure of persons in this age group to antigenically related influenza viruses
earlier in life, resulting in the development of cross-protective antibodies [17].
Underlying conditions that are associated with complications from seasonal
influenza also are risk factors for complications from 2009 H1N1 influenza
virus infection. Pregnant women (especially those in the second and third
trimester) and women less than 2 weeks post partum are overrepresented
among those with severe disease [35]. In addition, some studies report that
obesity (body mass index [BMI, calculated as weight in kilograms divided by
the square of height in meters] 30 kg/m2) and particularly morbid obesity
(BMI 40 kg/m2) are risk factors for hospitalization and death [17]. Additional
studies are needed to determine whether obesity is a risk factor specific to the
pandemic influenza A (H1N1) or a previously unrecognized risk factor for
influenza-related complications caused by other influenza viruses.
CLINICAL MANIFESTATIONS
Influenza is difficult to differentiate from other acute respiratory diseases in chil-
dren because the symptoms of influenza overlap with many other respiratory
virus infections. In general, influenza is more commonly associated with
nonspecific febrile and lower respiratory tract illnesses than other respiratory
viruses [36]. The clinical presentation of influenza varies among children of
different age groups [23]. In neonates and infants, influenza infection often
mimics bacterial septicemia and may present only with fever without localizing
signs, poor feeding, and lethargy or with nonspecific respiratory symptoms
such as apnea [37]. Young children are more likely to manifest fever and upper
respiratory symptoms (rhinorrhea, congestion) in addition to cough. The
classic presentation of sudden onset of fever and chills accompanied by head-
ache, sore throat, myalgia, malaise, anorexia, and nonproductive cough is more
common among older children. The cough is described as a dry, hacking
cough that peaks after 3 to 4 days and persists for more than 1 week after reso-
lution of the other symptoms. Sore throat occurs in more than half of the cases
and usually is associated with nonexudative pharyngitis. Ocular symptoms
including tearing, photophobia, and burning also can occur [23,38,39].
Gastrointestinal symptoms, including vomiting, abdominal pain, and diar-
rhea, are more common in children than in adults [40]. Influenza infection
can cause febrile seizures in infants and young children, with a reported rate
of approximately 5% [39,41]. Other clinical manifestations of influenza infec-
tion include a crouplike syndrome that may be more severe than the croup
caused by parainfluenza viruses, with a higher fever and more tenacious secre-
tions. Airway compromise is often more severe and is sometimes complicated
by bacterial superinfection [42].
Bronchopneumonia secondary to influenza occurs in 10% to 50% of cases,
but most episodes are mild and associated with complete recovery. Rarely,
influenza pneumonia can be fatal in previously healthy individuals [43].
Influenza-associated otitis media occurs in 3% to 5% of cases annually. Acute

otitis media typically manifests 3 to 4 days after the onset of upper respiratory
tract symptoms [44]. Concurrent viral and bacterial middle-ear infection signif-
icantly worsens the course of acute otitis media [44,45].
There is little published information about the differences in clinical presen-
tations between influenza A and B infections. A recent study suggested that
children with influenza B are older, and appear less ill than those with influenza
A. This study also reported a higher incidence of myalgia and myositis with
influenza B [39].
In most children without underlying risk factors for severe influenza, the
pandemic influenza A (H1N1) causes an uncomplicated respiratory tract
illness, signs, and symptoms similar to those associated with influenza B, and
no more severe than seasonal influenza [46]. Similar to previous pandemics,
secondary bacterial infection with Streptococcus pneumoniae and S pyogenes were
associated with the 2009 H1N1 outbreak [17,47].
DIAGNOSIS
The nonspecific clinical presentation of influenza in children emphasizes the
importance of laboratory diagnosis. A rapid diagnosis of influenza reduces
the use of unnecessary tests and antibiotics in pediatric patients, and allows
rational use of antivirals, early discharge from the hospital, and appropriate
infection control measures. In addition, isolation and identification of circu-
lating strains are critical to the preparation of annual vaccines [48–50].
Respiratory specimens should be obtained during the first 72 hours of illness
because the amount of virus shed decreases rapidly beyond this point. False-
negative results occur, especially for samples collected very early or late after
the onset of symptoms. Nasopharyngeal aspirates and washes, followed by naso-
pharyngeal swabs and miniturbinate swabs, are preferred over throat swabs for
detection of influenza. Combining 2 swabs, 1 from each nostril, into 1 vial further
enhances viral load [51].
Conventional viral cell culture remains the gold standard for diagnosis of
influenza infection, but time to detection ranges from 2 to 14 days, with a median
of 3 to 5 days. Diagnosis by cell culture relies on infectious virus and is less sensi-
tive than polymerase chain reaction (PCR) tests. Rapid cultures have replaced
conventional cultures in many laboratories because they are simpler to master
and faster to complete, with results available in 1 to 3 days [52].
Antigen detection assays are based on the detection of viral proteins by specific
antibodies. They are simple to perform and provide results in 10 to 30 minutes;
for this reason, these tests are the most commonly used diagnostic tests for influ-
enza. However, although their specificity is generally high (96%–99%), their
sensitivity varies by kit, ranging from 60% to 83% for seasonal influenza and
40% to 59% for novel H1N1 [53]. Because of the high false-negative results,
the US Centers for Disease Control and Prevention (CDC) advise that antiviral
therapy should not be withheld because of a negative rapid antigen detection
assay [54].
82 CARR
Direct fluorescent assay (DFA) detects viral antigens in exfoliated respiratory

epithelial cells applied to microscope slides, allows assessment of sample quality,
and is more sensitive than rapid antigen detection tests. Results are available
within 2 hours, and DFA detects 85% to 95% of culture-positive results. However,
DFA requires expertise for accurate interpretation, and sensitivities and specific-
ities vary between laboratories [55].
With a sensitivity of 98% and positive predictive value of 100%, reverse tran-
scriptase PCR (RT-PCR) test is one of the most accurate and sensitive tests for
detecting influenza viruses, including the pandemic influenza A (H1N1) [21].
The time required for testing and the limited availability of RT-PCR capable
of subtyping limit the usefulness of this test for medical management of indi-
vidual patients. RT-PCR tests for seasonal influenza are unable to provide sub-
typing information when used to test specimens from patients with 2009 H1N1
virus infections. RT-PCR tests for the detection of 2009 H1N1 virus were
developed by the CDC and distributed to state public health and other refer-
ence laboratories. One RT-PCR test that can distinguish 2009 H1N1 from
other influenza A viruses has been approved by the US Food and Drug Admin-
istration, and this test seems to have similar sensitivity and specificity compared
with the test developed by the CDC [21].
COMPLICATIONS
Children at higher risk of complications from influenza include children with
underlying chronic illness such as cardiac, pulmonary, immunologic, or neurologic
disease [32]. However, influenza-associated deaths occur in both children with
underlying medical conditions and healthy children. In 2003 to 2004, 47% of
influenza-associated pediatric deaths occurred in previously healthy children [56].
Bacterial infections of the respiratory tract, particularly pneumonia and otitis
media, are the most common complication of influenza [45]. The incidence of
complicating bacterial infections in community studies, including children of all
ages, is approximately 10%, and otitis media is the most frequent finding [57].
Studies of vaccine effectiveness support reports that influenza-associated acute
otitis media occurs in 30% to 40% of children in day care during the respiratory
disease season [58]. The proposed mechanisms for the development of acute
otitis media after influenza infection include eustachian tube dysfunction, direct
invasion of middle-ear epithelium, alteration of leukocyte function, enhanced
adherence of bacteria to respiratory tract epithelial cells, and decreased mucociliary
clearance [5].
Secondary bacterial pneumonia is characterized by fever and a productive
cough during convalescence, along with radiologic evidence of lobar consolida-
tion [41]. Although most cases of bacterial pneumonia as a complication of influ-
enza are pneumococcal [59], the 2 most severe pulmonary complications are
progressive primary viral pneumonia and staphylococcal pneumonia. Progres-
sive primary viral pneumonia has been observed most frequently in adult
patients with preexisting rheumatic heart disease, but it may occur in previously
healthy children as well [26,28]. Staphylococcal pneumonia may occur as
a postinfluenza lobar pneumonia progressing to pneumatoceles and empyema.

Necrotizing pneumonitis with microabscesses and positive lung cultures for
both influenza A virus and Staphylococcus aureus are characteristic [34].
Among children at high risk for complications of influenza, most have asthma;
children with a history of stable asthma can experience an acute exacerbation,
with progression to status asthmaticus during an influenza infection [33].
Acute myositis occurs in the setting of early convalescence from a typical
influenza illness [60]. The onset of severe pain and tenderness in the calves
of both legs is sudden, and the patient often refuses to walk. The gastrocnemius
and soleus muscle groups are affected in virtually all cases. Increased levels of
serum creatine kinase and aspartate aminotransferase are characteristic. This
complication occurs more commonly after infection with influenza B versus
influenza A [60]. The condition generally is self-limited, but rhabdomyolysis
with myoglobinuria and acute renal failure have been described [61].
Pericarditis and myocarditis with electrocardiographic changes and
increased levels of cardiac enzymes are rarely noted in association with influ-
enza A and B infection. It has been described in healthy adults and children
as well in those with preexisting heart disease [62,63].
Influenza infection has been associated with a variety of neurologic complica-
tions, including seizures, Reye syndrome, Guillain-Barré syndrome, transverse
myelitis, and encephalopathy. Seizures are the most frequently reported neuro-
logic complication, with most believed to be febrile seizures in young children
[45]. Influenza encephalopathy manifests with sudden onset of fever, convulsion,
and rapid progression to coma. Radiologic imaging reveals bilateral thalamic
necrosis and brainstem involvement in some cases. In most reported cases, influ-
enza infection was not shown in the cerebral fluid or brain. There is a high fatality
rate, with severe neurologic damage in survivors. The pathogenesis of this illness
remains uncertain but may result from direct viral invasion of the central
nervous system or from high levels of proinflammatory cytokines that breach
the blood-brain barrier, or from another factor such as medications used to treat
influenza [31]. Reye syndrome (encephalopathy and fatty degeneration of the
liver) has become uncommon since the association between concomitant influ-
enza infection and the use of aspirin was recognized [64].
Although influenza can cause severe disease in pregnant women, and evi-
dence of the transplacental passage of influenza virus to a 30-week-old male fetus
has been reported [65], there is no epidemiologic evidence of influenza virus
teratogenicity.
TREATMENT
Two classes of antiviral agents are licensed for treatment and prophylaxis of
influenza infection in the United States: adamantanes (rimantadine and aman-
tadine) and the NA inhibitors (NI) oseltamivir and zanamivir. The adaman-
tanes are effective only against influenza A viruses; they block the influx of
Hþ ions through the M2 ion channel, interfering with viral uncoating inside
the cell. The NIs have activity against influenza A and B viruses and they
84 CARR
inhibit the enzyme NA, thus preventing the release of new virions from the in-
fected cell surface [66]. Currently, all circulating influenza A viruses are resis-
tant to the adamantanes and these agents are therefore not recommended for
the treatment of influenza infections in the United States [2]. The pandemic
influenza A (H1N1) that is currently circulating is susceptible to the NIs oselta-
mivir and zanamivir, but is almost always resistant to amantadine and riman-
tadine [17]. However, antiviral resistance can emerge from one season to the
next and resistance patterns of influenza strains might lead to new guidance.
Clinicians should verify susceptibility information at the start of the influenza
season and monitor it during the season through either the American Academy
of Pediatrics (AAP) Web site (http://www.aap.org) or the CDC Web site
(http://www.cdc.gov/flu).
The AAP recommends antiviral treatment of: all children hospitalized with
presumed influenza or with severe, complicated, or progressive illness, regard-
less of influenza immunization status; all children with presumed influenza at
high risk for influenza-associated complications regardless of influenza severity;
and any otherwise healthy child with influenza for whom a decrease in duration
of clinical symptoms is warranted [2]. Treatment may also be considered for
previously healthy outpatients with confirmed or suspected influenza if treat-
ment can be initiated within 48 hours of illness onset [21]. From epidemiologic
studies of patients with seasonal influenza or pandemic influenza A (H1N1),
persons at higher risk for complications from influenza include:
Children younger than 2 years

Adults 65 years of age or older
Persons with chronic pulmonary (including asthma), cardiovascular (except hyper-
tension alone), renal, hepatic, hematologic (including sickle cell disease), or
metabolic (including diabetes mellitus) disorders or neurologic and neuro-
developmental conditions (including disorders of the brain, spinal cord, periph-
eral nerve, and muscle, such as cerebral palsy, epilepsy [seizure disorders],
stroke, or any condition that compromises respiratory function or handling of
secretions or that can increase the risk of aspiration
Persons with immunosuppression, including that caused by medications or by
human immunodeficiency virus (HIV) infection
Women who are pregnant or in the postpartum period (within 2 weeks after
delivery)
Persons younger than 19 years who are receiving long-term aspirin therapy
American Indian/Alaska Native persons
Persons who are morbidly obese (ie, BMI 40 kg/m2)
Residents of nursing homes and other chronic care facilities [2].
There is emphasis on the use of early (<48 hours) empiric antiviral therapy
for suspected influenza, because earlier treatment provides more optimal clin-
ical responses and should not be delayed while waiting for a definitive influenza
test result. However, treatment initiated later than 48 hours after the onset of
symptoms in children with moderate to severe disease or with progressive
disease may still be beneficial [2].
Table 1 summarizes the dosage and schedule of influenza antiviral medica-

tions for treatment and chemoprophylaxis for the 2011 to 2012 influenza season
in the United States [2]. Oseltamivir was the drug of choice to treat seasonal and
pandemic influenza A (H1N1) during this past season. In a randomized, double-
blind, placebo-controlled study that evaluated oseltamivir in 452 children 1 to 12
years of age with influenza, oseltamivir treatment was associated with rapid reso-
lution of the fever when given within 48 hours of the onset of illness. There was
also a 44% reduction in the number of patients with otitis media, resulting in
a concomitant 40% reduction in antibiotic use [67]. Oseltamivir has been re-
ported to be less effective against influenza B in young children (5 years of
age) compared with older children, probably because of the low sensitivity of
influenza B viruses to oseltamivir [68].
The incidence of oseltamivir resistant virus has been described to be approxi-
mately 5% to 6% in children [67] and 1% to 2% in adults [69]. Because renal clear-
ance of the active carboxylate metabolite of oseltamivir is significantly higher in
younger than in older children and adults, the dose must be adjusted based on age
[70]. The most common adverse effects of oseltamivir are nausea and vomiting.
Postmarketing reports, mostly from Japan, have noted self-injury and delirium
associated with approximately 1 in 100,000 oseltamivir prescriptions, primarily
in adolescents [31]. Recent data suggest that these events were related to influenza
disease rather than antiviral medication [71]. Zanamivir is licensed for the treat-
ment of influenza in children 7 years of age or older. This drug is not orally active
and is administered by inhalation, which consequently limits its potential for use
in children aged 5 years or younger. Zanamivir use has been associated with
bronchospasm in some people and is not recommended for use in patients with
underlying airway disease such as asthma [2]. For patients who are intubated,
use of the zanamivir disk inhaler is not possible because the licensed powder
formulation contained in the disk inhaler can clog ventilator tubing [2]. Zanami-
vir does not require dosing adjustment for renal insufficiency, given that it is
administered as an inhalant.
The recommended duration of antiviral therapy is 5 days. Longer treatment
regimens might be necessary in severely ill hospitalized patients or persons with
immunosuppression [31].
No antiviral agent is approved for use in infants younger than 12 months of
age. During the 2009 H1N1 pandemic, recommendations for oseltamivir
dosing of children aged less than 1 year were developed from limited pharma-
cokinetic data. Although the recommendation for this indication expired on
June 23, 2010, recommendations for the use of oseltamivir in this young age
group can still be followed and are provided in Table 1 [2].
Weight-based dosing recommendations for full-term infants are believed to
be inappropriate for premature infants, who might have slower clearance of
oseltamivir as a result of immature renal function, resulting in excessively
high plasma concentrations of the drug. Therefore, the data currently available
are insufficient to recommend a specific dose of oseltamivir for premature
infants [72].
Table 1
Recommended dosage and schedule of influenza antiviral medications for treatment and
chemoprophylaxis for the 2011 to 2012 influenza season: United States
Medication Treatment (5 d) Chemoprophylaxis (10 d)
a
Oseltamivir
Adults 75 mg bid 75 mg qd
Children >12 mo
Body weight
15 kg (33 lb) 30 mg bid 30 mg qd
>15–23 kg (33–51 lb) 45 mg bid 45 mg qd
>23–40 kg (>51–88 lb) 60 mg bid 60 mg qd
>40 kg (>88 lb) 75 mg bid 75 mg qd
Children 3 to <12 mob 3 mg/kg per dose bid 3 mg/kg per dose qd
Children 0 to <3 moc 3 mg/kg per dose bid Not recommended unless
situation judged critical,
because of limited data on
use in this age group
Zanamivird
Adults 10 mg (two 5-mg 10 mg (two 5-mg
inhalations) bid inhalations) qd
Children (7 y for treatment, 10 mg (two 5-mg 10 mg (two 5-mg
5 y for inhalations) bid inhalations) qd
chemoprophylaxis
a
Oseltamivir is manufactured by Roche Laboratories (Nutley, NJ) and is administered orally without regard
to meals, although administration with meals may improve gastrointestinal tolerability. Oseltamivir is avail-
able as Tamiflu in 30-mg, 45-mg, and 75-mg capsules and as a powder for oral suspension that is recon-
stituted to provide a final concentration of 6 mg/mL. The volume of oral suspension is being changed from
12 mg/mL to 6 mg/mL this year to reduce frothing when shaken. Oral suspensions in 12-mg/mL concen-
trations remain available until supplies run out. For the 6-mg/mL suspension, a 30-mg dose is given with
5 mL of oral suspension, 45-mg dose is given with 7.5 mL oral suspension, 60-mg dose is given with
10 mL oral suspension, and 75-mg dose is given with 12.5 mL oral suspension. If the commercially manu-
factured oral suspension is not available, the capsules may be opened and the contents mixed with a sweet-
ened liquid to mask the bitter taste, or a suspension can be compounded by retail pharmacies (final
concentration: 15 mg/mL). For patients with renal insufficiency, the dose should be adjusted by creatinine
clearance rate. For treatment of patients with a creatinine clearance rate of 10 to 30 mL/min: 75 mg once
daily for 5 days. For chemoprophylaxis of patients with a creatinine clearance rate of 10 to 30 mL/min: 30
mg once daily for 10 days after exposure or 75 mg once every other day for 10 days after exposure (5
doses). (See http://www.cdc.gov/flu/professionals/antivirals/antiviral-drug-resistance.htm.)
b
Weight-based dosing is preferred: however, if weight is not known, dosing according to age for treatment
(2 doses per day) or prophylaxis (1 dose per day) of influenza in term infants younger than 1 year may be
necessary: 0 to 3 months (treatment only), 12 mg (2 mL of 6 mg/mL commercial suspension); 4 to 5 months,
17 mg (2.8 mL of 6 mg/mL of commercial suspension); 6 to 11 months, 24 mg (4 mL of 6 mg/mL commer-
cial suspension). Although Emergency Use Authorization recommendations for use of oseltamivir in children
younger than 1 year expired on June 23, 2010, this drug remains appropriate for use when indicated.
c
Current weight-based dosing recommendations are not intended for preterm infants. Preterm infants may
have slower clearance of oseltamivir because of immature renal function, and doses recommended for
term infants may lead to high drug concentrations in this age group. Limited data from a cohort of preterm
infants who received an average dose of 1.7 mg/kg twice daily revealed drug concentrations higher than
those observed with the recommended treatment dose in term infants (3 mg/kg twice daily). Observed drug
concentrations were highly variable among preterm infants. These data are insufficient to recommend
a specific dose of oseltamivir for preterm infants.
d
Zanamivir is manufactured by GlaxoSmithKline (King of Prussia. PA) and is administered by inhalation using
a proprietary Diskhaler device distributed together with the medication. Zanamivir is a dry powder (not an aero-
sol) and should not be administered by using nebulizers, ventilators, or other devices typically used for adminis-
tering medications in aerosolized solutions. Zanamivir is not recommended for persons with chronic respiratory
diseases such as asthma or chronic obstructive pulmonary disease that increase the risk of bronchospasm.
Data from Fiore AE, Fry A, Shay D, et al. Centers for Disease Control and Prevention. Antiviral agents for the
treatment and chemoprophylaxis of influenza–recommendations of the Advisory Committee on Immunization
Practices (ACIP). MMWR Recomm Rep 2011;60(RR-1):1–24; From American Academy of Pediatrics Committee
on Infectious Diseases. Recommendations for prevention and control of influenza in children, 2011–2012. Pedi-
atrics 2011;128:822; with permission.
PROPHYLAXIS
Influenza vaccines
Annual influenza vaccination is the most effective method for preventing influ-
enza infection and its complications. Two influenza vaccines are currently avail-
able in the United States to prevent infection in the pediatric population:
injectable trivalent inactivated influenza vaccine (TIV) and intranasally adminis-
tered live-attenuated influenza vaccine (LAIV). Both LAIV and TIV contain
strains of influenza viruses that are equivalent antigenically to the annually rec-
ommended strains: 2 influenza A viruses (H3N2 and H1N1) and 1 influenza B
virus. The 2011 to 2012 vaccine contains A/California/7/2009 (H1N1)-like,
A/Perth/16/2009 (H3N2)-like, and B/Brisbane/60/2008-like antigens. The
vaccine composition for the 2011 to 2012 season was unchanged from the
2010 to 2011 influenza season. A comparison between the 2 influenza vaccines
recommended to prevent influenza infection during the 2011 to 2012 season is
summarized in Table 2.
Current recommendations for influenza vaccination

Routine influenza vaccination is recommended for all persons aged 6 months or
older. Efforts should be made to vaccinate people in the following groups [2]:
All children, including infants born prematurely, 6 months of age and older with
conditions that increase the risk of complications from influenza
All household contacts and out-of-home care providers of children with high-risk
conditions (see earlier discussion) and children younger than 5 years
All health care personnel
All women who are pregnant, considering pregnancy, or breastfeeding during
the influenza season
The number of trivalent seasonal influenza vaccine doses to be administered

depends on the child’s age at the time of the first administered dose and their
vaccine history:
No influenza vaccine is licensed for infants younger than 6 months.
Children 6 months to 8 years who did not receive any dose of vaccine last season
require 2 doses of vaccine administrated at least 4 weeks apart.
For children 6 months to 8 years of age who had received at least 1 dose of the
2010 to 2011 trivalent seasonal influenza vaccine (regardless if it was the first
time receiving influenza vaccine or not), only 1 dose of the 2011 to 2012
influenza vaccine was recommended. The first vaccine dose primes the
immune system and the second dose gives the adequate protection [73].
Because the vaccine strains for the 2011 to 2012 season were unchanged
from the last season, 1 dose this season coupled with 1 dose of last season
provides adequate protection.
Children 9 years of age and older need only 1 dose.
Although the above recommendations were made to the 2011-2012 influenza

season, it is recommended use them as a guide to vaccination until recommen-
dations to the 2012-2013 season are available from the CDC.
88 CARR
Table 2
LAIV compared with TIV
Vaccine characteristic LAIV TIV
Route of administration Intranasal spray Intramuscular or intradermal
injectiona
Type of vaccine Live virus Killed virus
Product Attenuated, cold-adapted Inactivated subvirion or
surface antigen
Number of included virus strains 3 (2 influenza A, 3 (2 influenza A,
1 influenza B) 1 influenza B)
Vaccine virus strains updated Annually Annually
Frequency of administrationb Annually Annually
Approved age groups All healthy persons All persons aged >6 mo
aged 2–49 y (intradermal 18–64 y)
Interval between 2 doses 4 wk 4 wk
in children
Can be given to persons with No Yes
medical risk factors for influenza-
related complications
Can be given to children with Noc Yes
asthma or children aged
2–4 y with wheezing in the
previous year
Can be simultaneously Yesd Yesd
administered with other vaccines
If not simultaneously administered, No, prudent to space Yes
can be administered within 4 wk 4 wk apart
of another live vaccine
Can be administered within Yes Yes
4 wk of an inactivated vaccine
a
The preferred site of TIV intramuscular injection for infants and young children is the anterolateral aspect of
the thigh.
b
See Fig. 3 for decision algorithm to determine the number of doses of 2011 to 2012 seasonal influenza
vaccine recommended for children this year [2].
c
LAIV is not recommended for children with a history of asthma. In the 2-year to 4-year age group, there are
children who have a history of wheezing with respiratory illnesses in whom reactive airways disease is
diagnosed and in whom asthma may later be diagnosed. Therefore, because of the potential for increased
wheezing after immunization, children 2 to 4 years of age with recurrent wheezing or a wheezing episode
in the previous 12 months should not receive LAIV. When offering LAIV to children in this age group, a clini-
cian should screen those who might be at higher risk of asthma by asking the parents/guardians of 2-year-
olds, 3-year-olds, and 4-year-olds (24-month-olds to 59-month-olds) the question, ‘‘In the previous 12
months, has a health care professional ever told you that your child had wheezing?’’ If the parents answer
‘‘Yes’’ to this question, LAIV is not recommended for these children.
d
LAIV coadministration has been evaluated systematically only among children 12 to 15 months of age with
measles-mumps-rubella and varicella vaccines. TIV coadministration has been evaluated systematically only
among adults with pneumococcal polysaccharide and zoster vaccines.
Data from American Academy of Pediatrics Committee on Infectious Diseases. Recommendations for
prevention and control of influenza in children, 2010–2011. Pediatrics 2010;126(4):816–26; and Fiore
AE, Fry A, Shay D, et al. Centers for Disease Control and Prevention. Antiviral agents for the treatment and
chemoprophylaxis of influenza–recommendations of the Advisory Committee on Immunization Practices
(ACIP). MMWR Recomm Rep 2011;60(RR-1):1–24. From American Academy of Pediatrics Committee
on Infectious Diseases. Recommendations for prevention and control of influenza in children, 2011-
2012. Pediatrics 2011;128:822; with permission.
Vaccination begins in September or whenever the vaccine becomes available

and should continue through the influenza season, which can have more than 1
disease peak and often extends into March or later.
This approach provides opportunity to administer a second dose of vaccine,
because children younger than 9 years might require 2 doses to confer optimal
protection. Annual influenza immunization is recommended because immunity
decreases during the year after immunization and because in most years, at
least one of the vaccine antigens is changed to match ongoing antigenic changes
in circulating strains.
Influenza vaccine to egg-allergic children
The influenza vaccine contains small but variable amounts of egg protein, there-
fore severe egg allergy has long been considered a contraindication to adminis-
tration of the influenza vaccine [4]. However, new data suggest that a single,
age-appropriate dose of an influenza vaccine with an ovalbumin content up to
0.7 lg/0.5 mL of a vaccine dose has been well tolerated by nearly all recipients
who have egg allergy [2]. More conservative approaches, such as skin testing
or a 2-step graded challenge, are no longer recommended. Influenza vaccine
can be given to children with a history of mild allergic reaction to eggs that is
defined as hives alone. Appropriate resuscitative equipment must be readily
available and the vaccine recipient should be observed in the office for 30 minutes
(the standard observation time after receiving immunotherapy). If a second dose
is needed, the same product brand, but not necessarily the same lot as the first
dose, is preferred. Children with a history of severe allergic reaction to eggs
(defined as severe reactions with systemic cardiovascular, respiratory, and
gastrointestinal changes, or reactions that require the use of epinephrine) should
have an allergist consult before influenza vaccine is given. No data are available
to support the use of LAIV in children with a history of egg allergy [2].
Influenza chemoprophylaxis
Chemoprophylaxis should be considered during periods of influenza activity
in children 1 year or older who are at high risk of developing influenza-
associated complications and in whom vaccination has not been received or
is contraindicated. It should be considered in high-risk children during seasons
when the influenza vaccine is documented to have low clinical effectiveness in
preventing infection. It also should be considered in high-risk patients during
the first 2 weeks after vaccination when antibody immune response is still inad-
equate. In children who were not previously vaccinated and require 2 doses,
the period of inadequate immune response extends to 6 weeks from the first
vaccine dose, and chemoprophylaxis should be continued through this period
in high-risk patients. In these circumstances, only the inactivated influenza
vaccine should be administered because antiviral medications can reduce the
effectiveness of the live, attenuated influenza vaccine [31]. In household
members exposed to influenza, the efficacy of preventing infection in individ-
uals was 68% to 89% with oseltamivir [74,75] and 79% to 82% with zanamivir
[76,77].
90 CARR
SUMMARY
Influenza is an important cause of respiratory illness in children, who have the
highest attack rates during the annual influenza outbreaks [60]. Clinical infec-
tion ranges from subclinical illness to complicated disease that affects multiple
organs. Annual vaccination remains the most effective strategy for the preven-
tion and control of influenza [2]. Recently developed antiviral drugs offer new
approaches to the prevention and treatment of influenza.
Acknowledgments
We thank Jane Carver for assistance with manuscript preparation.
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Immunization in Special Populations

Michael A. Miller, MDa,b, Mobeen H. Rathore, MD, CPEa,b,*
a
Department of Pediatric Infectious Diseases and Immunology, University of Florida 653-1 West
8th Street, L-13, Jacksonville, FL 32209, USA; bWolfson Children’s Hospital, 653-1 West 8th Street,
L-13, Jacksonville, FL 32209, USA
Keywords
Immunizations Immunocompromised Special populations
Pediatric populations
Key Points
Immunizations in special populations require understanding the underlying
disease and how it might affect the immune system’s ability to mount an antibody
response to vaccines.
Immunizations in special populations require understanding of how certain
patient populations are predisposed to developing certain serious infections.
There is a need for further research on the optimal timing of vaccines after
transplants and how to assess protection after immunization.
There is a need for further research whether certain groups (eg, HIV) need to be
revaccinated after a period of time if their antibody levels decline.
In addition, there are limited data on efficacy of the newer vaccines in these
special patient populations, which also requires further investigation.
W
ith improving survival rates after treatment of cancer, an increase in
hematopoietic stem cell (HSCT) and solid organ transplantation, the
use of highly active antiretroviral therapy (HAART) for human
immunodeficiency virus (HIV) infections, and immunosuppressive therapies
for patients with autoimmune and rheumatic diseases, the population of immu-
nocompromised children who have vaccination needs to consider is increasing.
Understanding the degree of immune compromise and prospective immune
recovery of these children is important in guiding the administration of vaccines.
For some of these disease states, all affected persons will be severely immuno-
compromised; for others (eg, HIV), the spectrum of severity caused by the
disease itself or stage of treatment will determine the degree of compromise of
the immune system. Killed or inactivated vaccines do not pose any risk to
patients with altered immunocompetence, but the effectiveness of such vaccines
*Corresponding author. Department of Pediatrics, 653-1 West 8th Street, L-13, Jacksonville,
FL 32209. E-mail address: mobeen.rathore@jax.ufl.edu

96 MILLER & RATHORE
may be suboptimal. Whenever an option is available, a killed or inactivated

vaccine should preferably be used in immune compromised children. In addi-
tion, higher doses, reimmunization, or more frequent boosters may be required,
although even with these additional actions, the immune response may still not
be optimal. For specific diseases, such as asplenia, patients may be at higher risk
for certain diseases, and additional vaccines, particularly bacterial polysaccha-
ride vaccines (Haemophilus influenzae type b [Hib], pneumococcal and meningo-
coccal), are recommended. Inactivated influenza immunization should be
administered annually to immunosuppressed children 6 months of age and older
before each influenza season. In general, severely immunocompromised chil-
dren should not receive live vaccines, either viral or bacterial, because of the risk
of disease caused by vaccine strains. Studies on the live attenuated influenza
vaccine (FluMist) are limited to small studies in HIV-infected children and mild
to moderately immunocompromised children on chemotherapy and/or radia-
tion where safety has been assessed but effectiveness has not been evaluated
[1–4]. Oral polio virus vaccine and live bacterial vaccines (eg, Bacillus
Calmette-Guerin [BCG], Salmonella typhi Ty21) are contraindicated for immuno-
compromised patients as well as their household contacts. Household contacts
and other close contacts of persons who are immunocompromised, however,
should receive all other age-appropriate vaccines, including the live oral rota-
virus vaccines. For the purposes of this review, we focus on the special vaccina-
tion needs in the following groups: preterm (PT) and low-birth weight (LBW)
infants, pregnant women, patients with primary immunodeficiencies, solid organ
transplant recipients, children with cancer, hematopoietic stem cell transplant
recipients, HIV-infected children, children on corticosteroids, children with hy-
posplenia/asplenia, international adoptees, and pediatric travelers.
PRETERM AND LOW-BIRTH WEIGHT INFANTS

PT (<37 weeks gestation) and LBW (<2.5 kg) infants are at a much greater risk
of increased morbidity from vaccine-preventable diseases. Because of the high
rates of complications related to premature birth and concerns regarding the
PT infant’s ability to develop protective immunity after receipt of routinely rec-
ommended vaccines, PT infants are less likely to receive vaccinations in
a timely manner [5–8]. Several studies have examined the safety, immunoge-
nicity, efficacy, and durability of immune responses to hepatitis B virus
(HBV); diphtheria, tetanus, and pertussis (DTaP); inactivated poliovirus
(IPV); Hib; influenza; and pneumococcal conjugate vaccines (PCV) given to
PT and LBW infants [9–11].
Hepatitis B vaccine
Since the introduction of the universal hepatitis B infant immunization policy in
1992, the American Academy of Pediatrics (AAP) has expressed a preference
that all infants receive hepatitis B vaccine at birth or before discharge home
from the hospital. The AAP published a policy statement in 1994 and then re-
affirmed its position in 1998 recommending that the first dose of HBV vaccine
IMMUNIZATION IN SPECIAL POPULATIONS 97
be deferred in infants weighing less than 2000 g who were born to hepatitis B
surface antigen (HBsAg)-negative mothers until they reached 2000 g or 2
months of age, whereas the Advisory Committee on Immunization Practices
of the Centers for Disease Control and Prevention (CDC/ACIP) states that
the vaccine may be given at 1 month or at hospital discharge. However, 2
studies demonstrated that a delay to 7 to 30 days of age was sufficient to allow
very low birth weight (VLBW) infants to respond to HBV vaccine and that
consistent weight gain was more predictive of response than birth weight
was [12,13]. Protection afforded by HBV immunization comparable to that
of full-term (FT) infants could be reasonably expected in medically stable
PT, VLBW and extremely low-birth weight (ELBW) infants [14]. Protective
concentrations of anti-HBs antibody are achieved in almost all PT infants by
9 to 12 months of age after receiving the recommended 3 doses of HBV
vaccine. The rates of decrease of anti-HBs antibody measured 3 and 7 years
after a completed HBV vaccination series are similar for FT and PT infants,
with protective antibody concentrations maintained throughout the time period
in both groups [10,15,16]. None of the studies since 1997 have described an
increased risk of vaccine-associated adverse reactions in medically stable PT
infants. The AAP and CDC/ACIP state that PT and LBW infants born to
HBsAg-positive mothers must receive HBV vaccine and Hepatitis B Immune
Globulin (HBIG) within 12 hours after birth, regardless of birth weight or
gestational age. Infants weighing less than 2 kg born to HBsAg-positive
mothers should also receive 3 doses of HBV vaccine starting at 1 month of
age in addition to the birth dose of HBV vaccine. All of the infants born to
HBsAg-positive mothers should be screened for anti-HBs antibody and HBsAg
at 9 to 15 months of age after they have completed their HBV vaccine series. If
the maternal HBsAg status is unknown, PT and LBW infants weighing more
than 2 kg at birth can wait up to 7 days after birth for the mother’s HBsAg test
results before giving HBIG, whereas infants weighing less than 2 kg should be
given HBIG within 12 hours of birth because of their less predictable response
to HBV vaccine.
DTaP, Hib, and IPV vaccines
All PT and LBW infants who are medically stable should begin their routine
immunization schedule with full doses of DTaP, Hib, and IPV vaccines at 2
months of age regardless of birth weight or gestational age. The safety, efficacy,
and immunogenicity of these vaccines in PT infants have been documented in
several studies over the years [11,16–21]. Although apnea has not been re-
ported after administration of acellular-pertussis-containing vaccines to
ELBW infants [17], it may be prudent to observe hospitalized ELBW infants
up to 72 hours after receipt of the vaccine for any adverse effects.
Pneumococcal conjugate vaccine
A clinical trial using PCV7 of almost 38,000 infants, including 1756 LBW
infants (including 131 VLBW and 17 ELBW infants) and 4340 premature
infants were assessed for PCV7 immunogenicity, efficacy, and safety [22,23].
98 MILLER & RATHORE
The PT and LBW infants in the trial were shown to have an increased risk of
invasive pneumococcal disease (relative risk [RR] 1.6 compared with FT and
RR 2.6 compared with normal birth weight infants). The trial also demon-
strated that the immune response of the PT infants was similar to that in FT
infants. There was no difference in terms of adverse events in the groups.
Although there are no studies performed in PT infants, the CDC/ACIP recom-
mends PCV13 in place of PCV7 and therefore, all medically stable PT patients
should receive full doses of PCV13 starting at 2 months of age.
Influenza vaccine
All preterm infants are considered at high risk of complications of influenza
infection [24]. A 1992 study comparing the humoral and cell-mediated immune
responses to inactivated influenza vaccine of PT infants compared with FT
infants demonstrated that nearly all PT infants were able to achieve and sustain
protective antibody concentrations to the 3 strains of influenza without any
significant adverse effects [25]. Therefore, all PT infants should be offered influ-
enza vaccine beginning at 6 months of age and those receiving the vaccine for
the first time should receive 2 doses of the influenza vaccine given 1 month
apart. The live attenuated influenza vaccine (FluMist) is not approved for
use in children younger than 24 months.
PREGNANT WOMEN
The risk to a developing fetus from vaccination during pregnancy is primarily
theoretical. Although there is no strong evidence that vaccines induce harm to
the fetus, pregnant women should receive a vaccine only when it is unlikely to
cause harm, the risk of disease exposure is high, and the infection would result
in serious consequences to the mother or fetus. To minimize theoretical
concern about causing harm to the fetus, a vaccine during pregnancy should
be delayed until the second or third trimester if possible.
Tdap
The AAP recommends that pregnant women be given the tetanus toxoid,
reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine if they
have not received a Td-containing booster within 2 years [22,23,26]. In addi-
tion, pregnant women who have not received 3 doses of a vaccine containing
diphtheria and tetanus toxoids should complete a vaccine series of 3 doses with
use of Tdap as one of the doses. The CDC/ACIP states that pregnant women
should generally receive Td if their last dose was more than 10 years ago,
although Tdap is not contraindicated and Tdap should be administered as
soon as possible following delivery. Both Tdap and Td are categorized as preg-
nancy category C agents by the Food and Drug Administration.
Influenza
Vaccination with inactivated influenza vaccine is recommended for women
who will be pregnant during the influenza season regardless of trimester.
One study of influenza administration of approximately 2000 pregnant women
demonstrated no adverse fetal effects. Immunization of pregnant women also

protects infants younger than 6 months by the so-called ‘‘cocoon effect.’’
Live-attenuated influenza vaccine should not be given to pregnant women. Flu-
Mist is a category C agent during pregnancy and it is unknown if it causes fetal
harm and should be given to pregnant women only if clearly needed (http://
www.medimmune.com/pdf/products/flumist_pi.pdf).
Other inactivated vaccines
Pneumococcal and meningococcal conjugate and polysaccharide vaccines can
be given to a pregnant woman at high risk of serious or complicated illness
from infection with pneumococcus or meningococcus. Hepatitis A or B
vaccines, if indicated, can be given to pregnant women, as severe disease can
result from infection in pregnant women and in case of Hepatitis B, chronic
infection in the newborn infant. Inactivated polio vaccine can be given to preg-
nant women who require a booster dose, are partially immunized, or have
never received the vaccine.
Live vaccines
Live-virus vaccines are contraindicated during pregnancy. The effects of vari-
cella vaccine on the fetus are unknown. Nonpregnant women should avoid
becoming pregnant for at least 1 month after they have received varicella
vaccine. Pregnancy in a household member is not a contraindication for vari-
cella immunization of a child in that household. Varicella Zoster Immune Glob-
ulin (VariZIG, Winnipeg, Canada), a product made by a Canadian company
(Cangene Corporation), should be strongly considered for susceptible, preg-
nant women who have been exposed. This product is not available in the
United States and can be used under a research protocol. Measles-mumps-
rubella (MMR) vaccine should not be administered to pregnant women, as
the risk to the fetus, although hypothetical, cannot be excluded. No cases of
embryopathy caused by the attenuated rubella vaccine strain have been
reported.
Other vaccines
Rabies vaccine should be given to pregnant women after exposure to rabies
under the same circumstances as nonpregnant women. The Japanese encepha-
litis vaccine should not be routinely administered during pregnancy except for
those traveling to an area of high risk for Japanese encephalitis. Oral typhoid
vaccine should be avoided during pregnancy and parenteral typhoid vaccine
should be used on a case-by-case basis. Human papillomavirus vaccine contains
no live virus but data on immunization in pregnancy are limited, so initiation of
immunization should be delayed until after pregnancy.
PRIMARY IMMUNE DEFICIENCIES

Primary disorders of the immune system are generally inherited, may involve
any part of the immune system (eg, humoral, cellular, phagocytic function,
complement), and share the common feature of susceptibility to infection
100 MILLER & RATHORE
with various organisms, some of which may be prevented by immunization,

depending on the specific type of immunodeficiency. The safety and efficacy
of vaccines in immunocompromised persons depends on the degree of
immunosuppression.
Live vaccines
Measles and varicella vaccines should be considered for children with B-lympho-
cyte disorders. Response to the vaccines may be suboptimal and intravenous
immunoglobulin (IVIG) may interfere with the immune response to these
vaccines. Oral poliovirus vaccine, which is no longer available in the United
States, is contraindicated because of increased incidence of paralytic disease in
children with combined immunodeficiency or B-lymphocyte disorders. Other
live vaccines (eg, smallpox, live influenza, BCG, oral typhoid, yellow fever) are
contraindicated for patients with B-lymphocyte dysfunction except for those
with immunoglobulin A (IgA) deficiency. All live vaccines are contraindicated
in patients with T-lymphocyte dysfunction, as cases of polio, measles, and
vaccinia after vaccination have occurred in these patients. Children who are inca-
pable of mounting an antibody response to vaccines may benefit from regular
doses of IVIG. Live attenuated rotavirus vaccines are of unknown safety in
infants with immunodeficiencies. The potential risks and benefits of rotavirus
vaccine should be considered in patients with suspected or known immune
compromise. Most experts believe that live-virus vaccines are safe to administer
to patients with altered phagocytic or complement function. Children with
compromised phagocytic function (eg, chronic granulomatous disease) can
receive all vaccines except for live bacterial vaccines (eg, BCG, oral typhoid)
[27]. The live attenuated influenza vaccine has been evaluated only in small
studies in HIV-infected children and children with mild to moderate immune
compromise secondary to cancer and, thus, there are no data on its use in children
with primary immune deficiencies [1–4].
Inactivated vaccines
The effectiveness of any vaccine depends on the degree of immune suppres-
sion. The risk from these vaccines is not increased in immunocompromised
people. However, the immune response to inactivated vaccines may be inade-
quate, although they are generally recommended in the same dose and on the
same schedule as for immunocompetent people. Higher doses and additional
doses, however, especially for patients who have undergone transplantation,
may be needed to ensure protection. All children with primary immunodefi-
ciencies should receive an annual inactivated influenza vaccine. Vaccines rec-
ommended for household contacts are influenza, MMR, and varicella
vaccine and only the live, attenuated poliovirus vaccine is contraindicated [28].
SOLID ORGAN TRANSPLANT RECIPIENTS

Transplant candidates and recipients are at increased risk of infectious compli-
cations. It is critical that every attempt be made to ensure that transplant candi-
dates, their household members, and health care workers have received all
recommended vaccines before transplantation. Transplant candidates should

be vaccinated early in the course of their disease, as the immune response to
many vaccines is suboptimal in organ failure. In general, vaccines will be
more immunogenic before transplantation, because the immunosuppressive
medications given after transplantation affect the number and/or function of
both B and T lymphocytes. Seroefficacy should be documented by serologic
assays, where available, a minimum of 4 weeks after vaccination; however,
serology may not be an accurate measure of immunity after transplantation
and assays for cellular immunity require further investigation in this population
[29]. Although the American Society of Transplantation’s guidelines for the
Prevention and Management of Infectious Complications of Solid Organ
Transplantation include tables of recommended vaccines for transplant candi-
dates and recipients [30], there continues to be a gap between guidelines and
their implementation into practice. Recommendations for pediatric vaccines
are presented in Table 1 [29]. One reason could be concern that immunizations
might trigger allograft rejection, although several large studies have not shown
an increase in rejection rates after standard immunizations. Household and
health care contacts of solid organ transplant recipients should be immunized
against poliovirus, MMR, varicella, influenza, and hepatitis A.
Live vaccines
Information about use of live-virus vaccines after solid-organ transplantation is
limited. Some transplant centers administer MMR and varicella vaccines 6
months after transplant for recipients who are receiving minimal immunosup-
pressive agents, who are clinically stable, and have not had any recent episodes
of graft rejection. Several recent studies suggest that varicella vaccine may be
safely administered to certain transplant recipients. For instance, Weinberg
and colleagues [31] immunized 16 varicella zoster virus (VZV)-naı̈ve pediatric
kidney and liver transplant recipients with evidence of humoral and cellular
immunity developing in 87% and 86% respectively. Khan and colleagues
[32] immunized 26 pediatric liver recipients with MMR and varicella vaccine
and seroconversion was documented in 73.0% and 64.5%, respectively. Serum
concentrations for measles, mumps, rubella, and varicella should be measured
in all patients 1 year after transplantation. Household and close contacts should
receive MMR and varicella vaccines. Data on the current rotavirus vaccine are
insufficient in terms of safety and efficacy in immunocompromised hosts; im-
munocompromise is a precaution and not a contraindication for use of rota-
virus vaccine (Parashar and colleagues [33]). It would be reasonable to
vaccinate infants living with transplant recipients against rotavirus, however,
to prevent transmission to the transplant recipients. The live attenuated influ-
enza vaccine has only been evaluated in small studies in HIV-infected children
and children with mild to moderate immune compromise secondary to cancer
and, thus, there are no data on its use in pediatric solid organ transplant recip-
ients. Live bacterial vaccines (eg, BCG and oral typhoid) are contraindicated in
patients receiving immunosuppressive medications after transplantation.
102
Table 1
Guidelines for vaccination of solid organ transplant candidates and recipients
Pediatric vaccines
Inactivated/ live Recommended before Recommended after
Vaccine attenuated (I/LA) transplantationa transplantation Monitor vaccine titers Quality of evidence
Influenza I Yes Yes No II-1
LA No No No III
Hepatitis B I Yes Yesb Yesb II-1
Hepatitis A I Yes Yes Yes II-1
Pertussis I Yes Yes No III
Diphtheria I Yes Yes No II
Tetanus I Yes Yes Yes II-1
Inactivated Polio I Yes Yes No II-2
vaccine
Haemophilus I Yes Yes Yesc II-1
influenzae
Streptococcus I Yes Yes Yesc II-1
pneumoniaed
(conjugate vaccine)
S pneumoniaed I Yes Yes Yesc II-1
(polysaccharide
vaccine)
Neisseria meningitidise I Yes Yes No III
MILLER & RATHORE

(MCV4)
Human papillomavirus I Yes Yes No III
(HPV)f
Rabiesg I Yes Yes No III
Varicella (live- LA Yes No Yes II-1
attenuated)c
Rotavirus LA Yes No No III
Measlesh LA Yes No Yes II-1
Mumpsh LA Yes No Yes II-1
Rubellah LA Yes No Yes II-1
BCGi LA Yes No No III
Smallpoxj LA No No No III
IMMUNIZATION IN SPECIAL POPULATIONS

Anthrax I No No No III
a
Whenever possible, the complete complement of vaccines should be administered before transplantation. Vaccines noted to be safe for administration after transplantation may
not be sufficiently immunogenic after transplantation.
b
Routine vaccine schedule recommended before transplantation and as early in the course of disease as possible; vaccine poorly immunogenic after transplantation, and accel-
erated schedules may be less immunogenic. Serial hepatitis B surface antibody titers should be assessed both before and every 6–12 months after transplantation to assess
ongoing immunity.
c
Serologic assessment recommended if available. Haemophilus influenzae type b titer greater than 0.15 mg/L is considered protective in the general population; however, the
absolute protective titer for Pneumococcus is unknown and may vary by serotype.
d
Children older than 5 years should receive Pneumovax. Children younger than 2 years should receive Prevnar. Those 2–5 years of age should receive pneumococcal vaccine as
follows:
Previous dose Recommendations
Four doses of Prevnar One dose of Pneumovax 6–8 weeks following last dose of Prevnar
One dose of Pneumovax 5 years after first dose of Pneumovax
Three doses of Prevnar One dose of Prevnar
One dose of Pneumovax 6–8 weeks following last dose of Prevnar
<3 doses of Prevnar Two doses of Prevnar at least 8 weeks apart
One dose of Pneumovax 6–8 weeks following last dose of Prevnar
One dose of Pneumovax Two doses of Prevnar, 6–8 weeks apart
None (see <3 doses of Prevnar)
e
All patients aged 11–18 years in the United States and certain patients (members of the military, travelers to high-risk areas, properdind-efficient, terminal complement compo-
nent deficient, those with functional or anatomic asplenia, college freshman living on campus) are candidates for the meningococcal vaccine in the United States and Canada.
f
Recommended for all females aged 9–26 years. Immunogenicity studies in posttransplant patients are not published and are an area for further study.
g
Not routinely administered. Recommended for exposures or potential exposures owing to vocation.
h
Although not routinely recommended, live-virus vaccines (Measles, Mumps, Rubella and Varivax) have been administered to selected organ transplant recipients on minimal
immunosuppression. Vaccination is at the discretion of the individual transplant center with the understanding of the potential risks for live-virus vaccination in this population.
i
The indications for Bacillus Calmette-Guerin (BCG) administration in the United States are limited to instances in which exposure to tuberculosis is unavoidable and where
measures to prevent its spread have failed or are not possible.
j
Transplant recipients who are face-to-face contacts of a patient with smallpox should be vaccinated; Vaccinia immune globulin may be administered concurrently if available.
103
Those who have less intimate contact should not be vaccinated.
Data from Danzinger-Isakov L, Kumar D. Guidelines for vaccination of solid organ transplant candidates and recipients. Am J Transplant 2009;9(Suppl 4):S258–62.
Most experts wait at least 6 months after transplantation to resume the immu-
nization schedule when immune suppression is less intense. There is little infor-
mation on the incidence or severity of pertussis in transplant recipients. In
accordance with ACIP guidelines, it would make sense to vaccinate transplant
candidates with Tdap during the pretransplant evaluation when a Td booster
would be recommended. Hepatitis B vaccine should be given before transplan-
tation and is recommended after transplantation; serial Hepatitis B surface anti-
body titers should be measured both before and every 6 to 12 months after
transplantation to assess ongoing immunity [30,34]. Hepatitis A vaccine should
be given to liver transplant recipients because of the increased severity of Hepa-
titis A infection in chronic liver disease. As yet, no comparative data on efficacy
of MCV4 and MPSV4 in transplant candidates and recipients has been re-
ported. As neither vaccine is a live vaccine, it is reasonable to follow guidelines
for the general population, particularly for pretransplant candidates in the 11-
year-old to 18-year-old age group [35]. Pneumococcal conjugate or polysaccha-
ride vaccine should be considered in all transplant recipients. Lin and
colleagues [36] assessed the safety and immunogenicity of the currently recom-
mended pneumococcal vaccination schedule in pediatric solid organ transplant
recipients. Recipients between 2 and 18 years of age received 2 doses of PCV7
and then 1 dose of polysaccharide pneumococcal vaccine (PPV23), whereas
age-matched controls received 1 dose of PCV7 followed by a single dose of
PPV23. Transplant recipients had lower antibody responses but did experience
a significant rise in serotype-specific pneumococcal antibodies. These responses
to PCV7 serotypes were not boosted by the second PCV7 or PPV23 vaccine.
The optimal number of doses and interval between doses require further study;
however, the CDC/ACIP now recommends that PCV13 be substituted for
PCV7 and PCV7 is no longer available in the United States. Annual influenza
vaccination is recommended before and after solid organ transplantation in
candidates/recipients, household contacts, and health care workers.
CHILDREN WITH CANCER

Children with cancer may be immunocompromised as a result of their primary
underlying malignancy as well as secondary to chemotherapy and/or radiation.
Even after chemotherapy is completed, these patients may continue to be im-
munosuppressed for several months [37]. The data suggest that degree of
compromise to the immune system varies according to the type of cancer,
age of the patient, and the intensity of the chemotherapy [38]. At the time of
disease presentation, most children with cancer seem to have a perfectly func-
tioning immune system, including normal levels of total immunoglobulins and
antibodies, whereas peripheral blood T-cell levels seem to be reduced in a small
number of cases [39–42]. After the start of chemotherapy, the immune system
is rapidly and significantly compromised [43,44]. The most important aspect of
chemotherapy-induced immunosuppression is lymphocyte depletion, having
a profound effect on the number and function of circulating CD3þ and
CD4þ T cells [43]. B cells are also depleted, with IgM and IgA levels decreasing
more substantially than IgG. These changes significantly limit the ability to
maintain previously acquired protection against vaccine antigens or respond
to new vaccines [37]. Nilsson and colleagues [45] found that younger children
are at higher risk of losing specific antibodies with their developing B-lympho-
cyte pools being more vulnerable during chemotherapy. Absolute lymphocyte
counts return to normal generally within 3 months and recovery of B cells is
rapid, whereas the recovery of CD8þ and CD4þ T cells and total immunoglob-
ulins may be slower [46–48]. As a result, a vaccination schedule has been devel-
oped with inactivated or recombinant vaccines being able to be administered 3
months after the end of chemotherapy, whereas live vaccines are deferred until
6 months after chemotherapy [49]. This schedule is presented in Table 2 [49].
Live attenuated vaccines
Most of the studies in the literature regarding MMR vaccine in children with
cancer involved patients with acute lymphocytic leukemia after stopping
chemotherapy [40,41,45,50,51]. Most of the data indicate that the immune
response of cancer patients 3 to 6 months after chemotherapy has been discon-
tinued is no different from children of the same age [41,52,53]. Nilsson and
colleagues [45], however, found that a considerable proportion of children
off therapy for at least 2 years, particularly the youngest revaccinated individ-
uals, did not develop protective levels of specific antibodies, and those who
completely lost their humoral immunity had only low-avidity antibodies. Chil-
dren with cancer should receive the varicella vaccine, as they are much more
prone to developing varicella-related complications [54–57]. Based on studies
by Gershon and colleagues in 437 VZV-seronegative children with acute
lymphocytic leukemia (ALL) and no history of varicella, the administration
of VZV vaccine is safe and efficacious in children who have been in remission
for more than 1 year, have a lymphocyte count higher than 700/lL and
a platelet count higher than 100,000/lL [58,59]. Most received 2 doses of the
vaccine separated by 3 months with 85% developing VZV antibody after the
first dose and an additional 12% seroconverting after the second dose
[60,61]. In 9 years of follow-up, only 36 cases of varicella were diagnosed
with only 1 being severe. Varicella vaccination also has been evaluated in
a small number of children with solid tumors and has been found to be immu-
nogenic [62–64]. The safety and immunogenicity of the live attenuated influ-
enza vaccine has been evaluated in children with mild to moderate immune
compromise secondary to cancer, and although the vaccine was well tolerated,
the serum antibody response against influenza A strains was greater with the
inactivated vaccine than with the live attenuated vaccine in children with
cancer [1,4].
Inactivated and recombinant vaccines
Most studies have found that diphtheria and tetanus antibody titers in children
on chemotherapy are higher than the lowest level needed for protection
[40,46,65–67]. Ercan and colleagues [41] and Zengin and Sarper [68] found
Table 2
106
Suggested vaccination schedule for children with cancer
Patients who have not started or not completed the Patients who have completed the vaccination schedule at
Vaccine vaccination schedule at the time of cancer diagnosis the time of cancer diagnosis
Live attenuated vaccine
MMR Two doses separated by at least 3 months in patients who Booster dose in patients who have been off-therapy for 6
have not received any dose and have been off-therapy for months
6 months
VZV vaccine Two doses separated by 3 months in patients in continuous Booster dose in patients in continuous remission for at least
remission for at least 1 year, with a lymphocyte count 1 year, with a lymphocyte count of >700/lL and
of >700/lL and a platelet count of >100,000/lL; if still a platelet count >100 103/lL; if still being treated in
being treated in an epidemic period, they should stop an epidemic period, they should stop drug administration
drug administration 1 week before and for 1 week after 1 week before and for 1 week after vaccination
vaccination
Inactivated or recombinant vaccine
DT Administration of the primary schedule in patients Booster dose in patients off-therapy for 3 months
off-therapy for 3 months
Pertussis Administration of the primary schedule in patients Not known whether a booster is required
Inactivated poliovirus Administration of the primary schedule in patients Booster dose in patients off-therapy for 3 months
Hib Administration of the primary schedule in patients Booster dose in patients off-therapy for 3 months
Pneumococcal vaccines Administration of the primary schedule in patients Booster dose in patients off-therapy for 3 months, but more
off-therapy for 3 months studies are required
MILLER & RATHORE

Meningococcal vaccines Administration of the primary schedule in patients Booster dose in patients off-therapy for 3 months, but more
off-therapy for 3 months studies are required
Inactivated influenza Two doses if ever vaccinated or aged <9 years; otherwise, Booster dose regardless of chemotherapy
1 dose regardless of chemotherapy
Hepatitis A Two doses separated by at least 6 months regardless of Booster dose regardless of chemotherapy in the presence of
chemotherapy in presence of epidemiologic risk epidemiologic risk
Hepatitis B Doses at r ¼ 0, 1 month, 2–6 months, 12 months regardless Two booster doses separated by 3 months regardless of
of chemotherapy in the presence of epidemiologic risk chemotherapy in the presence of epidemiologic risk
Abbreviations: DT, diphtheria and tetanus; Hib, Haemophilus influenzae type b; MMR, measles, mumps, and rubella; VZV, varicella zoster virus.
Data from Esposito S. et al. Vaccinations in children with cancer. Vaccine 2010;28(19):3278–84.
protective titers against diphtheria and tetanus in respectively 90% and 100% of
patients who were revaccinated with diphtheria and tetanus toxoids during
remission. There are few data regarding pertussis vaccine administration in
children with cancer [41,65]. Ercan and colleagues [41] found that those who
had discontinued chemotherapy for 3 to 6 months had antibody levels in the
same range as newly diagnosed patients and healthy controls. However, the
serologic correlate of protection is not known, and it is not possible therefore
to say whether children require a pertussis booster during or after maintenance
therapy. In the case of polio, the prevalence of children with protective anti-
body levels after completion of chemotherapy is 62% to 100%, and most
patients respond to revaccination, which is a simple and cost-effective means
of restoring humoral immunity [38,40,52]. Regardless of previous Hib immu-
nization status, most children responded adequately to Hib vaccine even
when given 1 month after completing chemotherapy, although the best results
were achieved 3 months after chemotherapy [69]. Patients with cancer are at
increased risk of invasive pneumococcal infection [70]. Only a few studies of
the use of pneumococcal vaccines in patients with cancer have been published.
One study of PCV7 has shown that it primes an antibody response to polysac-
charide pneumococcal vaccine after the treatment of childhood Hodgkin
disease [71]. In addition, studies have demonstrated the immunogenicity of
PCV7 in adults with leukemia, especially if administered at an early stage of
disease before starting chemotherapy [72,73]. Although no studies on
PCV13 in children with cancer have been performed, it is recommended
that PCV13 be substituted for PCV7 when PCV is indicated. There are also
very few studies of the use of meningococcal vaccine in children with cancer
receiving standard chemotherapy [52,74]. Yu and colleagues [74] administered
a cross-reactive material (CRM197) conjugated meningococcal C vaccine to 35
children aged 2 to 18 years, most with ALL, who were on maintenance therapy
or off chemotherapy for 3 and 18 months. Only 50% of the children showed
a serologic response, although the vaccine was safe and well-tolerated. Two
studies evaluating hepatitis A vaccine given in 2 doses separated by 6 months,
mainly to children with solid tumors on chemotherapy, found the vaccine to be
highly immunogenic and safe. One month after the second vaccine dose, 89%
of the patients demonstrated protective antibody levels [75,76]. Hepatitis B
vaccine also seems to be immunogenic and safe even when administered to
children on maintenance chemotherapy [76–78]. Meral and colleagues [76]
administered the second dose 1, 2, or 12 months after the first and demon-
strated anti-HB antibody in 94% of children with solid tumors, 90% of those
with leukemia and 74% of those with lymphoma.
HEMATOPOIETIC STEM CELL TRANSPLANT RECIPIENTS

In recent years, HSCT has been used more frequently in patients with malig-
nancies using curative high-dose chemotherapy and radiotherapy. The most
commonly used pretransplant conditioning regimen is cyclophosphamide
and total body irradiation for children older than 2 years. This combination
induces profound immunosuppression, particularly functional hyposplenia or

asplenia and thymic atrophy. In addition, graft-versus-host disease (GVHD)
is immunosuppressive, as are its prophylaxis and treatment. All of these factors
have an influence on the reconstitution of the immune system. Hematopoietic
stem cell transplant recipients are profoundly immunosuppressed for months,
even years after their transplant. The various components of the new immune
system develop and mature at different rates, thus dictating the timing of
specific infections and response to different antigens [79]. Immune reconstitu-
tion occurs faster after autologous HSCT than after allogeneic [80]. B-lympho-
cytes reach age-matched levels 3 to 6 months after transplantation, whereas
reconstitution of T-lymphocytes to normal levels can occur 1 to 2 years after
transplantation and more rapidly in younger HSCT recipients [47,81–85].
Guidelines on reimmunization of transplant recipients are based on a combina-
tion of expert opinion and limited published data. The British guidelines, pub-
lished in 2002, recommend that reimmunization commence 12 months after an
autologous and HLA-identical related donor allogeneic HSCT and 18 months
after any other allogeneic HSCT, as long as there is no evidence of chronic
GVHD, the child is off immunosuppressive therapy for at least 6 months
(12 months for live vaccines), and has not received IVIG for at least 3 months.
A suggested reimmunization schedule for hematopoietic stem cell transplant
recipients is presented in Table 3 [86].
DTaP
There are limited data on immunity against diphtheria after HSCT and its
timing and number of doses will be dictated by other components of
a combined vaccine [87]. Some studies have shown a well-maintained immu-
nity against tetanus and some have shown a significant decline after HSCT
[88–90]. A recent study of British pediatric HSCT recipients demonstrated
that all achieved protective antitetanus antibody titers after 3 doses [90].
Data are also not available on pertussis immunity and immune response to
the vaccine in HSCT recipients; however, a recent case report suggests that
inclusion of the pertussis vaccine in a reimmunization schedule be considered
in HSCT recipients older than 7 years [91].
Poliovirus vaccine
Inactivated polio vaccine is recommended for HSCT recipients and immunity
to polio declines after HSCT. A recent study demonstrated that only 11% of
British pediatric HSCT recipients were immune to the 3 poliovirus serotypes
after HSCT [90]. Reimmunization with IPV is effective and 3 doses are recom-
mended [90,92,93].
MMR
A loss of immunity has been demonstrated to all 3 vaccine antigens after
HSCT [90,94–96]. The data show that between 13% and 70% of patients retain
protective antibody concentrations to measles virus [90,94,97]. Machado and
colleagues [97] demonstrated that measles vaccine could be safely administered
Table 3
Suggested reimmunization schedule for hematopoietic stem cell transplant recipients
HLA-identical sibling, syngeneic,
Time after HSCT autologous HSCT Any other allogeneic HSCT
From 6 months Influenza vaccine every autumn (for
as long as patient considered
immunocompromised)
At 12 months 3 doses at 1–2 monthly intervals:
DTaP
IPV
Hib-conjugate
MCC (or MQC)
3 doses at 0-, 1-, 6-month schedule:

HepBa
At 12–15 months 2 doses of PCV7 at 1–2 monthly
intervals
At 18 months MMR-1 3 doses at 1–2 monthly intervals:
DTaP
IPV
Hib-conjugate
MCC (or MQC)
3 doses at 0-, 1-, 6-month schedule:

HepB
At 18–21 months 2 doses of PCV7 at 1–2 monthly
intervals
At 24 months MMR-2 þ Pn-PS23 MMR-1
At 30 months MMR-2 þ Pn-PS23
Based on Royal College of Pediatrics and Child Health guidelines. Specific vaccines to be used will be
dictated by current recommendations in different countries.
Abbreviations: DTaP, diphtheria/tetanus/acellular pertussis; HepB, hepatitis B; Hib-conjugate, Haemo-
philus influenzae type b-conjugate; IPV, inactivated poliovirus; MCC, Meningococcal C-conjugate; MMR,
measles, mumps, and rubella; MQC, meningococcal quadravalent (A, C, Y, W135) conjugate; PCV7, hep-
tavalent pneumococcal conjugate; Pn-PS23, 23-valent pneumococcal conjugate.
a
HepB is not part of the Royal College of Pediatrics and Child Health schedule, but for use in countries
where HepB is part of the routine schedule or in specific circumstances.
Data from Patel SR, Chisholm JC, Heath PT. Vaccinations in children treated with standard-dose cancer
therapy or hematopoietic stem cell transplantation. Pediatr Clin North Am 2008;55(1):169–86, xi.
to HSCT recipients on immunosuppressive therapy within 2 years of trans-

plantation, although it is generally recommended that 2 doses of MMR be
given to HSCT recipients not on immunosuppressive therapy who also do
not have GVHD. Only one published study has looked at the response to 2
doses of MMR; the first dose resulting in 91% and the second dose resulting
in 100% achieving protective measles-neutralizing antibody concentrations [90].
Influenza vaccine
There are limited data on the epidemiology of influenza infections after HSCT
and on influenza vaccination after HSCT. One study demonstrated that
seasonal exposure and more aggressive HSCT conditioning regimens increase

the risk of morbidity from influenza infection [98]. Since the antibody response
within the first six months of HSCT is poor, vaccination is advisable after 6
months and from then on, lifelong, for all HSCT candidates and recipients
[98,99]. However, recipients within the first 6 months of HSCT are at greatest
risk of severe disease, so it is strongly recommended that family members and
close or household contacts be vaccinated starting the season before HSCT and
continuing for more than 24 months after HSCT to prevent exposure to influ-
enza among HSCT candidates and recipients. The live attenuated influenza
vaccine has been evaluated only in small studies in HIV-infected children
and children with mild to moderate immune compromise secondary to cancer
and, thus, there are no data on its use in pediatric HSCT recipients.
Hib vaccine
There are also limited data on the incidence of Haemophilus influenzae type
b disease in HSCT recipients and on immune response to the Hib vaccine after
HSCT. One study found that 63% of subjects tested had protective anti-Hib
antibody concentrations before revaccination and that 3 doses of the vaccine
resulted in all subjects developing protective antibody levels [90]. In 2 studies,
vaccination 18 months after transplantation was more effective than earlier
vaccination [100,101], but in 2 other studies, the immune response was similar
when comparing vaccination at 6 and 18 months after HSCT [87,102].
Pneumococcal vaccine
Pneumococcal disease occurs late after HSCT, usually after 6 to 12 months
[103–106]. Studies indicated limited immunogenicity of the 23-valent pneumo-
coccal polysaccharide vaccine among HSCT recipients, but because of its
potential benefit, it should be administered to HSCT recipients at 12 and 24
months after HSCT [103,107,108]. Until recently, 2 doses of the polysaccha-
ride vaccine were recommended [109]. A recent study demonstrated that
a combination of PCV7 and the polysaccharide vaccine results in protective
antibody responses with the suggestion that 2 doses of conjugate vaccine are
more immunogenic than 1 dose of polysaccharide vaccine [90]. Another study
showed good responses to 2 doses of PCV7 when given 6 to 9 months after
HSCT [110]. Although no studies on PCV13 in pediatric HSCT candidates
and recipients have been performed, it is recommended that PCV13 be
substituted for PCV7 when pneumococcal conjugate vaccine is indicated.
HIV-INFECTED CHILDREN
Immune response to vaccines in HIV-infected patients in the pre-HAART era
was generally poor, particularly in patients with low CD4 count; cellular and
humoral responses often correlated with the CD4 count. Among those who
did respond to vaccines, there was an enhanced waning of antibody levels
compared with the HIV-uninfected controls. Several studies have demon-
strated a superior immune response in HIV-infected children on HAART to
vaccines such as PCV, PPV, Hib, and MMR [111]. However, other studies
have shown that although antibody responses were improved while on

HAART, the response was still suboptimal for vaccines including DTaP, hepa-
titis A, influenza, PCV, PPV, VZV, and MMR [111–115]. This suboptimal
response was particularly evident in patients who were severely immunosup-
pressed before HAART. Furthermore, some studies have demonstrated that
the CD4 count at the time of vaccination, after HAART had been started, is
more predictive of response to vaccines than the nadir CD4 count before
HAART [111,112,115]. For a number of vaccines (pertussis, measles, VZV,
PCV, PPV, hepatitis A, hepatitis B), an inverse relationship between HIV viral
load and vaccine response, independent of CD4 count, has been demonstrated,
especially when the viral load exceeds 1000 to 10,000 copies/mL
[111,112,114,115]. With consideration of all these factors, it may be reasonable
to vaccinate patients when they are on stable HAART, with good CD4
response and maximally suppressed viremia. Unfortunately, the heterogeneity
in response to vaccines even when on HAART, suggests that HIV-infected
children may not be uniformly protected. Inactivated vaccines pose no harm
to HIV-infected children and should be administered according to the routine
schedule. Data also suggest that MMR and VZV vaccines are also safe in HIV-
infected children with mild clinical disease and adequate CD4% counts (>15%)
[116]. Because of the demonstration of waning immunity over time to several
vaccines, however, the question of whether HIV-infected children on HAART
need to be revaccinated is being investigated. The recommended immunization
schedule for children infected with HIV is presented in Fig. 1.
Children and adolescents with asymptomatic or symptomatic HIV infection
should receive all routinely recommended inactivated vaccines, including
DTaP, Tdap, IPV, hepatitis B, hepatitis A, Hib, and pneumococcal and meningo-
coccal conjugate and/or polysaccharide vaccines, according to the routine recom-
mended immunization schedule for children and adolescents. Annual influenza
immunization of HIV-infected children 6 months and older and household
contacts is recommended as well. Because the ability of HIV-infected children to
respond to vaccines is likely related to the degree of immunosuppression at the
time of immunization, such response, therefore, may not be protective, and these
children should be considered susceptible to vaccine-preventable diseases even
after immunization, unless a recent serologic test has documented protection [116].
Many studies have sought to evaluate the initial antibody response and dura-
tion of immunity to inactived vaccines before and after HAART in HIV-
infected children. For such vaccines as DTaP, HBV, pneumococcal, and Hib,
the percentage of children with an immune response after starting HAART was
highly variable. The response rates were 38% to 77% for tetanus [117–121],
40% to 65% for diphtheria [120], 1% to 100% for HBV [120,122–124], and 25%
to 87% for different pneumococcal vaccine serotypes [111,125,126]. The duration
of HAART at the time the antibody concentrations were measured varied,
ranging from 28 weeks to 5.3 years. Two studies specifically investigated the effect
Fig. 1. (A) Recommended immunization schedule for HIV-infected children 0 to 6 years of

age—United States, 2009. (B) Recommended immunization schedule for HIV-infected children
7 to 18 years of age—United States, 2009. (From Kaplan JE, Masur H, Holmes KK. USPHS;
Infectious Disease Society of America. Guidelines for preventing opportunistic infections
among HIV-infected persons—2002. Recommendations of the US Public Health Service and
the Infectious Diseases Society of America. MMWR Recomm Rep 2002;51(RR 8):1–52.)
of HAART on antibody concentrations to tetanus before and after HAART

[117,121]. In the study performed by Farquhar and colleagues [121] in Kenya,
78% of children were seropositive before HAART, whereas only 59% were sero-
positive after 6 months of HAART. Surprisingly, 31% of children who were posi-
tive before HAART became seronegative after. However, another study found
FIg. 1. (Continued)
Fig. 1. (Continued)
Fig. 1. (Continued)
that 60% to 100% seroconverted after the primary series and 75% to 90% after the
booster dose. Protective concentrations were maintained in most children 6 to
30 months following vaccination [118]. In addition, one study from the United
States [127] reported a decline from 74% seropositive at 4 weeks to 38% at 32 weeks
after immunization, although in 3 other studies, 85% to 90% of children main-
tained immunity 1 year after vaccination [118,119,128]. In one study evaluating
response to diphtheria in HIV-infected children compared with HIV-exposed
but uninfected controls, 18% to 76% developed protective antibody levels,
whereas only 50% of those infants maintained protective levels 6 to 36 months
after the booster dose [129]. The immunogenicity of pertussis vaccine was evalu-
ated reporting antibody responses to all antigens (filamentous hemagglutinin;
a 69-kDa outer-membrane protein, pertactin; and fimbriae types 2 and 3) in 6 of
12 HIV-infected children but lower titers compared with uninfected children
[130]. For pertussis, antibody concentrations decreased from 22.3 EU/mL at
8 weeks to 10.1 EU/mL by 48 weeks and 6.8 EU/mL by 96 weeks after immuni-
zation [112]. In a study by Fernandes and colleagues, HIV-infected children not on
HAART (44%) and uninfected children (87%) were more likely to be seropositive
for HBV compared with children on HAART (17%) [122]. For Hib, 3 of 4 children
had detectable antibodies 4 weeks after immunization and 2 of 2 at 52 weeks [128].
Studies of DTaP, Hib, HBV, and pneumococcal and influenza vaccines involved
revaccination of children receiving HAART who had received the same vaccines
before HAART was initiated. Within the first 3 months after revaccination, 53%
to 100% responded to tetanus vaccine [118,119,121,127–129], 75% to Hib [128],
46% to 92% to HBV vaccine [124,131], 29% to 96% responded to the various sero-
types in the pneumococcal vaccine [111,125,126,130], and 50% to 100% to the
various influenza strains [2,132–134]. Studies of hepatitis A virus (HAV) involved
primary immunization of children after HAART was started and 72% to 97% of
these children responded after receiving 2 to 3 doses [115,119]. Two studies were
specifically designed to assess the effects of duration of HAART and timing of
HAART initiation in relation to vaccine responses. Rigaud and colleagues [119]
randomized children starting HAART to receive tetanus, then HAV or HAV,
and then tetanus at 8 weeks and 32 weeks after enrollment. The antibody concen-
trations for tetanus toxoid did not differ between the groups but children who
received HAV vaccine at 32 weeks had substantially higher antibody responses
to the HAV vaccine. Pensieroso and colleagues [135] evaluated responses to
vaccines among children who started HAART either within the first year of life
or later and found that antibody responses to tetanus vaccine were higher in the
earlier treatment group. In addition, within the late treatment group, higher
responses were observed in those who achieved HIV-1 suppression compared
with those who did not reach suppression. A similar trend was also noted for pneu-
mococcal vaccine responses. When compared with healthy, HIV-uninfected
controls, HIV-infected children on HAART had lower antibody concentrations
for pneumococcus and influenza [133,134]. Therefore, the timing of vaccines
and whether children receiving HAART should be revaccinated requires further
investigation in the HIV-infected population.
Live vaccines
Accumulating data suggest that live vaccines, such as MMR and VZV, are
safe for HIV-infected children with mild clinical disease and adequate CD4
counts (>15%) [116]. Children infected with HIV are at increased risk of
morbidity and mortality from wild-type virus infections with varicella as
well as measles. There have been reports of severe wild-type measles in
HIV-infected children, with as many as 40% of cases being fatal. Therefore,
it is recommended that HIV-infected children with CD4% greater than 15%
receive MMR at 12 months and then may receive the second dose as soon
as 28 days later. Severely immunocompromised patients with HIV infection
should not receive measles vaccine. Monovalent varicella vaccine should be
considered for HIV-infected children with CD4 count higher than 200 or
greater than 15% in 2 doses, 3 months apart. MMR and varicella (MMRV)
should not be administered as a substitute for monovalent varicella vaccine.
For MMR, the proportion of children with immune response after starting
HAART was 42% to 45% for measles and 27% to 66% for rubella virus
[120]. In a study by Bekker and colleagues [113], 63% of children were sero-
positive for measles before HAART, but 40% became seronegative after
a median of 205 weeks on HAART. The same was true for mumps and
rubella with 52% and 80% seropositive before HAART, respectively,
declining to 38% and 11%, respectively, after starting HAART [113]. Several
studies have identified potential factors predicting immune response including
lower HIV-1 viral load and higher CD4 cells after HAART [121], whereas
other studies did not [120,136]. For measles and rubella, low pre-HAART
antibody concentrations were predictive of loss of immunity [113,121]. In
HAART recipients, the proportion of children responding to measles within
3 months of revaccination was 64% to 90% [121,128,137,138], 61% for
mumps [138], 80% to 100% for rubella [138,139], 71% for varicella [114],
and 33% to 92% by strain for influenza [2,3]. One US study [128] reported
that detectable measles antibodies decreased from 83% at 4 weeks to 73%
at 52 weeks after vaccination, whereas varicella seropositivity was 71% at 8
weeks, 65% at 52 weeks, 47% at 104 weeks, and 38% at 156 weeks. In the
study by Pensieroso and colleagues [135], children started on HAART in
the first year of life had greater measles antibody concentrations and were
more likely to have protective immunity than those HIV-infected children
started on HAART later. When compared with a control group of people
not infected with HIV, HIV-infected children on HAART had lower antibody
concentrations for measles and rubella and were less likely to have protective
immunity. Therefore, although the benefit of MMR and varicella vaccine
outweighs the risk among HIV-infected children who are not immunocom-
promised, the proportion of children who respond initially to vaccines is
lower and these individuals tend to lose their protective immunity sooner.
Two studies on the live attenuated influenza vaccine (FluMist) have evaluated
safety and immunogenicity in HIV-infected children but the effectiveness of
FluMist in preventing influenza illness in HIV-infected children has not
been evaluated [2,3]. Once again, the question of whether antibody levels
should be followed and the potential benefit of revaccination of children on
HAART warrant further investigation.
CHILDREN ON CORTICOSTEROIDS
Children who are receiving systemic steroids can become immunosuppressed;
however, the amount and duration of corticosteroid therapy that is sufficient to
cause immunocompromise is not well defined. Other factors affecting the
degree of immunosuppression include the underlying disease, other therapies,
and the frequency and route of steroid therapy. There is substantial evidence,
however, that a dose of prednisone of greater than 2 mg/kg per day or a total
daily dose greater than 20 mg per day, especially when administered for more
than 14 days, raises concern about giving live-virus vaccines to these individ-
uals while concurrently receiving corticosteroid therapy. These children should
receive live vaccines no less than a month after discontinuation of therapy. For
children who receive such high doses of prednisone for fewer than 14 days,
some experts may give live vaccines immediately after discontinuing steroids,
whereas others recommend delaying vaccination for at least 2 weeks after dis-
continuing steroids. Topical, local injections, and aerosolized corticosteroids
usually do not result in severe immunosuppression; however, if there was other
clinical or laboratory evidence of systemic immunosuppression, consideration
should be given for delaying the administration of live vaccines for 1 month
after stopping topical, local injections, or aerosolized corticosteroid therapy.
In addition, children who have an underlying disease that suppresses the
immune system and who are currently receiving steroids should not be given
live-virus vaccines [116].
CHILDREN WITH HYPOSPLENIA/ASPLENIA

The risk of developing severe infection remains an important complication of
asplenia and hyposplenia, especially in children younger than 5 years. The
spleen plays a major role in the prevention of bacterial sepsis as an endothelial
filtration organ for bacteria through phagocytosis and production of opsonins,
alternate complement components, properdin, and tuftsin [140–142]. The most
common causes of asplenia are surgical removal, which may be because of
hematologic disease, hypersplenism, or trauma [143], whereas causes of hypo-
splenism are hematologic, autoimmune, chronic gastrointestinal disorders, liver
disease, infiltrative, vascular, and others (eg, HIV, GVHD). The incidence of
overwhelming postsplenectomy sepsis (OPSS) is greater in children with hemo-
globinopathies than in children who have a splenectomy performed secondary
to trauma. The most common organisms causing OPSS are encapsulated
bacteria (eg, pneumococcus, H influenzae, Escherichia coli, meningococcus) [143].
Other organisms include staphylococci, streptococci, Pseudomonas, Klebsiella,
and Salmonella, as well as malaria and babesia.
Children with asplenia or hyposplenia should be immunized according to
routine immunization schedules, as neither condition is a contraindication to
administration of inactivated or live vaccines [144]. In addition, vaccination

against pneumococcus, meningococcus, and H influenzae type b should be added
to the routine schedule for these patients [145]. The timing of presplenectomy
immunization is crucial for optimal immune response. The schedule should be
complete at least 2 weeks before elective splenectomy, which is shown in
Table 4 [146]. For emergency splenectomy, data indicate that a better response
to PPV23 was noted 14 days after splenectomy [147,148].
Both the polysaccharide (PPV23) and the conjugate vaccines (PCV13) are
currently available. Pneumococcal conjugate and/or polysaccharide vaccine is
indicated for all children with asplenia at the recommended age. However,
there is no response to the polysaccharide vaccine in children younger than
2. The polysaccharide vaccine should be given only to children with functional
asplenia who are older than 2 years and at least 8 weeks after the administra-
tion of conjugate pneumococcal vaccine. A booster dose of PPV23 is also rec-
ommended 5 years after the first dose of PPV23 [149]. For children with
asplenia who received conjugate and/or polysaccharide vaccine before 24
months of age, reimmunization with pneumococcal vaccine should be consid-
ered. Which vaccine should be given for reimmunization depends on the age
of the patient as well as which vaccine (polysaccharide or conjugate) was given
previously. Children 5 years of age and older who were previously immunized
with PCV7 or PPV23 may also be considered for immunization with PCV13,
which is now licensed for children 18 years and younger who have certain
medical conditions. Administration of only a single dose of PCV13 or
PPV23 is acceptable for children older than 5 years who are at increased
risk of invasive pneumococcal disease (eg, asplenic patients) and not previously
immunized. If both PPV23 and PCV13 are given, PCV13 should be adminis-
tered first followed by PPV23. In addition, a booster dose of PPV23 is
Table 4
Timing of vaccine administration presplenectomy
Timing of vaccine administration presplenectomy
Week Vaccine
0 Conjugate Haemophilus influenzae type b
0 Conjugate pneumococcal
0 Conjugate meningococcal
2 Polysaccharide meningococcala
8 Conjugate pneumococcal
16 Polysaccharide pneumococcal
a
If MCV-4 is administered as the conjugate meningococcal vaccine, then do not follow with the polysaccha-
ride meningococcal vaccine.
Data from Price VE, Blanchette VS, Ford-Jones EL. The prevention and management of infections in chil-
dren with asplenia or hyposplenia. Infect Dis Clin North Am 2007;21(3):697–710, viii-ix.
recommended: 3 years later in children who are younger than 10 years and 5
years later in children who are older than 10 years [116].
Hib vaccine
Hib vaccine has been shown to be immunogenic in asplenic children [150].
Infants should receive the primary series and booster doses according to the
regular schedule and children between 15 and 59 months who have not
received Hib vaccine should receive 1 dose.
Meningococcal vaccine
Tetravalent conjugate meningococcal vaccine should be administered to chil-
dren with asplenia from 9 months of age through adolescence, although the effi-
cacy in this patient population has not been established. Persons who
previously were vaccinated at age 7 years or older and are at prolonged
increased risk because of their underlying disease or travel/residence in an
endemic or hyperendemic area should be revaccinated 5 years after their last
dose of meningococcal vaccine. Persons who were initially vaccinated at 9
months to 6 years of age and who are at prolonged increased risk should be
revaccinated 3 years after their last meningococcal vaccine. Persons who
remain in one of these increased risk groups indefinitely should continue to
be revaccinated at 5-year intervals [116].
CHILDREN WITH RHEUMATOLOGIC DISEASES

Children with rheumatologic diseases (RD) are at greater risk of infection than
children without RD because of their frequent use of immunosuppressive
drugs and aberrant immunity [151]. They are more likely to develop serious
infections requiring hospitalization, such as septicemia and pneumonia [152].
The possibility of preventing various infectious diseases should lead to admin-
istering vaccines to children with RD routinely; however, this is questioned by
some experts because of the belief that the immune response in these patients is
impaired by immunosuppressive drugs and protective antibodies are not
produced. There is also the belief that vaccines could initiate a persistent auto-
immune response and result in a relapse of the RD [153,154]. As a result, chil-
dren with RD often do not receive the usual vaccinations recommended for
healthy children [155], resulting in about one-third of these children not being
vaccinated [156]. Analysis of the literature over the past 15 years reveals
a paucity of data on immunization in children with RDs. In some cases,
some vaccines have not been studied at all in this patient population. In other
cases, studies have involved small groups of patients and no randomized,
double-blind, controlled studies have been performed to evaluate the clinical
efficacy or effectiveness of vaccines in children with RDs. The available studies
reveal that the newer biologic agents (eg, anakinra, adalimumab) affect anti-
body production, whereas conventional RD therapy has a limited effect. The
evidence does not provide data on which drugs reduce the immune response
more than others, as well as which doses are required to produce that effect.
The current data suggest that vaccines are safe and efficacious in children
with stable RD. Pneumococcal and influenza vaccines should be strongly rec-
ommended because of the increased risk of these infections when children
are receiving immunosuppressive therapy. Vaccinations should be postponed
only in children with severe active RD until the child has stabilized. The
data suggest MMR is safe but other vaccines should be delayed in the presence
of severe immunosuppression [60,157–160].
DTaP
The only published study of diphtheria vaccine in children with RD showed
that the vaccine is safe and immunogenic in 95% of children 6 to 15 years of
age and results in prolonged protective antibody concentrations. Some of these
patients were receiving nonsteroidal anti-inflammatory drugs or maintenance
immunosuppressive agents at the time of vaccination [161]. Forty children
with systemic lupus erythematosus (SLE) were given tetanus vaccine, and
immunosuppressive therapy did not seem to interfere with the development
of immunity [162]. A study from Russia evaluated 72 children with RD who
received pertussis vaccine, 94.0% of whom were receiving immunosuppressive
therapy; 98.6% of these children developed IgG antibody against pertussis
toxin and 100.0% had IgG against the other antigens [163].
Hepatitis B vaccine
A study of 39 children with juvenile idiopathic arthritis (JIA) in remission and
41 healthy controls evaluated the safety and immunogenicity of HBV vaccine.
A significant antibody response was demonstrated in 38 or 39 of the children
with JIA, although their antibody levels were significantly lower than those of
the healthy controls [164].
One pediatric study looked at responses to PCV7 in children with JIA who
were being treated with anti–tumor necrosis factor (TNF) drugs plus conven-
tional disease-modifying antirheumatic drugs (DMARDs) or DMARDs alone.
Fifty percent of children receiving anti-TNF drugs and 25% of those on
DMARDs alone did not develop a fourfold increase in their baseline antibody
levels against at least 5 of the 7 serotypes [165]. Some information regarding the
protection offered by the 23-valent polysaccharide vaccine to older children can
be derived from studies of adult patients [166–170]. For example, Elkayam and
colleagues showed that average antibody titers after pneumococcal polysaccha-
ride vaccine in patients receiving conventional immunosuppressive agents and/
or cyclosporine were the same as or slightly lower than those seen in control
subjects [166]. They also found in a subsequent study that 33% of those
with rheumatoid arthritis and 21% of those with SLE showed only minimal
responses. Elkayam and colleagues [167] also compared patients receiving
methotrexate alone versus methotrexate plus etanercept or infliximab and
found that 31% of the patients receiving the TNF antagonists were poor
responders, whereas only 18% of patients receiving methotrexate alone were
considered poor responders [168].
An evaluation of the meningococcal serogroup C conjugate vaccine in 234 chil-
dren with JIA revealed adequate antibody levels even in those on highly immu-
nosuppressive medications [171].
Influenza vaccine
There are no randomized controlled trials of influenza vaccination in children
with RD and most of the studies were performed before 2000 so the effects of
newer biologic drugs were not considered. Both Malleson and colleagues [172]
and Olson and Lindsley [173] evaluated influenza vaccine in children with RD
and found protective antibody responses in most patients. Studies of the newer
biologic agents in adults indicate the immune responses of patients with RD
taking these drugs were similar or only slightly lower than untreated patients
or control subjects [174–178]. Use of the live attenuated influenza vaccine (Flu-
Mist) in children with rheumatic diseases has not been studied.
Live vaccines
Two published studies of MMR vaccine in children with JIA evaluated its
safety and immunogenicity [157,158]. Neither study observed any overt cases
of measles, mumps, or rubella or any secondary severe infections. Varicella
vaccine is contraindicated in patients taking steroids at doses of 2 mg/kg per
day or 20 mg per day for more than 14 days [60]. The immunogenicity and
tolerability of VZV vaccine was assessed in a study of 25 children with RD.
All 25 patients were receiving methotrexate; 13 were also receiving prednisone
and 5 were also receiving other disease-modifying antirheumatic drugs
(DMARDs). Positive VZV IgG titers were detected in 50% of the initially sero-
negative patients and 72.2% of the controls 4 to 6 weeks after immunization.
No episodes of overt varicella were observed during the follow-up period of
3 months [159].
INTERNATIONALLY ADOPTED CHILDREN

More than 200,000 children were internationally adopted in the past decade.
The AAP recommends that children undergo a comprehensive health assess-
ment shortly after arrival to the United States, including an assessment of previ-
ously administered vaccines. No clear consensus exists about which strategy is
optimal to ensure all international adoptees are immunized, despite several
options provided by the AAP, Infectious Disease Society of America, and
ACIP. Some of these strategies are as follows:
1. Accept all appropriate preadoption records of immunization.
2. Measure serum antibodies against vaccine-preventable pathogens for which
reliable testing is available; if present, accept all corresponding preadoption
records of immunization.
3. Measure serum antibodies against vaccine-preventable pathogens for which
reliable testing is available; if positive, consider the child to have received 1
immunization in the series.
4. Accept no preadoption records of immunization; immunize all adoptees with

age-appropriate vaccinations.
Lack of definitive and sometimes contradictory recommendations for immu-

nization decisions in internationally adopted children is likely because of the
varied results from previously published studies. Immunization records of
each internationally adopted child should be evaluated carefully for inconsis-
tencies and plausibility. Written records may be accepted as valid if the
numbers of doses, intervals between doses, dates of administration, and
patient’s age at the time of immunization are all consistent with the current
US or WHO schedule. Alternatively, measurement of antibody levels to diph-
theria, tetanus, measles, mumps, rubella, varicella, and each type of poliovirus,
as well as anti-HBs, HBsAg, and anti-HBc may be considered to determine
whether the child needs additional immunizations or initiation of a vaccination
schedule appropriate for the child’s age. Many children will have received
DTP, measles, hepatitis B, and poliovirus vaccines but most will not have
been administered Hib, pneumococcal, hepatitis A, rubella, mumps, and vari-
cella vaccines. Another option is to provide 1 dose of vaccine and perform sero-
logic testing 1 month later. Repeat administration of immunizations is
recommended when there are concerns if the vaccines were given properly
or whether they were immunogenic. In a study by Staat and colleagues
[179], serologic testing was performed to evaluate what proportion of children
had protective antibody by the number of documented immunizations for each
vaccine antigen. Briefly, the overall proportion of protective antibody was 80%
for diphtheria, 89% for tetanus, 90% for poliovirus, 60% for HBV, 32% for
Hib, 84% for measles, 54% for mumps, 54% for rubella, and 38% for varicella.
In this study, serology was found to be a useful tool for verifying a child’s
protection against vaccine-preventable diseases. Administering unnecessary
vaccines to internationally adopted children increases the number of clinic
visits, cost, and can negatively affect the transition for these children. Because
screening tests are recommended for all internationally adopted children at the
initial visit, serologic tests could be performed in addition to these screening
tests; however, because children with documentation of immunizations have
a high proportion of protective antibody levels, it would be reasonable to
consider birth country vaccine doses to be valid, and complete the series as
appropriate for the child’s age. Given the high proportion of protection in chil-
dren without vaccine documentation, serologic testing to determine immunity
should be done in to determine which, if any, vaccinations are necessary. Until
consensus statements are available, each internationally adopted child must be
evaluated individually for the best plan of action. Some consistency at each
institution will improve the overall quality of such evaluations. Additional
studies to examine the cost-effectiveness of different strategies for immunization
decisions in internationally adopted children should be considered while taking
into account the medical and psychological affects of administering unneces-
sary immunizations.
PEDIATRIC TRAVELERS
A basic rule is that all infants and children should be up-to-date on the immu-
nizations recommended for their age before international travel. To optimize
immunity before departure, vaccines may need to be given based on a catch-
up schedule. Not all travel-related vaccines are effective in infants and some
are specifically contraindicated.
IPV
Polio still remains endemic in a few countries in Africa and Asia. To ensure
protection, all pediatric travelers should be fully immunized against poliovirus.
Three doses of IPV vaccine should be given before departure and, if necessary,
the doses may be given at 4-week intervals, although 6- to 8-week intervals are
preferred. The fourth dose of IPV should be received between the ages of 4
and 6 years [171].
Measles
As importation of measles is an important source of measles cases in the United
States, all people traveling abroad should be immune to measles. For children
traveling to areas with a high rate of measles transmission, the age of initial
measles vaccination can be lowered to as young as 6 months of age. Children
6 to 11 months of age should receive 1 dose of a measles-containing vaccine.
Children who receive a dose of measles-containing vaccine before the age of
1 year should also receive 2 additional doses given at least 1 month apart start-
ing at 12 to 15 months of age [171].
Hepatitis B
Hepatitis B vaccine should be considered for all travelers visiting areas where
hepatitis B infection is endemic, including countries in Asia, Africa, and parts of
South America. Although the vaccine is recommended for all children in the
United Sates, an accelerated dosing schedule of hepatitis B vaccine (Engerix-
B; Merck and Co, Swiftwater, PA) may be given at 0, 1, and 2 months. If
the accelerated schedule is used, a fourth dose of hepatitis B vaccine should
be given 12 months after the third dose [171].
Hepatitis A
People traveling to any areas of the world except Canada, New Zealand,
Australia, Japan, and Western Europe should be immunized against HAV
infection. Inactivated vaccine is used for children 1 year and older, whereas
immunoglobulin (IG) is used for children younger than 1 year, which may
interfere with the immune response to MMR and varicella vaccines for up to
6 months. Children who are immunocompromised and older than 1 year
should receive both the vaccine and IG. One dose of the vaccine administered
at any time before departure can provide adequate protection for most children
[171].
DTaP
Two doses of DTaP can provide some protection but 3 doses is recommen-
ded for optimal protection against pertussis. While the vaccine is usually
administered at two, four, six and 15–18 months, the schedule can be acceler-
ated as soon as the infant is 6 weeks old with the second and third doses being
given at 4 week intervals. The fourth dose should not be given until the child is
at least 1 year of age [171].
Hib
Infants and children should have optimal protection before traveling, as Hib is
an endemic disease worldwide. Children may receive the first dose as early as 6
weeks of age and the primary series consists of 2 or 3 doses with a minimum of
4 weeks between doses depending on which vaccine is administered (PRP-T or
PRP-OMP). If unvaccinated, infants younger than 15 months should receive at
least 2 vaccine doses separated by at least 4 weeks. Unvaccinated infants of 15
to 59 months should receive a single dose of Hib vaccine, whereas children old-
er than 6 years should not get the vaccine unless they are immunocompro-
mised [171]. PRP-OMPC (PedvaxHib , Merck & Co., Swiftwater, PA) has
a 2-dose primary series and if time is a limitation, this is preferable, if available.
Varicella
Two doses of varicella vaccine are recommended for all children and adoles-
cents. The first dose is recommended at age 12 to 15 months and the second
dose typically at 4 to 6 years of age but no sooner than a minimum of 3 months
after the first dose. Children older than 13 years should receive 2 doses of vari-
cella vaccine 4 to 8 weeks apart [171].
Meningococcal epidemics occur in sub-Saharan Africa from December to June
and it is recommended that all travelers to this region, as well travelers to
Mecca during the annual Hajj be vaccinated. MedImmune (Novartis, Thou-
sand Oaks, CA) is Halal certified and is preferred by Muslims, including those
traveling for Hajj. Meningococcal conjugate vaccine is also recommended for
children as young as 9 months in a 2-dose series; the second dose can be given
as early as 2 months after the first for those who travel to or reside in areas
where meningococcus is hyperendemic or epidemic. Tetravalent meningo-
coccal (A, C, Y, and W-135) polysaccharide vaccine (MPSV4) (licensed for
people older than 2 years) can be used when neither quadrivalent meningo-
coccal conjugate vaccine (MenACWY-CRM, MCV4) vaccine is available.
The serogroup A polysaccharide in MPSV4 induces an antibody response in
some children as young as 3 months. For infants traveling to high-risk areas
for meningococcus serogroup A, this can provide some degree of protection
[171].
Yellow fever
Yellow fever is a disease transmitted by mosquitoes and is endemic in certain
regions of Africa and South America. Infants and children older than 9 months
can be vaccinated if they travel to countries within the yellow fever–endemic

zone. Vaccination of infants younger than 9 months is contraindicated because
of the risk of encephalitis, as 14 of 18 reported cases of postvaccination enceph-
alitis were in infants younger than 4 months. Whenever possible, travel by chil-
dren 6 to 8 months of age to yellow fever–endemic countries should be
postponed or avoided. If travel is unavoidable, decisions on immunization
against yellow fever need to balance the risk of yellow fever disease with the
risk for adverse events after vaccination [171].
Typhoid vaccine
Typhoid fever is a disease caused by the bacterium Salmonella enterica serotype Ty-
phi. Vaccination is recommended for travelers to areas where there is a recog-
nized risk of exposure to S typhi. Currently, there are 2 vaccine formulations
available: a Vi capsular polysaccharide vaccine (ViCPS), administered intra-
muscularly, and an oral, live, attenuated vaccine (Ty21a). Both vaccines induce
a protective response in 50% to 80% of recipients. The ViCPS vaccine can be
given to children who are 2 years or older, with a booster dose administered 2
years later, if continued protection is necessary. The oral Ty21a vaccine, which
is given in 4 capsules (1 taken every other day) can be administered to children
older than 6 years. A booster series for this vaccine should be taken every 5
years, if needed. All 4 doses should be taken at least 1 week before potential
exposure [171].
Japanese encephalitis vaccine

Japanese encephalitis (JE) virus is transmitted by mosquitoes and is endemic
throughout Asia. The risk is year-round in tropical climates and seasonal in
temperate climates. The risk for those who travel to urban centers or those
who are short-term travelers is low. Those who are planning on traveling for
longer than 1 month or take up residence in a JE-endemic area should be vacci-
nated. JE vaccine was licensed for children aged 1 to 16 years (JE-Vax) and is
given as a series of 3 injections on days 0, 7, and 30 and should be completed
at least 10 days before departure. However, the vaccine is no longer manufac-
tured and a new JE vaccine (Ixiaro, Novartis, Thousand Oaks, CA) was licensed
in March 2009 and is not approved for use in children younger than 17 years.
Pediatric clinical trials are being conducted for the use of Ixiaro in children [171].
Rabies vaccine
Rabies virus causes acute viral encephalitis that is virtually 100% fatal. A 3-dose
rabies preexposure series can be considered for travel to areas where contact
with wild animals is likely, or when destination activities are likely to increase
exposure to rabies. The 3-shot preexposure immunization series is given on
days 0, 7, and 21, or 28. In the event of a subsequent possible rabies virus expo-
sure, the child will require 2 more doses of rabies vaccine on days 0 and 3
[171].
SUMMARY
In summary, immunizations in special populations require understanding the
underlying disease and how it might affect the immune system’s ability to
mount an antibody response to vaccines or predispose certain patient popula-
tions to developing certain serious infections. There is still a great need for
research on the optimal timing of vaccines after transplants, how to assess
protection and development of a protective antibody response after immuniza-
tion, and whether certain groups (eg, HIV) need to be revaccinated after
a certain amount of time if their antibody levels decline. In addition, there
are limited data on efficacy of the newer vaccines in these special patient pop-
ulations, which also requires further investigation.
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Medical Update for Children With

Down Syndrome for the Pediatrician
and Family Practitioner
Fran Hickey, MDa,*, Erin Hickeya, Karen L. Summar, MD, MSb
a
Department of Pediatrics, Medical Director of The Anna and John Sie Center for Down
syndrome, Children’s Hospital Colorado, University of Colorado School of Medicine, 13123 East
16th Avenue, B155, Aurora, CO 80045, USA
b
Department of Pediatrics George Washington University, Children’s National Medical Center,
111 Michigan Avenue, NW, Washington, DC 20010, USA
Keywords
Down syndome Intellectual disability Congenital heart disease
Hypothyroidism Health guidelines
Key Points
Down syndrome (DS), with an incidence of 1 in 691 live births, is the most
common chromosomal cause of intellectual disability.
To avoid the pitfall of diagnostic overshadowing, the physician should remember
that people with DS are at an increased risk for certain comorbidiites and at risk
for the same illnesses that affect all children.
Frequent hearing and vision evaluations are indicated due to the high prevalence
of hearing and vision abnormalities (>50%) in individuals with DS.
The risk of thyroid disease in DS is in the 20-30% range (requiring yearly thyroid
labs); newly recognized comorbidities also needing screening are celiac disease
and autism (both in the 7% range).
The medical care of children with DS requires vigilance regarding their predis-
position to certain medical issues; however, after many years in caring for chil-
dren with DS and their families, this experience provides continuing rewards.
EPIDEMIOLOGY, GENETICS, AND PRENATAL DIAGNOSIS

OF DOWN SYNDROME
Down syndrome (DS), with an incidence of 1 in 691 live births, is the most
common chromosomal cause of intellectual disability.
In his treatise, ‘‘Observations on an Ethnic Classification of Idiots’’ (1866),
John Langdon Down chronicled the physical phenotype and intellectual
*Corresponding author. E-mail address: Francis.Hickey@childrenscolorado.org

138 HICKEY, HICKEY, & SUMMAR
disability of DS. He is accredited with the first phenotypic description of this

disorder, and the condition now carries his name. In addition to the description
of intellectual disability and physical traits, Down described many of the comor-
bidities that are well recognized today, including difficulty with circulation, poor
hearing and vision, seizures, and a shortened life span [1].
The molecular basis of DS, trisomy 21, was first discovered by Jerome
Lejeune in 1959 [2]. In greater than 90% of cases, DS occurs when maternal
meiotic nondisjunction results in trisomy 21. Other chromosomal abnormali-
ties that may result in DS include Robertsonian translocations, partial trisomy
of chromosome 21, isochromosomes, and ring chromosomes.
Historically, prenatal chromosome analysis was offered to women who were
considered to have the highest risk for having a child with DS. This increased
risk was determined by maternal age of 35 or greater at the time of delivery and/
or a pattern of serum biomarkers that are known to be associated with an increased
risk of DS. These serum biomarkers are known by many names, for example
a triple screen measures alpha-fetoprotein (AFP), human chorionic gonadotropin
(hCG), and unconjugated estriol. Furthermore, a quad screen measures the
hormone inhibin A, AFP, hCG, and unconjugated estriol. These serum biomarkers
are not diagnostic of trisomy 21, but the patterns of the markers yield a relative risk
of having a baby with DS.
In the past 5 years, two landmark medical events have come to pass that
involve the care of people with DS. In 2007, the American College of Obstetri-
cians and Gynecologists (ACOG) released a practice bulletin recommending
that all pregnant women, regardless of age at the time of delivery, consider
screening for DS before the 20th week of pregnancy [3]. After reviewing the liter-
ature, ACOG determined that screening all pregnancies with a combination of
ultrasound and serum markers was justified. This document further recommen-
ded that any woman with a positive screen should be offered genetic counseling
and access to chorionic villus sampling or amniocentesis for definitive diagnosis.
The second landmark medical event was the publication of an international clin-
ical validation study in 2011 [4]. This study led to a commercially available blood
test that is diagnostic for DS, which can be used as early as the first trimester of preg-
nancy. The new blood test detects DS with a 98.6% certainty by measuring fetal-
specific DNA sequences in maternal serum early in the first trimester. This method
has been touted as a way to reduce the need for invasive procedures during preg-
nancy to diagnose the presence of DS [4]. The ability to diagnosis DS in a fetus, with
98.6% certainty, underscores the critical need for bioethical discussions. Discus-
sions should include the methods in which caregivers provide expectant parents
with balanced information regarding issues related to raising a child with DS [5].
CLINICAL ASSESSMENT
The newborn period
DS is frequently suspected when the principal phenotypic features are recog-
nized in the newborn period; the diagnosis is then later confirmed by karyo-
type. These principal phenotypic features found in neonates were outlined
MEDICAL UPDATE FOR CHILDREN WITH DOWN SYNDROME 139
by Dr Bertil Hall [6] and are summarized in Table 1. Variability exists in every
aspect of the phenotype of DS. Despite this, the constellation of phenotypic
features is consistent and allows for clinical recognition (see Table 1).
Assessment of the newborn with DS should include a thorough medical history,
including attention to parental concerns, prenatal history, and family history. Review
of systems should specifically include feeding and the presence of vomiting or absence
of stools. These features are important markers because they can indicate possible
duodenal atresia, stenosis, web, or Hirschsprung disease. Particular attention should
also be paid to physical examination of the heart (congenital heart disease), the eyes
(congenital cataracts, glaucoma), the ears (hearing loss), and the skin (plethora, pete-
chiae) [7]. Evaluation of the newborn with DS should include a pediatric cardiology
evaluation with an electrocardiogram (ECG), an echocardiogram, and laboratory
work, including a karyotype, complete blood cell count, thyroid functions, and audi-
tory brainstem response or otoacoustic emission to assess hearing.
How to communicate the diagnosis of DS
Because families forever remember the manner in which a diagnosis of DS was
given, specific recommendations exist to guide pediatricians in this sensitive issue.
Studies have shown that families prefer to be given the diagnosis as soon as it is sus-
pected. Furthermore, they prefer that the doctor (obstetrician or pediatrician) give
the diagnosis to both parents at the same time, if possible, and with the infant present.
The desired setting is a quiet place that allows enough time for the parents to have all
of their questions answered. Most importantly, families feel that information pre-
sented in a language that conveys pity, such as, ‘‘I’m sorry to tell you that your
baby has Down syndrome,’’ is unprofessional [8]. Families should be given up-to-
date information regarding DS, including referral for early intervention services,
for developmental programs, and to local and national DS advocacy groups [8].
Childhood
Overview
Children with DS should receive well-child care, including all routine vaccina-
tions. These children are at risk for the same medical disorders that their
Table 1
Hall’s criteria for the diagnosis of DS in the newborn
Finding Frequency
Flat facial profile 90%
Poor Moro reflex 85%
Hypotonia 80%
Hyperflexibility of joints 80%
Excess skin back of neck 80%
Slanted palpebral fissures 80%
Anomalous auricles 70%
Dysplasia of pelvis 70%
Dysplasia of midphalanx of fifth finger 60%
Simian crease 45%
typically developing peers may have, but they also have a significantly
increased risk of several secondary medical conditions, including congenital
heart disease, congenital gastrointestinal malformation, leukemia, thyroid
disorders, diabetes mellitus, obesity, autism, seizures, and behavioral difficulties
[7,9]. These comorbidities are outlined in Table 2. A system-by-system
approach at each annual well-child visit will assure that no comorbidities go
undiagnosed (see Table 2).
At each visit, height, weight, and body mass index should be recorded.
Some debate exists about the use of DS-specific growth charts. These charts
are helpful in showing parents that their child with DS is within the acceptable
ranges for a child with DS, even though they may be shorter than other chil-
dren in the family. However, through using standard growth charts for typical
children, changes in trajectory of growth are more easily recognized in children
with DS. For example, it may be easier to detect that a child with DS is gaining
weight too quickly or has fallen off the height curve when using a typical growth
chart as opposed to the DS-specific growth chart. Because each has its own
advantages, many practices will use both standard and DS-specific growth
charts. Counseling about nutrition is extremely important for children with
DS because they are at increased risk for obesity and the complications that
ensue.
To assist pediatricians in preventative medical care for children with DS, the
American Academy of Pediatrics (AAP) has published guidelines for the health
care of these children [9].
Table 2
Medical comorbidities with increased frequency in children with Down syndrome
System Finding
Head, eyes, ear, Hearing loss: conductive, sensorineural, or mixed; may develop
nose, and throat at any time
Frequent and chronic otitis media
Sleep disordered breathing
Glaucoma, congenital cataracts, refractive errors, strabismus,
nystagmus
Cardiovascular Atrioventricular septal defect, ventricular septal defect, atrial
septal defect, patent ductus arteriosus, tetralogy of Fallot,
and persistent pulmonary hypertension
Adolescents and young adults: mitral valve prolapse and
aortic regurgitation
Endocrine Diabetes mellitus, hypothyroidism, hyperthyroidism
Gastrointestinal Constipation, celiac sprue
Hematologic Transient myeloproliferative disorder, leukemia
Neurologic Intellectual disability (mental retardation), hypotonia, seizures
Orthopedic Atlanto-occipital instability, pes planus, subluxation of patella,
developmental hip dysplasia
Dermatologic Hyperkeratosis, seborrhea, cutis marmorata, xerosis, folliculitis
in perigenital region, starting in adolescence
COMORBIDITIES BY SYSTEMS
Cardiovascular
All newborns with DS should be evaluated with ECG, echocardiogram and
undergo examination by a pediatric cardiologist because of the frequency and
severity of congenital heart disease in this population [9]. It is important to realize
that even if the baby has a normal examination without a murmur, the presence
of congenital heart disease (CHD) is still possible. The primary care physician
(PCP) is advised to monitor the neonate closely for plethora, poor feeding, and poly-
cythemia, and hypoxemia.
After discharge from the hospital, an infant with CHD requires close monitoring
for congestive heart failure (CHF) because shortly after birth, pulmonary vascular
resistance decreases, resulting in an increase in pulmonary blood flow [10]. This
sudden change can send the child into CHF, which presents with symptoms
such as poor feeding, tachypnea, and poor real weight gain. Currently, cardiologists
repair the cardiac defects between 3 and 4 months to decrease the risk of pulmonary
arterial hypertension (PAH) [11]. The pediatric cardiologist should coordinate the
cardiac follow-up for a child with CHD. It should also be noted that infants and chil-
dren with DS are at an increased risk of PAH even without CHD [12].
Approximately one-half of individuals with DS have CHD. In the largest
population-based study, cardiac evaluations were available on 227 of 243 live-born
infants with trisomy 21 identified by the Atlanta Down Syndrome Project [13]. Of
these, 44% had congenital heart defects. Table 3 summarizes the results of the study,
indicating the types and frequencies of congenital heart defects in children with DS.
All adolescents and young adults with DS need to be closely evaluated for
mitral and aortic valvular disease as these can develop later in life [14]. Accord-
ingly, the PCP is advised to obtain an echocardiogram in individuals with DS,
between the ages of 13 and 20 who have a history of shortness of breath, fatigue,
or increasing exertion intolerance [9].
Otolaryngology
Ear, nose, and throat (ENT) issues are prominent in children with DS.
Common ENT issues for children with DS include stenotic ear canals, eusta-
chian tube dysfunction, frequent otitis media, and hearing loss.
Table 3
Types and frequencies of congenital heart defects in individuals with Down syndrome
Congenital heart defect Frequency

Atrioventricular septal defect (also called endocardial cushion defect) with 45%
or without other lesions
Ventricular septal defect with or without other lesions 35%
Isolated secundum atrial septal defect 8%
Isolated persistent patent ductus arteriosus 7%
Isolated tetralogy of Fallot 4%
Other vascular ring (aberrant left subclavian artery and right aortic arch) 1%
Data from Freeman SB, Taft LF, Dooley KJ, et al. Population-based study of congenital heart defects in Down
syndrome. Am J Med Genet 1998;80(3):213–7.
Stenotic ear canals (narrow ear canals) are common in up to 40% to 50% of
infants with DS [15]. Narrow ear canals make the tympanic membrane difficult
and sometimes impossible to see. Children with DS who have stenotic ear
canals should be referred to an otolaryngologist with the ability to use a micro-
scope with an attached otoscope to properly evaluate the eardrum. Scheduled
visits with the ENT every 3 to 6 months will help avoid undiagnosed otitis
media and its complications, including hearing loss.
The midface hypoplasia of DS also predisposes children to chronic ear disease.
Approximately one-third of children with DS have recurrent and serous otitis
media that requires close monitoring [15]. The middle ear is aerated by the eusta-
chian tube and upper infections or allergies can cause the eustachian tube to
become swollen, trapping bacteria and causing ear infections. The hypotonia of
children with DS affects the opening and closing of the eustachian tube. This
dysfunction can cause negative pressure to build up in the middle ear space,
leading to fluid retention and infection. As a result, chronic eustachian tube
dysfunction typically lasts longer in children with DS [15]. Consequently, the
ears of children with DS should be monitored regularly for potential infections.
Placement of pressure equalization tubes needs to be considered earlier in chil-
dren with DS.
Hearing loss can affect a child’s educational, language, and social develop-
ment [16]. Even a mild hearing loss can accentuate the difficulty with intelligi-
bility that people with DS experience. This difficulty with speech clarity can
have long terms affects such as decreasing opportunities for employment.
Therefore, hearing loss must be diagnosed and treated aggressively. The
AAP recommends that the hearing of a child with DS be tested at birth, and
then every 6 months up to the age of 3 years [9], after which hearing tests
can be performed annually.
Hearing aids and/or frequency modulation systems should be considered
even with mild hearing loss to prevent delays in educational, speech, and
language development. Compliance with hearing aids is a serious problem,
because children with DS are unfamiliar with wearing the device and they
are highly sensitive to loud noises. Therefore, a desensitization program,
including slow increases in sound, should be implemented for children
prescribed hearing aids.
A tonsillectomy and adenoidectomy (T/A) is often recommended in children
with DS for treatment of upper airway obstruction, obstructive sleep apnea
(OSA) or chronic tonsillitis. A study by Goldstein and colleagues [17]
compared the length of hospitalization and postoperative outcomes of children
with and without DS who had tonsillectomies. They concluded that the rate of
postoperative respiratory complications is higher in children with DS, and that
the duration of time until adequate oral intake is resumed is longer in children
with DS. Because of the high complication rate, consideration should be given
to an overnight admission for a child with DS undergoing a T/A. For children
with DS and OSA, a T/A only improves one-half of the apnea symptoms, so for
these patients it is important to obtain a sleep study after the T/A.
Hematology and oncology

Frequently, on learning that a newborn has DS, a family will search the
internet, looking for information. They will almost immediately find that chil-
dren with DS have an increased risk for developing leukemia. It is important
for the PCP to provide the family with accurate information. Children with
DS have a 10- to 15-fold increased risk of developing leukemia, both acute
myeloid leukemia (AML) and acute lymphocytic leukemia (ALL) [18].
Although this represents a significantly increased risk for leukemia, it is impor-
tant to stress to parents that most children with DS do not have leukemia.
Dutch population studies [19] have shown that 3% to 5% of newborns with DS
have myeloid precursor cells in the liver that undergo somatic mutation in the gene
that codes for the transcription factor, GATA 1 [20]. The mutation to the GATA 1
gene results in a truncated protein, which causes a clinical picture of preleukemia.
This preleukemia is referred to as transient myeloproliferative disease (TMD) or transient
leukemia. TMD is classically recognized as a clinical disorder that can vary widely
in presentation. It has a propensity to resolve spontaneously but has a high
mortality rate (21%) before resolution. Approximately 25% of cases of TMD in
DS are asymptomatic. In symptomatic patients, the most common findings are
hepatosplenomegaly, petechiae, and effusions. In those who develop severe
complications, liver failure, coagulopathy, and ascites are seen [21].
It is well established that 20% of babies with DS who develop TMD will later
develop AML, almost always before 3 years of age [22]. Some debate exists
regarding whether the treatment of TMD will prevent AML in children with
DS. Should TMD progress to AML, it is also well established that AML is associ-
ated with a better prognosis in children with DS than in children who do not have
DS. The PCP who encounters TMD in a baby with DS should consult with a pedi-
atric hematologist immediately for management of this complicated disorder.
Children with DS are also at increased risk of developing ALL. Children
with DS who develop ALL have many of the same presenting findings as those
without DS, including age of onset (75% between 1 and 9 years), elevated white
blood cell count, elevated platelet count, low risk of central nervous system
disease at diagnosis (2%), hepatomegaly, and similar ethnicity. However,
children with ALL and DS have several significant differences from their peers
without DS, including increased risk of low platelet counts, unlikelihood of low
hemoglobin levels, less likelihood of having a mediastinal mass, almost never
presenting at younger than 1 year, and less significant adenopathy. In addition,
although survival has dramatically increased in those with DS and ALL (5-year
survival, 85%), they continue to have a poorer outcome than those without DS.
This difference in outcome has been attributed to a lower rate of remission and
increased toxicities from treatment [23].
Neurology
Cognition
Although cognitive impairment is nearly universal in children with DS, this
impairment does not uniformly affect all areas of development. For example,
social development is relatively spared in DS, whereas children with DS have

considerable difficulty with expressive language use [24]. Understanding these
individual developmental strengths will maximize the educational process for
children with DS. The Individuals with Disabilities Education Act of 1990
(IDEA) mandates that all children with developmental disabilities in the United
States receive an education that is directed by an Individualized Education
Program (IEP) [25].
Early intervention
Children with DS are almost always referred to early intervention programs
shortly after birth. Early intervention is a program of therapies, exercises,
and activities designed to specifically help children with developmental disabil-
ities. Federal law requires that each state provide early intervention services for
all children who qualify, with the goals of enhancing the development of infants
and toddlers, and helping families understand and meet the needs of their
children.
Through understanding the strengths and weaknesses of children with DS,
the PCP may advise the parents to maximize their child’s development. First,
children with DS have better receptive language than expressive language.
Furthermore, children with DS have strengths in visual processing and visual
memory. With this in mind, implementing the use of signs and visual informa-
tion/schedules can play to the children’s strengths in the acquisition of commu-
nication skills. The PCP should advise the parents and early intervention to
begin using sign language and initiating speech therapy as early as 9 months.
An excellent reference for parents is ‘‘Speech, language and communication
for individuals with Down syndrome–an overview,’’ written by Sue Buckley
and available online [26].
Seizures
The incidence of seizures in children with DS is between 5% and 10% [27].
This range of incidence is higher than that for the general population (1.5%–
5%) but lower than that for individuals with other forms of cognitive disabilities
(14%–44%). The symptoms of seizures are often exceedingly subtle in patients
with DS, with presentations such as loss of language skills or inattentiveness.
There appear to be two distinct age ranges at which the onset of epilepsy is
likely to develop in an individual with DS. The first is from birth to 2 years
of age, and seizures arising in this period are referred to as infantile spasms. Infan-
tile spasms occur more frequently in children with DS than in the general pop-
ulation [27,28]. Children with an infantile spasm may appear to be
experiencing a body spasm that lasts a few seconds. Alternatively, these
seizures can present as a quick drop of the head and/or shoulders of the
baby. Either way, infantile spasms may or may not affect the child’s state of
consciousness. Because of their subtle indications, infantile spasms often go
undiagnosed for months. Consequently, it is important for PCPs to be aware
of this comorbidity and catch the diagnosis early, because early diagnosis
has a significant positive impact on the child’s outcome.
The second age range at which people with DS tend to develop seizures is in
adulthood. These seizures usually start occurring between 20 and 30 years of
age, but they can also develop later in life [27]. The most common seizure in
this age range is the generalized tonic-clonic seizure (also referred to as gran
mal seizures) [27]; however, other types are also common, such as partial onset
seizures, reflex (myoclonic) seizures, and atonic (head-drop) seizures [27]. A
generalized tonic-clonic seizure is the type of seizure most often associated
with epilepsy; it is characterized by the stiffening of the trunk and exaggerated
twitching of the limbs. It involves the whole body and is typically followed by
a period of sleepiness. The treatment of epilepsy involves the use of anticonvul-
sants and a dietary treatment called the ketogenic diet, which has an anticon-
vulsant effect on the brain [29].
Early detection of epilepsy is essential for successful treatment, to avoid cogni-
tive regression (especially from infantile spasms), and to allow the brain to return
to previous developmental abilities [30]. Awareness of the association between
DS and epilepsy is important so that doctors can intervene early, which maxi-
mizes development and leads to an improvement in quality of life [27].
Behavior
Diagnostic overshadowing occurs when the symptoms of one disorder over-
shadow those of a secondary disorder; this overshadowing prevents the recog-
nition and diagnosis of the comorbidity [31]. Diagnostic overshadowing can
lead to the attribution of symptoms of a secondary disorder to an underlying
disorder [31]. This phenomenon plays an important role in the delayed diag-
nosis of comorbidities in people with DS. For example, an individual with
DS presents to his physician’s office with an extreme deterioration in behavior.
His physician may attribute his behavioral symptoms as ‘‘just Down
syndrome’’ and miss an opportunity for intervention that will dramatically
improve the life of the individual. Diagnostic overshadowing can occur when
an individual with DS presents with a new behavioral challenge because of
the onset of medical problems, such as thyroid issues, celiac disorder, obstruc-
tive sleep apnea (OSA), pneumonia, gastroesophageal reflux, and even frac-
tures. To avoid the pitfall of diagnostic overshadowing, the physician should
remember that people with DS are at an increased risk for some medical prob-
lems and at risk for the same illnesses that plague all children. The difference is
that presentation of secondary illness in patients with DS is complicated by
a more limited way of communication than in typical individuals.
Most children with DS do not experience severe behavior problems [32].
However, when maladaptive behaviors do occur, the underlying intellectual
disability is frequently blamed. This inherent linking of maladaptive behavior
to cognitive impairment frequently results in the failure to provide an adequate
evaluation of the problematic behavior. Common behavioral challenges, such
as inattentiveness, stubbornness, and a need for routine (sameness) [32], are
frequently seen in individuals with DS and can be diagnosed and treated,
just as strep throat can be treated with penicillin.
When evaluating people with DS who present with behavioral changes,

medical conditions must be ruled out. Although the workup for medical condi-
tions is being conducted, a behavior plan can also be developed. Through
applying the formula ‘‘A,B,C,’’ parents, pediatricians, and teachers can diag-
nose the behavioral challenge and develop a positive behavior plan to extin-
guish the undesired conduct. First, a period of observation is necessary.
During this period, the teacher or parent observes and records the behavior
that is to be changed. Parents and teachers are instructed to note the antecedent
(the ‘‘A’’) immediately before the behavior (‘‘B’’) and the consequence (the
‘‘C’’) immediately after the behavior. From these observations, a pattern
emerges that frequently demonstrates one of the following: (1) the child needs
to have better communication from the parent/teacher about preparing for
transition; (2) the child needs to be able to change tasks more frequently; (3)
and the child needs to be given simple choices whenever possible. If the teacher
would like the child to stay on a particular task a little longer, that behavior
might be encouraged with a timer, a visual schedule, and positive reinforce-
ment when the child stays on task. The parent who wants more cooperation
with school readiness in the morning might communicate those desires to
the child with a visual schedule and rewards when the child cooperates. These
behavioral techniques work for all children, but in a child who has DS, the
message may need to be repeated more frequently, the reinforcers may need
to be given for a longer period, and visual supports should be used to improve
communication.
Most children with DS do not have behavior problems, but the prevalence of
psychiatric comorbidity is estimated to be 18% to 38% [33]. Although these esti-
mates are higher than in typically developing children, they are lower than in
children with similar levels of intellectual disability from other causes. Aggres-
sion and self-injurious behaviors are less common in DS than in other intellec-
tual disabilities [33]; however, internalizing psychiatric illness is more common
in DS. This internalization is often overlooked because the symptoms of with-
draw and sadness may not be as evident to those not very familiar with the
individual with DS [33]. Nonetheless, an astute physician can screen for symp-
toms of anxiety and depression at preventative health visits and often provide
help that will allow the individual with DS to function well at school, work, and
interact in a healthy manner with the community. Early referral to mental
health professionals or DS-specific experts can improve the outcome when
mental health issues arise.
Autism in individuals with DS

The dual diagnosis of autism in people with DS was first described in 1979 [34],
and the variable presentation of autism and DS has been described [35–37].
Despite studies showing a 7% to 8% frequency of autism in people with DS
[37,38], a lack of recognition and resulting delay in diagnosis remains. This
delay leads to a negative impact on adaptive functioning in some individuals
with DS and autism.
The recognition and diagnosis of autism in an individual with DS can be

very difficult. The core symptoms of autism—language delay, social skills delay,
and restricted and repetitive behaviors—are more difficult to evaluate in an indi-
vidual with an underlying intellectual disability. This difficulty may explain
why autism is frequently diagnosed much later in individuals with DS than
in those without.
When autism is suspected in an individual with DS, the evaluation is ideally
conducted by an interdisciplinary team consisting of a physician, a speech pathol-
ogist, and a developmental psychologist. The initial medical evaluation should
include a complete blood cell count, iron studies (including ferritin and reticulo-
cyte), liver function studies, thyroid studies, celiac screening, lead test, and
sensory evaluations (audiologic and ophthalmologic). In addition, consideration
should be given to obtaining a sleep-deprived electroencephalogram, because
seizures are more common in children with DS (7%) and much more common
in children with autism (30%) [38]. The optimum psychological evaluation
includes autism-specific tools (Autism Diagnostic Observation Schedule and
Autism Diagnostic Interview - Revised) [39] and more general developmental
tools (Aberrant Behavior Checklist) [40] performed by someone well versed in
DS. Likewise, language and communication evaluation by a speech therapist
familiar with DS is crucial.
Children with autism alone and those with DS and autism frequently present
with developmental and/or language regression [41]. The symptom of regression
presents in approximately 30% of children with autism alone, and generally
occurs between 18 and 30 months of age. By contrast, regression is more common
in autistic children with DS, occurring in 50% of the individuals who have this
dual diagnosis. In addition, the age of regression in children with both autism
and DS is much later, around 61 months [41]. Because of the later presentation
of autism in children with DS, yearly questions regarding social, adaptive, and
language functioning and developmental screening are essential for these chil-
dren. The identification of autism in an individual with DS is important to appro-
priately tailor their developmental and educational programs.
Immunology
Immune deficits have been well-documented in individuals with DS for decades;
however, only a few small studies have identified the specifics of these deficits
[42]. Recurrent infections have a major impact on the morbidity and mortality
of the DS population, as described in the otolaryngology, pulmonology, and
dental sections. Children with DS have a decreased number of lymphocytes
[42] and, moreover, viral illnesses further exaggerate the children’s relative lym-
phocytopenia. Consequently, children with DS commonly present with lympho-
cytopenia, and therefore an accurate white blood cell count and the effect of
concurrent illnesses must be further evaluated to prevent unneeded studies and
interventions.
Additional common immune deficits in individuals with DS include impaired
T-cell proliferations, reduced antibody response to immunizations, and defects
of neutrophil chemotaxis [43]. Furthermore, reductions in subpopulations of

lymphocytes (CD4 T cells) have been identified [42] and are thought to play
a role in the increased susceptibility of individuals with DS to decreases in
IgG subclasses 4 and 2. However, a direct correlation between this reduction
of lymphocytes and the decrease in IgG subclasses has not yet been shown
in patients with DS.
The impaired pulmonary immunologic defenses of individuals with DS have
been speculated to be related to their low plasma levels of zinc. However, clin-
ical studies using oral doses of zinc have not shown a significant and reliable
clinical benefit to zinc supplementation [44]. Box 1 summarizes the immune
deficits common to individuals with DS. Further basic and epidemiologic
studies of individuals with DS are imperative to understand what is responsible
for the immune deficits this population faces.
Pulmonary and sleep

Children with DS have many physical and genetic anomalies that put them at
risk for multiple pulmonary dysfunctions, including airway disease, respiratory
disease, pulmonary hypertension, and Obstructive Sleep Apnea (OSA). Respi-
ratory infections are responsible for approximately 80% of hospitalizations and
intensive care unit admissions in this population [45]. The causes of the respi-
ratory illnesses in DS are multifocal.
OSA is a common comorbidity in individuals with DS, with an incidence of
50% to 70% [46]. The significant cognitive and behavioral effects of OSA reported
in the general pediatric population have not been studied in children with DS. A
study in 2004 found that 60% of children with DS were reported by their parents
to have respiratory conditions, including sleep apnea and asthma [47].
Additional pulmonary complications that are more common in children with
DS include lung structural anomalies, disorders of the pulmonary vasculature,
parenchymal lung disease, upper and lower airway abnormalities, chronic aspi-
ration, and subpleural cysts [45]. Anatomy and pathology studies indicate that
individuals with DS have an increased alveolar size and a decreased number of
alveoli, which may cause the small subpleural cysts [48]. These lung anomalies
must be considered in cases of recurrent pneumonias in the same area of the
lung, because the radiographic findings associated with these parenchymal
lesions are often mistaken for pneumonia.
Box 1: Immune deficits commonly diagnosed in individuals with DS

Lymphocytopenia
Impaired T-cell proliferation
Reduced antibody response to immunizations
Defects of neutrophil chemotaxis
Reductions in subpopulations of lymphocytes (CD4 T cells)
Low plasma level of zinc
Reactive airway disease (RAD), or asthma, has been described historically as

rare or nonexistent in this population. Recently, however, children with DS
have been reported to have RAD. Nonetheless, if a wheezing episode persists
and the patient is nonresponsive to conventional therapy, referral to a pulmo-
nologist for further evaluation is necessary. The wheeze may be explained by
anatomic problems, anomalies, or an infectious cause.
Pulmonary vascular issues

Pulmonary arterial hypertension (PAH) has an increased incidence in individ-
uals with DS compared with the general population in part due to cardiac and
pulmonary comordities. In addition, however, there is a poorly understood
additional predisposition in the DS population. In neonates with CHD, the
increased prevalence of PAH can be explained by the intracardiac shunting
from right to left that the infants experience. This increase in pulmonary blood
flow causes PAH. Other causes of PAH include OSA, hypoxia, chronic lung
disease, polycythemia, and possible genetic predisposition. Keeping these chil-
dren appropriately oxygenated is integral for prevention and treatment of
PAH. In addition, treating polycythemia more aggressively in the newborn
period may be advantageous to prevent this condition’s contribution to the
development of PAH.
Airway anomalies
Children with DS have an increased risk for laryngomalacia, tracheobroncho-
malacia, tracheal stenosis, tracheal bronchus, tracheal rings, and an aberrant
right upper lobe bronchus. A tracheal bronchus was found through endoscopy
in 21% of referred patients [49]. This anomaly may present with right upper
lobe pneumonia; however, right upper lobe pneumonia is also associated
with aspiration pneumonia.
Anesthesia
PCPs of children with DS must be aware of anesthesia risks specific to this pop-
ulation in case surgery is required. The information presented in Box 2 should
be related to anesthesiologists practicing outside a pediatric hospital.
Gastrointestinal
Infants and children with DS are high risk for feeding challenges because of their
hypotonia, relative macroglossia, small oral cavity, increased risk of oral-motor
dysfunction (dysphagia), increased incidence of sensory issues, and develop-
mental issues. Feeding issues are so common in this population that specific
screening for feeding difficulties should be performed on every child with DS.
Screening may be performed by conscientious PCPs who carefully question
the family about feeding concerns and closely follow growth parameters.
With adequate support, many infants with DS are able to nurse successfully.
They may require supplemental feeds until the coordination of sucking and
nursing develops adequately. Infants who have more difficulty feeding often
Box 2: Information that should be conveyed to anesthesiologists

treating children with DS
During intubation, maintain the child’s neck in neutral position.
Always assume the child has an unstable neck.
Normal cervical series does not guarantee the absence of AAI.
Children with DS require smaller endotracheal tubes.
Children with DS have an increased incidence of OSA, which may cause
pulmonary edema and PAH.
Consequently, an echocardiogram should be considered during the preoper-
ative period.
During the postoperative period, closely monitor the child for aspiration pneu-
monia. Children with DS have an increased incidence of gastroesophageal
reflux, which is related to the increased risk for aspiration pneumonia.
benefit from an evaluation by a feeding team, which is typically composed of

the physician and a feeding therapist familiar with DS. Together, the feeding
therapist, physician, and family can arrive at a plan to ensure adequate nutri-
tion. Feeding plans may include more frequent feeds (including waking a sleep
baby at night), increased caloric density, or gavage feeds. As the infant grows
and gains strength, these additional feeding supports should be discontinued.
Celiac disease (CD) occurs in approximately 7–10% of individuals with Down
syndrome [50]. In accordance with the AAP 2011 guidelines for children with the
DS [9], it is recommended if the child has any of the following symptoms, he or
she should be screened with a TTG and IgA initially: abdominal pain, diarrhea,
constipation, failure to thrive, or developmental or neurological issues. However,
many children with DS and celiac disease present with minimal or subclinical
symptoms, and are identified only because of screening. The North American
Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASP-
GHAN) 2005 guidelines recommend screening high-risk groups even in the
absence of symptoms. If the results are negative, the child needs retesting with
a TTG every three years as he/she is still considered part of a high-risk popula-
tion. If the TTG is elevated, which is indicative that the child has a high risk of
celiac disease, the child should be referred to a pediatric GI specialist.
Repeat testing for celiac disease has not been studied, but it is common prac-
tice in many Down syndrome clinics to retest every 3–4 years or if symptoms
consistent with celiac disease develop or persist. NASPGHAN has also sug-
gested that HLA testing could be considered to identify the specific subset of
children at particularly high risk for celiac disease [51]. The HLA test results
indicate which individuals have a genetic predisposition for celiac disease. If
the child with DS does not have the high-risk genes for celiac disease (present
in 40% of the general population), then the child does not need retesting. The
other 60% of these children may require retesting throughout childhood due to
their genetic HLA predisposition to celiac disease.
In addition to the surgical gastrointestinal issues associated with DS that

present in infancy (tracheoesophageal atresia, duodenal stenosis/atresia, Hirsch-
sprung disease, and anal atresia), functional gastrointestinal issues are also
responsible for many comorbidities in this population. These functional gastroin-
testinal issues include gastroesophageal reflux and constipation. Gastroesopha-
geal reflux is extremely common in babies with DS. Symptoms may include
arching, nipple refusal, grazing, better feeding at night, frequent spitting/vomit-
ing, poor weight gain, and fussiness with feeds, post feeds, or during the night.
Most gastroesophageal reflux in infants with DS is treated the same way as in
babies without DS. However, a modified barium swallow is recommended for
infants with marked hypotonia, choking with feeds, recurrent pneumonia, or
failure to thrive [9]. The possible treatments for gastroesophageal reflux are
summarized in Box 3.
In the past decade, reports have indicated that proton pump inhibitors may
improve the symptoms of gastroesophageal reflux in patients with disabilities
and neurologic issues. Antireflux surgery should only be considered in cases
of intractable or life-threatening symptoms of gastroesophageal reflux. This
surgery has significant morbidity and mortality risks that must be considered.
The postoperative period for this surgery requires close monitoring for chil-
dren with DS because of the serious associated morbidities.
Constipation is a widespread functional gastrointestinal symptom occurring
in 30% to 50% of this population. In addition to the expected symptoms of
abdominal pain, decreased appetite, and vomiting, behavioral changes may
herald the onset of constipation in an individual with DS. Often an abdominal
radiograph is the only way to diagnose significant constipation, or, after
Box 3: Possible treatments for gastrointestinal reflux in child with

DS
Conservative measures
Smaller feeds
Thickened formula
Elevation of the upper body to 60
Keep upright 20 to 30 minutes post feeding
Decrease environmental stimulation
Implement feeding routine
Medications
Proton pump inhibitors (eg, lansoprazole)
Histamine-2 receptor antagonists (eg, ranitidine)
Antacids: neutralizing gastric acids
Surgical treatment
Antireflux surgery to tighten the muscles at the bottom of the esophagus (the
tube that carries food from the mouth to the stomach)
treatment, to document evacuation of excessive stool. Treatment of constipa-

tion, as with typical children, includes dietary management. It can also be
treated with laxatives such as Miralax; however, keep in mind that the
prescribed dose of Miralax must be adjusted to guarantee that the fiber is
useful. The PCP must also be mindful that the child is taking in the necessary
fluids. Dietary instructions for constipation management include (1) eat a well-
balanced diet that includes fiber-rich foods, such as unprocessed bran, whole-
grain bread, and fresh fruits and vegetables; (2) drink plenty of fluids; and
(3) exercise regularly [52].
The PCP should keep in mind that hypothyroidism and medications such as
atypical antipsychotic medications can also cause constipation. Constipation is
rarely so severe that the assistance of a gastroenterologist is necessary.
These functional gastrointestinal issues can persist throughout the life of
a person with DS and can be extremely challenging for physicians. People
with DS, and particularly children, have difficulty communicating symptoms
such as abdominal pain, heartburn, or painful defecation, making early
detection of constipation or gastroesophageal reflux arduous. Difficulty with
communication and ability to comply with a medical regimen can also compli-
cate treatment of these motility issues.
Endocrinology
It is known that patients with DS have an increased prevalence of autoimmune
disorders affecting both endocrine and nonendocrine organs (hypothyroidism,
hyperthyroidism, allergic dermatitis, celiac disease, diabetes mellitus, rheuma-
toid arthritis, and alopecia areata) [53]. Most of the information regarding
this subject is based on cross-sectional studies, making exact incidence and
prevalence numbers difficult to state.
One small (n ¼ 85) longitudinal study found that one-third of children with
DS develop hypothyroidism before the age of 8 years [54]. A population-based
study found that 10.8% of children with DS were prescribed medication for
thyroid disorders over an 11-year period [55]. Hypothyroidism, characterized
by weight gain, dry skin, constipation, and cold intolerance, is difficult to
diagnose based on symptoms alone in many populations, including DS. Conse-
quently, annual screening of thyroid functions is recommended. Thyroid-
stimulating hormone and free T4 levels are monitored by most physicians
caring for people with DS. Despite published guidelines, evidence shows that
people with DS do not always get annual thyroid screening. Review of a state-
wide database showed a 73% increase in the incidence of medially treated
thyroid disease in children with DS after the AAP re-released guidelines recom-
mending annual screening [55]. These studies reiterate the increased frequency
of thyroid problems and the need for annual screening of thyroid function in
individuals with DS throughout their lifespan.
Diabetes mellitus is more common in individuals with DS than in the general
population. A recent study determined the incidence of diabetes mellitus to be
0.38% in the DS population, which is a 4.2-fold increase compared with the
general population [56]. Most people with DS who develop diabetes mellitus
have insulin-dependent diabetes. Recently, a population-based incidence study
in Denmark indicated that this disease is challenging for pediatricians to diag-
nose in patients with DS [56]. Early diagnosis is important because an increased
risk of complications in DS, including comas, has been reported. A study per-
formed in 2010 found that individuals with diabetes mellitus and DS had better
glycemic metabolic controls, lower insulin needs, and a younger age of presen-
tation (19% of DS <3 years vs 6.4 years in other patients) than those without
DS [57].
Further research in this area is needed to identify diabetes mellitus earlier in
this at-risk population, to identify why people with DS do not seem to have
increased rates of type 2 diabetes mellitus, and why individuals with DS and
diabetes mellitus have improved glycemic metabolic controls. This research
may benefit the management of all children with diabetes mellitus.
Orthopedics
DS is the prototypic disorder of hypotonia, which is defined as diminished tone
of the skeletal system. This condition presents as weakness and floppiness in
babies from nonprogressive weakness of skeletal muscles from birth. This
hypotonia results in a delayed acquisition of motor skills, and such delays
lead to difficulty with postural alignment, proprioception, and movement
patterns. These musculoskeletal symptoms are seen in all children with DS
to a varying degree.
Atlanto-occipital and atlantoaxial hypermobility (AAI), and bony anomalies
of the cervical spine, can produce atlanto-occipital and cervical instability [58].
Methods of screening for this instability, particularly with regard to participa-
tion in sports and hippotherapy, are a subject of controversy. By far the
most worrisome musculoskeletal abnormality is upper cervical or occipital
cervical instability because of the potential morbidity and mortality related to
this defect. The best method for diagnosing AAI is also very controversial.
The AAP has recently recommended against general screening because ‘‘plain
radiographs do not predict well which children are at increased risk of devel-
oping spine problems and do not provide assurance of not having a future
problem’’ [9]. The AAP guidelines go on to recommend that any child with
symptoms have radiographs obtained urgently, and should follow-up with
a neurosurgeon or orthopedist. The Special Olympics and hippotherapy
require cervical spine screening for participation. Most symptomatic instability
presents between 5 and 15 years of age. The most common clinical symptoms
are painful or stiff neck, a change in gait, and other myopathic signs, such as
clonus or a positive Babinski reflex. A positioned flexion/extension MRI
provides the best detail of both occiput–C1 and C1–C2.
Scoliosis, hip instability, slipped capital femoral epiphysis, patellar instability,
and foot deformities are other musculoskeletal conditions found in patients
with DS that can be challenging for orthopedic surgeons to treat. Scoliosis has
few indications for surgical reconstruction. The hips in patients with DS can be
difficult to treat. They are subject to spontaneous dislocation (up to 30%), with
otherwise normal-appearing hip joints on radiograph. Slipped capital femoral
epiphysis can also occur and may be associated with hypothyroidism. Patellar
instability may be either dynamic and reducible or fixed and irreducible. Surgical
procedures for the patellar subluxation have been described, all of which seem to
have a higher failure rate in children with DS than in typical children.
Physical therapy intervention in children with DS is essential. The book most
referenced for guidance is Gross Motor Skills in Children with Down Syndrome: A Guide
for Parents and Professionals (Topics in Down Syndrome), also by Pat Winders [59].
Physical therapy allows children with DS to progress at their own pace in all
areas of development by challenging them and giving them confidence as they
reach new goals. Physical therapy is also important to allow increased physical
exercise and social opportunities by making exercise fun and free of discomfort.
Another article by Pat Winders, ‘‘The goal and opportunity of physical therapy
for children with Down syndrome,’’ is a great reference for parents and is avail-
able online at http://www.ds-health.com/physther.htm [60].
Dental
Malformed teeth are common in DS, including an unusual eruption sequence, de-
layed eruption, and congenitally missing teeth. Prolonged fevers and severe illness
can lead to difficulties with calcification and hypoplasia of the patient’s teeth.
Although people with DS have fewer caries compared with other popula-
tions with intellectual disability [61], other dental problems exist. Periodontal
disease is a significant oral health problem in people with DS [62]. Children
experience rapid destructive periodontal disease. Consequently, many of
them lose their permanent anterior teeth in their early teens. Contributing
factors include poor oral hygiene, malocclusion, bruxism, conical-shaped tooth
roots, and abnormal host response because of a compromised immune system.
Dental examination by the first birthday and twice year thereafter is recom-
mended for children with DS [9]. Furthermore, independence in daily oral
hygiene should be taught early. Noncariogenic foods and beverages should
be encouraged as snacks, and caregivers should be advised to avoid using
sweets as incentives or rewards.
The medical care of children with DS requires vigilance regarding their
predisposition to certain medical issues; however, after many years in caring
for children with DS and their families, this experience provides continuing
rewards.
Acknowledgments
Thank you to Patti Mcvay, Pat Winders, and Erin Hickey for assistance in
writing this article.
Dedication: This article is dedicated to Dr Bonnie Patterson, who initiated the
Down Syndrome Clinic Meetings in 1984. These meeting grew into the forma-
tion of the Down Syndrome Medical Interest Group (DSMIG), and Bonnie
directed the DSMIG until her retirement in 2009. Over the span of her career,
Bonnie evaluated more than a thousand children with Down syndrome. She
was respected as the consummate clinician, a superb advocate for families, and
a well-published clinical researcher in Down syndrome. Her impact will
continue through her mentorship of hundreds of pediatricians, many of which
follow in her footsteps in dedicating their lives to caring for children with
Down syndrome.
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Content Barriers to Pediatric Uptake of

Electronic Health Records
Delaney Gracy, MD, MPHa,*, Jeb Weisman, PhDa,
Roy Grant, MAa, Jennifer Pruitta, Arturo Brito, MD, MPHb
a
Children’s Health Fund, 215 West 125th Street, New York, NY 10027, USA; bColumbia
University, Mailman School of Public Health, New York, NY, USA
Keywords
Electronic health record Medical informatics Information storage and retrieval
Pediatrics
Key Points
Despite the accelerating acceptance and use of electronic health record (EHR)
technology, available EHR systems generally do not adequately reflect the needs
of children and pediatric health care providers.
The health care needs of children require specific EHR content, eg, units of
measurement for age and medication dosing, notations for parents/caregiver
information, collateral contacts mental health issues.
There are important issues in EHR use that are still unresolved, e.g., confidenti-
ality of adolescent health records when information is shared electronically or
provided to parents/caregivers.
INTRODUCTION
The adoption of electronic health record (EHR)a systems has accelerated since
2009.b Many factors have contributed to this accelerated pace, most notably
federal mandates including the Health Information Technology for Economic
and Clinical Health Act (HITECH), a provision of the American Recovery
a
The term EHR represents a class of clinical record-keeping tools including electronic medical records and
electronic patient records. The authors use the term EHR to represent all these tools because it best captures
the broadly defined realms of care reflected in the application of health information technology (HIT) to the
notions of patient-centered medical or health home and the broad responsibilities of pediatric practitioners.
b
Although an increase in EHR uptake over time is difficult to dispute, the nature and quality of the suggested
increases is unclear. It is possible that uptake of EHR technology is only partial, limited by the technical capabilities
of products. See, for example: http://www.fiercehealthit.com/story/cdc-data-ehr-adoption-overlooks-inconvenient-
facts/2011-12-04?utm_medium¼nl&utm_source¼internal (accessed 12/5/2011).
*Corresponding author. E-mail address: dgracy@chfund.org

160 GRACY, WEISMAN, GRANT, ET AL
and Reinvestment Act (ARRA); the Centers for Medicaid and Medicare
Services (CMS); and the Child Health Insurance Program Reauthorization
Act (CHIPRA) of 2009 [1–3]. There has been a continual maturing of health
information technology (HIT), spurred on by, among other forces, financial
incentives including funding through ARRA/HITECH [4] and revenue
enhancements from insurers. In 2011, the American Board of Medical Special-
ties approved a certification for clinical informatics, which is expected to
further the adoption of EHRs [5]. A November 2011 report from IDC Health
Insights projected that, by 2016, more than 80% of health care providers will
be using an EHR [6].
The transition from paper charts to EHRs has faced difficulties. Issues have
included cost of equipment, provider comfort with technology, lost productivity
during the transition, availability of technical support and peripheral equipment,
limited interoperability among EHR systems, and the degree to which the tech-
nology fits the clinical activities in the practice. There have been ongoing
concerns about patient privacy and the security of electronically stored data,
with special considerations for children and adolescents. Many current EHRs
have limited ability to provide useful clinical decision support (through prompts,
reminders, warnings if an action is contraindicated), order and track laboratory
tests, and electronically communicate prescriptions to pharmacies (e-prescribing
or eRx), particularly in nontraditional clinical environments. There may be
transcription errors when importing information, including demographic data,
from paper charts to an electronic system [7–12]. Cost had been a particular
issue for individual or small group practices before 2009 [13]. Subsequently,
funding available through ARRA/HITECH and private insurers may offset
the cost of investment in HIT with the expectation of a significant savings
over time for the practice and for the health care system overall [14].
Although the issue of funding has been ameliorated for many potential users,
there remain additional challenges in designing EHRs for pediatrics. Most
current EHRs are not suitable for use with children and require child-specific
adaptation to be functional in a general pediatric practice. This requirement
makes it more difficult for pediatricians and other pediatric providers to
provide optimal quality of care to their patients [15]. The adoption of HIT
in general pediatrics has lagged behind other medical fields, including family
practice and pediatric subspecialties [16]. HIT use is especially low among
health care providers caring for medically underserved minority communities.
These same patient populations, in which health disparities are greatest, could
potentially benefit most from the integration of innovative technologies into
health care services [17,18].
In 2005, only 1 primary care pediatrician in 5 (21.3%) used an EHR [19].
Before the passage of ARRA/HITECH in 2009, there were incremental gains
made in EHR adoption, but many systems in use lacked important functional
elements [20]. In 2009, based on responses to an American Academy of Pedi-
atrics Periodic Survey, 41% of pediatricians reported using an EHR, but most
of these systems were neither fully functional nor pediatric specific [21].
PEDIATRIC UPTAKE OF ELECTRONIC HEALTH RECORDS 161
This article argues that, despite the accelerating adoption of EHR technolo-
gies, available systems do not adequately reflect the needs of pediatric primary
care providers and their patients. It discusses historical reasons for this, reviews
the special requirements for EHR design to meet pediatric needs, provides
sample cases in which EHR technology improves or hinders care, and offers
a set of recommendations and considerations for current systems and sugges-
tions for future action.
The observations and conclusions in this article are based on HIT work per-
formed and supported by Children’s Health Fund (CHF) and its national
network of clinical programs from 1988 to 2011. This work included the devel-
opment and/or modification of 4 generations of pediatric-focused EHRs and
HIT implementation at national academic medical centers and Federally Qual-
ified Health Center (FQHC) pediatric programs. The patient populations for
whom the systems were developed are located in urban and rural communities
in the United States that are federally designated Health Professional Shortage
Areas with high rates of poverty and multiple barriers to health care access.
Pediatric patients ranged from 0 to 24 years of age. All enrolled patients
received care considered to be consistent with CHF’s enhanced medical
home model [18]. The development of the EHR system (technology and
content) prioritized quality, breadth and depth of care, usability, and unique
needs of the target populations being served. Clinics’ facilities include primary
care fixed-site clinics, mobile medical units, and public health postdisaster crisis
environments [22]. Content focus, development, and usability work is based in
ongoing analysis of 330,000 anonymous, unduplicated patients and their asso-
ciated encounter notes and visit summary records.
A BRIEF HISTORY OF EHRS

The modern notion of an EHR for use in medical practices may be traced back
to Vannevar Bush’s [23] seminal 1945 publication of cybernetics, As We May
Think. The first scholarly treatments of electronic health care records date to
the early 1960s [24]. It was several decades before a range of commercially
developed comprehensive ambulatory care EHRs entered the market (eg,
Healthmatics, EPIC, PenChart in the 1990s), and some years before there
would be substantial growth in their use.
In April 2004, President George Bush signed executive order 13335 to estab-
lish a Nationwide Health Information Infrastructure and accompanying
Nationwide Health Information Network and the Office of the National Coor-
dinator for Health Information Technology (ONCHIT) to coordinate national
efforts to implement HITs and information exchanges [25]. This emphasis on
health information infrastructure development reflected a belief in the value of
the technology to improve patient care and reduce costs.c It has been estimated
c
Cost reductions were expected to come from reduction of medical errors [http://www.bos.frb.org/
economic/conf/conf50/conf50i.pdf; whereas the Government Accountability Office (GAO) identified other
opportunities [http://www.gao.gov/new.items/d05309r.pdf].
that broad use of EHRs and other HITs could reduce annual national health
care expenditures by as much as $81 billion while improving the quality and
safety of patient health care [26].
A 2006 systematic review of studies documenting the impact of EHR use on
clinical care found 3 principal areas of improvement: increased delivery of
best-practice, guideline-based care; improved surveillance and tracking; and
fewer medication errors [27]. The potential of EHRs to improve care coordi-
nation, a key feature of the patient-centered medical home, was also high-
lighted [28].
In addition to the financial incentives associated with ARRA/HITECH,
federally defined requirements have also contributed to greater EHR use.
Most providers receiving Medicare and Medicaid payment for services are ex-
pected to meet a series of benchmarks to show the acquisition and meaningful
use of HIT systems. The key features of meaningful use, as defined by the
CMS, are use ‘‘in a meaningful manner, such as e-prescribing,’’ use for ‘‘elec-
tronic exchange of health information to improve quality of health care,’’ and
use that shows outcomes through clinical quality measures [29]. Currently, the
Meaningful Use stage I criteria are in place. Negotiations and discussions are
underway to formalize Meaningful Use stage II and stage III [30–32]. Although
providers in general must show that at least 30% of their patient volume
receives Medicaid and Medicare benefits, the threshold for pediatricians is
set at 20%.
THE STATUS OF CURRENT EHRS FOR USE IN PEDIATRIC

PRACTICE
The development of EHRs reflects efforts to maximize usability in general
clinical practice as well as commercial considerations. Typically, EHR hard-
ware and software are commercial products developed by vendors, with
data elements that reflect the medical service needs of inpatient or ambulatory
adult and subspecialty patients [33], which reflects the higher proportion of
health care encounters and expenditures in these sectors compared with
general pediatrics [34] and has contributed to a poor fit between the design
elements of an off-the-shelf EHR product and the needs of child health care
providers. Stage 1 Meaningful Use measures reflect adult health care needs
for the most part, with pediatrics inadequately represented. If this holds
true for subsequent stages, this could further influence EHR development
away from the necessary adaptation of the technology to meet child health
care needs [35].
Issues around the design of EHRs that would accommodate practicing pedi-
atricians and other child health care providers have been discussed at least
since the early 1990s. It was proposed then that the EHR permit a combination
at the provider’s discretion of practice-specific, free-text notation and coded
data entry, with the latter being sufficiently consistent and detailed to allow
automated reporting to support tracking of clinical outcomes and clinical
research [36]. More than 15 years later, it remains a challenge to find a fully
functional EHR for primary care pediatric use that can reliably generate clinical
data reports for outcome tracking, the medical home model of care, continuous
quality improvement (CQI), and research.
This is in part because the practice of pediatrics intertwines multiple facets of
health care. From an HIT and EHR perspective, this broad constellation of
domains requires an organizationally and operationally different approach to
system design than many other fields of medicine. As if to underscore this
point, the Agency for Health care Quality and Research (AHRQ) and CMS
awarded a grant in 2010 for the design of a model pediatric EHR format to
improve the quality and cost of services, something that they have not done
for any other field of medicine [37]. The complexity of pediatric EHR develop-
ment is further underscored by the comprehensive nature of the medical or
health home model, which originated more than 40 years ago in pediatrics
[38]. The American Academy of Pediatrics (AAP), a proponent of the model,
has formally recognized the complexities of designing pediatric-specific content
for EHRs and the importance of HIT as part of the pediatric medical home
[39,40]. In practice, EHRs contribute to the transition of primary care practices
into medical/health homes through their ability to facilitate storage of patient-
derived health information. This storage improves patient-centered practice,
improves comprehensive and coordinated care by facilitating communication
among providers in diverse settings and across transitions from one setting
to another, and also improves patient self-management by facilitating informa-
tion sharing with patients or parents of pediatric patients [41].
Despite the challenges in developing child-specific EHRs, there is already
evidence that they can improve the quality of pediatric care:
The use of EHRs can improve the frequency with which pediatric primary care
providers use the National Heart, Lung and Blood Institute (NHLBI) best-practice
asthma guidelines in managing this highly prevalent ambulatory care sensitive
condition in their practices [42,43]
Prompts built into EHR platforms have been shown to contribute to higher
immunization rates and fewer missed opportunities [44]
Integrating pediatric growth charts into EHRs has enormous potential because
of the functionality of the electronic platform to perform calculations such as
percentiles for height/weight and head circumference, representing a major
improvement compared with paper charting for tracking infant growth and
managing high-risk pediatric patients in primary care [45]
With modifications to the standard EHR and a quality improvement approach,
the technology has contributed to better primary care prevention, identification,
and management of pediatric obesity [46]
EHR technology has been used to improve assessment of symptoms at well-care
visits for children diagnosed with attention deficit disorder [47]
EHR technology has been credited with improving the overall quality of care to
children in urban primary care settings, including through pediatrician consis-
tency in providing counseling and anticipatory guidance around health care
maintenance issues including diet and sleep, and addressing psychosocial
issues such as domestic violence and exposure to secondhand smoke [48].
EHRS IN PRACTICE: CASE STUDIES

The following case studies are examples of ways in which EHR technology
contributes to patient care in the primary pediatric setting, and some of the
complexities and limitations of EHR use in practice.
Case 1 is drawn from patient-provider EHR experiences and shows the
potential that EHRs hold to help clinicians provide more organized, compre-
hensive, and efficient care and to be more effective and efficient in quality
improvement and management of patient populations (Box 1). Prescriptions
are managed and patient histories, historical clinical data, and intervention
tools are automated. Reporting and uses secondary to support care are not
only possible but realistic, and support HIT Meaningful Use expectations.
Questions that could be asked or considered by the prospective user of an
EHR system about assumptions embedded in the example include:
1. Is an asthma flow sheet available in the system?
2. Are historical and current data entered into the flow sheet automatically, or does
this have to be done manually?
3. Does the EHR support health information exchange (HIE) and communicate with
local and statewide immunization registries?
4. Can diagnostic equipment, such as a spirometer, be integrated with the system so
that data collected by the mechanism automatically populate both the clinical
record and the flow sheet?
5. Can the flow sheet show recent or anticipated immunizations?
6. Are bilingual, interactive, and customizable documents and forms such as the
Asthma Action Plan available or possible?
7. How is prescribing handled by the system?
Box 1: Case 1
JL is an 8-year-old asthmatic boy. He comes in to see his provider for an asthma
follow-up visit. The pediatrician can see from his asthma flow chart in the EHR
that he is due for spirometry, that his peak flows have been decreasing
slightly, and that he is due for his flu shot. Because the EHR is interlinked
with the state’s immunization registry, the provider is able to see all of JL’s
immunizations, even those administered at other clinics. She evaluates him,
documents his classification for severity and control status using a set of
structured data questions, and adjusts his medication accordingly. The
electronic asthma action plan in the EHR retained the unchanged fields
from the prior visit, automatically pulls new data from today’s visit, allows
for manual editing where needed, and is printed out in multiple copies, in
English for the school and Spanish for the patient’s mother. Later, without
doing a manual chart review, the physician is able to include data from
JL’s visit in her CQI project, ensuring that her asthmatic patients are
classified for severity and control status and that the patients with persistent
asthma are on controller medications. This process is part of her
preparedness for applying for CMS Phase I Meaningful Use reimbursement
and for recognition as a Patient-Centered Medical Home.
8. When data are stored in the system, are they stored in a reportable way outside
a typical encounter note?
9. Is there a way to access the data to support unanticipated activities such as CQI
projects and Meaningful Use attestations?
Box 2: Case 2
A 16-year-old girl, LR, arrives at her pediatrician’s office for a routine health care
maintenance visit, accompanied by her mother. As she is waiting to be seen,
she completes a standardized psychosocial risk factor screening form on
paper, in which she notes that she is currently sexually active but does not use
any type of birth control. The pediatrician initially sees LR accompanied by her
mother, addressing general nonconfidential health and preventive care issues.
The mother expresses understanding about sensitive and private topics and
agrees to leave the room while the pediatrician speaks to her daughter.
With the mother no longer in the room, the pediatrician reviews the psychosocial
risk assessment with LR and counsels her accordingly. She is interested in birth
control, but requests that her mother not know about her sexual activity. The
pediatrician reassures her that information between them is private and
confidential. The pediatrician collects a urine sample for a pregnancy test,
chlamydia, and gonorrhea screens. The pregnancy test is negative, with
other results pending laboratory evaluation.
The pediatrician writes a prescription for birth control pills, strongly recommending
the additional consistent use of condoms. After their departure, the pediatrician
scans the risk factor screening form into her office’s EHR and enters all other
pertinent clinical information. A few days later, when pending laboratory
results return, she speaks with LR, documents the phone call, and enters the
data into the EHR. One month later, the patient’s mother calls the pediatrician’s
office to inform them that the family will be relocating to another state and will
therefore require copies of all medical records. One challenge is that, other
than the scanned psychosocial risk screening form, information regarding the
patient’s sexual activity, corresponding discussions, medication, and
laboratory results is intermixed with more general health data.
Each of the examples described earlier are possible, but often not included in
a typical EHR. Linkages to support the interface of a pediatric practice with
state and other municipal public health systems (eg, newborn screening regis-
tries, communicable disease registries) remain a challenge faced by EHR users
today, one that is not unique to pediatric practices [49]. The next case study
presents HIT issues distinctively found in pediatrics (Box 2).
In contrast with case 1, case 2 suggests a variety of barriers, challenges, and
pitfalls that may be associated with EHRs. Many of these are unique to pediatric
care and may directly affect the pediatric team’s ability to provide appropriate
services. The case describes a typical adolescent well-care visit. The completion
of the psychosocial risk screening form on paper suggests an opportunity to inte-
grate patient or consumer-side work into the system by incorporating standard-
ized screening forms in the EHR. However, this incorporation can be challenging
because copyrights on many screening tools may require permission, special
programming, and extra expense for use.
As was noted in case 1, EHRs improve and broaden the availability of data
for patient care, which is where an EHR can excel in supporting a pediatric
team’s work. A challenge arises when the paper-based screening form is re-
viewed externally to the EHR. It is usually possible to scan paper forms into
an EHR, but the information in the resulting document is not available for
computer-generated reporting. Failing to incorporate the content of the form
directly into the EHR is a missed opportunity to use screening results in mean-
ingful ways to enhance patient care and better describe population needs and
trends without a manual chart review.
There is a set of problems that is not necessarily unique to pediatrics, but
nonetheless of vital concern. These problems begin with the parental/caregiver
request for records as part of the family relocation.
How can the patient be assured that the parent will not receive the portions of
the record that are considered sensitive and are legally identifiable as such?
Does the EHR allow the clinic to mark portions of the record as sensitive and
control who may and may not have access to the information?
Is it possible for the EHR to alert the staff about a request that may be inap-
propriate or in violation of regulations?
Does a firewall exist to protect the patient from miscommunication of sensitive
information? What mechanisms exist when that firewall needs to be overridden?
Similar examples exist in human immunodeficiency virus (HIV) care, mental/
behavioral health care, and a variety of other areas of clinical care in which there
is likely to be sensitive information that may not, or should not, be shared.
Sharing electronic health data (HIE) is an issue that particularly affects pediatrics.
Box 3: Case 3
AD is a 14-year-old boy with a seizure disorder at his fourth visit to a community
health center clinic. On his first visit 6 months earlier, the pediatrician referred
him to a neurologist at a local academic institution to gain better control of his
seizures. Despite several visits with a pediatric neurologist, seizure activity had
continued. During the initial intake, the pediatrician also noted several
symptoms consistent with depression and that the patient repeatedly expressed
frustration and anger associated with his medical condition. He referred him
to the social worker in the clinic for additional evaluation and support.
At today’s visit, the mother tells the pediatrician that they saw the neurologist 2
weeks earlier and that he changed the patient’s medications. Neither she
nor AD can remember the name of the new medication, or the exact dose.
The patient has been complaining of stomach aches during the last week
and has not attended school. The provider looks in the EHR and finds that an
initial report from the neurologist was received by mail and scanned in to the
EHR. However, there were no follow-up reports from the 2 subsequent
neurology visits. AD has been seeing the clinic social worker regularly, and
all of her notes are present in full in the EHR. On review, the pediatrician
notes that the patient reported to the social worker that he has been the
target of bullying at school. He was reportedly tearful at the last visit when
he disclosed this to her, saying that he has never told this to anyone before
and that he does not want anyone to know.
Case 3 shows how EHRs may be used to improve communication on refer-

rals and how, given the appropriate availability of information, a better clinical
picture of a patient’s health status can lead to improved treatment (Box 3). In
principle, the EHR centralizes and notifies its users about activities and
outcomes for referrals. It ensures alignment between the onset of a set of symp-
toms and changes in medications and that providers are aware of psychosocial
concerns. The lack of alignment among the providers associated with this
referral indicates the degree to which the potential of the EHR technology is
not yet realized in terms of better managing transitions across provider systems
and improving care coordination.
Additional problems arise because adherence with subspecialist appoint-
ments may be hard to track when the providers are not part of a closed hospital
system or network. In this case, not all of the follow-up visits for the neurologist
are available in the electronic record, medication changes have not been re-
corded, and the intervention plan for this patient is unclear.
This case also shows another dilemma facing users of a shared EHR in
a comprehensive medical/health home model: is it appropriate for the primary
provider to have full access to the patient’s mental health reports? What are the
legal and ethical firewalls that should be considered to provide the best care for
patients, while also respecting their privacy [50]?
Box 4: Case 4
Dr S is excited that his clinic has implemented a new EHR, and that his providers
have been using it for about 6 months. He is trying to figure out the best way to
maximize the potential of his EHR to help him increase efficiency and quality of
patient care. He knows that many of his patients struggle with food insecurity
and would like to assess what percentage of new patients report this as
a problem. He works in a small practice that does not have an information
technology team for technical support. He knows that most of his colleagues
ask about food and housing, but, on exploration, realizes that they each use
their own protocol and document differently. Dr S calls the EHR vendor to
ask about the best way to extract this information from the EHR and is told
that he will have to do a manual chart review because they are not
structured data. The vendor tells him that requested data points can be
programmed into the EHR but the customization will be costly. In addition, if
he then wants them to create a report that can electronically extract that
information, he will have to pay an additional fee.
Case 4 reflects an increasingly common set of challenges in EHR systems

(Box 4). Data are entered and present a reasonable patient chart. However,
when there are opportunities to use data in other ways, including practice
management, trend analyses of patient needs and interventions, and quality
management, users face a variety of barriers. Some vendors are attempting
to build improved reporting systems, although this is a complex challenge

based in the sometimes conflicting requirements to produce and EHR system
that allows user flexibility versus a rigorous, highly structured method of
data entry that can yield reliable quantitative information.
STRUCTURED DATA, UNSTRUCTURED DATA, AND REQUIRED

FIELDS
The following are some essential data elements that must be considered in
designing an EHR for data reporting functionality:
Structured data
Structured data is a type of information that can be highly bounded and
defined. In any EHR, there is a place to write free text about a specific
issue affecting the patient. However, only structured content allows the
provider to select from a discrete set of choices to make it possible for infor-
mation to become ready for automated data extraction. In addition, the
specificity that is used by the provider is dictated by the choices. An
example of structured versus free-form content would be a Yes/No check
box to indicate whether a patient has been diagnosed with asthma con-
trasted with writing in the note, ‘‘Patient history is notable for asthma diag-
nosed at age 5 years.’’
Any data point that always follows a consistent format (eg, ICD-9/10 codes)
or whose characteristics can be tightly controlled (eg, a patient’s height in centi-
meters) can be structured. Recording the appropriate ICD-9/10 code for
asthma would also serve as a reportable way to identify a patient with this diag-
nosis and facilitate tracking and reporting. If the possible responses to a question
are limited, a drop-down list in the EHR can facilitate chart notation and enable
automated data extraction. An example is developmental screening results,
which can always be expressed as within normal limits (typical development),
at risk (monitor development), or suspected developmental delay (refer for full
evaluation). Using structured data facilitates simple reports using frequencies
(eg, how many patients have received a developmental screening), means
(eg, the average age of patients who screened positive for developmental delay),
and use (eg, how many patients appeared for a well-child visit this year). In the
traditional subjective, objective, assessment, plan (SOAP) evaluation and nota-
tion format, structured data elements are particularly well suited for objective,
assessment, and plan items.
In addition, structured data are often used as the trigger point for clinical
decision support. An ICD-9/10 code may trigger the system about the need
for public health reporting. Immunization information may alert the clinic
to an upcoming immunization opportunity. An electronic prescription may
set off an alarm about a drug-drug interaction or the need to refill an associ-
ated medication. The standardization and predictability of structured data
becomes the mechanism that activities and enables clinical decision support
tools.
Structured content can allow systematization of core questions that providers
in a clinic or clinic system ask and that reflect the population-specific needs, and
can make these elements reportable for internal process analyses and quality
improvement. This type of systematic data may allow better descriptions of
the patient populations, enabling more effective allocation of resources and
advocacy for appropriate support. Structured content is also useful in pediatric
training. The structured content helps new practitioners understand and meet
the norms, standards, and requirements of the clinic system. For vulnerable
patient populations where many of the questions are of a sensitive nature,
having a system that normalizes and accepts these content areas can also
make the patients more comfortable disclosing personal information, such as
homelessness, histories of abuse, illiteracy, and high-risk behaviors.
Unstructured data
Unstructured data is a type of data that is unpredictable or highly variable in
nature. Often, unstructured data are entered into free-text fields in which
anything can be typed. For example, where a numeric or positive/negative
laboratory result will do well as structured data, an adolescent patient’s descrip-
tion of personal issues may be important to record in terms of a structured diag-
nosis, but the description itself may be served best by a written note and
impressions. These free-text notations do not lend themselves to automated re-
porting out of the EHR. The best approach is often a measured combination of
structured and unstructured data, such that concerns around standardization
and reporting can be met, while allowing providers the opportunity to describe
patient-specific circumstances.
Required fields
One way to ensure that data for which there is a reporting requirement are
appropriately entered is to structure the data and make their entry required.
EHR technology allows the incorporation of required fields that can be used
to force a clinician to enter 1 or more data points into the electronic system.
Required fields can be used to force everyone following a clinic protocol to
document in a specific way. When a field is required, the user may not leave
the required section until each field is populated. This sort of requirement
can be useful, especially when undertaking quality improvement activities,
participating in clinical research activities, providing medical student and resi-
dent education, or formalizing data points for regulatory compliance [51].
Required fields must be balanced against an individual’s need for flexibility
and the inherent frustration and fatigue associated with over-requirement of
more data fields than necessary.
Pediatric EHRs are comprehensive data repositories describing a broad
range of patient issues, as well as quality and consistency or care. Making
effective use of EHR data, which entails getting the data out in the form of
automatically generated reports, is a significant challenge with responsibility
at the vendor and user level. An EHR or its vendor should:
Indicate clearly where data elements are unstructured (less suitable for report-
ing) and where they are structured (better for reporting)
Provide comprehensive references and training so that the practitioners will
understand what data they will be able to manage outside the encounter note
(eg, development of patient registries for overall care management and
communication) and what areas will require specialty programming (eg, report
development for outcomes research, trends specific to the practice, and quality
of care management)
Reflect a practice’s understanding of common and unique areas of interest or be
easily customizable. These may include food and nutrition issues, HIV/acquired
immune deficiency syndrome social support systems, or asthma prevalence and
outcomes
Facilitate provider ability to assess the status of interventions, such as immuni-
zations given or prevalence of diagnoses, in a subset of patients compared with
the practice as a whole at a point in time and over time
Include clear guidelines for standardized interpretation and recording of clin-
ical information. Even where data are unstructured and therefore less sympa-
thetic to reporting, consistency eases manual reviews and quality assessment.
CONSIDERATIONS IN THE DEVELOPMENT OF PEDIATRIC EHR

CLINICAL CONTENT
Optimally designed EHRs have content that reflects the population-specific needs
of the patients and operational context (ie, community health center, hospital
ambulatory clinic, private health system clinic) that are part of the practice. The
clinical content is the sum total of information that needs to be recorded, in struc-
tured or unstructured modes, during the course of all possible patient interactions
in the organization. The content is designed to flow in a way that providers find
intuitively matches the way the clinical encounter and other activities are
managed, which inevitably requires customization to meet the needs of patients
and providers in diverse health care settings. Clinical content in some EHRs
reflects the nature of care in clinical specialties and subspecialties such as cardi-
ology, obstetrics, neurology, and geriatrics. Each specialty has unique vocabulary
elements that describe systems, assessments, processes, and plans. A controlled
vocabulary performs the same role as published diagnostic and billing codes, stan-
dardizing clinical concepts for a high level of descriptive consistency. Pediatrics
has its own child-specific vocabulary, including diagnoses and care protocols
that might not be well represented in internal medicine or geriatrics.
This article presents 7 representative examples of pediatric-specific EHR
content, EHR functions, and pediatric EHR concerns. Each content example
is taken from an existing EHR with a large pediatric content set. This EHR
content set has been under development for 25 years and has been subject
to intensive research, field testing, feedback, and clinic-setting refinement
with general and priority pediatric populations.d,e The development process

involved health information technologists and a range of child health care
professionals, including pediatricians, nurse practitioners, and diversely creden-
tialed child and adolescent mental health professionals who provide care in an
extensive national network of comprehensive pediatric services for vulnerable
pediatric populations, all working within a medical home model.f Examples of
function and concern are derived from current pediatric HIT tools, practice,
and evolving clinical, regulatory, and pediatric practice mandates.
Structured data: history, orders, and plans

In pediatric care, and especially in medically underserved pediatric popula-
tions, the social history is an important part of understanding the context of
the patient. Knowing the circumstances of the child and family may be essential
to appropriate care. Categories in the social history that can be important
include those listed later, each of which should expand extensively into specific
structured data elements, many of which need to take on additional dimensions
in pediatric care. Examples include education, country of birth, housing situa-
tion, family social interactions, foster care, spiritual history, activities, work
history, depression, and self-image (Box 5).
The structured nature of the content is a framework from which to maximize
achievement of several goals.
1. It follows a logical order that reflects the feedback from providers in the clinic. It
follows a flow that makes sense to those who use it. In addition, without the aid of
specialized templates or forms, the content makes clinical sense and offers the
various choices typical of the pediatric population under care. Providers select
the components relevant to their patients.
2. The available choices provide consistent, efficient recording of data, minimizing
data entry errors, and making the task of collecting the data predictable. Because
the data are structured, they are easier to extract at a later time. Providers can see
practice-wide numbers and trends for their patients, to develop a deeper
understanding of the pediatric population education status and how this may
affect individual and community health. Accompanying unstructured fields are
important for more in-depth, descriptive information to be entered when needed,
but retrieval of this information necessitates a manual chart review.
3. The consistency of the content allows assessments to ensure that all practitioners
are properly completing the information, and the EHR system to support a high
quality of care.
As with the aspects of social history, structured clinical content elements that
are useful in EHRs include anticipatory guidance sets, specific plans for disease
d
Pediatric priority populations include vulnerable children in diverse settings and circumstances (eg, inner
city and rural poor, homeless, street youth, children in transient farm work families). See, for example: http://
www.ahrq.gov/populations/.
e
Further information on the Children’s Health Fund national network is available at: http://
www.childrenshealthfund.org/child-health-care/national-programs-by-project.
f
Further information about this process is available at: http://hunter.chfund.org/content/.
Box 5: Sample EHR content for social history (education)

Using education as an example from social history, the content in an EHR can be
structured, with the major item followed by 1 or more sets of check boxes or
drop-down lists with choices, as indicated. Free-text, nonstructured space can
accompany each item, enabling providers to expand and clarify
descriptively, when desired.
Education
Parent/caretaker
Completed: (drop-down list for highest completed)
Grade (specify)
Elementary school
Middle school
General Equivalency Diploma
High school
Some college
College
Some graduate school
Graduate school
Currently attending: (drop-down list)
Patient
In school:
Yes
No
Not in school because:
Dropped out
Moved
Graduated
Other
Grade level: (drop-down list)
Completed: (drop-down list)
Grades:
Mostly As
Mostly Bs
Mostly Cs
Mostly Ds
Mostly Fs
Grades have been:
Improving
Staying the same
Getting worse
Academic concerns: (multiselect)
None
Worsening grades
Learning difficulties
Reading difficulties
Math difficulties
Poor grades
Repeated a grade
Special education
English as a second language
Other
Nonacademic concerns: (multiselect)
None
Absenteeism
Attention problems
Disruptive, oppositional behavior
Appears sad, withdrawn
Suspension(s)
Expulsion(s)
Other
Patient has an adult at school to talk to:
Yes
No
Likes school:
Yes
No
Favorite subject: (drop-down list)
Least favorite subject: (drop-down list)
or visit types, and order sets. Having well-designed content can increase the
uniformity of care and intervention, when appropriate. They can be especially
useful in targeted initiatives focused on prevalent conditions affecting the pop-
ulations served. Box 6 shows how structured data may be used in the manage-
ment of asthma.g
g
Asthma content was developed by a team lead by CHF’s New York Program (Children’s Hospital at
Montefiore, Albert Einstein College of Medicine) and included the District of Columbia Children’s Health Project
(Children’s National Medical Center), and the Breathmobile Program at Phoenix Children’s Hospital. For additional
information see: http://www.childrenshealthfund.org/child-health-care/special-initiatives/childhood-asthma-initiative.
Box 6: Sample EHR content for asthma care plan

Asthma: care plan
Reclassification
Reclassification at today’s visit:
Not indicated
Intermittent
Mild persistent
Moderate persistent
Severe persistent
Controller
Controller for today’s visit:
Not indicated
Already on controller
New controller prescribed today
Flu vaccine
Flu vaccine plan for today’s visit:
Will give today
Not in season
Declined
Unavailable
Asthma tools
Patient has an asthma action plan:
Yes
No
Asthma items given to patient:
Asthma action plan
Family asthma guide
Spacer
Peak flow meter
Mattress/pillow cover
School medication administration form
Stress
Guardian finds taking care of child’s asthma to be stressful:
Yes
No
Guardian would like to talk to someone about stress:
Yes
No
Well-designed and well-organized content can contribute to a clear and repli-

cable record for a specific patient and to a comprehensive set of reports and
related activities across the clinic’s pediatric population and for broader public
health activities. If an EHR has special features that allow for the development
of specialized templates or forms, well-constructed data provide the building
blocks on which the tools can be built. However, if such special features are
not available or are cost-prohibitive to develop, well-constructed content is
more than adequate.
Ability to document caregiver information
A dilemma often faced by pediatric providers is how to document information
that reflects the parent or other caretaker, who may or may not be a patient in
the practice. For example, it is recommended and appropriate for pediatricians
to screen new mothers for postpartum depression using a standardized, vali-
dated tool [52]. However, there is seldom an appropriate place in the pediatric
note to house the screening tool for the mother, or even to document the
results. A similar case may be found in pediatric care when managing mental
health or psychosocial issues, for which collateral contacts are made with
parents, teachers, and others involved in the child’s care. Documentation of
the information is critical; however, mixing patient and caregiver data may
become confusing to those who access the notes later or when developing
data reports. Failure to provide a logical and clearly delineated way to enter
relevant caregiver information in the EHR may discourage the pediatric
provider from delivering optimal care. It is not enough to structure data; the
content must reflect the realities of use, and ideas must be tested in day-to-
day practice.
Units of measurement
One of the fundamental and often overlooked areas of differentiation in pedi-
atric versus adult EHR requirements may be found in units and precision of
measurement. This differentiation is notable in the units used for weight and
height beginning in infancy, underscoring the importance of this issue in pedi-
atrics. In the neonatal intensive care unit and the newborn nursery, age may
need to be measured in minutes, hours, or days. In a general pediatric practice,
the electronic record must have the ability to record age in units of days, weeks,
months, or years.
Prescribed medications for children must be dosed by weight, and the calcu-
lation is done in using the metric system. Dosing a medication erroneously
based on the weight in pounds can result in more than double the correct
dose of medication. The use of liquid preparations of oral medications, often
available in multiple concentrations, adds complexity to the dosing calculation
in pediatrics and thus increases the risk for error, but many EHRs do not
support this level of specificity. However, complete conversion to the metric
system is impractical for ambulatory pediatrics, because most parents in the
United States relate to their child’s weight in pounds (and height in feet and
inches), as do most required forms for daycare, school, and sports. This
preference necessitates at least some EHR-based conversion ability, both in

posted weight and in association with growth charts. An EHR that cannot
perform conversions undermines quality of care in general. One that does
not reflect the complex challenges of pediatric dosing and calculation of age
is inadequate.
Pediatric norms
Lack of pediatric norms is an area that may be problematic for pediatricians
using typical, adult-oriented EHRs. For example, for blood pressure, what is
normal depends on the age and gender of the child. Most EHRs only contain
alerts based on adult normal values. As such, EHRs are not fulfilling their
potential to provide clinically useful alerts based on the range of appropriate
norms for pediatric patients. At worst, lack of pediatric norms can be
dangerous by implying that a value is normal when it is not.
Normal values for spirometry and peak flows similarly depend on the indi-
vidual’s age, gender, and height (and even ethnicity, for spirometry). An EHR
that is sensitive to pediatric expectations and that can show patient results rela-
tive to accurate age, demographic, and anthropomorphic norms, especially in
graphical form, aids in clinical care rather than hindering it with confounding
adult standards and references. This challenge is also seen in growth chart
representations [40]. The basic charts may do an adequate job of representing
the patient’s growth, but they tend not to effectively represent special cases in
which children do not follow the typical pattern, as in the case of prematurity
or Down syndrome. Lack of incorporation of adequate tools for children with
special health care needs into the EHR may compromise quality of care [53].
Developmental screening
There is evidence that, when primary care providers routinely use standardized
developmental screening tools, early identification and referral for develop-
mental delay significantly improves [54]. Implementing EHR technology can
improve routine developmental screening by providing prompts at ages at which
a screening should be done and facilitating tracking of screening results [55].
An optimal pediatric EHR would incorporate standardized screening tools.
One important concern is that many developmental screening tools are propri-
etary. Their use in EHRs may require licensing fees for the EHR vendor or
end user. As with growth charts, the lack of integrated screening tools may
decrease regular, formalized screening. Although scanning forms into a patient’s
electronic record is one solution, it undermines the ability to follow changes by
leveraging structured data elements, and scanned forms are less likely to be
referenced during the encounter.
Referral tracking
Comprehensive referral tracking is emerging as an important component of
EHRs, including the ability to ensure that the specialist note is received,
charted, and discussed with the patient/caregiver (closing the loop). This part
of care coordination is clinically important to the patient and is a measure of
effective interpractice communications. Although the degree to which pediatri-

cians engage in the various details of referral management varies, care coordi-
nation is seen as critical to the medical home model and overall quality of care.
Lack of coordination in the pediatric referral process is often a significant
barrier to care for low-income and medically underserved children and adoles-
cents [56,57]. Understanding patient adherence with referrals can increase prac-
tice efficiency and improve patient/caregiver-pediatrician communications.
An EHR should provide a means to accommodate externally sourced data
including laboratory results and subspecialty reports. As seen in the earlier
cases, the pediatric practice needs to develop processes that support timeliness
and accuracy of information generated outside the practice. The pediatric
patient and parent are also participants in the child’s medical/health home. On-
line tools such as patient portals can be used both to provide families with
health information and to remind them of upcoming referrals and other sched-
ules activities such as follow-up visits.
Confidentiality, behavioral health, and sensitive health information

There are patient privacy and confidentiality considerations that are reflected
in all fields of health care practice. There are also domains that are unique
to pediatrics, especially adolescent health. The Society for Adolescent Health
and Medicine (SAHM) considers effective, and effectively communicated,
confidentiality policies to be essential for adolescents to seek and receive care
for sensitive concerns and to disclose sensitive issues to their health care
providers [58]. As described in case 2, this remains a major challenge in the
functionality of pediatric EHRs. How EHRs handle the identification, segmen-
tation, and sharing/exchange of this information remains a challenge toward
the goal of EHR adoption in pediatrics. Case 2 reflects some of these chal-
lenges. When a minor may legally consent to care varies across states, and
how sensitive information is to be treated in the face of a parent or guardian’s
request is still to be standardized at a technological level.
The quality of safeguards to protect children and adolescents in the face of
inappropriate disclosure of data, despite standards established through the
Health Insurance Portability and Accountability Act, has not been well ad-
dressed in current EHRs [59]. These issues are most prominent when sensitive
health information (eg, reproductive health options, mental health care) are
involved. The issues around appropriate standards to send and receive docu-
ments containing protected health information are not limited to issues around
minor consent and privacy. The ethical and legal implications of health informa-
tion storage, including patient opt-out provisions, remain among the unresolved
issues affecting broader EHR adoption and use [60] and the fulfillment of their
potential to improve patient care and promote patient safety [61].
SUMMARY
EHR systems provide significant opportunities to enhance pediatric care. Well-
constructed clinical content, HIE, automated reminders and alerts, and reporting
at practice, community, and public health levels are available in several current
systems and products. However, the general focus on inpatient and adult popu-
lations in the design and marketing of these systems should be seen as a significant
barrier to EHR adoption among pediatric primary care providers. Weight-based
medication dosing, specialty growth charts, units of measurement and time, and
measures to address minor consent and adolescent confidentiality are not
universal in quality and availability to the pediatric practice. However, there
are opportunities for pediatricians to provide input and to clearly state minimum
requirements when dealing with vendors or when government agencies (eg,
ONCHIT and AHRQ) seek comment on standards, practices, and expectations.
This article uses cases and examples to describe some areas in which pediatricians
should take an active role to advocate for pediatric-appropriate EHR tools. Virtu-
ally every child born and cared for in the United States today will have their data
and information recorded in an EHR. The quality of the information and the HIT
in which it is recorded can affect the care they get as children, and the information
they carry into adulthood.
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Sudden Infant Death Syndrome,

Sudden Unexpected Infant Death, and
Apparent Life-Threatening Events
Carol D. Berkowitz, MD
Department of Pediatrics, Harbor-UCLA Medical Center, David Geffen School of Medicine at
UCLA, 1000 West Carson Street, Box 437, Torrance CA 90509, USA
Keywords
Sudden infant death syndrome Sudden unexpected infant death
Apparent life-threatening event Infant death
Key Points
Most Sudden Unexpected Infant Deaths (SUIDs) are the result of preventable
circumstances that include unsafe sleeping conditions, such as side or prone-
sleeping, bed-sharing and sofa sleeping.
Prenatal exposure to factors such as parental smoking, and substance abuse
increases the risk of SUID when the infant is exposed to certain extrinsic conditions.
There is no evidence that infants who experience an ALTE will succumb to SUIDs.
Caretaker education is a key strategy to reduce the incidence of SUIDs.
Case: A 2-month-old previously healthy male infant was found by his mother
at 5:30 AM in his crib, prone, blue, lifeless, and with white frothy
material around his mouth. He had been born after a 35-week gestation to
a 29-year-old gravida 2 para 1–2 mother by normal spontaneous vaginal
delivery. He had been fed his infant formula at 2:00 AM, and placed on his
side in his crib because his mother was concerned that he might spit up
and choke. A scene investigation using a doll reenactment revealed a crib
with bumper pads, stuffed animals, and several blankets, in which the infant
had been swaddled. The autopsy revealed scattered thymic petechiae but
was otherwise normal. The mode of death was undetermined, with hyper-
thermia and accidental asphyxia as possible contributing factors.
S
udden infant death syndrome (SIDS) was first formally defined in 1969
by a National Institutes of Health (NIH) Consensus Panel [1]. SIDS and
our understanding of it has evolved in the intervening 50 years as we
have learned more about the contributing factors and have become focused
on prevention.
E-mail address: carolb@pol.net

184 BERKOWITZ
DEFINITION
The NIH panel initially defined SIDS as the ‘‘sudden death of an infant or
young child, which is unexpected by history, and in which a thorough post-
mortem examination fails to demonstrate an adequate cause’’ [1]. An autopsy
was included as part of this initial definition to eliminate any other cause of
death, although not all infants who died suddenly or unexpectedly were sub-
jected to a postmortem examination. A death scene investigation was added
to the criteria based on results of a 1986 study that reported that such an inves-
tigation revealed environmental factors including accidental asphyxia, over-
laying, hyperthermia, and abusive head trauma as contributing factors.
Therefore some SIDS deaths could be attributed to specific environmental
phenomena [2]. To attribute an infant death to SIDS now also requires a review
of the infant’s clinical history as well as family history and a detailed scene
investigation [3,4]. A more encompassing term that is now used is sudden unex-
pected infant death (SUID), also sometimes termed sudden unexpected death
in infancy (SUDI). These terms are more expansive, and include any unex-
pected death, whether explained or unexplained. Included in SUIDs are deaths
related to asphyxia, suffocation, intoxications (eg, methylamphetamine or
cocaine), channelopathies, and inborn errors of metabolism. The presence of
even a mild infection may be associated with an immune reaction and cytokine
cascade beyond what is anticipated based on the severity of the infection.
There is evidence that polymorphism in the interleukin 10 (IL-10) gene
promoter or partial deletions in the C4 gene may contribute to infection-
related SIDS [5].
The term SIDS is now reserved for those SUIDs for which no explanation
(intrinsic or extrinsic) is present after a complete autopsy, review of the medical
and family history, and death scene investigation that excludes predisposing
environmental factors such as prone sleeping or other unsafe sleep environ-
ments. Some of the decrease in the reported incidence of SIDS may be related
not only to a true reduction in SIDS but also to a reclassification of sudden
unexpected deaths based on a more extensive investigation (eg, an infant’s
death may be secondary to accidental suffocation rather than SIDS) [6].
EPIDEMIOLOGY
Initial studies focused heavily on examining the epidemiology of SIDS. Associ-
ated factors included lower socioeconomic status, but this is true for all infant
deaths and is not unique to SIDS. Maternal age was noted to be another factor,
particularly maternal age less than 20 years (teenage mother). Other maternal
risk factors included nonwhite ethnicity, lower educational level, unwed status,
fewer prepartum and postpartum visits, smoking, and use of illicit substances
[7,8]. Maternal as well as paternal smoking remains highly correlated with
SIDS, and there seems to be evidence of a neurophysiologic basis for this
association [9,10].
SIDS was long considered a natural death the cause of which was unknown
[11–13]. Infants who died of SIDS were believed to be intrinsically normal.
SIDS, SUID, AND ALTES 185
Aside from the epidemiologic considerations, there were at least 70 different

conditions that were posited as causing SIDS. These conditions included
thymic enlargement (status thymicolymphaticus), overlaying (which was noted
in the Bible), milk allergy, cardiac arrhythmias (Wolff-Parkinson-White
syndrome and long QT interval), respiratory infection such as respiratory
syncytial virus, and disorders of ventilatory control [14].
Recent studies have shown a change in the epidemiology of SIDS since the
initiation of the Back to Sleep campaign [15]. Some of the change relates to
a decrease in the number of infants who die while sleeping alone in a crib. A
study from the United Kingdom revealed that the number of deceased infants
who had been sleeping with their parents increased from 12% to 50%, although
the number of infant death has decreased by half. More affected infants come
from socioeconomically disadvantaged families (percentage increased from
47% to 74%), have a history of maternal smoking (57%–86%), and were
preterm infants (12%–34%).
APNEA AND SIDS: A HISTORICAL PERSPECTIVE

Apnea as the pathophysiologic basis for SIDS was first proposed in 1972 based
on studies of siblings of SIDS victims [16]. In addition, a relationship between
SIDS and apnea was taken as an indication of disordered ventilatory control.
Evidence for disordered ventilatory control came from 2 sources: pathologic
findings noted at the time of autopsy and pulmonary studies performed in
infants who were believed to have experienced a near-miss or aborted SIDS.
Pathologic findings were believed to indicate long-standing hypoxemia and
included smooth muscle thickening of the pulmonary arteries, right ventricular
hypertrophy, hematopoiesis of the liver, periadrenal fat, adrenal medullary
hyperplasia, abnormalities involving the carotid body, brainstem gliosis, and
increased neuronal apoptosis [12,13,17]. Subsequent studies did not corrobo-
rate these findings, or the hypothesis that these infants had evidence of chronic
hypoxia. In addition to pathologic findings were studies on infants who were
found blue and limp, but successfully resuscitated. Southall [18] postulated
that these infants fell into 1 of 3 categories: those with central apnea, which
affected premature infants and those who had experienced a head injury or
had malformations of the central nervous system (CNS); those with obstructive
apnea, particularly infants with nasal obstruction, hypotonia of the hypo-
pharynx (eg, infants with Down syndrome), and glossoptosis; and those with
prolonged expiratory apnea. The third group was believed to be at the greatest
risk of death because these infants experienced sudden atelectasis and ventila-
tion perfusion inequalities. The infants who suffered near-miss SIDS were
admitted to hospital, where they underwent pneumograms and associated
cardiac monitoring. Sometimes, they were subjected to studies involving expo-
sure to increased environmental CO2 to see if their respiratory effort increased
in the face of that environmental challenge [11]. Management of these infants
involved the use of caffeine or theophylline and home monitoring devices.
Both of these modalities were initially used for the management of apnea of
186 BERKOWITZ
prematurity. In particular, apnea monitoring was initially restricted to use in

the hospital [19]. Home use of such devices required 24-hour servicing, and
more false alarms were reported than true ones. Scientific evidence that
home monitoring prevented SIDS was lacking but there developed a home
cardiorespiratory monitoring industry that built on parental anxiety. As early
as 1975, the American Academy of Pediatrics (AAP) Committee on Infant
and Preschool Child suggested that home monitoring to prevent SIDS should
be limited to research studies and not routinely prescribed [20].
APPARENT LIFE-THREATENING EVENT

In 1987, the National Institute of Health convened a Consensus Development
Conference on Infantile Apnea and Home Monitoring [21]. Although the focus
was on the value of home monitoring, the conference changed the face of the
evaluation of the infant who appeared to have experienced a near-miss SIDS.
The consensus was that there was insufficient evidence to conclude that these
events preceded a more significant one, but that an apparent life-threatening
event (ALTE) was not a diagnosis but rather a description of ‘‘an episode
that is frightening to the observer and is characterized by some combination
of apnea (central or occasionally obstructive), color change (usually cyanosis
or pallid but occasionally erythematous or plethoric), marked change in muscle
tone (usually marked limpness), choking or gagging.’’ The term ALTE then
became a wastepaper basket of diagnostic possibilities joined by a symptom
complex that included apnea. However, the link between apnea and SIDS
had never been established. Even before the 1987 NIH consensus statement,
the AAP had issued a statement that ‘‘a causal relationship between prolonged
apnea and SIDS has not been established’’ [22].
Although few investigators continue to believe that infants who present with
ALTEs are at higher risk for subsequent ALTEs and death, the current
consensus is that SIDS, apnea, and ALTEs are not related [23]. However, there
remains an element of confusion about the ALTE workup based in part on the
historical connection between near-miss SIDS and ALTEs. A wide spectrum of
conditions have been associated with an ALTE, and numerous reports have
tried to define a strategy for the evaluation of a child who has experienced
an ALTE [24–27]. Brand and colleagues [24] in a classic study proposed that
infants presenting with an ALTE can be grouped into 4 categories. The first
group includes infants in whom the history and physical examination suggest
a cause that is confirmed by the laboratory studies. Group 2 also has a diagnosis
suggested by the history and physical examination, but the diagnostic studies
are all normal. Group 3 has positive diagnostic studies, but the history and
physical examination are noncontributory. This group with an unrevealing
history and physical examination is subjected to multiple studies in the hope
of finding a diagnosis. Group 4 consists of infants in whom nothing is positive:
not the history, physical examination, or diagnostic studies. The yield in Brand
and colleagues’ study, which was retrospective, was low: there were 243
patients and 3776 tests, but no protocol was prospectively followed. Overall,
17.7% of the tests were positive, but the positive test contributed to the
diagnosis in only 5.9%.
As expected, common conditions such as gastroesophageal reflux (GER)
were frequently found [28]. However, studies based on polygraphic recordings
suggest that GER may be associated with an ALTE in only 19% of cases of
GER [29]. Brief apnea precedes reflux in most of the cases. The mechanism
by which GER and ALTEs are related is speculative. GER is physiologic
and occurs in most infants. Second, it is unclear what level of reflux exceeds
physiologic expectations. It is hypothesized that reflux to the level of the
pharynx, especially in a prone sleeping infant, can induce reflex apnea by
stimulation of laryngeal chemoreceptors. Other predisposing conditions linking
ALTE and GER include prematurity, upper respiratory infections, sedatives,
and seizures [30]. On the other hand, treatment of reflux with fundoplication
has been reported to alleviate the recurrence of an ALTE in 1 study involving
81 infants over a 5-year period [31].
Infection has also been implemented as a cause of ALTEs, and many physi-
cians routinely conduct a rule-out sepsis evaluation even in an afebrile infant
younger than 60 days who presents with an ALTE. The yield on such an eval-
uation is low, and was reported as 2.7% in a retrospective study involving 182
infants over a 3-year period [32]. Only 29.1% of the infants in this study had
a full rule-out sepsis workup. The major risk factor was a history of
prematurity, in which the incidence of a serious bacterial infection was
increased by 8-fold. In a prospective study involving previously healthy
patients less than 12 months of age seen over a 3-year period, age less than
1 month and multiple ALTE episodes were the identified risk factors for
a more serious condition. The investigators concluded, based on their study
of 59 infants, that those experiencing a single episode who were older than
30 days did not require admission to hospital [33].
The consensus statement from the European Society for the Study and
Prevention of Infant Death says: ‘‘There is no standard minimal workup in
the evaluation of an ALTE’’ [34]. Likewise, Brand and colleagues [24] believe
that it is time to revise the definition of an ALTE: ‘‘Until the definitional
problem is resolved, inconsistent use of the term will continue to present an
ongoing challenge for ALTE research and the clinical application of the
research findings.’’ Although apnea is an integral part of the ALTE definition,
there is no scientific link between apnea and SIDS [35,36]. It is also apparent
that home apnea monitoring is not a routine part of the ALTE picture, and
ALTEs and SIDS, or near-miss SIDS, are not related [37]. Home apnea moni-
toring may be considered for infants with recurrent ALTEs and those with
other conditions including tracheostomies or anatomic airway anomalies, meta-
bolic or neurologic disorders that affect ventilatory control, and those with
chronic lung disease [37].
However, it would be incorrect to conclude that infants who present with an
ALTE are not at risk for subsequent death or an adverse health condition. In
a 5.1-year follow-up of 471 infants 12 months of age or younger who had no
188 BERKOWITZ
apparent cause of their ALTE, Bonkowsky and colleagues [38] reported that 2
infants died (0.42%), both related to chronic epilepsy and severe developmental
delay. Chronic neurologic problems were diagnosed in 23 (4.9%). Fifty-four
infants (11%) were diagnosed with child abuse. Altman and colleagues [25] re-
ported that 2.5% of 243 infants younger than 12 months admitted for an ALTE
were diagnosed with abusive head trauma. Pitetti and colleagues [39] reported
an incidence of inflicted trauma in 2.3%, in a study involving 128 infants pre-
senting to an emergency department. There was a single infant in whom the
presence of retinal hemorrhages provided a clue to the diagnosis of inflicted
trauma. In studies looking at infants who are diagnosed with abusive head
trauma, more than 30% of them had been seen within the previous 3 weeks
with nonspecific complaints, including an ALTE [40].
A CHANGING PICTURE OF SIDS

Although numerous epidemiologic risk factors for SIDS had been identified, it
was not until 1992 that the risk of prone sleeping was brought to the attention
of the public, reinforced by the campaign waged by the AAP as Back to Sleep.
Evidence for the protective effect of supine sleeping came from studies around
the world showing that the incidence of SIDS was significantly lower in socie-
ties in which infants slept supine [41]. Physiologically (Fig. 1), prone sleeping
places the esophagus above the trachea, increasing the risk for aspiration,
contrary to what was previously taught. In addition, prone sleeping puts the
infant at risk for airway obstruction, particularly in an infant who fails to
Fig. 1. The relationship of the trachea and esophagus in the supine versus the prone positions.
(From Eunice Kennedy Shriver National Institute of Child Health and Human Development. SIDS
risk reduction: curriculum for nurses. NIH Publication No. 06-6005; 2006. Available at: http://
www.nichd.nih.gov/publications/pubs/upload/Cont_Educ_Prog_Nurses_SIDS_rev.pdf.)
arouse and move their head should their face become embedded in the
mattress. Rebreathing expired air leads to decreased levels of oxygen and
increased levels of CO2 [42–45]. When prone, the vulnerable infant (see later
discussion) fails to lift their face from the sleep surface. There is absence of
arousal and hypoxic coma develops. There is bradycardia and gasping, but
insufficient autoresuscitation, and the infant expires.
Hyperthermia is also associated with SUIDs. Hyperthermia is attributed to
decreased heat loss, with subsequent increase in body temperature when prone
sleeping infants are compared with supine sleeping infants [46,47]. Prone
sleeping seems to alter an infant’s autonomic control of their cardiovascular
system, particularly between 2 and 3 months of age, a change that is associated
with decreased cerebral oxygenation [48,49]. Prone sleeping increases the risk
of SIDS from 2.3-fold to 13.1-fold [50–54]. Side sleeping, a position that some
caregivers choose as a compromise, having been accustomed to prone sleeping,
carries the same if not higher risk for SIDS as prone sleeping (odds ratio [OR],
2.0–2.6) [51]. Some parents mistakenly opt for side sleeping in case the infant
spits up, to lessen their risk of choking. Side sleeping is particularly risky for the
infant who rolls from their side to their stomach (OR, 8.7) [51].
The Back to Sleep campaign has been successful, although this did not happen
overnight nor have all populations benefitted from the advice. Data suggest
that the prevalence of supine sleeping has not changed for nearly a decade
[55]. Evidence of the initial success of the Back to Sleep campaign came from
the overall decrease in the United States in the incidence of deaths from
SIDS from about 2/1000 or 10,000 cases a year to 0.5/1000 or about 2500 cases
a year. The incidence varies in different populations and remains high in
Native Americans and African Americans [56–60]. There is also an increased
incidence among Maoris of New Zealand and aboriginal Australians [61].
Studies from the 1980s and 1990s reported that African American infants
were twice as likely, and Native American infants were 2 to 3.5 times as likely,
to die from SIDS as white infants [57,62]. For African American infants, these
differences were attributable to unsafe sleep practices, including prone sleeping.
Greater racial differences were noted after the Back to Sleep campaign; specifi-
cally, the decline in SIDS was more marked for Hispanics than for African
American infants [59]. In addition to prone sleeping, other unsafe sleep prac-
tices were noted among African American families, particularly bed sharing
and placing an infant on a soft sleep surface [58,60]. Parents who chose
a soft sleep surface believed that their infant was more comfortable when
placed on such a surface, despite the risk of accidental asphyxia. The increased
mortality among Native American infants from the Northern Plains Indians,
using case-control studies, implicated maternal binge drinking as a prevalent
risk factor [56].
When queried about decisions to have infants sleep in a prone position,
parents raise concern about the risk of aspiration, particularly in infants who
are diagnosed with GER. The recommendations of the AAP and North Amer-
ican Society for Pediatric Gastroenterology, Hepatology and Nutrition are for
190 BERKOWITZ
supine sleeping in infants with GER disease unless such infants also have
airway anomalies (eg, laryngeal clefts) that affect their protective mechanisms.
Parents should also be cautioned against elevating the head of the bed to
prevent reflux, because such maneuvers have not been shown to have any
effect on the reflux, and the infant is at risk for sliding to the foot of the bed
and further compromising their ventilatory abilities [63–65]. Parents may
also correctly appreciate that their infants sleep for longer when they are
sleeping in a prone position. Studies have verified this observation [66–73],
but the ability to arouse from sleep is believed to be protective and contributes
to the decrease in SIDS with supine sleeping [74–78]. Some parents, particularly
those with preterm infants, may have seen their infants placed in a prone posi-
tion while in the neonatal intensive care unit (NICU). Prone sleeping improves
the respiratory mechanisms [79,80]. However, premature infants should be
placed supine (not side) once they are 32 weeks’ postmenstrual age [81,82].
Premature infants are at increased risk for SIDS, and this may be related to
longer sleep duration, increased episodes of central apnea, and fewer arousals
from sleep [66]. In addition, hospital practice strongly influences what parents
do after discharge, and surveys reveal that only 50% of NICU nurses place
preterm infants supine when they are moving to a crib, and 20% never place
preterm infants supine [83]. Such practices need to be addressed if we are to
have any impact on unsafe sleep in this population.
Some believe that additional factors are related to the decrease in the inci-
dence of SIDS, and these factors include a reclassification of what in the past
had been categorized as SIDS [6]. Some of these factors may contribute to
the higher incidence of SIDS in premature infants.
SUID
SUID is a term that denotes any sudden and unexpected infant death whether
explained or unexplained (ie, SIDS is reserved for unexplained SUID). Part of
the change in the incidence of SIDS is that current more extensive investiga-
tions may delineate a predisposing condition such as inborn errors of metabo-
lism, infection (including mild infections with an abnormal immune response),
trauma (child abuse), cardiac channelopathies, or unsafe sleeping environments
(sofas and bed sharing) and positions (prone or side sleeping).
INBORN ERRORS OF METABOLISM

Disorders of fatty acid metabolism have been associated with sudden death in
infancy in about 1% of SUIDs [84–86]. These disorders are caused by a defect
in the mitochondrial b-oxidation of fatty acids. Fatty acid oxidation is needed to
supply energy when glucose is limited or when the energy needs of the indi-
vidual exceed the availability of glucose. The most common fatty acid oxida-
tion disorder is medium chain acyl-coenzyme A (CoA) dehydrogenase
deficiency (MCADD). This condition is detected by newborn screening, but
may manifest itself before the screening results are available to the pediatrician
or infant’s family. In MCADD, inadequate energy supply can precipitate an
acute metabolic crisis and even death. Similarly, very long-chain acyl-CoA
dehydrogenase deficiency, an autosomal-recessive disorder of fatty acid metab-
olism, can be associated with sudden unexpected death in the neonatal period.
A history of neonatal deaths of previous siblings, although always concerning
for child abuse (either inflicted trauma or intentional suffocation), should
initiate a search for inborn errors of metabolism.
Likewise, certain genetic conditions may occur with an increased frequency
in certain populations, in part accounting for the increased prevalence of SIDS
within that group. For instance, Alaska natives have a high frequency of a single
sequence variant in the gene coding for carnitine palmitoyltransferase 1A
(CPT1A allele). The rate of infant deaths for infants homozygous for the
variant is reported as 33/1000, for those who are heterozygous for the variant
as 9/1000, and for those without the variant as 0/1000 [85]. In this particular
report, all deceased infants had a respiratory infection at the time of death,
highlighting the multiple risk basis for SIDS that has been proposed [6,87–89].
GENE POLYMORPHISMS
Several gene polymorphisms may affect the immune response in the face of
what seems to be nothing more than a mild infection [5]. Results of some
studies are equivocal as relating to the relationship between partial deletions
of the C4A or C4B gene, mild infection, and SIDS. Partial deletion of the C4
gene is common and reported in 5% to 20% of white individuals [90].
However, studies in Europe detected an association between slight infection
before death and the presence of partial deletions of either C4A or C4B [91].
IL-10 gene promoter is associated with polymorphisms that include single
nucleotides. IL-10 is important in the response to infection. As with C4, studies
of SIDS victims show variable findings related to IL-10 haplotypes. However, it
seems that in certain situations, an infant with an unfavorable IL-10 genotype
may have abnormal IL-10 production, which may play a role in the infant’s
sudden unexpected death [5]. Routine autopsies do not systematically evaluate
for these polymorphisms.
CHILD ABUSE
It is highly likely that in the past and in the absence of a comprehensive autopsy
some infants who died as a result of having sustained abusive physical injuries
including head trauma were termed SIDS [92]. The recommendation for
a complete autopsy including a skeletal series and eye examination has allowed
for the detection of what would otherwise be occult injuries. As noted in the
discussion of ALTEs, some infants who present with what is considered an
ALTE have findings, either on examination or on diagnostic imaging, of phys-
ical injury [25,38].
However, it is more challenging to detect cases of intentional suffocation.
Case: A 1-month-old male infant was transported by paramedics to the
emergency department. The infant was pulseless and apneic when
192 BERKOWITZ
paramedics arrived and cardiopulmonary resuscitation was initiated. A

small abrasion was noted around the infant’s nose. Pediatric advanced
life support was initiated, including medications in the emergency depart-
ment, but the infant could not be resuscitated. The history was that the infant
had increased irritability for 2 weeks before his demise and had been seen
by his physician and diagnosed with colic. A scene investigation with doll
reenactment revealed the infant had been placed to sleep supine in
a playpen. A plastic shopping bag from a drug store was found in the
corner of the playpen. Red blood stains were found on the mattress, infant’s
bib, and plastic bag. The father stated that the plastic bag was over the
infant’s face when he found the infant, although the mother said it was
not on the infant’s face but in the corner of the playpen. The death was
believed to be suspicious.
The incidence of intentional suffocation or infanticide is reported to be between

1% and 5% [92]. Data about intentional suffocation come from video surveillance
of infants admitted to the hospital for an ALTE [93]. As shown by this case, the
death scene investigation may prove revealing. In the absence of such scene-
related evidence, concern about intentional suffocation arises from a history of
recurrent episodes of ALTEs, apnea, or cyanosis while under the supervision
of the same caretaker, an episode in an infant younger than 6 months, unex-
plained deaths of 1 or more siblings, deaths of other infants while in the care of
the same unrelated person, simultaneous death of twins, or evidence of previous
pulmonary hemorrhage from siderophages in the lung. Aside from the last path-
ologic finding, the anatomic findings of accidental and intentional asphyxia are
indistinguishable [92].
CHANNELOPATHIES: PROLONGED QT SYNDROME

Cardiac arrhythmias were considered a potential cause of SIDS as early as the
mid-1970s [94], but the link between prolonged QT syndrome and SIDS was
first established through prospective electrocardiographic monitoring over 19
years in 34,000 infants in whom a prolonged QT interval on days 3 to 4 of
life was associated with an increased risk of SIDS [95]. In studies of adults,
QT prolongation (>460 milliseconds) affects approximately 1 in 5000. Channe-
lopathies may account for 5% to 10% of SUIDs. In a postmortem study of 49
cases of noninfant sudden unexpected deaths among young patients (average
age 14.2 years) in whom the autopsy was negative, 10 (20%) were determined
to have long QT syndrome (LQTS)-associated mutations [96]. These muta-
tions/polymorphisms were associated with KCNQ1, KCNH2, and SCN5A and
are responsible for the channelopathy.
LQTS is related to a channelopathy, and 6 identified chromosomal loci and 5
cardiac ion channel genes have been implicated [97]. Five percent to 10% of
LQTS are attributed to SCN5A, the cardiac sodium channel gene. Affected indi-
viduals have an increased risk of sudden death during sleep. Disturbances related
to potassium channel variants can contribute to SIDS when there are conditions
associated with increased sympathetic activity such as rapid eye movement sleep,
mild respiratory infections leading to hypoxemia, and sudden noises and startle.
Technology has advanced so that postmortem molecular analysis can be per-
formed to detect defects in SCN5A. A prospective study evaluating nearly
45,000 infants between the ages of 15 and 25 days revealed a prevalence of an
LQTS in 1/2534 apparently healthy infants [98]. The mutations noted were
mainly KCNQ1 and KCNH2. In a study of SIDS victims, the prevalence of
SCN5A was 2% [97]. If screening is expanded to cover 7 of the genes associated
with LQTS (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, KCNJ2, CAV3), the
prevalence increases to 9.5% [99]. The challenge is to determine if these infants
can be detected in a noninvasive cost-effective way before death.
TRIPLE-RISK MODEL
As early as 1969, Dr Abe Bergman expressed the notion that the interplay of
multiple factors led to the sudden and unexpected death of an infant when he
stated that SIDS resulted from an interaction of various factors [1]. This concept
was elaborated on in 1972 by Wedgwood [87], who articulated these triple factors
as (1) general (nonspecific, including prematurity, poverty, race, and gender), (2)
age-specific related to an infant’s developmental level, and (3) precipitating, such
as an infection, position, or sleep state. This risk model was termed a fatal triangle
by Rognum and Saugstad [100]. The 3 factors were renamed by Filiano and Kin-
ney [88] in 1994 as (1) a vulnerable infant, (2) a critical period of development
related to homeostatic control, and (3) an exogenous stressor. More recently, Kin-
ney and colleagues [6] discussed intrinsic risk factors (genetic, developmental,
and environmental) and extrinsic risk factors (mild infections and unsafe sleep
environments).
Intrinsic risk factors
Filiano and Kinney [88] believed that vulnerability developed during the prenatal
period, and they cited 4 lines of evidence for the prenatal basis of this vulnerability:
changes in the CNS or systemic changes that could be detected on autopsy; subtle
changes in neurologic or autonomic function detected in the neonatal period in
some infants who ultimately succumbed to SIDS; abnormalities in cry, ventilatory
control, cardiac patterns, or state organization in some future SIDS victims; and
maternal and pregnancy factors associated with increased risk of SIDS in their
infants. Guntheroth and Spiers [89] challenged the significance of the intrinsic
factors, although acknowledging the role of external stressors.
Kinney and Thach [6] have reframed the triple-risk model since the earlier
version. Intrinsic risk factors relate to certain conditions in the infant. Males
are at greater risk, with a ratio of 2:1. Prematurity and developmental level
were also associated factors. As noted earlier, genetic polymorphisms have
been associated with SIDS.
Role of neurotransmitters
Multiple serotonergic brainstem abnormalities have been described in the
brainstem of some infants who died of SIDS. These findings emanated from
a study looking at SIDS and control infants between 1997 and 2005. This
194 BERKOWITZ
extensive study was possible because of a California law (Government Code

Section 27491.41) that called for an autopsy to be performed as soon as
possible in an infant in whom there was a sudden unexpected death [101].
When brainstems of these infants were examined, there were higher counts
of 5-hydroxytryptamine neurons (5-HT) in infants who died of SIDS as well
as higher neuron density. On the other hand, there was lower 5-HT1A receptor
density in infants who died of SIDS and in males. These sites are responsible
for upper airway control, respiration, temperature control, heart rate, and
blood pressure [102–104].
There has been particular interest in polymorphism of the gene encoding the
promoter region of the serotonin transporter as a risk factor for SIDS [102–
104]. However, results in testing for such polymorphism in SIDS victims
have not been uniformly supportive of this hypothesis. The increased incidence
of SUID in African American and Native American infants may be related to
genetic polymorphism in this region.
Environmental factors
Certain prenatal and postnatal environmental factors may predispose infants to
SUID. Prenatal and perinatal smoking may alter an intrinsic response in arousal
and make an infant more vulnerable. Parental alcohol and drug use as well as
socioeconomic disadvantage are additional risk factors. Although poverty has
been associated with SIDS, lower socioeconomic status is also associated with
other identified risk factors, including smoking, alcohol use, and bed sharing [6].
Extrinsic risk factors

Multiple risk factors in the infant’s sleep environment are associated with SUID
[3,4]. As noted earlier, side or prone sleeping is reported in 30% to 50% of these
deaths. Soft bedding, including sleeping on memory foam pads or mattresses,
may occlude an infant’s airway. Memory foam is particularly hazardous for
infants. It consists of polyurethane and has increased density and viscosity.
The pad molds to the warm body within minutes. An infant sleeping prone
on a memory foam pad is at risk for rapid airway obstruction. Prone sleeping
and a soft mattress increase the risk of SUID 20-fold and the risk is additive.
Bed sharing is reported to be noted in 50% of such deaths [105–109]. Sofa
sleeping is equally hazardous because infants can become wedged between
the cushions of the sofa. Hyperthermia is also associated with SUID. Death
scene investigations frequently reveal infants swaddled in thick polyethylene
blankets, sometimes with the face and airway partially or completely covered
by the blanket. Even mild infections increase the risk of SUID in certain vulner-
able populations, as noted earlier.
DEATH SCENE INVESTIGATION

Case of infant in day care: A 9-month-old Asian male died while in the care
of a baby-sitter. The infant had been born after a full-term normal vaginal
delivery with a birth weight of 3.7 kg (8 pounds 3 ounces). He and his
3-year-old sister were dropped off at the day care center at 8:20 AM in the
morning. The infant had a history of a cold for the antecedent week. He
was reported to have been placed in a crib at 9:30 AM, on his back. To
prevent him from rolling over, 2 large pillows were placed on either side
of his head, to wedge his head in position. At 10:00 AM his breathing
was noted to be wheezy. When checked 20 minutes later, he was not
breathing. 911 was called at 10:30 AM and paramedics were on the scene
at 10:39 AM. The infant was taken to a nearby hospital, where he was in
asystole and could not be resuscitated. He was pronounced dead at 12:01
PM. His autopsy revealed mild to moderate tracheobronchitis, with
an inflammatory cell infiltrate. Toxicology revealed doxylamine at 0.09
lg/mL in his heart blood. Doxylamine is not used in pediatrics but is
a common over-the-counter sleeping aid for adults. The patient’s level
was in the therapeutic range and would have had a sedating effect. This
patient’s death was attributed to the sedation and the presence of the
pillows, which led to asphyxia.
The death scene investigation has been pivotal in delineating factors that may
have contributed to the infant’s death. The initial study highlighting the value
of the scene investigation detected unanticipated environmental conditions
including increased levels of carbon monoxide, entrapment, accidental suffoca-
tion, and inflicted trauma [2]. The Centers for Disease Control as well as local
medical examiners have developed forms to facilitate collection of detailed epide-
miologic information as well as scene specifics in a concerted effort to learn more
about all SUID risk factors that may be preventable [110,111]. When the coroner
investigates a death, the cause as well as the mode or manner of death is assigned
to each case. The mode or manner of death falls into 1 of 5 categories: natural,
accidental, suicide, homicide, or undetermined. In the past, SIDS was moded
as natural, although the cause of SIDS (specific pathophysiology) was unknown.
Many SUIDs are now moded as undetermined when environmental factors such
as bed sharing may have played a role in the infant’s death. Current investigative
protocols include a list of critical specific questions that focus on the circumstances
surrounding the infant’s death.
As part of the scene investigation, families and other relevant witnesses are in-
terviewed in an effort to reconstruct what happened. Questions include, for
instance, when the infant was put to sleep, what position the infant was placed
in, who found the infant, and what position the infant was in when found.
Many jurisdictions include a reenactment using a doll to represent the infant.
The scene investigation is best performed close in time to the infant’s death so
that bedding is still in place. Such bedding is examined and photographed. Often
there is evidence of airway occlusion, which is indicated by the presence of blood-
tinged infant secretions on sheets, blankets, pillow cases, or caregiver’s clothing.
Figs. 2–6 are examples of scene reenactments that detect key contributing factors
to an infant’s death. Such a reenactment may reveal extrinsic factors that have
contributed to an infant’s death. As noted earlier, unsafe sleep surfaces, bed
sharing, and hyperthermia are frequent contributing factors. Other such factors
may be detected by autopsy or a careful review of the past medical or social
196 BERKOWITZ
Fig. 2. (A) Multiple blankets and cluttered environment in an infant’s crib. (B) Multiple blan-
kets and cluttered environment in an infant’s crib. Head of infant now seen under blankets.
(C) Multiple blankets and cluttered environment in an infant’s crib. Position of infant’s head
shows risk of rebreathing exhaled air. (Courtesy of the Los Angeles County Department of
the Coroner; with permission.)
history. Some but not all jurisdictions take radiographic images of deceased
infants less than 1 year of age to detect occult fractures. There should be a full skel-
etal survey, because a babygram is inadequate to detect subtle fractures, particu-
larly classic metaphyseal and rib fractures. The presence of healing fractures
precludes the diagnosis of SIDS and declaring the mode of death as natural.
The eyes may be removed and examined for the presence of retinal hemorrhages
Fig. 3. Hole in door. Evidence of physical violence (domestic violence) in the home. (Courtesy
of the Los Angeles County Department of the Coroner; with permission.)
Fig. 4. Mother fell asleep holding infant on a recliner after working a night shift and awoke to
find the infant wedged between the recliner and her back (doll reenactment).
and level of electrolytes and for toxicology. The presence of frank blood in the
nose or airway before any cardiopulmonary resuscitation (which indicates inten-
tional suffocation), previous nutritional or developmental abnormalities (failure
to thrive, environmental neglect), previous unexplained sibling death, history of
domestic violence, and previous involvement with Child Protective Services or
law enforcement may result in an SUID being moded as undetermined. The
goal of such a review is to reveal factors (particularly preventable ones) that could
have contributed to the death of the infant.
Fig. 5. Hyperthermia related to swaddling an infant in multiple layers. (Courtesy of the Los
Angeles County Department of the Coroner; with permission.)
198 BERKOWITZ
Fig. 6. (A) Infant placed on side, with blanket and pillow used to maintain position. (B) Infant
found prone with face in pillow. (Courtesy of the Los Angeles County Department of the
Coroner; with permission.)
UNSAFE SLEEP ENVIRONMENTS: BEYOND BACK TO SLEEP

Bed-sharing risks
Evidence continues to accumulate about the role of bed sharing and the risk of
SUID. The terminology about bed sharing should be clarified because studies often
use the term cosleeping and bed sharing interchangeably [105,107,109,112,113].
Room sharing is another term that is used. Cosleeping is less specific and may
be used to indicate bed sharing or room sharing. It is more precise to delineate
the exact sleep circumstances and use bed sharing to denote an infant sleeping in
an adult bed with another individual, adult, or child. Room sharing indicates the
infant is sleeping in the same room, but not in the same bed. Couch or sofa sleeping
indicates the infant was sleeping on a sofa. Couch or sofa sleeping is particularly
risky because sofas are usually soft and the infant may become wedged between
the cushions [114,115].
Numerous studies delineate an increased risk of SUID in infants who bed
share [105,107,109,116,117]. Studies from the Consumer Product Safety
Commission and the National Institute of Child Health and Human Develop-
ment for data collected between 1995 and 1998 showed that infant deaths while
in a crib was 0.63/100,000, whereas death in an adult bed was 25.5/100,000,
a 40-fold increase [118]. Studies from Europe (the European Concerted Action
on SIDS) reported an OR of 27.0 of succumbing to SUID for an infant
bed sharing in the first few weeks of life with an adult who smoked [54].
An increased OR was also noted for bed sharing with an adult who drank
alcohol, and the OR increased by 1.66 for each drink that was consumed.
Case-controlled studies from Scotland have reported similar findings: overall
OR for SUID related to bed sharing is 12.78; even if the parent is a
nonsmoker, the OR is about 8.01 to 8.51; couch sharing increases the OR to
66.9 [119–121].
Although the data about the risk of SUID associated with bed sharing seem
strong, there are challenges related to alternative opinions. Three areas that
need to be thoughtfully addressed relate to concerns about breastfeeding,
cultural considerations, and advice from grandparents.
Breastfeeding and bed sharing

Breastfeeding provides an infant and mother with numerous advantages both
in the early years as well as throughout life. These advantages are both medical
and emotional and relate to bonding and comportment [122]. Some breastfeed-
ing proponents believe that bed sharing is critical to successful nursing:
Bed sharing allows the mother to feed without fully awakening, contributing
to her total sleep. Some working mothers find that night feedings are the
only realistic way to maintain milk production, and sleeping with the infant
is the only way to combine breastfeeding, working and sleeping! [123]
Studies suggest there is a different positional relationship when a nursing

mother and infant bed share. McKenna [124] in a simulated sleep laboratory
has shown that nursing mothers and infants lie on their sides, with the infant
at the level of the mother’s nipple and not in a face-to face position. Previous
studies by Mosko and colleagues (including Dr McKenna) [125] showed that
bed-sharing mothers and infants spent 67% 27% of their sleep time in
a face-to-face position, with an average distance of 20 cm between the 2. As
a result, there were increased pockets of CO2, and although nonlethal, based
on level could affect a vulnerable infant [125]. McKenna discounts a role for
hypercapnia in nursing infants because of this observed difference in mother-
infant position [124].
Adult bedding, not just the presence of the adult, is a contributing risk factor,
and anyone counseling a nursing mother about the potential benefits of bed
sharing for nursing needs to be specific about the dangers of soft sleep surfaces
as well as bedding or the presence of other individuals in the bed [126,127].
It is also important to counsel breastfeeding mothers about other risks that
may mitigate the benefit against SIDS that has been attributed to breastfeeding.
These risks include maternal smoking, alcohol or substance abuse, and obesity.
The mother should be advised of alternative sleep surfaces that put the infant
close to the mother, although not in the bed. Commercial products have been
promoted as allowing for safe bed sharing (cosleeping), but such claims have
not been substantiated, and the Consumer Product Safety Commission has
stated that such claims are unfounded. There have been deaths of infants re-
ported for bed sharing using those products. Similarly, wedges and positioning
devices are promoted as helping to maintain an infant in a supine or side posi-
tion to reduce GER, SIDS, or accidental suffocation. The soft and compressible
nature of such devices may increase the risk of suffocation, particularly when
infants are placed prone or in a side position [127,128].
Other products that can be used adjacent to a bed include the traditional
bassinet, Moses basket, or specific side sleeper. For years, people have
recommended that drawers, removed from the dresser, can be placed on the
floor or chairs next to the bed to facilitate parental access to an infant, ensuring
that the infant is maintained in a safe environment. Other inexpensive products
include using a laundry basket to keep the baby in a safe and accessible sleep
environment.
200 BERKOWITZ
Parents are helped by being told what to do, not just what not to do. Positive
messages geared at facilitating breastfeeding and promoting safe sleep are
viewed as most helpful [127].
BED SHARING AND CULTURAL AND SOCIOECONOMIC

CONSIDERATIONS
The exact prevalence of bed sharing as well as other unsafe sleep practices is
unknown, although a survey performed in Los Angeles in 2007 showed that
such practices are highly prevalent, with 29% of mothers placing their infants on
their sides for sleep, 5.7% placing them on their stomach for sleep, and 79.1% saying
that their infant has ever slept with another person [129]. Table 1 shows that the
prevalence varies between different areas of Los Angeles County. Such variations
reflect both cultural practices as well as socioeconomic differences. Some studies
suggest significant differences in safe sleep practices between different racial and
ethnic groups [130]. Our experience in Los Angeles has been that bed sharing is
promoted as the norm in certain communities, and other factors including limited
space (eg, family living in a garage) and resources affect the acceptance of safe sleep
recommendations.
THE ROLE OF GRANDPARENTS

Grandparents provide a valuable resource to families, but may be less familiar
with changes in the understanding of injury prevention. Many of today’s
parents slept in the prone position and in a bed with parents or siblings. We
know that the risk of SUID can be reduced by modifying an infant’s sleep envi-
ronment. Grandparents, when available, should be involved in the educational
process. Much like the changes related to motor vehicle safety (eg, extending
the age for the use of booster seats), new knowledge can improve infant
survival. The Task Force of the AAP has developed an extensive list of recom-
mendations about reducing the risk of SUIDs from unsafe sleep.
RECOMMENDATIONS OF THE AAP TO PROMOTE SAFE SLEEP

Although we have reviewed much of the background information related to
promoting safe sleep, it is appropriate to conclude with the recent recommen-
dations from the AAP Task Force on Sudden Infant Death Syndrome [3,4].
These recommendations are listed in Box 1. The key message relates to supine
sleeping in an appropriate sleep environment, without soft objects (no pillows
blankets, stuffed animals, or bumpers), in a room with the parents but not in
their bed. Breastfeeding is highly recommended. Infants should not be over-
bundeled. The use of pacifiers and room fans seems to also have a mitigating
effect against SUID [131–133]. Open discussions including grandparents’ help
ensure that cultural considerations and family influences are adequately ad-
dressed. Tummy time while awake is also strongly recommended. Parents
can be advised to offer tummy time with each diaper change starting at birth,
and, of course, only when the infant is awake and being supervised.
SIDS, SUID, AND ALTES
Table 1
Sleep environment of infants and mothers from 2007 Los Angeles Mommy and Baby Survey
SPA 1
Baby’s sleep Los Angeles antelope SPA 2 san SPA 3 san SPA 4 SPA 5 SPA 6 SPA 7 SPA 8
environment county (%) valley (%) fernando (%) gabriel (%) metro (%) west (%) south (%) east (%) south bay (%)
Sleeps on their side 29.0 26.1 28.4 25.9 34.0 19.8 34.1 25.8 31.6
Sleeps on their back 65.3 67.5 64.6 68.2 61.6 73.7 60.9 67.9 64.1
Sleeps on their 5.7 6.4 7.0 5.9 4.4 6.5 5.1 6.3 4.3
stomach
Ever slept with 79.1 76.4 77.6 78.8 84.1 78.7 85.2 75.1 76.2
another person
Abbreviation: SPA, Service Planning Area.
Data from Los Angeles Mommy and Baby (LAMB) Survey 2007 Survey data by, race/ethnicity, Service Planning Area and Supervisorial District. Los Angeles, County Depart-
ment of Public Health. Maternal Child and Adolescent Health, programs. Available at: http://www.publichealth.lacounty.gov/mch/lamb/LAMBFAQ.html.
201
202 BERKOWITZ
Box 1: Recommendations of the AAP to reduce the risk of SUID

Back to sleep for every sleep
Use a firm sleep surface
Room sharing without bed sharing is recommended
Keep soft objects and loose bedding out of the crib.
Pregnant women should receive regular prenatal care
Avoid smoke exposure during pregnancy and after birth
Avoid alcohol and illicit drug use during pregnancy and after birth
Breastfeeding is recommended
Consider offering a pacifier at nap time and bedtime
Avoid overheating
Immunize infants
Avoid commercial devices marketed to reduce the risk of SIDS
Do not use home cardiorespiratory monitors as a strategy to reduce the risk of SIDS
Supervised, awake tummy time
Health care professionals endorse the SIDS risk-reduction recommendations
from birth.
Media and manufacturers should follow safe sleep guidelines in their
messaging and advertising.
Expand the national campaign to reduce the risk of SIDS.
Continue research and surveillance on risk factors, causes, and
pathophysiology.
Data from Task Force on Sudden Infant Death Syndrome. SIDS and other sleep-related infant
deaths: expansion of recommendations for a safe infant sleeping environment. Pediatrics
2011;128:e1341–67.
A QUALITY IMPROVEMENT MODEL

Although parents learn from multiple sources including family, friends, and the
media, nursery personnel including physicians have an excellent opportunity to
emphasize the safe sleeping recommendations. Nurses should always place
newborns on their backs and appropriately clothed. Birth hospitals should be
advised if an infant born at their facility has died as a result of an unsafe sleep
environment. Hospitals should be held accountable to improve their parent-
education program and continue to monitor their success as parent educations.
The goal should be zero infant deaths from unsafe sleep environments.
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Expanded Newborn Screening for

Inborn Errors of Metabolism
Overview and Outcomes
Angela Sun, MDa,1, Christina Lam, MDb,1,

Derek A. Wong, MDb,*
a
The Medical Genetics Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los
Angeles, CA 90048, USA; bDivision of Medical Genetics, Department of Pediatrics, David Geffen
School of Medicine at UCLA, 10833 LeConte Avenue, CHS 32-231, Los Angeles, CA 90095, USA
Keywords
Newborn screening Inborn errors of metabolism Tandem mass spectrometry
Outcomes
Key Points
Newborn screening has resulted in better outcomes for some but not all screened
disorders.
There are some identifiable causes of false negative and false positive results in
the newborn screen.
Newborn screening has identified patients with milder phenotypes that were
previously unknown or undiagnosed.
There are numerous ethical issues surrounding newborn screening.
INTRODUCTION
During the past decade, the use of tandem mass spectrometry (MS/MS) has led
to a remarkable increase in diseases detected by newborn screening [1]. An
expert panel recommended 29 disorders, including 22 metabolic disorders,
as primary targets, based on a stringent review process that included expert
review of screening availability, treatment efficacy, and other criteria [2]. In
addition, there were 22 secondary metabolic disorders that were detected as
part of the differential diagnosis of the primary disorders. This panel has
been adapted in some form by nearly all states. Several additional diseases
are being considered for inclusion in the newborn screening panel, including
lysosomal storage disorders.
1
These authors contributed equally to this work.
*Corresponding author. E-mail address: DAWong@mednet.ucla.edu

210 SUN, LAM, & WONG
Most newborn screening reviews have focused on the history of newborn

screening, a description of the technology, and ethical issues related to newborn
screening [1,3]. Recent articles have stressed the need for long-term outcome
studies that require solutions to complex problems of information exchange
and will take years to implement [4]. The aim of this review is to summarize
outcomes data that have accumulated over the past 25 years, concentrating on
recent data accumulated from disorders tested by MS/MS. The vast majority
of the published literature is based on clinically diagnosed cases. Although
most outcome studies on rare diseases are small and may not reach statistical
significance, the combined worldwide experience of newborn screening–diag-
nosed cases is important to parents of affected patients. This information includes
positive effects from early diagnosis, the presence of common minor disease
alleles, and both false-negative and false-positive screens. This article includes
data from disorders organized by category of illness and a brief discussion of
the ethics and the future of newborn screening.
CARBOHYDRATE DISORDERS–GALACTOSEMIA
Three enzymes are involved in the metabolism of galactose: galactose-1-
phosphate uridyltransferase (GALT), UDP galactose 49 -epimerase (GALE),
and galactokinase (GALK). Classic galactosemia is caused by deficiency of the
GALT enzyme, which leads to accumulation of galactose-1-phosphate. Alternate
pathways of degradation result in galactonate and galactitol production, the latter
causing cataract formation in the eye. Untreated classic galactosemia presents in
the neonatal period with vomiting, failure to thrive, jaundice, hepatomegaly,
bleeding diathesis, cataracts, and gram-negative sepsis. Later in life, patients
may develop intellectual disability, speech problems, tremor, ataxia, and prema-
ture ovarian insufficiency (in women) despite adequate dietary control.
Cataracts are the only early clinical manifestation of GALK deficiency. They
are typically bilateral, and onset may be in the neonatal period. GALE defi-
ciency is the rarest form of galactosemia and has been classified into 3 subtypes:
a generalized form, in which enzyme activity is severely reduced in all cells, and
the so-called peripheral and intermediate forms, characterized by varying
degrees of enzyme activity in red and white blood cells and other tissues.
Patients with the generalized form have features resembling classic galacto-
semia whereas those with the other 2 types generally remain healthy [5].
All states screen for classic galactosemia by measuring GALT enzyme
activity from dried blood spots and quantification of red blood cell galactose-
1-phosphate. Infants with classic galactosemia have enzyme activity less than
5% of control values, have galactose-1-phosphate levels greater than 20 mg/dL,
and are usually found to be homozygous for the Q188R or other severe muta-
tions [6]. When an individual is compound heterozygous for a severe mutation
and the Duarte variant (N314D mutation with associated promoter mutation),
the residual enzyme activity is approximately 25% of normal [7,8]. Infants who
receive an exchange transfusion for hyperbilirubinemia or other reasons may
have a false-negative newborn screen. Infants who have not been fed milk
SCREENING FOR INBORN ERRORS OF METABOLISM 211
and are exclusively on intravenous (IV) fluids with glucose may also have
a false-negative result [9]. Under these circumstances, if there is suspicion for
galactosemia, measurement of urinary galactitol can aid in diagnosis.
Treatment of classic galactosemia consists of lactose-free, soy-based infant
formulas and a lifelong galactose-restricted diet. Periodic measurement of
red blood cell galactose-1-phosphate levels allows therapy to be tailored
accordingly. There is no consensus regarding the necessity of treating patients
with Duarte variant galactosemia. Temporary lactose restriction for several
months to 1 year of life has been advocated by some investigators, but others
have suggested that the condition is benign and does not require intervention
[10,11].
Early diagnosis through newborn screening and institution of dietary
therapy can reduce life-threatening complications associated with classic galac-
tosemia, but long-term sequelae are not uncommon [8,12] and can include intel-
lectual disability in 30% to 50% of patients [13], cataracts, speech problems,
tremor, ataxia, low bone mineral density, and premature ovarian insufficiency,
which occurs in more than 80% of patients [14]. Mean IQ scores for patients
with classic galactosemia are in the 70s [15]. Patients with Duarte galactosemia
seem to have good outcomes regardless of whether or not a lactose-free diet is
followed during the first year of life [16]. One pilot study compared 17 lactose-
restricted Duarte variant patients to 11 patients on an unrestricted diet and
found no difference on IQ and language scores and no evidence of cataracts
up to 6 years of age. Although there were differences in adaptive scores, it
was difficult to draw conclusions at that age [16]. A second study showed
that there was the possibility of increased rates of speech and language issues
despite galactose restriction until 1 year of age, although the number of subjects
was small [17]. Determining the contribution of the Duarte variant to develop-
ment will require large scale, long-term outcome studies.
Galactose and galactose 1-phosphate screening is available in approximately
half of states, which allows them to screen for GALK and GALE deficiency.
Patients with generalized GALE and GALK deficiency require a galactose-
restricted diet. In infants diagnosed with GALK deficiency through newborn
screening and initiated on appropriate diet, cataracts and visual impairment
may be prevented [18]. Some patients with GALK deficiency develop pseudo-
tumor cerebri, microcephaly, intellectual disability, failure to thrive, hepatosple-
nomegaly, or hypoglycemia, but these complications are usually found in those
patients who are noncompliant with the diet [18,19].
Few patients with the severe generalized form of GALE deficiency have been
followed longitudinally, but some reports have documented developmental
delay, learning difficulties, and hearing loss, whereas other cases have had
normal psychomotor development with dietary intervention [20,21]. Patients
with generalized GALE deficiency typically do not develop premature ovarian
insufficiency [20]. Patients with the peripheral form of GALE deficiency remain
asymptomatic, and those with the intermediate form who are treated with die-
tary galactose restriction generally do well [5].
AMINO ACID DISORDERS

Phenylketonuria and hyperphenylalaninemia
Phenylketonuria (PKU) is the result of a deficiency of phenylalanine hydroxy-
lase, which converts phenylalanine to tyrosine. The major clinical phenotype of
untreated or partially treated PKU in infancy and childhood is profound intel-
lectual disability. Although adults and teenagers are less susceptible to the
neurotoxic effects of phenylalanine, many have difficulties related to increased
phenylalanine levels, such as problems with executive function.
Patients with impaired phenylalanine hydroxylase have been categorized by
their phenylalanine levels, although the classification is not consistent between
practitioners. In general, patients with phenylalanine levels greater than
600 lmol/L are considered to have PKU and may be subdivided into classic
(>1200 lmol/L) and mild (600–1200 lmol/L) forms. Infants and children with
these levels are restricted in their dietary phenylalanine intake, although control
usually worsens in older children and adults. Difficulty with compliance is
evident from a German study that showed that 28% of children under 10 years
of age and 79% of adolescents were found unable to meet their target phenylal-
anine level [22]. Recent studies have noted that even patients with early and strict
adherence to diet may have suboptimal cognitive outcomes, specifically, difficul-
ties in planning, organizing, working memory, and inhibitory control. Even with
a normal IQ, patients with PKU have a higher frequency of attention-deficit/
hyperactivity disorder, decreased autonomy, and school problems compared
with healthy controls or chronically ill peers. Also, from birth to 12 years of
age, each 100 lmol/L increase in phenylalanine levels is correlated with a 1.3-
point to 3.1-point decrease in IQ. A more stable phenylalanine level predicts
better outcome [23]. Although it is impractical to provide a detailed summary
of the PKU literature in this review, a review of the adult literature indicates
that PKU has a significantly detrimental effect on health outcomes [24]. Future
studies will concentrate on the effect of improvements in therapies, including
more palatable diets, cofactor therapy, and large neutral amino acids.
Patients with phenylalanine levels from 360 lmol/L to 600 lmol/L are classi-
fied as having mild hyperphenylalanemia. There is much debate as to whether
these patients require therapy [25,26], and resolution of this question awaits
larger studies. Occasionally, children with levels in the hyperphenylalaninemia
range have an increase to levels in the mild PKU range, so it is recommended
that these patients be carefully monitored up to 1 year of age. Additionally, hy-
perphenylalaninemia is a known teratogen, and pregnant women with PKU
should be carefully managed with a phenylalanine-restricted diet during preg-
nancy with the goal of normalizing phenylalanine levels. Breastfeeding a hetero-
zygous or normal infant with the breast milk of a mother with PKU is not
harmful [27].
The sensitivity of PKU newborn screening has been reported at 98% to 99%
[28]. The use of phenylalanine-to-tyrosine ratios can reduce false-positive rates
dramatically, especially in newborns with early hospital discharge [29]. Approx-
imately 1 in 70 or fewer cases of PKU are missed with the principal causes of
nondetection being noncompliance with screening, errors in screening proce-

dure, and occasionally true biologic variation, which occurs more frequently
in patients and with non-PKU causes of hyperphenylalaninemia.
Disorders of biopterin metabolism
Some patients with elevated phenylalanine have a deficiency of 1 of 4 enzymes
involved with biosynthesis or regeneration of tetrahydrobiopterin, a natural
cofactor for many enzymes, including phenylalanine hydroxylase. Patients
with biopterin disorders have a neurotransmitter deficiency that results in
many symptoms, including intellectual disability, convulsions, diurnal variation
of neurologic symptoms, oculogyric spasms, and microcephaly. Although
untreated patients usually die within a few years, treatment with replacement tet-
rahydrobiopterin and neurotransmitters may result in favorable outcomes [30].
The work-up of these disorders usually requires specialized urine and cerebro-
spinal fluid (CSF) pterin analysis and CSF neurotransmitter studies. In
a 30-year European study, 73 tetrahydrobiopterin-deficient babies were identi-
fied, representing approximately 3% of all patients with a positive phenylalanine
screen [31]. Clinical outcomes for newborn screening have been published for
one of the disorders, 6-pyruvoyltetrahydropterin synthase (PTPS) deficiency.
In Taiwan, 12 newborns were diagnosed with PTPS deficiency by newborn
screening. The mean IQ score of these 12 patients was 96.7 (range 86–119),
and all were asymptomatic except for 1 subject with transient borderline truncal
hypotonia [32]. There have also been several reports of less-favorable outcomes
in many of the newborn screen–diagnosed PTPS-deficient patients despite detec-
tion by newborn screening and early treatment, with some groups exhibiting
average IQs at 3 years of 76. Treatment regimens are not completely standard-
ized, and delays in treatment seem to have a large effect on outcome [33–35].
In a Swiss study of 36 patients, 20% were normal, 80% were delayed; and low
CSF neurotransmitter levels were correlated with developmental delay [36].
Tyrosinemia type I (hepatorenal)
Tyrosinemia type I is caused by a deficiency of fumarylacetoacetate hydrolase.
Affected patients may present in childhood with acute hepatic failure, coagulop-
athy, and/or renal tubular dysfunction and growth failure. Patients may smell like
boiled cabbage and usually have markedly elevated a-fetoprotein levels. Long-
term complications include porphyria-like neurologic crises, rickets, and hepatic
adenoma or hepatocellular carcinoma due to exposure to succinylacetone, the
major toxic metabolite in this condition. Early treatment with nitisinone, which
blocks formation of succinylacetone, presumably reduces the risk of adenoma
formation.
Newborn screening using tyrosine levels has significant limitations. In a UK
study, only 6 of 447 infants with elevated tyrosine levels assayed by chromatog-
raphy had persistently elevated tyrosine levels at 6 weeks of age [37]. Five of the 6
infants had tyrosinemia type I, 1 had tyrosinemia type III, and the
remainder presumably had transient tyrosinemia of the newborn or hepatic
dysfunction. Two other infants had a normal tyrosine at birth and presented
later. A more-sensitive method of screening for tyrosinemia type I was developed

using MS/MS analysis of succinylacetone [38]. The rapid succinylacetone rise
after birth was demonstrated in a patient with prenatally diagnosed tyrosinemia
type I who had a succinylacetone level of 87 lmol/L (normal <5 lmol/L) at 12
hours of age [39]. A retrospective analysis of diagnosed cases using a modified
version of this method decreased the false-negative rate from 28% with tyrosine
to 0% with succinylacetone [40]. In the New York State Newborn Screening
program, 2 of 5 infants with elevated succinylacetone had proved tyrosinemia
type I, although there was no mention of false-negative patients [41].
Patients with a confirmed diagnosis of tyrosinemia type I should be referred
to a metabolic specialist for initiation of nitisinone therapy as well as a low-
tyrosine/phenylalanine diet.
Tyrosinemia type II (oculocutaneous)

Tyrosinemia type II is caused by a deficiency of tyrosine aminotransferase.
Affected patients have corneal ulceration with scleral inflammation and pain in
the first year of life and plantopalmar keratosis after the first year of life [42].
Some patients have developmental delay. Treatment consists of a low-
tyrosine/phenylalanine formula. Although tyrosinemia type II is detected by
MS/MS screening, there is little published literature. Because the metabolic block
is in the first step of tyrosine metabolism, tyrosine levels presumably rise quickly,
without significant elevations in phenylalanine or methionine. An affected sibling
of a known tyrosinemia type II patient had a tyrosine level of 705 lmnol/L at 4
days of age (normal 30–100 lmol/L) and had normal development with intermit-
tent ocular symptoms [43,44]. Patients with positive newborn screens should be
tested for succinylacetone, and those with tyrosinemia type II should be started
on diet when the diagnosis is confirmed.
There are 4 reported cases of mothers with tyrosinemia type II and high
tyrosine levels during pregnancy. Their infants had microcephaly and develop-
mental delay [45,46].
Tyrosinemia type III

Tyrosinemia type III is a rarely described condition resulting from deficiency of
4-hydroxyphenylpyruvate dioxygenase. Affected patients may have develop-
mental delay, although it is unclear if there is benefit to treating with a low-
tyrosine/phenylalanine diet. Three of five patients detected by newborn
screening had developmental delay, although there was known parental consan-
guinity [47]. Six of seven surviving late-onset patients also had developmental
delay. Patients with hawkinsinuria, who have dominant mutations in the same
enzyme, are not expected to have tyrosine elevations high enough to be detected
by newborn screening [48,49].
Homocystinuria
Homocystinuria due to cystathionine b-synthase deficiency was one of the first
disorders considered for newborn screening. Untreated patients suffer from
thromboembolism, a Marfan-like phenotype, including dislocated lenses, and
developmental delay. Treatment includes betaine, which remethylates homocys-

teine to methionine, dietary restriction, and pyridoxine in responsive patients.
Newborn screening is based on a high methionine level and a high homocys-
teine level on follow-up testing. In Ireland, 15 of 18 patients treated from birth
with median homocysteine levels less than 11 lmol/L had no complications,
whereas 3 of 18 with presumably poorer compliance and higher homocysteine
levels developed ectopia lentis and/or developmental delay [50]. The compliant
patients had a mean IQ of 106 versus 81 in the noncompliant patients in the
same group [51]. Pyridoxine nonresponsive patients may have more severe
disease, and the compliant versus noncompliant IQ scores were 100 and 58
in one UK study [52]. There is also a significant increase in myopia in late
treated patients that occurs before lens dislocation [53].
Methionine screening is effective but not ideal for homocystinuria. Lowering
methionine cutoffs from 2 mg/dL to 1 mg/dL in the New England states
increased the identified infants by 64%, at the expense of increasing the false-
positive rate from 0.006% to 0.03%. An estimated 20% of patients, however,
were missed by the new cutoff [54].
Methionine adenosyltransferase and related disorders
Methionine adenosyltransferase types I and III are isozymes that catalyze the first
step in the conversion of methionine to homocysteine. Affected patients have
high methionine levels, but their homocysteine levels are usually normal or
less elevated than patients with homocystinuria, and S-adenosylmethionine
levels are low. Some patients have a dominant R264H mutation and have
a benign clinical course [55]. Although most patients with 2 mutations are also
asymptomatic, a few patients with high methionine levels (>1000 lmol/L)
may have cerebral edema and demyelination that may respond to a restricted
diet and/or adoMet administration [56]. Some centers are treating methionine ad-
enosyltransferase types I/III–deficient patients [57], whereas others who have
a predominance of R264H patients are not [58]. One patient with delayed mye-
lination responded to adoMet therapy without methionine restriction [59].
Although other defects in the pathways may cause elevated methionine in the
newborn period, no newborn screening cases have been reported for glycine
N-methyltransferase deficiency. S-adenosylhomocysteine hydrolase deficiency,
which causes myopathy and developmental delay, is also detectable by newborn
screen [60,61]. It is unclear whether this disease is a treatable condition.
Biotinidase deficiency
Biotinidase deficiency results in reduced or absent biotin recycling, leading to
excess degradation of several critical holocarboxylase enzymes. Infants or chil-
dren with profound biotinidase deficiency (<10% enzyme activity) present
with hypotonia, ataxia, seizures, hearing loss, visual loss, eczema, and alopecia.
Patients with partial biotinidase deficiency (10%–30% enzyme activity) are
usually asymptomatic, although some patients may develop symptoms during
illness [62]. Therapy with biotin is curative and may reverse some, but not all,
symptoms. In particular, hearing loss develops in 75% of untreated patients
with profound biotinidase deficiency and does not resolve unless treated early in
life [63].
Newborn screening for biotinidase deficiency by colorimetric assay began in
1984, and screening programs were set up worldwide [64]. In an Austrian
study of patients with profound biotinidase deficiency, 12 patients who started
early biotin therapy (after newborn screen) had normal IQs, whereas 9 patients
with delayed therapy or poor compliance had IQs 2 SDs below the mean [65].
Similar results were reported from a Swiss study, in which all 24 presympto-
matically treated profound biotinidase deficient patients were normal, whereas
others had symptoms, including optic atrophy [66]. One patient with an incon-
clusive newborn screen who did not receive confirmatory testing presented
with brain MRI changes, irreversible hearing loss, and intellectual disability
at 15 months of age [67].
Maple syrup urine disease

Maple syrup urine disease (MSUD) is a disorder with deficient branched-chain
a-keto acid dehydrogenase complex, resulting in the accumulation of leucine,
isoleucine, and valine along with their a-keto acids as well as a characteristic eleva-
tion of alloisoleucine. Elevated leucine levels result in brain injury and neurologic
symptoms. Eighty percent of patients with MSUD have an infantile presentation
with poor feeding, lethargy, and opisthotonus [68]. The remainder of MSUD
patients have variant forms, with less severe metabolic crises than in classic
patients. Intermediate MSUD is characterized by growth deficiency and develop-
mental delay, whereas intermittent MSUD patients present with illness or fasting-
induced episodes of ketoacidosis, ataxia, and encephalopathy. These patients
may have normal or only slightly elevated plasma concentrations of the
branched-chain amino acids when well. Treatment of MSUD consists of a special
diet, fasting avoidance, thiamine, and liver transplantation in severe cases.
Newborn screening for MSUD results in earlier diagnosis, lower plasma
leucine levels at the time of diagnosis, fewer clinical symptoms at the time of diag-
nosis, and faster reduction of plasma leucine levels below 1000 lmol/L in
screened patients compared with those who are clinically ascertained [69]. It
has been shown in patients with classic MSUD that long-term metabolic control
has an impact on cognitive function, specifically, that plasma leucine levels and IQ
scores are inversely related [70]. Early diagnosis of MSUD in the newborn period
and aggressive management during illnesses can result in a low rate of hospitali-
zations and good neurologic outcomes [68,71]. Some patients, however, still
suffer from metabolic crises and life-threatening cerebral edema [71,72].
Patients with intermediate MSUD that is not detected on newborn screening
typically have baseline cognitive impairment at the time of clinical diagnosis
and may not show improvement with dietary therapy [68,73,74]. Individuals
with intermittent MSUD suffer metabolic crises that can be equal in severity
to those with classic MSUD; cerebral edema and death can occur in this group
[75–77]. With dietary treatment, patients with intermittent MSUD can have
normal psychomotor development [68].
The newborn screen for MSUD involves measurement of plasma amino

acids from dried blood spots. Variant forms of MSUD with partial enzyme
deficiency may be missed on newborn screening [73,78]. In addition, false-
positive results may be seen in patients with hydroxyyprolinemia, which is
considered a benign condition [79]. The use of alloisoleucine as a second-tier
test is a promising approach that will allow lowering of cutoffs to increase detec-
tion of variant MSUD while at the same time reducing false-positive cases [80].
Urea cycle disorders

The urea cycle is responsible for the disposal of excess nitrogen from the break-
down of protein and other nitrogen containing molecules. There are 6 known
enzymes and 2 transporters that are essential to urea cycle function. The classic
presentation of inborn errors in most of these molecules results in neonatal hy-
perammonemia, vomiting, lethargy, coma, and death. Partial deficiency of
these enzymes may result in delayed onset of symptoms, including protein
intolerance, neurologic symptoms, and developmental delay. Exceptions to
these presentations are discussed later.
Newborn screening for urea cycle disorders (UCDs) has not enjoyed the
same success as in other inborn errors of metabolism. The prediction made
by Claude Bachmann [81] that greater than 50% of symptomatic patients
would present before the availability of newborn screening results has been
borne out by experience. During the first several years of Australian MS/MS
screening, 19 of 28 patients with detectable UCDs presented by day 5, and 8
died by age 7 days [82].
Any newborn with a positive newborn screen for a UCD with symptoms, such
as poor feeding, vomiting, or lethargy, should have emergency evaluation with
metabolic consultation. An ammonia level may be recommended for symptom-
atic patients. Therapy may involve IV glucose administration, short-term protein
restriction, nitrogen scavenging medications, and dialysis.
Ornithine transcarbamylase deficiency

Ornithine transcarbamylase deficiency, an X-linked disorder, is the most
common UCD and accounts for a majority of early presenting UCDs. Patients
with ornithine transcarbamylase deficiency are detected with low citrulline
levels. Although newborn screening is unreliable for ornithine transcarbamy-
lase deficiency (especially in female newborns), there is no published informa-
tion on the sensitivity of citrulline levels. Low citrulline levels may be seen with
low protein intake [83] and with intestinal disease [84], and the high false-
positive rate is borne out in the authors’ experience.
Citrullinemia
Citrullinemia (argininosuccinate synthase deficiency) is detected with a high
citrulline level. A German study revealed 12 patients with citrullinemia, 3
patients with arininosuccinate lyase deficiency, and 2 false-positive results
[85]. Only 4 of 12 citrullinemia patients had classic neonatal-onset citrullinemia,
with the others having a normal course. Further studies show that both white
[86] and Asian [87] patients have mild variants of citrullinemia whose severity
cannot be predicted by citrulline levels. Some of these patients did not develop
symptoms despite lack of diet.
Argininosuccinate lyase deficiency
Argininosuccinate lyase deficiency is also detected with elevated citrulline
levels, although published sensitivity data are lacking. There have been 2
studies of outcome measures of argininosuccinate lyase deficiency newborn
screening, neither of which used citrulline as a screen. The US study screened
with argininosuccinate levels—8 of 13 patients had normal development, and 4
of the remaining 5 patients with developmental delay had discontinued their
diet at an early age [88]. In Austria, newborn screening for argininosuccinate
lyase deficient using enzyme assay was conducted over 27 years, with 1 patient
diagnosed clinically before the newborn screening results and the other 23 all
detected through elevated argininosuccinic acid levels [89]. Approximately 60%
of the newborn screening–positive cohort had normal intelligence, and the
results were suggestive of a positive effect on outcome.
Other urea cycle disorders
Arginase deficiency patients often present with lower-extremity spasticity, and
many have normal ammonia levels. Multiple patients with arginase deficiency
have been detected by newborn screening in both the United States [90] and
in Mexico. Early diagnosis presumably would help outcomes, but there are no
long-term data. Hyperammonemia-hyperornithinemia-homocitrullinuria syn-
drome may present with elevated ornithine levels in the newborn period, but at least
2 Canadian patients with later-onset hyperammonemia-hyperornithinemia-
homocitrullinuria deficiency had low ornithine values on newborn screening
[91]. At this time, carbamoyl phosphate synthetase 1 deficiency and N-acetyl gluta-
mate synthase deficiency [92] are not screened using current technology.
Citrin deficiency
Citrin deficiency is a condition that may present with neonatal intrahepatic
cholestasis that usually resolves spontaneously. In teens and adults, a group
of symptoms, including carbohydrate intolerance, abnormal behaviors, and
seizures, previously known as citrullinemia type II, may occur. Because citrin
is an aspartate glutamate carrier, its absence results in lack of cytosolic aspar-
tate, reduced argininosuccinate synthesis, and increased citrulline. Newborns
with citrin deficiency may have elevated citrulline and methionine, with smaller
elevations of phenylalanine, tyrosine, and arginine, and elevation in galactose
and serum bile acids [93]. Citrulline, however, remains the critical metabolite
for newborn screening.
ORGANIC ACID DISORDERS

Overview
Organic acidemias are a group of disorders that have in common the excessive
excretion in the urine of an acidic biochemical compound lacking nitrogen. Many
of these disorders result from the dysfunction of an enzyme involved in amino acid
degradation after the nitrogen of the amino acid is transferred away. The majority of
these disorders are autosomal recessive in their inheritance, with the exceptions of
Barth syndrome (also known as 3-methylglutaconicaciduria type II) and 2-methyl-3-
OH butyryl-CoA dehydrogenase deficiency, which are X-linked.
Organic acidemias have a range of clinical symptoms. A subset of patients
presents during the neonatal period with vomiting, poor feeding, toxic encepha-
lopathy, ketoacidosis, seizures, poor tone, and lethargy progressing into coma.
Another subset of patients presents later during childhood into adulthood with
intellectual dysfunction, ataxia, focal neurologic signs, Reye syndrome, recur-
rent ketoacidosis, or psychiatric symptoms. With newborn screening, it has
also been observed that some patients remain asymptomatic into adulthood.
The pathophysiology of many of the clinical findings is not known, but hypoth-
eses include toxic effects of accumulated compounds, oxidative stress, deficiency
of an essential downstream compound, and impaired mitochondrial function.
Treatment principally involves preventing catabolism during times of increased
metabolic stress (febrile illnesses or episodes of vomiting/diarrhea/poor oral
intake), dietary restriction of precursor amino acids, and use of adjunctive
compounds to dispose of toxic metabolites or increase activity of deficient
enzymes. Dietary and medication management may not be required for all types
of organic acidemias and is a topic of much ongoing research [1,94].
Newborn screening for organic acidemias is accomplished by MS/MS to
measure the levels and patterns of carnitine esters in dried blood spots. There
are 10 organic acidemias classified as core conditions and 7 classified as secondary
conditions on the mandatory screening list for the United States. Several organic
acidemias, not part of this list, have been screened for in smaller forums [95].
Descriptions and outcome data of individual organic acidemia are detailed below.
Propionic acidemia
Propionic acidemia is caused by a deficiency of propionyl-CoA carboxylase, an
enzyme involved in the metabolism of valine, isoleucine, and a variety of other
metabolites. There is little published literature on propionic acidemia and
newborn screening. In Japan, a project found a high incidence of a mild allele
Y235C in PCCB, which codes for one of the subunits of the enzyme. All homo-
zygotes and compound heterozygotes with this mutation were asymptomatic
[96]. One German study showed that patients with 1 of the 3 main
branched-chain organic acidemias (propionic, methylmalonic, and isovaleric)
had better outcomes at an average of 1.7 years of age. Specifically, there
were fewer patients with neurocognitive delay, decreased mortality, and fewer
decompensations in the newborn screening compared with the clinically iden-
tified cases [97]. Propionylcarnitine is one of the analytes most frequently
responsible for false-positive results, with some studies showing a positive
predictive value as low as 4% [98], although adjusted cutoffs have substantially
altered this value. Patients with hyperbilirubinemia may have an unexplained
increase in propionylcarnitine.
Isovaleric acidemia
Isovaleric acidemia is caused by a deficiency of isovaleryl-CoA dehydrogenase,
an enzyme involved in leucine metabolism. In Bavaria, no false-negative cases
were detected from 1999 to 2010. The positive predictive value for newborn
screening for isovaleric acidemia in various studies ranged from 1.8% to
10.8% [99]. Prior to newborn screening, half of the reported cases presented
during the neonatal period with the distinctive feature of a ‘‘sweaty socks’’
smell, and the other half presented later with chronic intermittent symptoms,
including failure to thrive, developmental delay, and episodes of acidosis and
metabolic decompensation [100]. Since expanded newborn screening began,
a significant cohort of patients with isovaleric acidemia has been identified
with an A282V mutation that seems to confer a mild phenotype. Many patients
in Europe, the United States, and Asia with this mutation remained asymptom-
atic, and some did not require treatment [101–103].
Methylmalonic acidemia types mut0/mut-
Methylmalonic acidemia types mut0/mut- (MMA) is caused by a defect in meth-
ylmalonyl CoA mutase, which is involved in the metabolism of branched-chain
amino acids. The clinical course of MMA differs from other organic acidurias in
that tubulointerstitial nephritis with progressive renal failure is a frequent compli-
cation. There have been at least 2 published false-negative screens for MMA
[104]. Several groups have attempted to improve the sensitivity through
modeling algorithms and second-tier testing, but none is used universally
[98,105]. Dionisi-Vici and colleagues [97] reported that expanded newborn
screening decreases early mortality and symptoms at diagnosis and improves
short-term neurodevelopmental outcome, although only 4 patients with MMA
were in the reported series. In the clinically diagnosed cohort, signs of chronic
renal failure were detectable in all MMA patients after age 6 compared with 1
subject with mild renal dysfunction of 4 in the screened group. Four patients
with severe MMA detected by newborn screening in Taiwan at an average of
age 10 days all had varying degrees of hyperammonemia (127–1244 lmol/L)
during their initial episode. Despite the lack of further episodes of metabolic
decompensation, all 4 patients had a developmental quotient of 50 when assessed
at 8 months to 2 years [106]. A case report of MMA patients who developed renal
failure and neurologic deterioration after liver transplantation underlines the
difficulty in changing outcomes in severe MMA patients [107].
Cobalamin A/B/C/D1
Cobalamin is a cofactor of several enzymes, including methylmalonyl-CoA
mutase and methionine synthase. Cobalamin A/B/C/D1 are inborn errors
involving the transport, synthesis, or metabolism of cobalamin that have
increased methylmalonic acid and homocysteine. Clinically, these disorders
each have variable phenotypes, although in general the symptoms are more
of a progressive neurologic deterioration rather than metabolic decompensa-
tion. Treatments include intramuscular hydroxycobalamin, and betaine to
facilitate conversion of homocysteine to methionine. Published newborn
screening clinical outcomes are only available for cobalamin C deficiency. In

New York, 8 of 10 patients identified through newborn screen were started
on a protein-restricted diet and hydroxycobalamin within the first 2 months
of life, and betaine was started later in 7 of 8 cases for refractory hyperhomo-
cysteinemia. In spite of early treatment, all 3 of the patients with the common
271dupA genotype had developmental delay [108]. A maternal diagnosis of
cobalamin C deficiency was made through an infant who screened positive
with low carnitine. The only symptoms the mother had were tingling of the
hands and normocytic anemia [109].
3-methylcrotonyl-CoA-carboxylase deficiency
3-Methylcrotonyl-CoA-carboxylase deficiency is caused by deficiency of an
enzyme involved in leucine degradation. Most patients are asymptomatic
throughout their lives, but a few have presentations similar to patients with
other organic acidurias, including episodic ketoacidosis, developmental delay,
failure to thrive, neurologic complications, Reye-like syndrome, and early
death [27]. Treatment is controversial, but the most recent recommendations
include giving patients fasting precautions, instituting an emergency protocol,
and considering carnitine supplementation, especially if patients are carnitine
deficient [110]. Many maternal cases of 3-methylcrotonyl-CoA-carboxylase
deficiency have been diagnosed as a result of newborn screening and these
mothers are asymptomatic or only mildly symptomatic (nausea with high
protein intake) with and without treatment [111,112]. Unfortunately, not all
newborn screen–detected cases have been asymptomatic [113]. Germany
removed 3-methylcrotonyl-CoA-carboxylase deficiency from their mandated
newborn screening list because 29 of 31 cases were asymptomatic, whereas
the remaining 2 cases exhibited mild symptoms [114].
HMG-CoA-lyase deficiency
HMG-CoA lyase deficiency is a disorder of leucine and ketone metabolism.
The disorder is usually well tolerated if treated. If untreated patients present
with symptoms similar to fatty acid oxidation disorders, including hypoketotic
hypoglycemia, seizures, and developmental delay. Management is similar to
that of a fatty acid oxidation disorder with fasting avoidance, IV carbohydrate
administration during metabolic crises, avoidance of excess dietary fat intake,
and possible carnitine supplementation [27]. There are no published data on
clinical outcomes of cases detected through newborn screening.
Holocarboxylase synthetase deficiency

Holocarboxylase synthetase (HCS) deficiency is caused by deficiency of the
enzyme that catalyzes biotin incorporation into 4 different carboxylases. In
addition to the typical symptoms of organic acidemias, alopecia and an eczem-
atous rash are more prominent, similar to biotinidase deficiency. Oral biotin is
the mainstay of therapy in this disorder. Both partial and profound holocarbox-
ylase synthase deficiency can be detected by newborn screening. Depending on
the cutoff set for hydroxyisovalerylcarnitine (C5-OH), however, cases of HCS
deficiency can be missed; there are known cases in which the C5-OH level and
C5-OH/free carnitine (C0) ratio in the dried blood spots were low [115].
Although no large outcomes series have been published on HCS deficiency
diagnosed through newborn screening, there is concern that these individuals
may develop complications because some patients are only partially responsive
to biotin. Because many cases respond well to biotin, however, the hope is that
newborn screening will decrease mortality and morbidity [116]. The few re-
ported cases of HCS deficiency diagnosed through newborn screening have
had normal developmental outcomes at their latest follow-up at the age of 3
years. Symptoms, such as eczema, do occur when there is a lapse in treatment
[115]. There is at least one asymptomatic maternal case of HCS deficiency diag-
nosed because her infant screened positive for C5-OH [117].
2-methyl-3OH butyryl-CoA dehydrogenase deficiency
2-methyl-3OH butyryl-CoA dehydrogenase deficiency is a defect of isoleucine
degradation and mitochondrial b-oxidation. The clinical phenotype is predomi-
nantly neurologic and is characterized by normal or mildly delayed development
in the first months or year of life, followed by regression. Other symptoms include
seizures, hypotonia, optic atrophy, pigmentary and nonpigmentary retinopathy,
sensorineural deafness, ataxia, dystonia, metabolic acidosis, hyperammonemia,
and changes on brain MRI. There is no known effective treatment. Isoleucine
restriction has been attempted but was unsuccessful [118]. In Germany, only 1
case of MHBD deficiency was diagnosed in more than 800,000 newborns, and
that patient showed progressive neurologic impairment [119].
2-methylbutyrylglycinuria
2-Methylbutyrylglycinuria (MBG) is caused by a deficiency of an enzyme
involved in isoleucine and straight-chain acyl-CoA esters metabolism. Clinical
phenotype described before newborn screening is typical for an organic acidemia
[118,120–123]. Given the low incidence of this condition and lack of comprehen-
sive long-term outcomes, the need for therapy is unclear. Early cases were treated
with low-protein diet, fasting avoidance, and carnitine supplementation. Because
of the seemingly benign nature of the cases detected by newborn screening,
however, some experts advocate a normal diet and only maintaining vigilance
during intercurrent illness [124,125]. There has been at least one report of this
disorder being missed on newborn screening [126] and one asymptomatic
mother diagnosed with MBG because her child was found to also have MBG
[123]. The Wisconsin Newborn Screening Program has detected an unusually
large number of MBG cases among the Hmong population. At the time of diag-
nosis, all 27 cases were asymptomatic and were started on a 1.5-g/kg to 1.8-g/kg
protein restriction and L-carnitine supplementation with variable compliance.
The only symptoms noted in the Hmong cohort were 2 infants with transient
hypotonia, and the phenotype of the non-Hmong (white) infant was dominated
by his additional diagnosis of nonketotic hyperglycinemia [127]. There have
been several other reports of MBG cases diagnosed through newborn screening,
and all have been asymptomatic [124,128].
b-ketothiolase deficiency
b-Ketothiolase deficiency (BKD) is caused by a defect in the last step of isoleu-
cine degradation [118]. Clinical symptoms and treatment are typical for an
organic acidemia. Carnitine therapy can be considered. Unlike many organic
acidemias, however, frequent feeding is not required, and in addition to
protein-rich diets, patients must avoid ketogenic diets. Few cases have been
diagnosed through newborn screening. There have been cases, both symptom-
atic and asymptomatic, of BKD missed by newborn screening [129]. In
Australia only 1 case out of 137,120 newborns screened was diagnosed
[130]; in Italy, 1 asymptomatic case of BKD was found of 8800 dried blood
samples during the pilot newborn screening program [131]; in Minnesota,
the single BKD patient reported is asymptomatic [129].
Glutaric aciduria type I
Glutaric aciduria type I (GA-I) is caused by a deficiency of an enzyme involved
in lysine oxidation and in tryptophan and hydroxylysine metabolism. Typical
symptoms include macrocephaly with minor neurologic signs, followed by
a catastrophic encephalopathic episode with basal ganglia stroke during respi-
ratory or gastrointestinal illness. Patients experience a variety of neurologic
symptoms, including hypotonia, dystonia and dyskinesia, loss of head control,
seizures, opisthotonus, and rigidity. The risk of metabolic crises is greatly
decreased after age 6, but 10% to 20% of patients have had neurologic disease
without any documented encephalopathic crisis. Treatment involves a special
diet, carnitine, and the usual principles in treating organic acidurias [132].
There is a substantial proportion of GA-I patients who have been missed by
newborn screening [132–134]. Despite treatment, many patients with GA-I
experience permanent neurologic sequelae, especially motor deficits, and
abnormal findings on brain imaging [135–140]. With prompt and early treat-
ment, however, the number of acute encephalopathic crises significantly
decreases, the proportion of patients with normal neurologic outcomes is high-
er, and the neurologic outcome is improved [137,141–143]. There have also
been cases of asymptomatic maternal GA-I diagnosed through newborn screen
programs due to low carnitine levels in their infants [144,145]. The unaffected
children of these mothers may have brain MRI abnormalities, possibly because
of the abnormal prenatal environment. These MRI findings, however, are not
the same as those seen in GA-I patients [146].
Isobutyrylglycinuria
Isobutyrylglycinuria is caused by deficiency of an enzyme involved in valine
catabolism. This disorder is rare and its clinical significance is uncertain. Revers-
ible cardiomyopathy, anemia, carnitine deficiency, ketoacidosis, facial dysmor-
phism, cerebral anomalies, and mild developmental delay have been noted
[147]. Appropriate management is also unclear, but carnitine supplementation
and protein restriction may be beneficial [125]. The majority of patients diag-
nosed through newborn screening are asymptomatic, some even without treat-
ment [148–150]. Patients with symptoms most commonly experience muscular
hypotonia, emesis, intermittent lethargy, mild developmental delay, and reduced

carnitine levels [148,149,151,152]. Some of these cases are confounded by coex-
isting conditions, however, such as, GA-I and chromosomal abnormalities
[149,153].
3-methylglutaconic aciduria
3-Methylglutaconic aciduria is a clinically heterogeneous group of disorders
with the common feature of increased excretion of 3-methylglutaconic acid
in the urine. It has been divided into 4 types: type I—3-methylglutaconyl-
CoA hydratase deficiency; type II—Barth syndrome; type III—Costeff optic
atrophy syndrome; and type IV—unclassified [154]. Each subtype has a different
clinical spectrum. Type I 3-methylglutaconic aciduria is the only type detect-
able by newborn screening, and there is one case report that describes a single
patient diagnosed by newborn screening with type I 3-methylglutaconic acidu-
ria who was asymptomatic at 2 years of age [155].
Ethylmalonic encephalopathy
Ethylmalonic encephalopathy is caused by deficiency of a mitochondrial sulfur
dioxygenase, which results in an inability to detoxify sulfide. Affected individ-
uals manifest with encephalopathy, neurodevelopmental regression, seizures,
petechiae, orthostatic acrocyanosis, and chronic diarrhea, eventually evolving
into spasticity, dystonia, and other pyramidal and extrapyramidal signs. Brain
MRI may reveal atrophy and signal hyperintensity on T2-weighted images in
the basal ganglia. No universal treatment protocol currently exists but carni-
tine, riboflavin, coenzyme Q10, metronidazole, N-acetylcysteine, and vitamin
supplements have been used with varying degrees of success [156,157]. Individ-
uals have been reported with mild disease and normal biochemical markers
during periods of wellness [158], which raises concern for potentially false-
negative results from newborn screening. Although newborn screening has
identified mildly affected individuals, there have also been cases of recurrent
metabolic crises ultimately resulting in neurologic deterioration and death
[159,160].
Malonic aciduria
Malonic aciduria is caused by a deficiency of malonyl-CoA decarboxylase, the
enzyme that catalyzes the conversion of malonyl-CoA to acetyl-CoA and
carbon dioxide. Prior to newborn screening, patients were reported to have
developmental delay, hypotonia, hypoglycemia, metabolic acidosis, cardiomy-
opathy, gastrointestinal distress, structural brain abnormalities, and early
death. The majority of the cases were mild [27,161]. No effective treatment
has been defined. A high-carbohydrate diet low in long-chain fatty acids with
medium-chain triglyceride supplementation has been attempted with varied
success [27]. Only one patient with malonic aciduria detected by newborn
screening has been described and that patient was asymptomatic at 6 months
of age despite an episode of acute gastroenteritis [162].
DISORDERS OF FATTY ACID OXIDATION

Overview
Fatty acids are a source of energy when glucose is not available, such as during
fasting or exercise. Although all the disorders of fatty acid oxidation are character-
ized by a basic defect in energy production, the individual disorders are nonethe-
less varied in their clinical presentation and biochemical profiles. In general, the
predominant signs and symptoms include fasting intolerance, nonketotic or hypo-
ketotic hypoglycemia, lethargy, myopathy involving the skeletal and/or cardiac
muscles, and hepatic dysfunction, sometimes presenting as a Reye-like syndrome.
Other symptoms that are present in some, but not all, disorders are rhabdomyol-
ysis, cardiac arrhythmias, and organ malformations (eg, carnitine palmitoyltrans-
ferase type II [CPT-II] deficiency and glutaric aciduria type II [GA-II]).
Retinopathy and peripheral neuropathy are complications unique to long-chain
3-hydroxyacyl-CoA dehydrogenase (LCHAD) and trifunctional protein (TFP)
deficiency. A distinguishing feature of medium/short-chain 3-hydroxyacyl-CoA
dehydrogenase (M/SCHAD) deficiency is the association of hypoglycemia with
hyperinsulinism. As a whole, disorders of fatty acid oxidation are believed to
account for 1% to 3% of cases of sudden infant death syndrome [163].
Fatty acid oxidation defects give rise to several maternal complications. An
affected fetus can produce disease in an otherwise healthy mother. Short-chain
acyl-CoA dehydrogenase (SCAD) deficiency, medium-chain acyl-CoA dehydro-
genase (MCAD) deficiency, CPT type I (CPT-I) deficiency, LCHAD deficiency,
and TFP deficiency have all been reported to cause maternal acute fatty liver of
pregnancy and/or HELLP (hemolysis, elevated liver enzymes, and low platelet
count preeclampsia) syndrome [164–169]. Second, newborn screening has re-
sulted in the diagnosis of mothers with inborn errors of metabolism through
an abnormal result in their infants. In particular, babies who screen positive
for carnitine transporter deficiency (CTD) have led to the diagnoses of maternal
CTD [170,171], 3-methylcrotonyl-CoA carboxylase deficiency [111,172], GA-I
[145], and MCAD deficiency [173]. Maternal very-long-chain acyl-CoA dehy-
drogenase (VLCAD) deficiency has been diagnosed through an abnormal
newborn screen in an infant who was later identified as a carrier [174].
Treatment of fatty acid oxidation disorders is primarily aimed at maintaining
a constant energy supply for the body by providing feedings at regular intervals to
avoid a catabolic state. The diet should be high in carbohydrates and low in fats
with restriction of long-chain fats. Patients with specific types of fatty acid oxida-
tion defects may also require supplementation with medium-chain triglycerides
(MCTs) oil and carnitine. During an acute illness, patients should be taken to
the nearest emergency department for evaluation, IV hydration, and glucose
infusion. Care should be coordinated with a metabolic team, including a geneti-
cist, nurse, and dietitian.
SCAD deficiency
Newborn screening has missed cases of SCAD deficiency [175] but overall has
identified more cases than previously thought to exist. The infants picked up
by screening may have 2 mutations in the ACADS gene or 1 mutation with

a common polymorphism. The c.625G>A and c.511C>T polymorphisms are
present in 29% of the US white population [176]. A large majority of patients
with SCAD deficiency are asymptomatic, which has led to the suggestion by
some that SCAD deficiency should not be included in newborn screening panels
[177]. The general outcome for patients with SCAD deficiency identified through
newborn screening programs is good, and symptoms, if present, tend to improve
with age [178,179]. Given the benign clinical course and the questionable benefit
of chronic therapies, the need for long-term treatment has been debated [179].
Longitudinal follow-up of these cases is necessary to fully characterize the natural
history of the disorder in this cohort. Those patients diagnosed based on clinical
ascertainment were reported to have hypotonia, hypoglycemia, lethargy, and
developmental delay; however, confounding factors, such as prematurity and
perinatal asphyxia, must be considered in some of these cases [175].
MCAD deficiency
Prior to the advent of newborn screening, MCAD deficiency was associated with
a 19% to 25% mortality rate as well as a substantial risk of comorbidities, including
developmental delay, behavioral problems, chronic muscle weakness, and failure
to thrive [180,181]. Since the institution of newborn screening programs, the rate
of detection of MCAD deficiency has approximately doubled [182]. Screened
patients generally have an excellent prognosis and experience fewer clinically
significant disabilities than those diagnosed clinically [183]. One study showed
the relative risk of an adverse event by age 2 years in a screened versus unscreened
cohort was 0.26 (95% CI, 0.07–0.97) [182]. The number of hospital admissions
was fewer and length of stay was shorter in the screened versus unscreened group.
Differences in intellectual function and adaptive behavior were not statistically
significant between the 2 groups. Unfortunately, sudden infant death syndrome
may be the first presentation of MCAD deficiency [184,185], even in those cases
ascertained through newborn screening [186]. Thus far, no false-negative results
have been reported from newborn screening [182,187,188]. False-positive results
may result from infants being treated with MCT oil or valproic acid.
VLCAD deficiency
Newborn screening can miss cases of VLCAD deficiency if an infant is well fed,
on IV glucose infusion, or has a mild phenotype [189]. False-negative results have
been reported both from the initial screen and the follow-up testing [190–193],
sometimes with fatal consequences [194]. Thus, all abnormal newborn screens
should be followed by VLCAD gene sequencing [192,195]. With regard to
outcome, infants with the neonatal form of VLCAD deficiency suffer from early
and severe complications, and the mortality rate in untreated patients has been
estimated at 75% [196]. Infants who are detected through newborn screening
and who are initiated on a low-fat diet with MCT oil and carnitine supplemen-
tation generally do well, and many remain asymptomatic [197–199]. Despite
adherence to therapy, 38% of patients with VLCAD deficiency experience inter-
mittent muscle pain, weakness, and/or myoglobinuria [199].
CPT-I deficiency
CPT-I deficiency is the only disorder of fatty acid oxidation with the finding of
increased carnitine levels, mainly in its free form. Patients with CPT-I defi-
ciency can have a normal outcome with appropriate treatment, but some suffer
neurologic impairment from repeated episodes of metabolic decompensation
[200,201]. Renal tubular acidosis may occur during attacks [200]. Although
there are few published data on severe CPT-I deficiency in newborn screening,
there is a sequence variant c.1436C>T (p.P479L) that is present in homozy-
gous form in 7% of Alaska Native infants and has created large numbers of
positive newborn screens [202]. Although the variant is postulated to provide
a selective advantage for persons with a high-fat diet, there is an association
between infant mortality and the variant [203], and impaired fasting tolerance
has been demonstrated in homozygotes [204].
CPT-II deficiency
In some cases of CPT-II deficiency identified on newborn screening, results of
confirmatory testing may not show abnormalities, particularly if an infant is not
ill [205]. Additionally, the mild, adult form of CPT-II deficiency may be missed
[206]. CPT-II deficiency cannot be distinguished from carnitine/acylcarnitine
translocase (CACT) deficiency on the newborn screen. Assay of CPT-II or
CACT enzyme activity or molecular testing is required for definitive diagnosis.
Patients with the severe, neonatal form of CPT-II deficiency die within the first
days to months. Those with the intermediate form have been reported survive
into young adulthood [207]. Adults with the myopathic form of CPT-II defi-
ciency can experience myoglobinuria after strenuous exercise, which can
lead to renal failure and death [201]. Patients with the myopathic form of
CPT-II deficiency should be advised to avoid prolonged or strenuous exercise,
which can trigger rhabdomyolysis. MCT oil loading before exercise may help
prevent complications [206].
CACT deficiency
CACT deficiency is one of the most severe disorders of fatty acid oxidation
and is usually lethal. The most common presentation is sudden death in the
neonatal period [198,206]. Despite newborn screening, the neonatal mortality
rate remains high and the prognosis poor in most infants, in part due to the
early presentation of CACT deficiency before results of newborn screening
are available [198,208]. Early treatment can be successful in some cases
[201,209], but surviving patients may suffer profound developmental delay,
seizures, and other complications [209,210]. Reversal of cardiomyopathy and
prevention of arrhythmia has been reported with MCT oil and carnitine
supplementation [211]. Milder phenotypes associated with higher degrees of
residual enzyme activity have been reported but are rare [212], and the degree
of enzyme activity does not necessarily correlate with clinical disease severity
[213]. CACT deficiency cannot be distinguished from CPT-II deficiency on
the newborn screen. Assay of CACT or CPT-II enzyme activity or molecular
genetic testing is required for definitive diagnosis.
CTD deficiency
Because carnitine crosses the placenta, a newborn’s plasma carnitine concentra-
tion is often reflective of the mother’s plasma carnitine concentration. Pregnant
women are known to have physiologically lower carnitine levels than nonpreg-
nant women [214,215]. False-positive results may occur on the newborn screen
for this reason or, under more worrisome circumstances, when the mother
herself has CTD or another metabolic condition (discussed previously).
Conversely, an infant affected with CTD who has been supplied with carnitine
while in utero may have an apparently normal level of carnitine, particularly if
the newborn screening sample is obtained too early [201,216], which results in
a false-negative screen. False-positive results may also occur if the mother has
taken antibiotics containing pivalic acid, which conjugates with carnitine and
causes it to be excreted in the urine, thereby depleting the carnitine pool [217].
Before newborn screening, most patients with CTD died in infancy or early
childhood from cardiomyopathy or apparent sudden infant death syndrome
[201,218,219]. Since the advent of expanded newborn screening, asymptomatic
mothers have been identified with CTD, illustrating the broad range of clinical
severity of this disorder [170,171,216,220], although some of these individuals
may have silent cardiomyopathy or report mild symptoms, such as fatigue.
Carnitine is a life-saving therapy in patients with CTD and leads to signifi-
cantly improved outcomes and good long-term prognosis [198,201,221].
Cardiomyopathy improves with treatment [219,221,222]. In apparently asymp-
tomatic individuals who are diagnosed as adults, there is still a risk of sudden
death, and supplementation with carnitine is recommended [170,216].
LCHAD and TFP deficiency
Newborn screening cannot differentiate between LCHAD and TFP deficiency.
Isolated LCHAD deficiency is most commonly caused by the c.1528G>C
(E474Q) mutation in the HADHA gene, which only affects the dehydrogenase
activity of the protein, whereas deficiency of all 3 enzymes is termed, TFP defi-
ciency. Many patients with severe LCHAD or TFP deficiency are already
symptomatic at the time of diagnosis and do not survive past the first few
days [199,223]. Data from one study showed that patients diagnosed with
LCHAD/TFP deficiency through newborn screening, family screening, or clin-
ical presentation had the following complications: 65% experienced skeletal
myopathy, 21% developed irreversible peripheral neuropathy, and 43% had
retinopathy [199]. Early diagnosis through newborn screening and timely insti-
tution of therapy improves outcome in some cases but does not necessarily
prevent morbidity and mortality, especially in those patients with TFP defi-
ciency [223,224]. The survival rate of patients with TFP deficiency is poorer
than that for patients with isolated LCHAD deficiency [198,199].
M/SCHAD deficiency
M/SCHAD deficiency is a recently recognized disorder of fatty acid oxidation.
Fewer than 10 cases of M/SCHAD deficiency have been reported worldwide
[225]. In addition to standard biochemical tests, a patient with a positive
newborn screen may require a work-up for hyperinsulinism, which is classi-

cally seen in patients with M/SCHAD deficiency. Diazoxide is used to treat
hypoglycemia because it inhibits insulin secretion from the pancreas. The
outcome of M/SCHAD deficiency seems to depend on the age at which
patients are diagnosed and started on therapy. Patients receiving a later diag-
nosis have severe intellectual disability and microcephaly, whereas those diag-
nosed at a younger age can have normal development [225,226]. M/SCHAD
deficiency may be fatal if undiagnosed [225,227,228].
GA-II/multiple acyl-CoA dehydrogenase deficiency

Acylcarnitine analysis may not be sensitive enough to detect milder cases of
GA-II [229,230], potentially resulting in false-negative screens. In addition to
treatment with a low-fat diet and fasting avoidance, some patients respond to
riboflavin, which is a cofactor for electron transfer flavoprotein and electron
transfer flavoprotein dehydrogenase. Administration of carnitine and glycine
may help bind toxic acyl-CoA species. With regard to outcome, patients
with neonatal-onset GA-II do not survive beyond the first few weeks to months
of life. Those with the milder, later-onset form are still at risk for episodes of
acute decompensation during intercurrent illnesses as well as sudden death
[231,232]. Even in those individuals identified through newborn screening
and initiated on treatment, sudden death or acute, life-threatening events
may occur [233,234].
LYSOSOMAL STORAGE DISEASES

Overview
Lysosomal storage diseases are a heterogeneous group of almost 50 disorders
in which there is a defect in lysosomal function, including defects in lysosomal
enzymes, enzyme receptors, activator proteins, membrane proteins, or trans-
porters. Typically, these defects cause an accumulation of substrates that leads
to deterioration of cellular and tissue function. The affected tissues and organs
depend on which cells contain the substrate, and the clinical phenotype
depends on which tissues are affected. All lysosomal storage disorders are in-
herited in an autosomal recessive fashion with the exceptions of Hunter
syndrome, Fabry disease, and Danon disease, which are X-linked. As a group,
lysosomal storage disorders have an approximate frequency of 1 in 7000 to
8000 live births [27,235].
Newborn screening for lysosomal storage disorders is in its infancy.
Currently, none of the lysosomal storage disorders are part of the mandated
screening panel established by the American College of Medical Genetics
[236]. A subset of these disorders, described later, has been considered potential
targets for future inclusion in newborn screening programs, and several pilot
screening projects have been implemented. At this time, the most appropriate
technology for screening for lysosomal storage disorders is not yet agreed
on. MS/MS, direct flurometric methods, immunocapture enzyme assays, or
digital microfluidic platforms are all possible screening methods [235,237].
Pompe disease
Pompe disease is a lysosomal storage disorder that is also categorized as a glycogen
storage disease. Symptoms may include progressive left ventricular hypertrophy,
cardiomyopathy, generalized muscular hypotonia and weakness, hepatomegaly,
macroglossia, and respiratory muscle weakness, leading to respiratory failure and
early death [27,235]. In addition to supportive and anticipatory treatment,
enzyme replacement therapy is also available. For patients with infantile Pompe
disease, enzyme replacement therapy should be initiated promptly, but for those
with noninfantile Pompe, the optimal time to initiate enzyme replacement therapy
is unclear. Screening cannot distinguish between infantile and late-onset Pompe
disease [238]. The high frequency of a-glucosidase pseudodeficiency in Asian pop-
ulations [239] may necessitate improvements in screening methodology [240]. A
Taiwan Pompe disease newborn screening pilot program diagnosed 6 newborns
of 206,088 screened. Enzyme replacement therapy was started in the patients
when they developed radiographic or clinical signs of cardiomyopathy or motor
delays, and there is evidence that treatment improved their clinical outcome. At 14
months to 33 months of age, all 6 infants were alive, were normal for weight and
motor skills, and did not require mechanical ventilation. Survival in early treated
patients was significantly improved when compared with untreated children, and
improved when compared with clinically diagnosed patients [241].
Krabbe disease
Krabbe disease has 2 major clinical phenotypes: the infantile form and the late-
onset/adult form. Infantile-onset Krabbe disease is characterized by presentation
at 3 to 6 months, rapidly progressive severe mental and motor deterioration, and
death in early childhood. Late-onset/adult Krabbe disease typically presents with
blindness, spastic paraparesis, ataxia, and dementia. Usually there is an initial
rapid deterioration followed by a more gradual progression [27]. Umbilical
cord blood or stem cell transplantation has some promise for improvement in
late-onset cases and presymptomatic early-onset cases [242–244]. Once the diag-
nosis is made, it is recommended to pursue early (preferably <30 days of age)
bone marrow/stem cell transplantation from cord blood in cases predicted to
have early infantile Krabbe disease [235]. In New York, 550,000 newborns
were screened for Krabbe disease. Fifteen low-risk children and 6 moderate-
risk children were identified who are asymptomatic to date without transplanta-
tion, and 4 high-risk children were identified, 2 of whom were chosen to undergo
unrelated donor umbilical cord blood transplantation before 28 days of age. One
of these 2 children died during transplantation from vaso-occlusive disease and
multisystem organ failure. The other child has not developed signs or symptoms
of early infantile Krabbe disease but is developmentally delayed. The other 2
high-risk children who did not receive transplants were neurologically and
developmentally normal at 16 months and 8 months of age [245].
Fabry disease
Fabry disease results from an accumulation of glycosphingolipids in most
visceral tissues and body fluids [27]. Classic hemizygous patients with no
detectable a-galactosidase A activity usually present during childhood or

adolescence. Clinical findings include paresthesias, angiokeratoma, hypohidro-
sis, gastrointestinal dysmotility, corneal opacities, renal impairment, cardiac
involvement, and cerebrovascular disease. There is also a cohort of atypical
hemizygotes with residual enzyme activity that may be asymptomatic or
have late-onset primarily cardiac involvement [27]. Heterozygous patients
range from being asymptomatic to as severely affected as patients [246].
Newborn screening may fail to detect a substantial percentage of female infants
with Fabry disease [247]. From an experimental newborn screening pilot in
Italy, the incidence of Fabry disease was found to be 1 in 3100, with an 11:1
ratio of patients with later-onset phenotype [248]. In Taiwan, the frequency
of classic Fabry disease was found to be 1:22,570 compared with 1:1390 for
the late-onset phenotype [247,249].
Other lysosomal storage disorders

There are many other lysosomal disorders that are able to be screened by
current technologies, including treatable disorders, such as Hurler disease
and Gaucher disease [237].
ETHICAL ISSUES
Many ethical concerns have been raised since expanded newborn screening
began. In the 1960s, Wilson and Jungner [250] established criteria to help guide
the selection of disorders included in the newborn screen. These criteria
include having an understanding of the natural history of the condition, a suit-
able test, a definition of whom to treat, an accepted treatment, and a favorable
cost-benefit ratio. With technologic advancement and the ability to screen for
a multitude of disorders using a single assay (MS/MS), many diseases are
now included in newborn screening programs that do not fulfill the original
criteria. Issues that have arisen as a result of this expanded testing and of
newborn screening in general include the following:
Parental anxiety—screening tests have an inherent false-positive rate, and
parents of a newborn with a false-positive result experience increased stress
and altered parent-child relationships [251,252]. In one study, 36% of the
parents of these normal infants reported concern about the health of their infant
because of the repeat testing, although this concern was greater in parents
reporting that they had not received sufficient information about the testing
process and its significance for the health of their infant [253]. Some patients
have an extended period of uncertainty in their precise diagnosis, resulting in
increased anxiety for the parents of these patients in-waiting [254,255].
Uncertainty of results—the identification of common variations in the ACADS
gene has led to the discussion of whether or not these alleles are truly disease
causing and whether or not SCAD deficiency should be included in the newborn
screen [176,177]. In the case of Krabbe disease, a lysosomal storage disorder
that causes neurologic deterioration and premature death, neither enzyme
activity nor genotype can accurately predict the clinical phenotype [256,257].
Lack of treatment—although some states are beginning to include lysosomal

storage diseases in their newborn screening panels, there is currently no proven
effective treatment for Krabbe disease, although hematopoietic stem cell
transplantation is under investigation [243].
Stigmatization or the effect of labeling—despite some protection offered by the
Genetic Information Nondiscrimination Act with regard to health insurance and
employment [258], individuals with genetic conditions may experience stig-
matization and unfavorable bias when it comes to life insurance, disability
insurance, and long-term care insurance [259].
Noncompliance with treatment—parents may refuse treatment of a potentially
life-threatening condition, in part because the child looks well [260].
These are just a few of the ethical issues that have arisen in the ongoing
debate surrounding newborn screening. For a more detailed discussion, readers
are referred to the articles by Dhondt [261], Wilcken [262], and Kerruish and
Robertson [263].
FUTURE DEVELOPMENTS
The addition of treatable disorders, such as remethylation disorders [264] and
disorders of creatine metabolism [265], promises to increase the value of
newborn screening. One of the most exciting developments is the work arising
from the Region 4 Genetics Collaborative, which includes clinical validation of
cutoff target ranges that will allow better differentiation of abnormal values and
reduce false-positive screens [266]. The Newborn Screening Translational
Research Network (www.nbstrn.org) promises to facilitate large-scale multi-
state research projects by a network of clinical centers, laboratories, and data
repositories. The development of rapid, inexpensive, high-throughput
sequencing methods has the potential to greatly expand the number of treatable
disorders, although implementing such a strategy will require a large degree of
ethical and policy debate.
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Wilms Tumor
Andrew M. Davidoff, MDa,b,c,d,*
a
Department of Surgery, St. Jude Children’s Research Hospital, Memphis, TN, USA; bDepartment
of Surgery, University of Tennessee Health Science Center, Memphis, TN, USA; cDepartment of
Pediatrics, University of Tennessee Health Science Center, Memphis, TN, USA; dDepartment of
Pathology & Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN, USA
Keywords
Wilms tumor Nephroblastoma NWTS COG
Key Points
The overall survival for children with Wilms tumor is >90%.
Current therapy aims to maintain this high rate of cure while minimizing toxicity.
Histology and stage remain important prognostic factors but the impact molec-
ular genetic factors is becoming increasingly recognized.
INTRODUCTION
Wilms tumor is the second most common intraabdominal cancer of childhood
and the fifth most common pediatric malignancy overall. It represents approx-
imately 6% of all pediatric cancers and accounts for more than 95% of all
tumors of the kidney in the pediatric age group [1,2]. In the United States
there are approximately eight cases of Wilms tumor per million children less
than 15 years of age per year, with the total number of new cases being esti-
mated at about 650 cases per year [3]. Approximately 75% of the cases occur
in children less than 5 years of age with a peak incidence at 2 to 3 years of
age. Survival for patients with Wilms tumor when considered as a whole,
once <30%, is currently greater than 90%, making it one of the real successes
of modern medicine. This dramatic improvement in survival is due, in part, to
the systematic manner in which the approach to therapy has evolved. Begin-
ning in 1969, the National Wilms Tumor Study (NWTS) Group, which was
incorporated into the Children’s Oncology Group (COG) in 2001, evaluated
different treatment strategies conducted through multi-institutional trials in
This work was supported in part by NIH grant CA 021765 and by the American Lebanese Syrian Associated
Charities (ALSAC).
*Department of Surgery, St. Jude Children’s Research Hospital, 262 Danny Thomas Place,
Memphis, TN 38105-3678. E-mail address: andrew.davidoff@stjude.org

248 DAVIDOFF
which the primary goals were (and remain) to treat patients according to well-
defined risk groups to achieve the highest cure rates, decrease the frequency
and intensity of acute and late toxicity, and minimize cost. Surgery has always
been a critical component of Wilms tumor therapy; the addition and refine-
ment of chemotherapy, and, in certain circumstances, radiation therapy,
have also had a significant impact on achieving improved survival rates.
PATHOLOGY
Classic Wilms tumor has a triphasic appearance, with the three cell types being
stromal, epithelial, and blastemal. All three elements are not required, however,
to have a diagnosis of Wilms tumor. The neoplastic cells can often be seen to
be forming primitive tubules and glomeruli. One of the major contributions of
the NWTS was a report by Beckwith and Palmer [4] that separated Wilms
tumors into distinct histopathologic categories based on prognosis. An analysis
of 427 specimens found that 11% of the total patients in this study contributed
to 52% of the mortality. Since that study, two distinct histopathologic types of
Wilms tumor have become recognized—favorable and unfavorable. The unfa-
vorable group comprises Wilms tumors with anaplasia (extreme nuclear and
cytologic atypia). Anaplasia is present in about 5% of Wilms tumors and is
more common in older children, reaching a peak at approximately 5 years
of age [5]. This histopathologic variant is also more frequent in African Amer-
ican patients. Anaplasia can be focal or diffuse in nature, with the focal subtype
being somewhat more favorable.
GENETICS
Childhood tumors, including Wilms tumor, have long been favorite models for
unraveling the molecular events of carcinogenesis because the early age of
onset suggests that only a few events are required to establish a neoplastic
phenotype. As with many cancer genes, the first clue to the location of a Wilms
tumor gene came from the cytogenetic analysis of DNA from patients with
Wilms tumor in whom there were commonly associated, genetically deter-
mined anomalies (Table 1). Because of the association of seemingly unrelated
phenotypic abnormalities, a large chromosomal disruption would be predicted.
This strategy revealed a constitutional deletion of band 13 of the short arm of
chromosome 11 in patients with the rare congenital syndrome consisting of
Wilms tumor, aniridia, genitourinary abnormalities or gonadoblastoma, and
mental retardation (WAGR syndrome). Loss of genetic material from this
region was associated with tumorigenesis, suggesting that the critical loss was
of a tumor-suppressor gene. Candidate genes were sought from the minimum
deletion region of chromosome 11p13 and, ultimately, the WT1 gene was iso-
lated and cloned [6]. Sequence analysis suggests that WT1 is a transcriptional
regulator whose protein product binds to specific DNA motifs. Although the
exact function of the WT1 protein has not been clearly defined, the pattern
of WT1 expression suggests that it has a role in metanephric stem cell differ-
entiation [7]. This may explain the finding of associated genitourinary
WILMS TUMOR
Table 1
Syndromes related to the WT1 and WT2 loci
Syndrome Locus Genetic lesion Phenotype Wilms tumor risk (%)
WAGR syndrome 11p13 Deletion WT1 gene Aniridia, genitourinary anomalies, delayed- 30
onset renal failure
Denys-Drash 11p13 Point mutation in zinc-finger regions of WT1 Ambiguous genitalia, diffuse mesangial 90
gene sclerosis
Frasier 11p13 Point mutation in WT1 intron 9 donor Ambiguous genitalia, streak gonads, focal Low
splice site segmental glomerulosclerosis
Beckwith-Wiedemann 11p15 Precise genetic lesion unclear; Organomegaly, large birth weight, 5
loss of imprinting of several genes macroglossia, omphalocele,
including hemihypertrophy, ear pits and creases,
IGF2, H19, and p57kip2 implicated neonatal hypoglycemia
Abbreviation: WAGR, Wilms’ tumor, aniridia, genitourinary abnormalities or gonadoblastoma, and mental retardation.
Data from Dome JS, Coppes MF. Recent advances in Wilms tumor genetics. Curr Opin Pediatr 2002;14(1):5–11.
249
250 DAVIDOFF
abnormalities. In patients with isolated Wilms tumor, however, evidence for

WT1 mutation exists in only about 5% to 10% of the cases.
Another syndrome associated with constitutional abnormalities of the WT1
gene is the Denys-Drash syndrome. In this syndrome, patients have severe
genitourinary abnormalities (eg, male pseudohermaphroditism) and renal
failure secondary to progressive, diffuse glomerular nephropathy. Fifty percent
to 90% of these patients will develop Wilms tumor [8]. The alteration of the
WT1 gene in patients with this syndrome seems to be a missense mutation
within the DNA-binding region of this transcription factor.
The Beckwith-Wiedemann syndrome (BWS) is another syndrome of which
Wilms tumor is a common component. This syndrome consists of several abnor-
malities, including macroglossia, macrosomia, hypoglycemia, visceromegaly,
and omphalocele, in addition to a predisposition to several tumors, most
commonly Wilms tumor. The locus for BWS seems also to be on the short-
arm of chromosome 11 but at a site distinct from WT1, that being 11p15, as iden-
tified by large karyotypic abnormalities and linkage analysis of BWS families [9].
In sporadic Wilms tumor, there seems to be a small percentage of patients with
loss of one copy of genetic material in the 11p15 region. Nearly always, there
has been a loss of the maternal allele, suggesting that genetic imprinting occurs
at this locus. In rare patients, uniparental paternal disomy has occurred whereby
there is inheritance of two paternal copies of this region. Several genes have been
identified within the 11p15 region that demonstrate genomic imprinting; alter-
ations of one of these may be responsible for the development of BWS.
Familial Wilms tumor occurs at an incidence of approximately 5%. Linkage
analysis shows, however, that the locus for this predisposition is not WT1 or
WT2, suggesting that there are other loci involved in the genesis or predispo-
sition for Wilms tumor. An additional Wilms tumor locus at 16q was suggested
by loss of heterozygosity (LOH; loss of one of two copies of a chromosomal
region) for chromosome 16q markers in about 20% of Wilms tumors [10].
LOH at a locus mapping to the distal chromosome 1p has also been found
in a small group of patients with Wilms tumor (w12%) and at 11p in 33%
of Wilms tumor patients [11]. Patients with LOH for chromosome 16q had
relapse rates 3.3 times higher and a mortality rate 12 times higher than patients
without LOH for chromosome 16q [12], suggesting that a gene within this site
may be involved in disease progression to a more aggressive phenotype.
Another gene that seems to have some prognostic importance when acti-
vated in Wilms tumors is p53. The p53 gene encodes a protein that, among
many functions, seems to play a role in cell cycle arrest in cases in which
DNA damage has occurred. When the damage cannot be corrected, p53
induces the cell to apoptose. Although p53 alterations are the most common
genetic abnormality detected in adult tumors, they are rare in pediatric malig-
nancies, including Wilms tumor. However, there is a high incidence of p53
gene mutation in the anaplastic histologic subtype of Wilms tumor [13]. This
may explain why these tumors do not respond well to chemotherapy—their
p53-dependent apoptotic pathway may have become inactivated.
WILMS TUMOR 251
Increasingly, array-based studies are being performed to further investigate

the molecular genetics of Wilms tumor. One recent study used array compar-
ative genomic hybridization and complementary DNA microarray expression
profiling to compare anaplastic and favorable histology Wilms tumor. Gain
of 1q and MYCN, and loss of 16q, were common to both histologies, whereas
genome loss of 4q and 14q were specific for anaplastic tumors [14]. A second
study evaluated the utility gene expression analysis to predict relapse in favor-
able histology Wilms tumor and found that stratifying local stage III tumors
using a classifier of fewer than 50 genes was feasible and modestly accurate
[15]. Several similar analyses are ongoing at a variety of institutions.
Determining additional molecular characteristics of Wilms tumor will be
important so that refinements in therapy can continue. Further genetic studies
may identify those patients at high risk for relapse so that intensification of
therapy can be instituted in this select group of patients. Similarly, genetic char-
acterization of patients with Wilms tumor will likely lead to the identification of
subgroups of patients with a more favorable prognosis who can be managed
according to a minimal therapeutic regimen.
PRESENTATION
Children with Wilms tumor typically present with an asymptomatic abdominal
mass. It is not uncommon for the tumor to be discovered by a parent while
bathing the child or by a relative who notices a protuberant abdomen. Associ-
ated signs and symptoms such as malaise, pain, and either microscopic or gross
hematuria are found in approximately 20% to 30% of the children. Hyperten-
sion, presumably because of increased renin activity, is present in approxi-
mately 25% of children with Wilms tumor. Occasionally, a child will present
with a rapidly enlarging abdominal mass, anemia, hypertension, pain, and
fever. These children usually have a subcapsular hemorrhage within the tumor
that leads to these symptoms.
EVALUATION
The work-up of a child with an intraabdominal mass suspected of being
a Wilms tumor should proceed in a systematic fashion. Real-time ultrasonog-
raphy is usually the initial study and can determine whether or not the mass
is intrarenal or extrarenal, and whether the lesion is cystic or solid. A CT
scan of the abdomen and pelvis is generally the imaging study of choice for
those patients suspected of having a renal tumor. This will confirm the pres-
ence of a solid renal mass and will afford the opportunity to visualize the
contralateral kidney to confirm its presence (and function) and to exclude
synchronous bilateral disease with a high degree of sensitivity.
Intravenous tumor extension of Wilms tumor occurs in about 11% of cases,
with the thrombus extending into the inferior vena cava in about 6% of cases
[16]. Therefore, this should be specifically investigated in the preoperative eval-
uation of all children with a renal mass because it may alter the conduct of
surgery. This can generally be done most easily and accurately with Doppler
252 DAVIDOFF
ultrasonography. However, a recent study suggests that contrast-enhanced CT

scans using current technology have high sensitivity and specificity for detec-
tion of cavoatrial tumor thrombus and may obviate Doppler ultrasonography,
given that CT scanning is performed routinely in children with an abdominal
mass [17]. A CT scan may, therefore, be sufficient because only cavoatrial
tumor extent needs to be identified preoperatively because it might change
the treatment approach; thrombus in the renal vein should be identified at
the time of surgery by palpation of the renal vein before tying and dividing
it. MRI can also be used to assess intravascular tumor extension but usually
requires sedation in young children and is not routinely used. However, it
may be helpful in defining an extensive tumor thrombus that extends up to
the level of the hepatic veins or even into the right atrium. In addition, MRI
may be useful in distinguishing Wilms tumor from nephrogenic rests. Finally,
echocardiography may be useful in rare circumstances to demonstrate (or
exclude) intracardiac tumor extension.
The most common site of metastatic spread of Wilms tumor is the lungs;
chest CT scan is the preferred imaging modality for evaluating this site. Other
rare sites of metastases, such as the liver, are usually well evaluated with the
initial abdominopelvic CT scan.
STAGING
Accurate staging of patients with Wilms tumor is imperative and the staging
system developed by the NWTS and currently in use in the COG is a surgicopa-
thologic staging system (Box 1). Because appropriate therapy, as well as prog-
nosis, is based on tumor stage, accurate staging of patients with Wilms tumor
at the time of diagnosis is imperative. In particular, careful regional lymph
node sampling is important because the presence of nodal involvement is associ-
ated with an increased incidence of tumor relapse and a poorer prognosis.
NWTS
Owing to the rarity of Wilms tumor, organized clinical investigation was limited
until the establishment of the NWTS in 1969. This represented a cooperative
effort among several groups to treat patients in a clearly defined manner so
that statistically relevant comparisons of treatment variations could be made.
Five sequential trials have been completed, with the basic goal of each successive
NWTS trial having been to maintain a high cure rate for patients with Wilms
tumor, while reducing the intensity and duration of therapy, based on surgical
stage and histologic evaluation. Although the importance of surgery in the treat-
ment of Wilms tumor has long been recognized, the roles for chemotherapy and
radiation therapy have evolved based on the results of the NWTS trials.
NWTS-1 showed that postoperative abdominal radiotherapy was not neces-
sary for children who were less than 2 years of age whose tumors were limited
to the kidney and completely resected [18]. In addition, the combination of
vincristine and dactinomycin was shown to be more effective for the treatment
of children with tumors that extended beyond the kidney than either drug
WILMS TUMOR 253
Box 1: Wilms tumor staging system (COG)

1. Tumor limited to kidney and completely excised. The surface of the renal
capsule is intact. Tumor was not ruptured before or during removal. There is
no residual tumor apparent beyond the margins of excision.
2. Tumor extends beyond the kidney, but is completely excised. There is regional
extension of the tumor; ie, penetration through the outer surface of the renal
capsule into perirenal soft tissues. Vessels outside the kidney substance are in-
filtrated or contain tumor thrombus. There is no residual tumor apparent at or
beyond the margins of excision.
3. Residual nonhematogenous tumor confined to abdomen. Any one or more of
the following occur:
a. Lymph nodes are involved with tumor.
b. There has been peritoneal contamination by tumor such as by biopsy or
rupture of the tumor before or during surgery, or by tumor growth that
has penetrated through the peritoneal surface.
c. Implants are found on the peritoneal surfaces.
d. The tumor extends beyond the surgical margins either microscopically or
grossly.
e. The tumor is not completely resectable because of local infiltration into vital
structures.
4. Hematogenous metastases. Deposits beyond stage III; ie, lung, liver, bone,
and brain.
5. Bilateral renal involvement at diagnosis. An attempt should be made to stage
each side according to the above criteria on the basis of extent of local
disease.
alone. NWTS-2 demonstrated that 6 months of combination chemotherapy

with vincristine and dactinomycin was effective treatment of children with
tumors limited to the kidney and completely resected, none of whom received
abdominal radiation. The addition of doxorubicin hydrochloride (Adriamycin)
to the combination of vincristine and dactinomycin was found to improve the
relapse-free survival of other patients [19]. The separation of Wilms tumor into
distinct histopathologic categories based on prognosis was used to stratify
patients in NWTS-3 [20]. This study also began to define the low dose of
ionizing radiation to be used, when necessary, and showed that the addition
of cyclophosphamide did not improve survival over that generated with
three-drug therapy. NWTS-4 examined the utility of dose intensive scheduling
to cut down on the duration of therapy [21]. The more recently concluded
NWTS-5, a single-arm therapeutic trial designed to evaluate the prognostic
value of certain biologic markers in Wilms tumor, demonstrated that LOH
for genetic material on chromosomes 1p and 16q in stage I and II favorable
histology Wilms tumor was associated with a poorer prognosis [22]. This infor-
mation, LOH of 1p and 16q, is now being used to further stratify patients in the
current COG trial for Wilms tumor.
254 DAVIDOFF
CURRENT PROTOCOLS
Historically, the most important prognostic variables for patients with Wilms
tumor have been the histopathologic tumor classification and surgical stage
[23]. Survival statistics based on these factors, which have largely guided treat-
ment, are shown in Table 2. The staging system developed by the NWTS and
currently in common use, is shown in Box 1. Because appropriate therapy, as
well as prognosis, is based on tumor stage, accurate staging of patients with
Wilms tumor at the time of diagnosis is imperative and includes histologic
assessment of regional lymph node involvement.
It has recently been recognized that a Wilms tumor risk-stratification system
based on histology and stage alone does not accurately identify all patients at
risk for recurrence. New clinical and genetic risk factors for recurrence have
been validated and have now been incorporated into the assigning of therapy
in the current COG clinical trials for patients with Wilms tumor. These factors
include patient age at the time of diagnosis, tumor weight, histologic response
to therapy, and the allelic status of chromosomes 1p and 16q in resected tumors.
Since 2006, four clinical trials have opened within COG for the treatment of
patients with Wilms tumor. Together these protocols cover the entire spectrum
of Wilms tumor. Central to the approach to therapy for these patients is a risk
classification scheme, which is defined in Table 3. To facilitate accurate and
timely risk assessment, enrollment in an overarching tumor collection and
biology classification protocol, AREN03B2: Renal Tumors Classification,
Biology, and Banking Study, is a prerequisite (Fig. 1). Patients are then enrolled
on one of the therapeutic protocols.
AREN0532: treatment of very low-risk and standard-risk favorable

histology Wilms tumor
Only patients with nonmetastatic, favorable histology disease are eligible (Fig. 2).
The very low-risk arm of this protocol proscribes surgery alone as definitive treat-
ment of children less than 2 years of age with stage I disease in which the tumor
(plus kidney) weight is less than 550 gm. It should be noted that a critical compo-
nent of the entry criteria is that adequate lymph node sampling be performed at
the time of tumor resection to ensure accurate confirmation of stage I disease.
Table 2
Ten-year outcomes for patients with Wilms tumor treated on NWTS-4
Histology Stage 10 y relapse-free survival (%) 10 y overall survival (%)
Favorable I 91 96
II 85 93
III 84 89
IV 75 81
V 65 78
Anaplastic I 69 82
II–III 43 49
IV 18 18
WILMS TUMOR 255
Table 3
Risk stratification and treatment assignment for patients with favorable histology Wilms tumor
(COG)
Patient age Tumor weight Stage LOH Rapid response Final-risk group Treatment study
<2 y <550 g I Any N/A Very Low AREN0532
Any 550 g I None N/A Low None
2 y Any I None N/A Low None
Any Any II None N/A Low None
2 y Any I LOH N/A Standard AREN0532
Any 550 g I LOH N/A Standard AREN0532
Any Any II LOH N/A Standard AREN0532
Any Any III None Any Standard AREN0532
Any Any III LOH Any Higher AREN0533
Any Any IV LOH Any Higher AREN0533
Any Any IV None Yes Standard AREN0533
Any Any IV None No Higher AREN0533
Any Any V Any Any Bilateral AREN0534
These children were thought to be at such low risk for recurrence that the risks of
adjuvant chemotherapy might outweigh the risks of recurrence. Therefore, in
NWTS-5, these patients were treated with surgery alone. However, because
the 2-year event-free survival (EFS), 86.5%, did not meet the required EFS of
90%, this arm of the trial was stopped [24]. Further follow-up has revealed that
patients treated with surgery alone had a 5-year EFS of 84% while comparable
patients, who also received two-drug chemotherapy, had a 5-year EFS of 97%
(P ¼ .002). However, the estimated 5-year overall survival was 98% and 99%,
respectively (P ¼ .7) because almost all patients treated with surgery alone who
relapsed could be salvaged [25]. Therefore, this approach has been reinstated
as a COG protocol to eliminate the potential toxic side-effects of chemotherapy
for most patients. Of additional interest are recent studies that suggest that the
AREN03B2 Classif ication Study

(Central Review)
Favorable Histology Anaplastic Bilateral
AREN0532 AREN0533
AREN03B2 AREN0321
1. Very Low Risk 1. Higher Risk AREN0534
1. Low Risk 1. High Risk
2. Standard Risk 2. Standard Risk
Fig. 1. COG protocols for patients with Wilms tumor. Patients being treated for low-risk
disease stage I to II, favorable histology, without 1p and 16q LOH are treated with regimen
EE-4A and are followed on AREN03B2.
256 DAVIDOFF
Fig. 2. Treatment outline for patients with favorable histology Wilms tumor on AREN0532:
Treatment of very low and standard risk favorable histology Wilms tumor.
small subset of patients with very low-risk Wilms tumor with a higher likelihood
of recurrence can be identified by molecular analysis of the resected tumors [26].
Specifically, WT1 mutation and 11p15 LOH were found to be associated with
relapse in patients who did not receive adjuvant chemotherapy [27]. These
biomarkers may be used as part of the entry criteria to future protocols that
use a surgery-only approach.
Children with stage I disease who do not qualify for surgery alone and those
with stage II disease are still considered low–risk. However, in addition to
surgery, they are started on treatment with 22 weeks (seven cycles) of two-
drug chemotherapy (vincristine and dactinomycin) on regimen EE-4A. These
patients are technically not treated on a protocol but are followed on
AREN03B2. However, if the tumor from these patients is subsequently found
to have LOH of both 1p and 16q, these patients are switched to standard-risk
therapy consisting of 28 weeks (nine cycles) of three-drug chemotherapy in
which doxorubicin is added to vincristine and dactinomycin, on regimen
DD-4A. Patients with stage III disease whose tumors do not have 1p and
16q are also treated with standard-risk DD-4A, plus radiation therapy.
However, if the tumor is subsequently found to have both 1p and 16q
LOH, these patients with stage III disease, are considered higher risk and
are switched to AREN0533 (see later discussion).
AREN0533: treatment of newly diagnosed higher risk favorable
histology Wilms tumors
Patients eligible for this protocol have favorable histology tumors and either
stage III disease that is found to have 1p and 16q LOH, or stage IV (metastatic)
WILMS TUMOR 257
disease (Fig. 3). Those with stage III disease and 1p and 16q LOH are treated
for 33 weeks (11 cycles) with vincristine, dactinomycin, and doxorubicin, plus
cyclophosphamide and etoposide, on regimen M, as well as abdominal radia-
tion. Patients with stage IV disease without 1p and 16q whose pulmonary
lesions respond rapidly and completely (see later discussion) are treated with
regimen DD-4A chemotherapy and no pulmonary radiation. All other patients
with metastatic disease—those with 1p and 16q LOH, those with slow, incom-
plete response of their pulmonary disease (see later discussion), or those whose
metastases are extrapulmonary—are treated with regimen M and radiation to
the sites of metastatic disease. Of note, however, is a recent study that has sug-
gested that the presence of hepatic metastases at diagnosis is not an indepen-
dent adverse prognostic factor [28].
AREN0321: treatment of high-risk renal tumors

All patients with anaplastic Wilms tumor are treated on this protocol. For risk
assessment and treatment purposes, a distinction is made between focal
(anaplasia confined to one or a few discrete loci within the primary tumor, with
no anaplasia or marked nuclear atypia elsewhere) and diffuse anaplasia. Patients
whose tumors have focal anaplasia, stage I to III, or diffuse anaplasia stage I, are
treated with regimen DD-4A. Patients with stage IV focal anaplasia, stage II to III
diffuse anaplasia, and stage IV diffuse anaplasia without measurable disease are
treated for 30 weeks with cyclophosphamide-carboplatin-etoposide and
Fig. 3. Treatment of patients enrolled on AREN0533: treatment of newly diagnosed, higher

risk favorable histology Wilms tumor.
258 DAVIDOFF
vincristine-doxorubicin-cyclophosphamide plus radiation therapy (regimen UH-

1). Patients with stage IV diffuse anaplasia with measurable disease are treated
with one to two cycles of irinotecan-vincristine as window therapy to evaluate
tumor response and determine whether this combination should be added to
the backbone treatment with UH-1.
AREN0534: treatment of patients with bilateral, multicentric, or
bilaterally predisposed unilateral Wilms tumor
Owing to an increased risk of renal failure in patients with bilateral Wilms
tumor, these patients receive neoadjuvant therapy with three-drug chemo-
therapy of regimen DD-4A in an effort to shrink the tumors before surgery
and facilitate the preservation of renal parenchyma, thereby preserving renal
function. Also eligible for enrollment on this protocol are patients with Wilms
tumor arising in a solitary kidney or those patients less than 1 year of age with
a unilateral Wilms tumor who are at an increased risk for a metachronous
tumor. Patients with several genetic syndromes, particularly those associated
with abnormalities of the Wilms tumor 1 (WT1) and Wilms tumor 2
(WT2) genes on the short arm of chromosome 11, carry this risk (see Table 1).
Patients with unilateral Wilms tumor and a Wilms tumor predisposition
syndrome are treated with regimen EE-4A if their disease is stage I to II but
DD-4A if the disease is stage III to IV. Postoperative chemotherapy (and radi-
ation) are determined by the histopathologic findings at the time of surgery,
which should occur after 6 weeks (two cycles) or, at the latest, 12 weeks
(four cycles) of preoperative chemotherapy. Protracted courses of chemo-
therapy in an effort to make the lesions more amenable to nephron-sparing
surgery should not be undertaken.
SURGERY FOR WILMS TUMOR

The role of surgery in the therapy of Wilms tumor is paramount because
a meticulous and well-performed procedure will accurately determine the stage
of the disease and future therapy. A poorly performed procedure can lead to
inadequate therapy if the patient’s disease is not appropriately staged or to
unnecessarily intensive therapy if operative spill of the tumor occurs or if
incomplete resection of the primary tumor is performed. The main responsi-
bility of the surgeon is to remove the primary tumor completely, without
spillage, and to accurately assess the extent to which the tumor has spread,
with particular attention to adequately assessing lymph node involvement.
Timing of surgery
One of the main controversies in the treatment of children with unilateral
Wilms tumor is whether or not to administer preoperative chemotherapy
[29,30]. The International Society of Pediatric Oncology (SIOP) recommends
giving vincristine and dactinomycin chemotherapy before nephrectomy for
localized renal tumors. A core needle biopsy obtained via a posterior approach
can be performed without upstaging the patient’s disease but should only be
performed in cases of unusual presentation (older age, signs of infection,
WILMS TUMOR 259
inflammation) or unusual imaging findings (significant adenopathy, no renal

parenchyma seen, intratumoral calcification). Posttreatment histology-based
risk classification (Box 2) and stage dictate postoperative chemotherapy
(Table 4). Of note, the presence of necrotic tumor or chemotherapy-induced
changes in a lymph node or at the resection margin is regarded as proof of
previous tumor and, therefore, considered stage III. Proponents of preoperative
therapy suggest that the tumor is easier to resect with a decreased incidence of
tumor spill (and need for abdominal radiation) [31] and a lower mortality and
morbidity. The COG espouses the use of upfront nephrectomy to more accu-
rately assess tumor histology and stage so as to avoid either overtreatment or
undertreatment. Evidence to support the dangers of undertreatment comes
from a SIOP study that showed an increased incidence of intraabdominal
relapses in patients who did not receive postoperative radiation therapy [32].
Likely, patients with lymph node involvement were missed due to preoperative
chemotherapy. However, specific patient groups can be identified who would
seem to benefit from preoperative chemotherapy. These are patients with bilat-
eral tumors, patients with inferior vena cava and intra-atrial involvement, and
patients with massive tumors considered by the operating surgeon to be unre-
sectable without undue risk to the patient.
Surgical exploration
A radical nephrectomy should be performed through a generous transverse,
transperitoneal incision. A thoracic extension may be necessary but has been
associated with a higher complication rate [33]. Isolation of the hilar vessels
Box 2: Classification of pretreated renal tumors of childhood (SIOP)

Low-risk tumors
Mesoblastic nephroma
Cystic partially differentiated nephroblastoma
Completely necrotic nephroblastoma
Intermediate-risk tumors
Nephroblastoma: epithelial type
Nephroblastoma: stromal type
Nephroblastoma: mixed
Nephroblastoma: regressive type
Nephroblastoma: focal anaplasia
High-risk tumors
Nephroblastoma: blastemal type
Nephroblastoma: diffuse anaplasia
Clear cell sarcoma of the kidney
Rhabdoid tumor of the kidney
260 DAVIDOFF
Table 4
Summary of postoperative treatment strategies for localized tumors (SIOP)
Stage I Stage II Stage III
a
Low-risk No further treatment AV-2 AV-2
Intermediate-risk AV-1b Randomize to Randomize to
AVDc RT or AVD
or or
AV-2 RT or AV-2
High-risk AVD HRd þ RT HR þ RT
Abbreviations: HR, high-risk; RT, radiation therapy.
a
Vincristine weekly for 8 weeks, then on days 1 and 7 with a 2-week interval between courses for 6 courses,
actinomycin D every 3 weeks for 9 doses.
b
Vincristine weekly for 4 weeks, actinomycin D at day 7.
c
Vincristine, actinomycin as per AV-2, doxorubicin every 6 weeks for 4 doses.
d
Cyclophosphamide-doxorubicin alternating with etoposide-carboplatin for 34 weeks.
before mobilization of the primary tumor is no longer recommended because

major vascular injury to the mesenteric arteries, celiac vessels, and aorta
have been reported [34]. Palpation of the renal vein before dividing it is recom-
mended to exclude the possibility of a tumor thrombus, which occurs in about
11% of cases. Biopsy of the primary tumor should not be performed before
removal and a meticulous dissection to avoid rupture of the tumor capsule
with spillage of tumor cells is imperative because tumor spill is strongly associ-
ated with recurrence [35]. During tumor resection, the ureter is ligated and
divided as low as possible, but complete removal of the ureter down to the
bladder is not necessary. Intraoperative inspection of the liver and the contra-
lateral kidney are no longer required, unless lesions were identified on preop-
erative imaging studies, because of the high accuracy of current imaging
modalities. However, lymph node sampling is critically important, despite
the absence of abnormal nodes on preoperative imaging or on gross inspection
during operative exploration, because a review of lymph node sampling by the
NWTS demonstrated a false-negative rate of 31% and a false-positive rate of
18% based on preoperative and intraoperative assessment [36]. Unfortunately,
there is currently a fairly high incidence of inadequate intraoperative staging,
primarily due to failure to sample lymph nodes [37].
There are reports of surgeons performing partial nephrectomy for unilateral
Wilms tumor, particularly in Europe where children routinely receive preoper-
ative chemotherapy [38–40], despite the very low incidence of renal failure after
unilateral radical nephrectomy. Although the cumulative incidence of end-stage
renal disease due to chronic renal failure 20 years after Wilms tumor diagnosis
is less than 1% [41], some studies are suggesting that these patients may have
more subtle but significant degrees of renal insufficiency that may be minimized
by a nephron-sparing approach to all Wilms tumors [42]. However, other
studies have reported an increased risk of local recurrence after partial nephrec-
tomy for unilateral Wilms tumors [38] and survival for patients with intraabdo-
minal recurrence is markedly diminished. One recent meta-analysis did
WILMS TUMOR 261
suggest, however, that in highly selected patients, oncologic outcomes of partial

versus radical nephrectomy for unilateral Wilms tumor did not differ [43].
However, the percentage of patients whose tumor might be amenable to
a partial nephrectomy is low, ranging from 8% to 33% [44], based on criteria,
including size, location, and degree of kidney uninvolvement. One additional
concern is that upwards of 40% of kidneys with unilateral Wilms tumor will
have nephrogenic rests outside of the tumor [45]. The natural history of these
lesions that would be left behind with a partial nephrectomy when treated with
vincristine and dactinomycin is unknown. Thus, the appropriateness,
adequacy, and benefits of a nephron-sparing approach to unilateral Wilms
tumor have not been confirmed and partial nephrectomy for unilateral Wilms
tumor is not currently endorsed by the COG.
Similarly, the use of a minimally invasive (laparoscopic) approach to nephrec-
tomy (radical or partial) for Wilms tumor is also not currently endorsed by the
COG, given the importance of the accurate assessment of the surgical margins
and the adverse consequences of tumor spill. Nevertheless, laparoscopic radical
nephrectomy is emerging as the treatment of choice for localized renal malignan-
cies in adults and for benign renal disease in infants and children and a few
reports have been published describing small series of patients whose tumor
has been removed by this approach [46–48]. Of note, however, one recent case
report described the consequences of the unsuccessful use of this approach
[49]. Thus, this is another aspect of the surgery for Wilms tumor that needs to
be carefully investigated.
Bilateral Wilms tumor

Synchronous disease in both kidneys at presentation occurs in approximately 5%
of children with Wilms tumor. Unfavorable histology is seen in approximately
10% of the cases and there can be discordant histology between kidneys.
However, because tumor biopsy, regardless of the technique, is very unlikely
to document anaplastic histology [50] and because there are few other things,
other than Wilms tumor, in the differential diagnosis for a child with bilateral
renal masses, biopsy at presentation is now discouraged by COG.
Because surgery is a critical component in the treatment of Wilms tumor, the
challenge in the management of patients with bilateral disease is to achieve
a high cure rate while maintaining adequate long-term renal function. Several
studies have demonstrated that patients with bilateral Wilms tumor are at risk
for developing renal failure [51–54]. The exact cause of renal failure is not
always clear and is likely multifactorial [52,54]. However, because of an
increasing appreciation of the potential for renal failure in these patients, the
management of synchronous bilateral Wilms tumor has evolved from primary
kidney resection to renal-preserving surgical approaches, facilitated by the use
of preoperative chemotherapy. A review of the experience at St. Jude Chil-
dren’s Research Hospital found that bilateral partial nephrectomies could be
performed in nearly all patients (>90%) with favorable histology disease,
despite occasionally foreboding preoperative imaging [55]. Complications
262 DAVIDOFF
were minimal and long-term renal function and survival have been excellent.
Definitive operative intervention should be done early, by 12 weeks after initi-
ation of chemotherapy because little significant further change in tumor size is
likely [56] and it is important to determine the exact tumor histology [50,57].
The finding of either anaplastic or blastemal predominant histology would
mandate intensification of therapy if it is not stage I disease, whereas certain
other circumstances would allow for discontinuation of doxorubicin.
Intravascular tumor extension
Vena cava and intra-atrial extension of Wilms tumor can occur in patients with
Wilms tumor, with an incidence of approximately 6%. Survival does not seem
to be affected and the prognosis is comparable stage by stage to children without
intravascular involvement. Localization of the thrombus should be determined
before operation using real-time ultrasonography and/or CT scanning; echocardi-
ography and MRI can sometimes provide additional information. Surgical excision
of the primary tumor and thrombus is recommended when technically feasible. An
intraabdominal approach is sufficient for infrahepatic lesions with extraction of the
caval thrombus after proximal and distal control of the vena cava are obtained.
Free-floating thrombi that are easily removed are classified as stage II, but thrombi
that invade the vessel or are extremely adherent to the wall of the vessel are clas-
sified as stage III. Patients with atrial extension of a tumor thrombus require cardio-
pulmonary bypass for thrombus removal. In these patients, a midline abdominal
incision with a median sternotomy can be used. Alternatively, strong consideration
should be given to the use of preoperative chemotherapy [16,58–60].
Metastatic disease
The primary distant site for Wilms tumor metastases is the lungs; hepatic metas-
tases are much less common. Approximately 12% of Wilms tumor patients will
have evidence of hematogenous metastases at diagnosis, with 80% having pulmo-
nary metastases. Patients with stage IV favorable histology tumors at diagnosis
still have a good prognosis, whereas unfavorable histology patients and patients
who relapse with metastatic disease have a grave prognosis. Approximately 20%
of favorable histology patients will relapse following therapy with most relapses
occurring in the lungs. Patients with pulmonary metastases usually can be
managed by combined chemotherapy and radiation therapy [61]; pulmonary
resection is rarely indicated because chemotherapy is effective. Although histo-
logic confirmation of pulmonary relapse may be indicated, complete removal
of pulmonary metastases at relapse probably does not increase survival.
A new response-based approach is now being taken for patients with stage IV
disease in AREN0533. Those patients treated with regimen DD-4A, who have
complete radiographic disappearance of their lung metastases (or who have tissue
confirmation that residual nodules do not contain viable tumor) at the 6-week
reevaluation, are considered rapid responders, continue on DD-4A, and do
not receive pulmonary radiation. Patients who do not have complete resolution
of pulmonary nodules are considered slow, incomplete responders, are switched
to regimen M, and receive whole lung radiation. Those patients who, at the time
WILMS TUMOR 263
of diagnosis have pulmonary metastases confirmed histologically and have the

lesions completely resected (and, therefore, have no residual disease available
for response monitoring) are treated with DD-4A but also are required to receive
whole lung radiation. Therefore, consideration should be given to the implica-
tions of resecting pulmonary lesions at the time of diagnosis. If the lesions are
found to be benign, the patient will have been spared doxorubicin (if local stage
I–II) and pulmonary radiation. However, if the lesions are metastatic Wilms
tumor and are removed completely, the patient will have lost the opportunity
to be considered a rapid responder and avoid whole lung radiation.
Recurrent disease
Approximately 15% of favorable histology and 50% of anaplastic histology
Wilms tumor will recur [62], with most relapses occurring early (within 2 years
of diagnosis). Relapse occurs most often in the lungs (60%) but can also occur
in the abdomen (30%). More rarely, Wilms tumor recurs in the bone or brain.
Factors that influence survival after relapse include tumor histology and initial
therapy. Survival with favorable histology Wilms tumor is still about 60%,
whereas for anaplastic histology it is very poor. A worse outcome is associated
with the use of doxorubicin as a part of the initial chemotherapy[62]. Time to
recurrence and site of recurrence, once thought to be prognostic, are no longer
thought to be so. Therapeutic regimens for relapse include drugs that are not
generally used during initial treatment, such as ifosfamide, carboplatin, etopo-
side, and cyclophosphamide. The roles of surgery and radiation therapy for
relapsed Wilms tumor have yet to be precisely defined, although some recent
studies suggest that complete surgical resection and radiation of previously un-
radiated fields may improve survival [63]. The role of high-dose chemotherapy
with stem cell rescue for relapsed Wilms tumor is uncertain.
LATE EFFECTS
With the marked improvement in survival for children with Wilms tumor has
come the opportunity to observe the long-term complications of the therapy
they received. Doxorubicin, used in the treatment of unfavorable histology
and high-stage favorable histology Wilms tumor, is associated with an increased
risk of cardiac toxicity that is lifelong and dose-dependent, with the greatest risk
being to those who received a cumulative dose greater than 250 mg/m2 [64].
NWTS studies suggest that the rate of congestive heart failure 20 years after diag-
nosis was 4.4% for patients treated with doxorubicin at initial diagnosis [65];
more subtle abnormalities in cardiac function may exist in a much higher
percentage of patients. The consequences of ionizing radiation are also signifi-
cant, particularly when administered to young children. Sequelae include muscu-
loskeletal growth defects, infertility (particularly in females), and, rarely,
secondary malignancies, estimated to occur in approximately 3% of children
treated for Wilms tumor [66].
The occurrence of renal failure is multifactorial and depends on both genetic
predisposition and therapy. The overall incidence of renal failure in children
264 DAVIDOFF
treated for Wilms tumor is less than 1% [41], although, as with cardiac toxicity,
the incidence of more subtle abnormalities in renal function is likely higher.
Patients with Denys-Drash syndrome have a 20-year cumulative incidence of
renal failure of 82.7%, whereas for those with WAGR syndrome it is 43.3%. In
those with clinical features consistent with WT1 abnormalities, such as cryptor-
chidism and hypospadias, the incidence may be as high as 16% [41]. Other
contributors to renal failure include the use of abdominal radiation and, of course,
surgical resection of the kidneys due to progressive bilateral disease.
Thus, because of these potential late effects in patients treated for Wilms tumor
in childhood, there is an increasing effort both to increase the vigilance in the
follow-up of these patients and to decrease the toxicity of current therapy.
SUMMARY
Significant improvement has been made in the treatment of children with
Wilms tumor. New protocols are in place designed to maintain a high rate
of cure for these patients while minimizing toxicity, based on refinement of
the risk-stratification system.
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Treatment Outcomes in Congenital

Adrenal Hyperplasia
Tina Q. Cheng, DOa,*, Phyllis W. Speiser, MDa,b
a
Division of Pediatric Endocrinology, Cohen Children’s Medical Center of New York, 269-01 76th
Avenue, New Hyde Park, NY 11040, USA; bHofstra North Shore LIJ School of Medicine, 1991
Marcus Avenue, Suite M100, Lake Success, NY 11042, USA
Keywords
Adrenal hyperplasia Congenital Treatment
Key Points
Newborn screening for CAH has improved survival, and other outcome measures.
Judicious steroid dosing in early childhood & adolescence improves adult
stature.
Psychosexual health should be monitored and treated in females affected with
genital anomalies.
Systematic literature review and meta-analysis guided by expert opinion has
refined current approaches to the treatment of 21-hydroxylase deficiency CAH.
C
ongenital adrenal hyperplasia (CAH) involves a group of autosomal
recessive disorders that affect the production of cortisol, aldosterone,
or sex hormones in the adrenal glands (Fig. 1). Fig. 1 shows a simplified
chart of steroid hormone synthesis.
21-HYDROXYLASE DEFICIENCY CAH

Deficiency of the 21-hydroxylase enzyme is the most common form of CAH and
accounts for approximately 90% to 95% of all cases Table 1. This defect blocks
the production of mineralocorticoids deoxycorticosterone (DOC) and aldoste-
rone from progesterone and blocks the production of glucocorticoids 11-deoxy-
cortisol and cortisol from 17-hydroxyprogesterone (17-OHP). There is also
excessive production of adrenal sex steroids. Patients with 21-hydroxylase defi-
ciency can be divided into several phenotypes: classical salt wasting (0% enzy-
matic activity in w75% of cases), classical simple virilizing (w1% enzymatic
activity), and later-onset nonclassical (NC) (20%–50% enzymatic activity) [1,2].
All newborn screening programs in the United States and most developed
countries incorporate screening for classical 21-hydroxylase deficiency CAH.
*Corresponding author. E-mail address: Tcheng@NSHS.edu

270 CHENG & SPEISER
Fig. 1. Steroid hormone synthesis takes place mainly in the adrenal cortex and gonads. The
3 adrenal cortical zones produce distinct classes of hormones as shown at the top of the figure.
The adrenal zona reticularis produces androstenedione; but in healthy individuals, most
testosterone is made by the testes. In the most common form of CAH caused by mutations or
deletions in the 21-hydroxylase gene (CYP21A2), potent androgens are produced by the
adrenal because of the accumulation of steroid precursors above the solid line. Other
types of CAH include 11-hydroxylase deficiency, 3-beta-hydroxysteroid dehydrogenase defi-
ciency, 17-hydroxylase/17,20-lyase deficiency, P450 side-chain cleavage deficiency, and
P450 oxidoreductase deficiency. Each type of enzyme defect produces a characteristic
phenotype depending on the hormones that are overproduced or underproduced. DHEA, de-
hydroepiandrosterone; DOC, deoxycorticosterone; 17-OH, 17-hydroxyprogesterone; 18-OH,
18-hydroxyprogesterone.
Typically, these programs rely on immunoassays to measure blood levels of 17-

OHP from filter-paper samples. The worldwide incidence of classical 21-hydrox-
ylase deficiency is approximately 1 in 14,000 to 16,000 live births, with equal
prevalence among boys and girls when all cases are detected at birth. The birth
prevalence rate in the United States from 1996 to 2000 was slightly lower at
approximately 1 in 20,800 live births [3].
Girls affected with classical salt-wasting and simple-virilizing CAH are
exposed to excess androgens starting in utero and are born with virilized
external genitalia. Typical external genital physical findings include clitoral
enlargement, partially fused labia majora, or a common urogenital sinus in
lieu of a separate urethra and vagina. The extent of virilization is variable
and can range from a nearly male appearance to minimal clitoromegaly.
Typically, girls with the more severe salt-wasting variant have a greater
TREATMENT OUTCOMES IN CONGENITAL
Table 1
Types of CAH
Type of CAH Gene High levels Low levels Classic phenotype
21-hydroxylase CYP21A2 17-OHP, P4, aldo, andro, T, F, aldo AGf, SW
deficiency PRA
11b-hydroxylase CYP11B1 DOC, S, T PRA AGf, HTN
deficiency
17a-hydroxylase CYP17A1 DOC, B PRA, sex hormones AGm, HTN, HH
deficiency
3b-hydroxysteroid HSD3B2 DHEA, 17-OHPreg, PRA F, aldo, sex hormones AGf, AGm, SW
dehydrogenase
deficiency
P450 side-chain cleavage CYP11A1 None All AGm, SW
deficiency
P450 oxidoreductase POR (PD/[THEþTHFþ_ 5aTHF]) — Variable AGm, AGf, SW,
deficiency urinary profile skeletal defects
Levels are measured in blood for 17-hydroxyprogesterone.
Phenotypes: ambiguous genitalia in genetic females, ambiguous genitalia in genetic males, salt wasting, hypertension, and hypergonadotropic hypogonadism.
To diagnose POR deficiency, a urine mass spectrometry profile involving cortisol precursors and cortisol metabolites is examined: pregnanediol (a pregnenolone metabolite),
tetrahydrocortisone, and tetrahydrocortisol.
P450 oxidoreductase serves as a cofactor to several key enzymes (21-hydroxylase, 17-hydroxylase, and aromatase), hence the variable phenotypic presentation.
Abbreviations: AGf, ambiguous genitalia in genetic females; AGm, ambiguous genitalia in genetic males; aldo, aldosterone; andro, androstenedione; B, corticosterone; DHEA,
dehydroepiandrosterone; DOC, deoxycorticosterone; F, cortisol; HH, hypergonadotropic hypogonadism; HTN, hypertension; 17-OHP, 17-hydroxyprogesterone; 17-OHPreg,
17-hydroxypregnenolone; PD, pregnanediol; P4, progesterone; PRA, plasma renin activity; S, 11-deoxycortisol; SW, salt wasting; T, testosterone; THE, tetrahydrocortisone; THF,
tetrahydrocortisol.
271
272 CHENG & SPEISER
degree of genital ambiguity. Female infants are usually evaluated and diag-
nosed earlier than male infants because of genital ambiguity at birth. Before
the introduction of widespread newborn screening, affected boys were diag-
nosed during an episode of dehydration or shock associated with hyponatre-
mia and hyperkalemia [4]. If untreated in infancy, children of both sexes
have early onset of pseudopuberty caused by the overproduction of adrenal
androgens and often progress to central precocious puberty and short
stature caused by early epiphyseal fusion. Proper medical management
can avoid these adverse outcomes.
The prevalence of NC 21-hydroxylase deficiency CAH (NCCAH) is 0.1%
to 0.2% in the general Caucasian population but is greatest among Ashkenazi
Jews (up to 1%–2%) [5]. NCCAH is not detected in most newborn screening
programs. Individuals with NCCAH have milder enzymatic deficiency and
girls generally have no genital ambiguity at birth. Children may show accel-
erated linear growth and advanced bone maturation, potentially leading to
premature epiphyseal fusion and diminished stature in adulthood, but these
manifestations are more variable and less pronounced than in classical
CAH. Prepubertal boys may have phallic enlargement without testicular
enlargement. In adolescents and adults, signs of hyperandrogenism associated
with NCCAH include (in order of frequency) hirsutism, menstrual irregular-
ities, acne, or decreased fertility. Hirsutism, oligomenorrhea, and acne are
typical in polycystic ovarian syndrome as well as NCCAH. The modified
Ferriman-Gallwey score assesses the magnitude of hair growth in areas,
such as the face, chin, upper chest, abdomen, and back, and a score of
more than 8 is considered significant [6]. NCCAH may be distinguished
from polycystic ovary syndrome by the specific early morning follicular phase
serum 17-OHP level and the postcosyntropin stimulated level of this hormone
[7]. Severe cystic acne refractory to oral antibiotics and retinoic acid has been
attributed to patients with NCCAH [8].
The gold standard of biochemical evaluation of individuals suspected of
having either classical CAH or NCCAH is performed through an adrenocor-
ticotropic hormone (ACTH 1–24, cosyntropin) stimulation test. This test
involves drawing baseline laboratory studies that include 17-OHP and a full
panel of other precursor adrenal hormones before administering Cortrosyn,
typically 250 lg intravenously, and then obtaining a second blood sample
60 minutes later. It is best to perform the assays for steroid hormone analytes
through liquid chromatography/tandem mass spectrometry because they are
more specific and sensitive than radioimmunoassays. A comprehensive panel
of hormone measurements can also help differentiate 21-hydroxylase defi-
ciency from other rarer forms of CAH.
11b-HYDROXYLASE DEFICIENCY CAH

11b-hydroxylase deficiency CAH is the second most frequent form of CAH
and represents about 5% to 8% of all CAH cases. The incidence of 11b-hydrox-
ylase deficiency CAH is 1 in 100,000 births, with the highest number of cases
TREATMENT OUTCOMES IN CONGENITAL 273
among Moroccan Jews (1 in 5000–7000). There is a defect in the conversion of

DOC to corticosterone and the conversion of 11-deoxycortisol (compound S)
to cortisol. The CYP11B1 gene is located on chromosome 8q21 [9] and is
expressed in the adrenal zona fasciculata. Deficiency of CYP11B1 causes
steroid precursors to be shunted into the androgen synthesis pathway causing
hyperandrogenism and external genital virilization in female patients, similar to
that of 21-hydroxylase deficiency CAH (see Table 1). Unlike 21-hydroxylase
deficiency CAH, patients with 11b-hydroxylase deficiency (CYP11B1 defects)
can have low renin hypertension caused by an overproduction of DOC,
which possesses mineralocorticoid activity [10]. Primary treatment consists of
low-dose glucocorticoids to suppress excess adrenal mineralocorticoid and
androgen production. NC 11b-hydroxylase deficiency may present similarly
to NC 21-hydroxylase deficiency. Hypertension is not a typical feature in
this milder form of the disease.
A highly homologous gene, CYP11B2, is primarily expressed in the zona glo-
merulosa and encodes the enzyme responsible for conversion of DOC to aldoste-
rone. Defects in CYP11B2 lead to salt wasting and failure to thrive and no
associated genital ambiguity among affected girls.
17a-HYDROXYLASE/17,20-LYASE DEFICIENCY CAH

This form of CAH accounts for approximately 1% of CAH cases worldwide
but is the second most frequent form of CAH in Brazil (5%–7% of all cases).
Low 17a-hydroxylase activity and 17,20-lyase activity leads to the impaired
production of cortisol and sex hormones. High levels of corticosterone and de-
oxycorticosterone, which have glucocorticoid and mineralocorticoid activity
respectively, prevent shock. Thus, these patients with CAH have the unique
presentation of 46,XY individuals with genital ambiguity and 46,XX individ-
uals with normal female external genitalia. Both boys and girls have delayed
puberty with hypergonadotropic hypogonadism and low renin hypertension
[11]. The CYP17 gene is mapped to chromosome 10q24.3 and is expressed
in the zona reticularis and zona fasciculata of the adrenal glands, Leydig cells
of the testes, and theca cells of the ovary [11].
To treat hypertension, low doses of glucocorticoids are given to suppress DOC
levels. However, in both 11- and 17-hydroxylase deficiencies, long-standing
exposure to excessive DOC, hypertension may require adjunctive drugs to block
mineralocorticoid action and treat the hypertension. Losartan, or other aldoste-
rone receptor blockers, can be considered as the second-line treatment of refrac-
tory hypertension. Sex hormone replacement is required for both sexes to induce
and maintain secondary sexual characteristics.
3b-HYDROXYSTEROID DEHYDROGENASE DEFICIENCY CAH

This type of CAH is rare, although nonspecific hormone assay artifacts often
lead to the overdiagnosis of 3b-hydroxysteroid dehydrogenase (3bHSD) defi-
ciency. The function of 3bHSD is necessary for the conversion of pregneno-
lone to progesterone, 17-OH pregnenolone to 17-OH progesterone, and
274 CHENG & SPEISER
dehydroepiandrosterone to androstenedione. The phenotypic presentation of

classic 3bHSD deficiency includes a variable degree of salt wasting with or
without ambiguous genitalia and hypogonadism in patients with either
46,XX or XY. The type II 3bHSD gene (HSD3B2) is located on chromosome
1p11-13 and is expressed primarily in the adrenals and gonads [12,13]. A mild
nonclassical variant can be a cause of premature pubarche in children and
hirsutism with menstrual dysfunction in adolescent girls and women. Markedly
elevated ACTH-stimulated serum 17-OH pregnenolone levels and 17-OH
pregnenolone to cortisol ratios are diagnostic [13,14].
CONGENITAL LIPOID ADRENAL HYPERPLASIA

Congenital lipoid adrenal hyperplasia (CLAH), rare in most countries, is the
second most common form of CAH in Japan and Korea. This form of CAH
is characterized by deficiency of all adrenal and gonadal hormones, leading
to failure to thrive, hyperpigmentation, salt-wasting crisis, hyponatremia, hypo-
volemia, and hyperkalemia. CLAH is lethal in its complete form. Individuals
with this condition have inactivating recessive mutations in CYP11A1, which
is a cholesterol side-chain cleavage enzyme, or in steroidogenic acute regulatory
protein important in the import of cholesterol to the mitochondria for steroid
production. Male infants with this disorder have either ambiguous or female
external genitalia caused by a lack of androgens. In a few instances, girls
have been reported to undergo spontaneous puberty but are generally infertile
and present with large ovarian cysts [15].
P450 OXIDOREDUCTASE DEFICIENCY

This form is another rare and only recently recognized form of CAH [16].
Its unique aspect is the frequent association with skeletal malformations
described in Antley-Bixler syndrome (Online Mendelian Inheritance in
Man 207,410). Rather than a discrete enzyme deficiency, P450 oxidoreduc-
tase is a cofactor required for normal activity of 3 different key steroidogenic
enzymes (21-hydroxylase, 17-hydroxylase, and aromatase) and other P450
enzymes, including those involved in sterol precursor synthesis. These latter
blocks in enzyme activity are thought to account for the skeletal defects.
Complete POR deficiency is probably lethal. The urinary mass spectrometry
profile of cortisol precursors to metabolites (see Table 1) is diagnostic [17].
The POR gene is mapped to chromosome 7q11.2 and is expressed in tissues
expressing cytochromes P450. Depending on the type of mutation, the
enzymes’ activities are variably diminished, hence the variable phenotypic
presentation. Most patients described have either 46,XX or 46,XY disorders
of sex development with genital ambiguity. The treatment depends on the
symptoms and hormonal profile, but glucocorticoids are the mainstay of
replacement therapy.
All patients affected with CAH are at risk for subfertility and deserve consul-
tation with reproductive endocrinology when appropriate.
UPDATE ON SPECIFIC 21-HYDROXYLASE DEFICIENCY

TREATMENT GUIDELINES
In 2010, The Endocrine Society’s Task Force published updated evidence-
based guidelines for the treatment of 21-hydroxylase deficiency CAH [18].
Newborn screening
The Endocrine Society’s Task Force recommends that screening for 21-hydroxylase
deficiency be incorporated into all newborn screening programs because the
disorder is common and potentially fatal. Morbidity and mortality are reduced
with early diagnosis and treatment to prevent severe salt-wasting crises. The proba-
bility of infant death caused by salt-wasting crises was approximately 4% in countries
without screening for CAH. This rate can be higher in populations with limited
awareness or access to care [4].
Currently, most US laboratories use birth-weight adjusted cutoffs for 17-
OHP values obtained via immunoassay. It has been suggested that using actual
gestational age rather than birth weight will improve positive predictive value
of screening because 17-OHP levels are much better correlated with gestational
age [19]. The treatment of infants with positive newborn screens, electrolyte
abnormalities, and vascular compromise should never be delayed for Cortro-
syn stimulation testing because baseline levels will undoubtedly be markedly
elevated. The task force did not recommend the treatment of asymptomatic
infants with the nonclassical form of 21-hydroxylase deficiency occasionally de-
tected via hormonal screening.
Prenatal treatment of CAH

Prenatal therapy with dexamethasone in pregnancies at risk for CAH remains
controversial and experimental. This finding was decided by the expert panel
because of the potential for unrecognized long-term adverse outcomes. In order
for dexamethasone to be effective, the medication must be implemented during
the early first trimester, which is a critical stage of development. The goal of
prenatal therapy with dexamethasone is to minimize virilization in affected
female fetuses, which represent 1 of 8 pregnancies. Prenatal dexamethasone
does not cure the disease. Thus, it is difficult to justify such treatment unless
and until there are more precise ways of identifying those who will benefit and
defining the risks to those who will not benefit.
With limited data, The Endocrine Society’s Task Force concluded that
parents should be informed of potential risks and benefits of this treatment
and that this only be pursued through protocols approved by institutional
review boards at designated centers.
Medical treatment
Individuals with classic salt-wasting 21-hydroxylase deficiency CAH require
supplementation of mineralocorticoids, glucocorticoids, and sodium chloride
(Tables 2 and 3). The glucocorticoid supplementation of choice is hydrocorti-
sone and should be prescribed in tablet form. In infants, the tablet can be
crushed, weighed on a prorated basis in a compounding pharmacy, and mixed
276 CHENG & SPEISER
Table 2
Maintenance therapy in growing patients with CAH
Medication Total daily dosage Dosing regimen
2
Glucocorticoids: hydrocortisone tablets 10–15 mg/m /d 3 times/d
Mineralocorticoids: 0.05–0.2 mg/d 1–2 times/d
fludrocortisone tablets
Sodium chloride supplements 1–2 g/d in infancy Divided into several feeds
Data from Speiser PW, Azziz R, Baskin LS, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxy-
lase deficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2010;95:4133–60.
with a small amount of liquid to be administered orally via syringe. It is inad-

visable to use prepared suspensions because published reports indicate the drug
was not adequately distributed in such preparations [20].
The use of long-acting glucocorticoid replacement has been studied in
small subgroups. Longer-acting glucocorticoid replacement, such as predniso-
lone and dexamethasone, has been used to treat refractory cases. Prednisone
is associated with decreased adult height. Prednisolone, the bioactive product
of prednisone, is estimated to have up to a 15-fold greater growth suppressive
effect compared with hydrocortisone [21]. Dexamethasone may be up to 70- to
80-fold more potent than hydrocortisone in suppressing growth [22].
Most reports of treatment with these potent glucocorticoids do not include
long-term evaluation or adult heights. Rivkees and colleagues [22,23] reported
managing infants and children with once-daily low-dose dexamethasone (0.25
mg/m2/d) and achieving normal linear growth, weight gain, and skeletal matu-
ration. Dauber and colleagues [24] also have discussed the feasibility of
nocturnal administration of dexamethasone given at 1/50th of the total daily
hydrocortisone dose for the treatment of CAH.
Despite feasibility of such regimens, the Endocrine Society’s practice guide-
lines [18] discourage chronic usage of long-acting glucocorticoids in children
because of the potential for growth suppression.
Patients with classic CAH should also receive mineralocorticoid supplemen-
tation, with oral fludrocortisone acetate, and sodium chloride supplements,
especially during the newborn period and infancy. The requirement for sodium
Table 3
Maintenance therapy in fully grown patients with CAH
Medication Total daily dosage Dosing regimen
Hydrocortisone 15–25 mg/d 2–3 times/d
Prednisone 5.0–7.5 mg/d 2 times/d
Prednisolone 4–6 mg/d 2 times/d
Dexamethasone 0.25–0.5 mg/d Once daily
Fludrocortisone 0.05–0.2 mg/d Once daily
Data from Speiser PW, Azziz R, Baskin LS, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxy-
lase deficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2010;95:4133–60.
in normally growing infants is approximately 2-4 meq/kg/day and is adequately

provided by human milk or infant formulas, which has about 7 to 9 mmol/L
sodium [25]. However, in patients with salt-wasting CAH, the sodium content
in breast milk or infant formulas is insufficient to maintain plasma sodium
levels and plasma renin activity in the normal range [26].
Additionally, patients and families should be given information about
increasing glucocorticoid dosage during periods of increased stress, including
febrile illness (>101 F), gastroenteritis with dehydration, surgery with general
anesthesia, and major trauma. Information about other steroid delivery methods,
including suppositories and intramuscular injections, should be reviewed and
demonstrated to the family in case of an emergency. Patients should always
wear a medical alert tag indicating the need for treatment in the setting of adrenal
insufficiency. The CARES Foundation Web site has a template for such emer-
gency management information: http://www.caresfoundation.org/productcart/
pc/images/EmergencyInstructions.pdf (see Tables 2 and 3).
NCCAH
Individuals with NCCAH should be treated based on symptoms and signs.
Children who present with inappropriately early onset and rapid progression
of pubarche and bone age should be treated with low-dose hydrocortisone.
Adolescent patients with severe hirsutism, irregular menses, or severe acne
should also be treated medically to suppress adrenal androgens. The effective
treatment of hirsutism may require the addition of an oral contraceptive or
antiandrogens and cosmetic interventions. However, individuals who are
asymptomatic need not be treated with glucocorticoids. With 20% to 50% enzy-
matic activity, there is no convincing evidence that NCCAH is associated with
clinically significant adrenal insufficiency.
Growth and development

Overtreatment or undertreatment of these individuals may lead to adverse
effects. Inadequate glucocorticoid therapy may increase the risk of adrenal
crisis in patients with severe forms of CAH. Additionally, insufficient glucocor-
ticoid replacement leads to androgen excess with associated accelerated growth
and epiphyseal maturation (probably via the actions of estrogens, which is a by-
product of androgen excess) with advanced bone age and compromised adult
height. Overtreatment may suppress growth, increase blood pressure, and lead
to cushingoid features. Excessive doses of glucocorticoids, especially during the
first 1 to 2 years of life and during puberty, can cause growth failure.
After the initial reduction of markedly elevated adrenal hormone levels in
newly diagnosed infants with classic forms of CAH, it is important to rapidly
reduce the dose once target steroid levels are reached and to continue to closely
monitor blood pressure and growth parameters at office visits. When chronic
hydrocortisone dosages exceed 20 mg/m2/d in infants and 15 to 17 mg/m2/d in
adolescents [27], there is a loss of height standard deviation (SD) score and
shorter adult height potential.
278 CHENG & SPEISER
A systemic review of 35 studies, most published before universal newborn

screening, suggest that the final height of patients with classic CAH treated
with glucocorticoids is slightly lower than the population norm. Meta-analysis
shows that mean final adult height is approximately -1.38 SD less than the
mean of the general population but only -1.0 SD when corrected for parental
heights [28]. These heights translate to about 66’’ in boys or 62’’ in girls accord-
ing to North American growth standards. Thus, there is no compelling medical
indication to treat all patients with CAH with growth-enhancing drugs. There
are limited studies evaluating drugs that enhance growth in children with
CAH, such as growth hormone, gonadotropin-releasing hormone analogues,
or aromatase inhibitors. These treatments should be limited to clinical research
trials.
Based on systematic review and meta-analysis, the task force concluded that
normal height can be achieved with close monitoring and prudent use of stan-
dard glucocorticoid and mineralocorticoid therapies. Height-enhancing drugs
are not recommended for individuals whose height is expected to be more
than -2.25 SD.
Surgical intervention
There are no randomized controlled studies of either the best age or the best
methods for feminizing surgery. All procedures should be performed by an expe-
rienced surgeon in a center with experienced pediatric endocrinologist and
mental health services. The extent of vaginal surgery depends on the degree of
virilization. Long-term follow-up and outcome studies are necessary to under-
stand the risks and benefits of early versus late surgical treatment.
Psychosexual health
Most chromosomal women with CAH who are raised women identify them-
selves as women and live in their assigned gender. In a study with 250 patients,
only 13 had gender dysphoria [29]. Although most women demonstrate
heterosexual preferences, rates of bisexual and homosexual orientation are
increased in women with CAH compared with controls. There is some corre-
lation with the degree of prenatal androgenization [30]. Some women with
CAH shun any sexual liaisons. The initial degree of virilization at birth has
been directly associated with older age of first intercourse and poor body
image.
Whether and when to perform surgery for genital anomalies remains a topic
of active discussion. The task force concluded that surgical outcomes depend
on the type of surgery and skill of the surgical team. Total or partial urethral
mobilization is currently considered the procedure of choice and is usually
easiest to perform in infancy. Older women with CAH may need to receive
counseling to cope with hormone replacement therapy and vaginoplasty or
dilatation. Counseling should be available during adult life [31].
Patients with psychosocial problems associated with disorders of sexual
development should be referred to mental health professionals who specialize
in the management of these problems.
Genetic testing/counseling
Genetic testing should not be the first-line diagnostic study in individuals with
suspicion of having CAH. Genetic testing may be useful in affected individuals
and their family members for family planning or when hormone tests are
inconclusive. Genetic counseling should be provided to parents of a child
with CAH and to adolescents at the transition to adult care.
Transition to adult care

Pediatric endocrinology care is often transferred to adult care around 18 years of
age. A gradual transition of the adolescent to an adult endocrinologist will allow
the adolescent to develop a rapport with the adult endocrinologist while maintain-
ing a relationship with the pediatric specialist. Male adolescents require continued
monitoring or consultation with a urologist, whereas female adolescents require
consultation with an experienced gynecologist and urologist.
Pregnancy and fertility

Patients with CAH should continue treatment with prepregnancy doses of gluco-
corticoid and mineralocorticoid therapy. Doses of maintenance medications should
be adjusted if signs and symptoms of adrenal insufficiency occur. Stress doses of
glucocorticoid therapy should be implemented during labor and delivery.
Individuals with CAH who may have impaired fertility should consult
a reproductive endocrinologist or fertility specialist. Adolescent and adult males
with CAH should be routinely monitored for testicular adrenal rest tumors
(TARTs) via ultrasonography. TARTs increase with age and can affect fertility
by impairing spermatogenesis [32].
Subfertility in women with NCCAH is mild compared with classical CAH
and seems to be mainly caused by hormonal imbalance. In classic CAH,
numerous additional factors influence childbearing. Hydrocortisone treatment,
with or without Clomid, can normalize menstrual cycles, induce ovulation, and
help achieve pregnancy [33].
SUMMARY
Systematic literature review and meta-analysis guided by expert opinion has
refined current approaches to the treatment of CAH. The advent of wide-
spread newborn screening has improved outcomes, with lower morbidities
and mortality. Future advances may be recognized in the form of more efficient
diagnostic tools, physiologic drug delivery, improved surgical methods, and as-
sisted reproductive technologies.
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Surgical and Ethical Challenges in

Disorders of Sexual Development
Mary E. Fallat, MDa,b,*, Paige Hertweck, MDb,c,
Steven J. Ralston, MD, MPHd
a
Division of Pediatric Surgery, Department of Surgery, University of Louisville, 315 East
Broadway, Suite 565, Louisville, KY 40202, USA; bKosair Children’s Hospital, Norton Healthcare,
210 East Gray Street Suite 600, Louisville, KY 40202, USA; cDepartment of Pediatrics, University
of Louisville, Louisville, KY, USA; dHarvard Medical School, 750 Washington Street, Box 360
Boston, MA 02111-1526, USA
Keywords
Disorders of sexual development (DSD) Adolescent
Congenital adrenal hyperplasia (CAH) Complete androgen insensitivity
Gonadal dysgenesis Vaginal atresia Ovotesticular DSD
Key Points
Disorders of sexual development are rare and are best managed by a multidis-
ciplinary team.
The most important times for interdisciplinary management and counseling are at
the time of DSD diagnosis, time of any surgical procedure, and at the beginning
of major developmental stages.
Current optimal management of DSD involves delaying non-emergent surgical
and medical treatments that are irreversible with provision of age appropriate
counseling and education for both parents and children.
INTRODUCTION
Disorders of sexual development (DSDs) occur with an incidence of 1 in 4500
live births and have protean causes [1–3]. A DSD is defined by a congenital
condition in which the development of the chromosomal, gonadal, or anatomic
sex is atypical. Although an atypical appearance of the genitalia is most often
seen at birth, the diagnosis may be made at a remote time, including at puberty
or as an adult [4]. This article primarily focuses on how older patients present,
how to begin a work-up that facilitates a diagnosis, some of the anatomic and
functional challenges that adolescents face if they have a DSD, ethical issues of
importance, and how these disorders may affect overall development and
health as individuals approach adulthood.
*Corresponding author. E-mail address: mefall01@louisville.edu

284 FALLAT, HERTWECK, & RALSTON
The overall management of a person with a DSD is complex and necessitates

the involvement of a team, even when the presentation is delayed [5]. The first
medical provider that an adolescent who has an occult DSD sees may be
a primary care physician or a specialist such as a gynecologist, endocrinologist,
or psychiatrist. Table 1 summarizes some of the chief complaints that may be
the precipitating reason to see a physician and the diagnostic tests of choice to
begin the process of determining a specific cause. Operative procedures that
could be needed for a given condition are included in the last column. An
external examination may provide a clue to the differential diagnosis.
If a DSD was obvious at birth, gender assignment or the process by which the
sex of rearing was decided should have taken into account the cause of the
disorder, the magnitude of the anatomic abnormalities, the natural history of
the disorder and the ultimate prediction of gender identity, the potential for future
sexual and reproductive function, and the capabilities and/or limitations of
surgical reconstruction [1,6]. In most, but not all, cases, the initial sex of rearing
for both early-onset and late-onset DSDs will be congruent with future gender
identity [7–9].
Gender identity refers to a person’s conscious and unconscious feelings of
belonging to one sex or the other [10]. Individuals born with the greatest discor-
dance between genetic sex and phenotypic appearance are at most risk for
psychological consequences as a result of confusion of gender identity [6]. Specif-
ically, sex assignment is most challenging in partial androgen insensitivity,
androgen biosynthetic defects, or incomplete gonadal dysgenesis, in which
almost a quarter of patients ultimately report dissatisfaction with their sex of rear-
ing [6]. Gender dysphoria is the feeling that one’s gender identity may be incor-
rect [10]. Persons with a DSD who present as adolescents generally present with
a symptom complex or anatomic change that is defined by their specific abnor-
mality but they may also occasionally present with gender dysphoria.
This article describes some of the disorders that a pediatrician may see, some
of the ethical issues of significance in DSD and how to approach them as the
primary care provider, and a series of illustrative patients. A few cases that
involve contemporary infants with a complex DSD who will pose future ethical
challenges are also described.
DSD CATEGORIES
Developmental abnormalities causing intersex conditions may be categorized
into 3 main groups: genetically female with phenotypic masculinization (female
DSD), genetically male with phenotypic feminization (male DSD), and gonadal
ambiguities or absence resulting from chromosomal abnormalities or syndromes
(see Table 1).
Female DSD
Congenital adrenal hyperplasia (CAH) or the adrenogenital syndrome, caused
by excessive endogenous androgen production in genetically female individ-
uals, is the main cause of masculinization of the external genitalia in 46,XX
DISORDERS OF SEXUAL DEVELOPMENT
Table 1
Aids in diagnosis of DSD
Chief complaint Diagnosisa Laboratory Imaging Operative procedure
Primary amenorrhea CAIS (1) hCG Pelvic ultrasound Video-assisted gonadectomy
Inguinal hernia with mass Uterovaginal agenesis (2)/vaginal FSH MRI pelvis Possible creation neovagina
atresia TSH
Prolactin
Mixed gonadal dysgenesis (3) Video-assisted gonadectomy
Estradiol
Delayed puberty Pure gonadal dysgenesis Testosterone Video-assisted gonadectomy
Turner syndrome (mosaic) DHT Video-assisted gonadectomy
CAH (prior surgery) DHEAS Genitoscopy
17-OH Prog Vaginoplasty if needed
17-OH Preg
Clitoromegaly CAH (late presentation) Genitoscopy
MIS or AMH
Vaginoplasty if needed
Karyotype
Inadequate vagina/foul-smelling Cloacal/bladder exstrophy (4) Pelvic ultrasound Genitoscopy
discharge; prolonged menses Partial vaginal atresia (5) MRI pelvis Vaginoplasty
CAH (prior surgery) (9)
Genital ambiguity: clitoromegaly or Mixed gonadal dysgenesis (6) (7) Estradiol Pelvic ultrasound Video-assisted gonadectomy
small phallus with posterior labial Ovotesticular DSD (8) Testosterone MRI pelvis Video-assisted gonadectomy
fusion or labial mass DHT Ultrasound of labia mass Genitoscopy
CAH
Gender dysphoria DHEAS Vaginoplasty if needed
17-OH Prog
17-OH Preg
MIS or AMH
Karyotype
Abbreviations: AMH, antimüllerian hormone; CAH, congenital adrenal hyperplasia; CAIS, complete androgen insensitivity; DHEAS, dehydroepiandrosterone sulfate; DHT,
dihydrotestosterone; FSH, follicle-stimulating hormone; hCG, human chorionic gonadotropin; MIS, müllerian inhibiting substance; MRI, magnetic resonance imaging; 17-OH
Prog, 17-OH progesterone; 17-OH Preg, 17-OH pregnenolone; TSH, thyroid-stimulating hormone.
285
a
Numbers in parentheses correspond with case representations.
individuals [3]. The cause in most (90%) cases is a deficiency of the P450c21
oxidase enzyme on chromosome 6. A small number of cases occur because
of deficiencies of the p450c11 or 3b-hydroxysteroid dehydrogenase enzymes.
Formation of the ovaries, uterus, and fallopian tubes is normal, but the vagina
is foreshortened and joins the urethra. In severely masculinized forms, the
vagina ends in a fistula at approximately the location of the external urethral
sphincter. In less severe forms, the vagina ends more distally in a common
urogenital sinus. The external genitalia are characterized by clitoral enlarge-
ment ranging from minimal to an almost normal-appearing phallus and labial
masculinization ranging from labioscrotal folds to complete scrotal fusion.
Gonadal descent never occurs because the ovaries are normal.
The enzymatic deficiencies in the adrenogenital syndrome result in deficient
cortisol biosynthesis. Release of feedback inhibition results in increased cortico-
tropin production and adrenal stimulation, resulting in adrenal hyperplasia and
overproduction of products proximal to the enzymatic defect. Preferential overpro-
duction of androgenic steroids results in the variable degrees of masculinization.
Most individuals with the adrenogenital syndrome present in infancy, but
there are exceptions or nonclassic forms including 21-hydroxylase (CYP21A),
11-hydroxylase (CYP11B1), and 3b-hydroxysteroid dehydrogenase (HSD3B2)
deficiencies. Patients with these disorders have a phenotypic female appearance
of the external genitalia and present with early adrenarche or pubarche, hir-
sutism, amenorrhea, or menstrual dysfunction [4].
A subset of adolescents with the more severe virilizing forms of CAH who pre-
sented in infancy with salt wasting and who often had procedures done during
infancy or childhood, present as adolescents with an inadequate vagina, amenor-
rhea, or clitoral enlargement. Clitoral enlargement is common in adolescents
who are not compliant with their medication [11].
Another condition presenting in pubertal girls with poor sexual development
and abnormal virilization is aromatase deficiency [12].
Male DSD
Mediation of the effects of both testosterone and dihydrotestosterone (DHT)
requires a functional androgen receptor (AR) to induce expression of androgen-
dependent genes. Gene mutations of variable type and severity result in a spec-
trum of forms of the androgen insensitivity syndrome (AIS), the most common
cause of a male DSD [8,9]. Affected individuals have a 46,XY karyotype and
normal symmetric testes that may be intra-abdominal or descended, with the
external genital phenotype varying from normal male (partial AIS [PAIS]) to
normal female (complete AIS [CAIS]). More than 250 mutations in the AR
gene have been identified and characterized in individuals with AIS. The 2
primary types of AR defect associated with AIS are attributed to either abnormal-
ities of androgen binding or abnormalities of DNA binding. Müllerian structures
are normally regressed.
In spite of advances in the molecular analysis of AR defects, clinical factors
remain of primary importance in assigning the sex of rearing. Assigning the sex
DISORDERS OF SEXUAL DEVELOPMENT 287
of rearing is straightforward for those with the mildest or most severe degrees
of feminization, but remains the subject of greatest concern for individuals
whose phallic size is considered inadequate, because some individuals with
PAIS have successfully responded to high-dose testosterone treatment. Because
persons with CAIS have normal female external genitalia, the 2 more common
ways that an individual with CAIS presents are with a testis in an inguinal
hernia sac or with amenorrhea as an older adolescent [4].
Other causes of insufficient masculinization of a 46,XY genetically male indi-
vidual include insufficient testosterone production or an inability to convert testos-
terone to DHT. Deficiency of androgen production may occur because of genetic
defects in the enzymes responsible for the conversion of cholesterol to testosterone.
The 4 P450 enzymes involved in adrenal steroidogenesis include P450scc, or
cholesterol side chain cleavage enzyme; P450c11, which mediates both 11-hydrox-
ylase and 18-hydroxylase; P450c17, which mediates the 17 a-hydroxylase and
17,20-lyase activities; and P450c21, which mediates the 21-hydroxylase of both
the glucocorticoid and mineralocorticoid pathways. These children produce little
or no serum testosterone but müllerian inhibiting substance (MIS) levels are normal
for age. The testes may be undescended, small, or both, and müllerian structures
are absent. The penis may be small and hypospadic. Individuals who have a pheno-
typic female appearance may present with amenorrhea at puberty or later.
Other enzymes that may be responsible for deficient androgenization include 3
b-hydroxysteroid dehydrogenase and 17-ketosteroid reductase. The former
enzyme controls essential steps in the production of both glucocorticoids and miner-
alocorticoids, as well as converting dehydroepiandrosterone (DHEA) to androste-
nedione in the testis. The latter converts androstenedione to testosterone. Type II
male DSD, caused by 5 a-reductase deficiency, causes failure of conversion of testos-
terone to dihydrotestosterone in peripheral target tissues, which is an autosomal
recessive disorder that includes severe hypospadias, undescended testes, a prepenile
scrotum, and enlarged prostatic utricle. The type 2 isoform located on chromosome
19 is the one that is predominantly expressed in the external genitalia.
The persistent müllerian duct syndrome (PMDS), caused by deficient MIS or
its receptor, occurs when usually phenotypic male individuals, often with unde-
scended testes, have persistent müllerian structures. The gonads in this condition
are normal, although the undescended gonads pose a risk for future testicular
cancer. The descended testis may pull the fallopian tube and uterus into the track
through which it has descended (hernia uteri inguinalis) or the undescended
testis from the other side of the body may be pulled into the same track (trans-
verse testicular ectopia). The vas deferens may enter the retained müllerian
duct structures, accounting for future infertility.
Gonadal ambiguities resulting from chromosomal abnormalities or

syndromes
An abnormality of the sex chromosomes usually results in failed, incomplete, or
asymmetric gonadal development. The most common of these abnormalities is
mixed gonadal dysgenesis associated with a 45,X/46,XY karyotype. In this
condition, there is usually a small dysgenetic testis on one side and a streak gonad
on the other. In spite of its size, the small testis produces sufficient testosterone to
cause masculinization. There may be a phallus that appears almost normal, or
clitoral hypertrophy. There may be a urogenital sinus defect. In individuals
with a 46,XY karyotype or pure gonadal dysgenesis, a defective Y chromosome
may result in bilateral streak gonads. Both testosterone and müllerian inhibiting
substances are usually low or absent, resulting in a phenotypic female individual
and preservation of müllerian duct structures.
Ovotesticular DSDs are rare and usually characterized by asymmetric
gonads. They may have nondysgenetic ovarian and testicular development
that is separated on both sides or combined in 1 or both gonads as an ovotestis.
In a combined gonad, the testis is always centrally located, and is not prone to
neoplastic transformation. The müllerian structures are regressed on the side of
testicular tissue. The vagina enters the urethra in a urogenital sinus defect.
A DSD resulting from a developmental disorder or syndrome is also possible,
including children who have abnormities of the reproductive tract caused by cloacal
or bladder exstrophy, cloacal abnormalities, the caudal regression syndrome, or the
vertebral, anal, cardiac, tracheoesophageal, renal, limb (VACTERL) syndrome.
Vaginal and müllerian abnormalities, in particular, are common enough in these
syndromes that an examination under anesthesia during infancy at the time of
other operative procedures may be proactively included and instructive enough
to preempt functional problems at puberty. Possible abnormalities include a vaginal
septum, vaginal atresia, vaginal fistula to the bowel, or uterine abnormalities.
Neoplasia arising in abnormal gonads

Many long-term studies have detailed the incidence of neoplasia arising in
abnormal gonads [13,14]. Occurrence of neoplasia and dysgenetic gonads is
primarily associated with the Y chromosome containing karyotypes, and is less
common in patients with 45,XO gonadal dysgenesis. If the müllerian system is
developed and a Y chromosome or fragment is present, there is approximately
a 25% incidence of neoplasia [6,13]. Early exploration and gonadectomy should
be performed in these children. Adult patients presenting with primary or
secondary amenorrhea and abnormal sexual development such as infantile
external or internal genitalia and atrophic vaginal mucosa should be thoroughly
evaluated for an intersex disorder and gonadectomy, if indicated. In individuals
with mixed gonadal dysgenesis who lack 2 gonads at laparotomy, a yearly pelvic
or abdominal ultrasound evaluation is indicated. Scrotal testes are not likely to
become neoplastic in such patients. This type of patient rarely presents in adoles-
cence [13,14].
DIAGNOSTIC EVALUATION
Initial laboratory evaluation (see Table 1) generally includes an evaluation of
pituitary and sex steroids and a karyotype. This information and the external
physical examination may dictate additional studies including radiographs and
an examination under anesthesia. Fluorescent markers (florescence in situ
hybridization [FISH]) to detect the distal arm of the Y chromosome, polymerase

chain reaction analysis, and Y-specific gene probes, such as sex-determining
region Y (SRY), are standard for more complex cases [14]. Radiographic assess-
ment tends to be an instrumental part of diagnosis and management. Options
include ultrasound, which poses no radiation risk and is a screening test that
allows evaluation of both the genital and urinary tracts looking for abnormal dila-
tion of normal or abnormal structures and presence of intra-abdominal gonads.
Magnetic resonance imaging (MRI) scan allows for more definitive evaluation of
individual structures and the pelvic floor, although it may require sedation.
Contrast genitogram and urinary tract evaluation in both the anteroposterior
and lateral views with catheters in place allows delineation of the reproductive
and urinary tracts in relation to each other. Ultimately, a careful and thorough
cystoscopy and vaginoscopy done under anesthesia by the multidisciplinary
operative team is integral to planning any surgical procedure and counseling
both the patient and family of invasive and noninvasive treatment options.
ETHICAL ISSUES
The available medical literature suggests that most patients with DSDs are
heterosexual based on sex of rearing [1,7–9]. It is best to counsel parents and
educate developing children in a way that parallels chronologic and conceptual
growth. Defined periods of family crisis in which counseling and education
become important are at the time of diagnosis, at the time of any surgical proce-
dure, and at the beginning of major developmental stages. Historically, children
were often left uninformed until someone judged them old and mature enough to
comprehend how they were different. These attempts to protect individual chil-
dren from their condition may have left them vulnerable to a personal crisis at an
age when sexual identity and identity with a peer group are important.
Compliance with medications is important for some of the DSDs including
congenital adrenal hyperplasia. Although the traditional age of noncompliance
with medication begins at 6 to 8 years old, the early to midadolescent years are
another time when the need for peer group conformity may take precedence
over compliance with medication. By this time, it is essential that the child
grasp that therapy is essential for maintenance of personal health.
The history of medical and surgical approaches to children born with ambig-
uous genitalia or unclear sex is replete with examples of doctors’ desires to
quickly and definitively classify children as male or female and to achieve
concordance between the assigned sex and the appearance of the genitalia
[15]. Given the paucity of information that was available to these doctors at
the time, it is difficult to condemn these efforts. However, there are increasing
data available that previous assumptions about outcomes and what would be in
the best interest of the child may still be evolving [1,16,17].
Initial presentation
‘‘Is it a boy or a girl?’’ is often the first question parents ask at the time of
a prenatal ultrasound, or at the birth of a child. It is often the same first
question that friends and family members ask because the sex of a child has
such important social and cultural significance. When the medical establish-
ment is unable to answer this seemingly simple question expeditiously and
unequivocally, the parents and their extended community may be thrown
into turmoil. DSDs [18] are rare enough that parents are typically not well
informed or prepared to contend with the wide range of emotions that they
are bound to face when a child is born with abnormal, ambiguous, or unex-
pected genitalia.
Once a diagnosis is made, physicians and parents are inevitably faced with
decisions about what is the best course of action to address the disorder.
Some decisions are easy. There are medical and surgical treatments necessary
for the immediate survival of the child and no ethical framework would deny
a child these treatments: a child with salt-wasting CAH requires medical
therapy; a child with a cloaca or a cloacal exstrophy and bifid or poorly devel-
oped genitalia needs early and multiple-stage surgery.
Some decisions can be delayed until the child is older and can participate in the
decision-making process with little impact on the outcome for the child. For
example, children with complete androgen insensitivity may need a gonadectomy
to prevent cancer, but this surgery can be performed after puberty with little risk
of cancer [19]. If the child has a late-onset disorder or recognition of a DSD, there
may also be an opportunity for that child to actively participate in medical and
surgical treatment decisions, which respects their personal autonomy. However,
there are a wide range of treatments that, although medically not crucial, may
simplify sex assignment. How should these treatments be approached from
a biomedical ethics standpoint?
Informed consent and the pediatric patient

In American medical practice, patient autonomy continues to be significant in the
medical decision-making process. Although this makes sense within a variety of
ethical frameworks for competent adult patients, its application to pediatric patients
is limited: children (especially young children) cannot comprehend or express their
desires sufficiently well to allow an informed consent process. Older children and
adolescents are often asked to assent to the care being provided within their limits
of understanding, but the overarching goal of care for providers and decision
makers (usually the parents) is to do what is in the best interests of the child [20].
The best interests standard has historical roots dating to early Judeo-
Christian teachings: Solomon resolves a conflict between 2 women claiming
to be a child’s mother by threatening to divide the child in half, the true mother
being revealed when she rescinds her claim for the good of the child. Parents
are presumed to be the best decision makers for their children because parents
make their children’s interests paramount. However, for children born with
DSDs, the determination of what is in the child’s best interests is complicated
and fraught with problems of bias and limited data on outcomes.
The discussion of a DSD not only may involve confusing concepts, but deci-
sions may have profound ramifications and, in some cases, irreversible
consequences for the person involved. Delaying medical decisions that are not
emergent and irreversible is now the norm. Involving an affected adolescent in
these decisions is appropriate but may inevitably result in exposing the family
to a variety of emotional and psychological feelings that make immediate deci-
sions difficult. However, some of the more involved decisions, such as when or
whether to augment or create a vagina, can wait several months or years
because the patient must be cooperative in the postoperative care.
What should be done in the context of what is being asked for?

Modern physicians are still limited by the lack of good outcome data on the treat-
ments available for many DSDs. Evidenced-based medicine is the bedrock of
beneficence-based treatments, but it is hampered by the poor data available on
these disorders, data that is often plagued by small numbers and the heteroge-
neity of treatments and underlying pathologies studied. The data are often retro-
spective and subject to selection biases. It is difficult for physicians to know what
is good for patients when the basis for their conclusions is shaky at best. More-
over, research itself may be stigmatizing and harmful to these patients [21].
Reiner [22] summarized these difficulties succinctly: ‘‘What we need to know
for appropriate interventions for these children and their families is precisely
what is lacking.’’
Furthermore, it is unclear which outcomes should be the basis for parents’ and
physicians’ conclusions regarding treatments for DSDs. Is the cosmetic appear-
ance of the genitals important for an infant or small child or is this a concern
more of the parents and family? In some cultures, the eventual sexual orientation
of the adult-to-be would be an important outcome of interest, but there are good
arguments why this outcome should be secondary at best, or even be considered
medically irrelevant [23]. The focus would be better positioned on the eventual
genital function, fertility, and sexual satisfaction of the adult-to-be [24,25].
The correct action for any individual child is not always clear and a balance
must be struck between the apparent needs of the child, the desires of the
parents, the needs of the adult the child will become, and the biases of the
physicians involved [26]. Children deserve accurate information about their
bodies and medical histories, and this should be provided to them in an age-
appropriate fashion [27]. Greatest caution should be used in considering treat-
ments or surgeries that have irreversible consequences for the child and the
adult the child will become.
TREATMENT OPTIONS
Several decades ago, there was an evolution toward early operation for patients
with DSDs, because it was thought that this was the best way to establish
gender identity [1]. Early operation purportedly would lead to better adjust-
ment of the child as well as easier adjustment for the family. Surgeons learned
techniques that allowed modification of the clitoris, and creation or modifica-
tion of an existing vagina. Specialty surgeons and gynecologists may therefore
see a variety of conditions in adolescents, including those who have already

had genital modifications and those who have not.
Treatment options in adolescents, particularly if they have already had oper-
ations in the past, may include medical therapy, reconstructive surgery, or active
interventions by the patient that are age appropriate and self-motivated, such as
vaginal dilation. Appreciation of the need for regular appraisal of the endocrine,
metabolic, and biochemical elements is essential for any type of procedural
success. This article subsequently describes in brief a series of patients who pre-
sented with some aspect of genital abnormality or a genital functional disorder
requiring work-up and treatment. All but 2 of the patients presented after
infancy. Most of these patients were cared for between 5 and 20 years ago.
The infants are contemporary and the diagnostic testing far more sophisticated.
Case 1: CAIS
A 10-year-old prepubertal phenotypic female presented with bilateral inguinal
hernias. At the time of hernia repair, testicles were present in the hernia sacs,
which were removed. Anatomy included a normal labia majora and minora,
vagina, and clitoris and absent uterus. The patients karyotype was 46,XY.
The family was counseled and referred to the CAIS Web site. The child
initially appeared to have an adequate vagina and was referred to a pediatric
and adolescent gynecologist and to a pediatric endocrinologist for future post-
pubertal needs.
Case 2: Müllerian agenesis
A 17-year-old obese girl presented to her pediatrician with amenorrhea. She
experienced breast development at age 10 and pubic hair growth at age 11.
The patient’s follicle-stimulating hormone (FSH), thyroid-stimulating hormone
(TSH), prolactin, and estradiol levels were normal. The patient was sent to
a gynecologist who found absence of a vaginal opening on examination
(Fig. 1). A pelvic ultrasound confirmed the absence of a uterus and a more
Fig. 1. A 17-year-old girl with amenorrhea and absent uterus and vagina (case 2). The peri-
neal opening is a dilated urethra.
centrally placed patulous urethra. The patient attempted vaginal dilation to

create a neovagina without surgery, but found it difficult to avoid dilating the
urethra. A split-thickness skin graft was used to surgically create a neovagina.
The patient is now married, successfully having intercourse, and has adopted
her first child.
Case 3: Mixed gonadal dysgenesis
A 15-year-old black girl presented with amenorrhea. On physical examination,
she had Tanner stage I breasts, Tanner 4 pubic hair growth, moderate clitoro-
megaly, with an adequate vagina and small palpable uterus. Her work-up
included a pelvic ultrasound that revealed a rudimentary uterus and a unilateral
left gonad, and laboratory data of testosterone 1.1 pg/mL, estradiol 28 pg/mL
(follicular phase 11–212 pg/mL), FSH 107 IU/L (>40 IU/L indicates ovarian
failure), luteinizing hormone 41.5 IU/L, and TSH 1.12 lIU/mL. The increased
FSH prompted evaluation of her karyotype, which was 46,XY.
Findings at the time of laparoscopic surgery confirmed a small uterus, bilateral
fallopian tubes, and round ligaments. On the left side, she had a gonad that ap-
peared to be a testicle, with a rudimentary vas deferens approaching the internal
ring. On the right side, she had a small streak gonad with ovarian-appearing
vessels. Both gonads were removed with preservation of the fallopian tubes and
uterus. The left gonad was a hypoplastic testis and the right gonad was a fibrous
streak. An MIS level drawn the day of surgery was 0.468 ng/mL, which was signif-
icantly less than normal. Other laboratory tests included sex hormone–binding
globulin 92 nmol/L (11–120 nmol/L), testosterone 114 ng/dL (8–41 ng/dL), and
free testosterone 9.7 pg/mL (1.0–6.2 pg/mL). The patient is now on hormone
replacement therapy and normally menstruating.
Case 4: Anatomic developmental abnormality after bladder exstrophy
repair
A 17-year-old girl with history of bladder exstrophy repair at birth presented
with inability to place a tampon. On physical examination, the patient had
normal labia majora and minora. There was scarring over the pubic symphysis
extending down toward the clitoris as a result of her bladder exstrophy repair.
The urethral opening was separate from the vaginal opening. The vaginal
opening allowed only placement of a small urethral swab of 2 to 3 mm in diam-
eter. MRI revealed an arcuate uterus without obstruction or hematometrocol-
pos. The vagina was small and the ovaries were normal. Examination under
anesthesia at time of a planned surgical vaginoplasty revealed a urogenital sinus
variant with a tiny introitus (Fig. 2A). A U-flap vaginoplasty was completed to
allow placement of 2 digits and a small vaginal speculum (see Fig. 2B, C). At
the postoperative visit, the vaginal opening allowed placement of 2 digits, with
a short vagina and cervix 2 cm from the introitus on the anterior vaginal wall.
The apex of the vagina was 4 cm from the cervix and access to this portion of
the vagina required moving past the cervix protruding from the anterior vaginal
wall. The patient has since been able to have intercourse and successful vaginal
delivery of her children.
Fig. 2. A 17-year-old patient with history of bladder exstrophy at birth (case 4). (A) Appear-
ance of the perineum at presentation, showing catheter in the urethra and a tiny vaginal
opening below this. (B) Completed flap vaginoplasty. (C) Postoperative appearance with stent
in place.
Case 5: Vaginal atresia

A 10-year-old premenarchal girl presented to her primary care physician with
persistent foul-smelling vaginal discharge. After failing initial treatment of vagi-
nitis, a vaginal septum or foreign body was suspected and the patient was sent
to a pediatric gynecologist. The physical examination was significant for Tanner
II breast development and Tanner II pubic hair growth without signs of perineal
estrogenization. A suspected high transverse vaginal septum was seen when
labial traction was used to visualize the lower vagina. Imaging studies including
MRI and ultrasound confirmed a high vaginal septum and suggested an infected
mucocolpos. There were no other associated malformations of the urogenital
system and the anus was normal. The malformation was confirmed on examina-
tion under anesthesia and a fistulous tract between the upper and lower vagina
was suspected as the source of the patient’s persistent vaginal infections. A poste-
rior sagittal approach vaginoplasty was completed and the septum and fistulous
tract were identified and completely removed with reapproximation of the upper
and lower vaginas to make a single cavity (Fig. 3). The patient has had several
examinations under anesthesia to confirm patency. The patient is now menstru-
ating and is able to use tampons with no further problems with vaginal infections.

A 12-year-old white girl presented to the gynecologist for evaluation for pubertal
virilization noted on basketball physical examination. Past medical history was
significant for congenital underdevelopment of the right eye with corneal opaci-
fication. The patient’s mother and 3 sisters had normal puberty and menses. On
physical examination, the patient was tall, thin, and masculine appearing at 170
cm (5 feet 7 inches) tall and weighing 52.6 kg (116 pounds). Further notable find-
ings included presence of a thin growth of upper lip hair, ptosis of the right eye,
Tanner 1 breast development, male escutcheon on abdominal examination,
palpable mass in the left inguinal area, Tanner stage 5 pubic hair development
with a 4-cm clitoris, prominent labia majora, small labia minora, small normally
placed urethra, small atrophic vagina, and infantile uterus on rectal examination
(Fig. 4). Laboratory assessment was significant for an increased FSH, which
prompted a karyotype, which returned 46,XY. Testosterone, DHT, dehydroe-
piandrosterone sulfate (DHEAS), 17-OH progesterone, and prolactin were all
within normal limits. A pelvic ultrasound revealed normal prepubertal uterus,
ovaries, and vagina. MRI similarly revealed a nonhormonally stimulated uterus
and ovaries but also noted the presence of a 2 3 cm left inguinal/subcutaneous
mass. A voiding cystourethrogram and genitogram showed a normal excretory
urogram and normal vagina, cervix, and uterus, and a single fallopian tube.
The inguinal mass proved to be a gonadoblastoma and was removed. The other
gonad was never identified despite an exhaustive search. The patient had a femi-
nizing genitoplasty and hormonal replacement therapy for a female phenotype,
although she later presented for office follow-up with a female partner and had
significant psychological problems requiring inpatient psychiatry.
Fig. 3. A 10-year-old patient with unusual variant of vaginal atresia with fistula between
upper and lower vagina (Case 5). (A) High vaginal septum visualized in vaginal orifice. (B)
Uterus and cervix are associated with a dilated upper vagina that is connected to the septated
lower vagina by a fistula. (C) Surgical approach was posterior sagittal; the rectum was
dissected and retracted posteriorly. The proximal hydrocolpos was located using aspiration.
(D) Sutures join the upper and lower portions of the vagina.

An infant boy was born by cesarean section at 37 weeks’ gestation with a weight of
2.5 kg (5 pounds 8 ounces). He had a left nonpalpable testis, an ipsilateral hypo-
plastic left scrotum, and a palpably normal gonad in the right scrotal sac. The
scrotal sac and phallus appeared phenotypically normal male. At diagnostic lapa-
roscopy, a left gonad resembling an ovary, a left fallopian tube, and rudimentary
hemiuterus was seen on the left side (Fig. 5). There was a contralateral vas and
vessels traversing a closed right internal ring associated with the palpable de-
scended gonad. Biopsy of the internal gonad was most consistent with a streak
gonad. Subsequent cytogenetic testing was abnormal and showed chromosomal
mosaicism with 45,X (85%) and 46,X (psu idic) (Y) (p11.3) (15%). Laboratory
Fig. 4. A 12-year-old girl with pubertal virilization who had mixed gonadal dysgenesis and
an inguinal gonadoblastoma (case 6). Preoperative appearance of the perineum with
enlarged clitoris and normal vagina.
Fig. 5. Infant boy with mixed gonadal dysgenesis. Left intra-abdominal gonad was a streak
gonad associated with a fallopian tube and rudimentary uterus (case 7).
results included an antimüllerian hormone of 135 ng/mL (15.5–48.1) and normal

levels of estrone, total estrogen, sex hormone globulin, and testosterone. A second
surgery was completed to remove the streak gonad laparoscopically and perform
a biopsy of the descended testis. The rudimentary müllerian structures were
removed down to the lower uterine remnant, but the right vas was entering
this structure and was not removed. The testis proved to be azoospermic.
Case 8: Ovotesticular DSD
A Cuban newborn infant with an SDS was seen initially in the hospital. She
had an enlarged clitoris of 2 cm (normal is <1 cm). At the base of the clitoris
was a urethral opening and a small vaginal opening with posterior fusion of the
labial folds. The labia were scrotalized and there were no palpable testes. The
patient’s electrolytes were normal. Initial laboratory data revealed normal T4,
17-OH pregnenolone, testosterone, DHEA, 11-deoxcortisol, and 17-OH
progesterone. Routine infant screening for CAH was normal. The initial karyo-
type based on 25 metaphases revealed a normal female 46,XX karyotype. The
infant was assigned the female gender. Repeat karyotype with GTG bands
based on 40 metaphases showed a 46,XXþ SRY-positive duplication. On
FISH, 26.7% of cells were found to contain the extra chromosome Y material.
Additional laboratory data included an antimüllerian hormone level of 87.64
ng/mL (normal female levels 0–16 years, 0–7.10 ng/mL; normal male levels
14 days to 6 months, 39.10–91.10 ng/mL). These findings indicated the pres-
ence of testicular tissue. A pelvic ultrasound revealed a uterus behind the
bladder, but no gonads. Genitogram showed a single genitourinary orifice
leading to a urethra and vagina. At 8 months of age, a diagnostic laparoscopy
with cystoscopy and vaginoscopy was performed to evaluate the gonads and
delineate the internal genital organs (Fig. 6). Findings included a normal-
appearing testicle on the left in an intra-abdominal location. The left internal
inguinal ring was closed. A vas deferens traversed the peritoneal reflection
toward the bladder, but seemed to end near the bladder as visualized from
Fig. 6. An 8-month-old infant with ovotesticular DSD. (A) Normal-appearing left testicle in
intra-abdominal location. (B) Normal infant right ovary, tube, and remnant of uterine horn.
There was no connection between the vagina and uterine remnant and there was a normal
round ligament traversing the internal ring.
the concurrent vaginoscopy and laparoscopy. On the right side, the patient had
a normal-appearing infant ovary, normal tube, and remnant of a uterine horn.
There appeared to be no connection between the vagina and the uterine
remnant and there was a normal round ligament traversing the internal ring.
After discussion with the family, a decision was made to do a left orchiectomy
and this was completed laparoscopically. The left gonad was removed and the
pathology revealed that this was an ovotestis with epididymis, rete testis, and
vas deferens. A repeat MIS level after orchiectomy was 0.26 ng/mL, a level
seen in normal girls and indicating no additional testicular tissue. The family
does not intend to return to Cuba, but was comfortable continuing to rear their
daughter as a girl and allowing her to make a gender decision at puberty,
because they were familiar with persons from their native country who had
similar disorders. She will be seen annually by a multidisciplinary team.
Case 9: CAH presenting after early reconstruction with inadequate
vagina
This 14-year-old girl with CAH had surgical reconstruction as an infant of a high
vaginal atresia that was a consequence of 21-hydroxylase deficiency. Following
her initial reconstruction, she had 2 minor procedures to dilate the vagina and
urethra. On examination, the patient had no axillary hair, Tanner stage III breast
development, and Tanner stage III pubic hair growth. Inspection of the external
genitalia revealed normal-appearing labia majora and minora, the clitoris was
palpable and nontender, and the urethral and vaginal orifices could be visualized
as separate openings but in close proximity. A vaginoscopy and cystoscopy were
completed confirming these findings. The vagina was dilated to allow placement
of a small vaginal speculum to assist with menstrual egress and use of tampons.
The patient has subsequently married and had successful intercourse and vaginal
delivery of infants.
TREATMENT EFFECTIVENESS AND PATIENT OUTCOMES

Exposure of the brain to normal levels of testosterone in utero, neonatally, and at
puberty are major contributors to formation of gender identity in boys [6,26]. The
highest rates of sex reversal occur in genetically male individuals with single-gene
mutations that impair testosterone formation or action (17-bHSD,5-aRD) and
genetically male individuals who have a predominantly female phenotype at birth
and have been reared as girls. The central nervous system androgen effect and
exposure to sex-determining genes is pervasive and overrides sex assignment/
rearing in these cases [6,10]. The lowest rate of sex reversal is seen in genetically
male individuals with mutations that impair the function of the AR, including
CAIS [9]. Individuals with partial AIS seem to adapt well to the assigned sex,
whether it be male or female [8].
CAH
Long-term follow-up of patients with CAH has been detailed in a few reports
[11]. When compared with control women, individuals with CAH are more
often single and childless. At least some of the women experience impairments
with regard to body image and attitudes toward sexuality. However, many
follow-up studies do not indicate an increase in homosexual preference among
even the most severely masculinized women. At least 1 study documented
a self-admission compliance rate of only 50% with medication. Most women
have a final height that is less than average for the mean of the control group.
Many of the women are thought to be well adjusted, having developed ex-
cellent social networks and coping strategies commensurate with their
disorder.
In a study in which the salt-losing and non–salt-losing forms of CAH were
compared, individuals with the salt-losing form generally had decreased preg-
nancy rates and a higher incidence of hirsutism and poor medical follow-up.
They also had more menstrual irregularities, which likely factored into a decrease
in overall fertility. There was a high incidence of stenosis of the introitus in
women who had previous vaginal reconstruction, contributing to a decrease in
heterosexual activity [11].
Vaginal atresia
A few reports have detailed the outcome of women with vaginal atresia [11,28]
Regardless of whether or not a vaginal reconstruction was performed in
infancy or childhood, if there is vaginal stenosis present or a de novo vaginal
dimple, the method of dilation with increasing sizes of acrylic molds has met
with some success. This method requires the patient to be psychologically
mature and motivated when it is initiated. Daily care and dilatation is also
required after any type of surgical neovagina to achieve and maintain function.
Results following the McIndoe with dilatation or the Frank dilatation method
of a vaginal dimple can be excellent, because the neovagina responds to cyclic
stimulation by the ovary or exogenous hormones. Distention and lubrication
may be less than normal, but do not seem to detract from sexual satisfaction.
The major inconvenience of a bowel vagina is the production of mucus. Daily
vaginal irrigations are usually required because of the odor and concretions
that tend to accumulate.
Clitoral procedures
Surgeons learned techniques that allowed preservation of the neurovascular
bundle during reduction and/or recession of the clitoris. Long-term failures
of recession resulted from continued secretion of androgens and poor compli-
ance with medical regimens. Follow-up studies indicate that women who had
removal of the clitoris often fail to achieve orgasm, whereas some who have
a clitoral-preserving operation generally achieve orgasm but may have painful
or unusual sensations in the clitoris if they are sexually active [11]. Follow-up
studies suffer from inadequate numbers of patients to make reliable
conclusions.
SUMMARY
A resolution to the difficulties faced by parents, physicians, and pediatric
patients in treating DSDs will only come with better communication and
improved research methodologies. Advocacy groups and the Internet have al-
lowed the intersex community to have a larger role in guiding the research and
the ethical frameworks that are used in treating these disorders. These disor-
ders are unusual and collaboration across medical centers should be the rule
rather than the exception. When possible, treatments that are innovative or
experimental should be subjected to rigorous research oversight [29,30].
Defined periods of family crisis in which counseling and education become
important are at the time of diagnosis [30,31], at the time of any surgical proce-
dure, and at the beginning of major developmental stages. Historically, children
were often left uninformed until someone judged them old and mature enough to
comprehend how they were different. These attempts to protect individual chil-
dren from their condition may have left them vulnerable to a personal crisis at an
age when sexual identity and identity with a peer group are important.
Both the needs of the child and the adult the child will become should be
considered in making treatment decisions for children and adolescents with
DSDs. It is best to counsel parents and educate developing children in a way
that parallels chronologic and conceptual growth. When possible, the child
should be involved in an age-appropriate fashion in the decision-making
process and accurate information about the child’s history and body should
be made available. In addition, parents and families need as much information
as possible and support systems that will help them navigate these challenging
situations.
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[3] Hughes IA. Disorders of sex development: a new definition and classification. Best Pract Res
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[5] Brain CE, Creighton SM, Mushtaq I, et al. Holistic management of DSD. Best Pract Res Clin
Endocrinol Metab 2010;24:335–54.
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[7] Meyer-Bahlburg HF, Migeon CJ, Berkovitz GD, et al. Attitudes of adult 46, XY intersex
persons to clinical management policies. J Urol 2004;171:1615–9.
[8] Mazur T. Gender dysphoria and gender change in androgen insensitivity or micropenis.
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ciency in infancy, childhood and adolescence. Horm Res 2009;72:321–30.
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[14] Bidarkar SS, Hutson JM. Evaluation and management of the abnormal gonad. Semin
Pediatr Surg 2005;14:118–23.
[15] Dreger A. Hermaphrodites and the medical invention of sex. Boston: Harvard University
Press; 1998.
[16] Slijper FM, Drop SL, Molenaar JC, et al. Long-term psychological evaluation of intersex chil-
dren. Arch Sex Behav 1998;27:125–44.
[17] Creighton SM, Minto CL, Steele SJ. Objective cosmetic and anatomical outcomes at adoles-
cence of feminizing surgery for ambiguous genitalia done in childhood. Lancet 2001;358:
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[18] Even the naming of these conditions is controversial Feder EK, Karkazis K. What’s in
a name? The controversy over ‘disorders of sex development’. Hastings Cent Rep
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[19] Cools M, Drop SL, Wolffenbuttel KP, et al. Germ cell tumors in the intersex gonad: old paths,
new directions, moving frontiers. Endocr Rev 2006;27:468–84.
[20] Informed consent, parental permission, and assent in pediatric patients, Committee on
Bioethics AAP.org. Pediatrics 1995;95(2):314–7.
[21] Creighton S, Anderson J, Brown S, et al. Medical photography: ethics, consent and the
intersex patient. BJU Int 2002;89:67–72.
[22] Reiner WG. Mixed-method research for child outcomes in intersex conditions. BJU Int
2004;93(Suppl 3):51–3.
[23] Dreger A, Feder E, Tamar-Mattis, A. Preventing homosexuality (and uppity women) in
the womb? Bioethics forum blog 2010. Available at: http://www.thehastingscenter.org/
Bioethicsforum/Post.aspx?id¼4754&blogid¼140. Accessed June 5, 2012.
[24] Dittmann RW, Kappes ME, Kappes MH. Sexual behavior in adolescent and adult females
with congenital adrenal hyperplasia. Psychoneuroendocrinology 1992;17:153–70.
[25] Minto CL, Liao LM, Woodhouse CR, et al. The effect of clitoral surgery on sexual outcome in
individuals who have intersex conditions with ambiguous genitalia: a cross sectional study.
Lancet 2003;361:1252–7.
[26] Wiesemann C, Ude-Koeller S, Sinnecker GH, et al. Ethical principles and recommendations
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[27] Frader J, Alderson P, Asch A, et al. Health care professionals and intersex conditions. Arch
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Update on Care of Children with Type 1

Diabetes
Shideh Majidi, MDa,b, David M. Maahs, MD, PhDa,b,*
a
Department of Pediatrics, Children’s Hospital Colorado, 13123 East 16th Avenue, Aurora, CO
80045, USA; bDepartment of Pediatrics, Barbara Davis Center for Childhood Diabetes, University
of Colorado Denver, Anschutz Medical Campus, 1775 Aurora Court, Aurora, CO 80045, USA
Keywords
Type 1 Diabetes (T1D) Hemoglobin A1c (A1c) Autoantibodies
Diabetes ketoacidosis (DKA) Closed-loop systems
Key Points
Incidence of T1D is increasing.
T1D is a lifelong condition that can result in acute and chronic complications.
Diagnosis of T1D is based on clinical symptoms, blood glucose levels, and
hemoglobin A1c.
Intensive glycemic control decreases complications of T1D, which include
cardiovascular disease, nephropathy, retinopathy, and neuropathy.
Significant research is continuing in the field of T1D, including investigations into
the prevention and cure of T1D.
T
ype 1 diabetes (T1D) is a chronic metabolic disorder caused by insulin
deficiency as a result of autoimmune destruction of the b cells. The over-
all incidence of T1D has been increasing worldwide by 2% to 5% annu-
ally over the past 20 years [1,2]. The diagnosis of T1D results in a lifelong
dependence on insulin, as well as the risks of acute complications of diabetic
ketoacidosis (DKA), hypoglycemia, and chronic macrovascular and microvas-
cular complications. This article discusses the incidence and prevalence, path-
ogenesis, management and complications of T1D, current research in T1D,
updates on investigation in prevention and cure, and serves as a T1D-
specific update on the 2004 article in Advances in Pediatrics [3] in which childhood
diabetes in general was reviewed. Examples of advances in the care of youth
with T1D in the past 8 years include continuous glucose monitoring (CGM),
closed-loop systems, and newer insulins. Additional updates are provided on
discoveries in the prevention of T1D and its clinical care.
*Corresponding author. Barbara Davis Center for Childhood Diabetes, University of Colorado
Denver, Mail Stop A140, Aurora, CO 80045. E-mail address: david.maahs@ucdenver.edu

304 MAJIDI & MAAHS
INCIDENCE AND PREVALENCE

T1D is a worldwide disease, with variation in incidence and prevalence across
countries and race/ethnic groups. In the United States, the SEARCH (The
SEARCH for Diabetes in Youth Study) trial estimated incidence and preva-
lence of diabetes in youth less than 20 years of age. Youth between 5 and 14
years of age have the highest incidence of T1D, with a similar rate between
males and females. Non-Hispanic Whites (NHW) have the highest incidence
of T1D, 26.1 per 100,000 person-years, compared with other race/ethnicity
groups, followed by black youth, and then Hispanic youth [1]. The prevalence
of T1D is 1.54 per 1000 youth, with higher prevalence in the 10- to 19-year-old
age group versus the 0- to 9-year-old age group. NHW have higher prevalence
of T1D in both age groups [4].
Internationally, 2 registries (The Epidemiology and Prevention of Diabetes
[EURODIAB] and Diabetes Mondiale [DIAMOND]) estimated worldwide inci-
dence of T1D in youth. EURODIAB evaluated the incidence trend for youth
across 17 European countries, starting in 1989 [5]. The DIAMOND project [6],
initiated by the World Health Organization, gathered information from 50 coun-
tries around the world, starting in 1990. These registries showed wide differences
in incidence in different parts of the world, and even within regions of certain coun-
tries. The areas with the highest incidence include Sardinia, Finland, Sweden,
Norway, Portugal, the United Kingdom, Canada, and New Zealand. The lowest
incidences of T1D are seen in China and Venezuela. Finland has the highest inci-
dence, with more than 40/100,000 per year incidence. This incidence is compared
with 16/100,000 in the United States and 0.1/100,000 in the Zunyi region of China,
which has the lowest reported incidence of T1D. The incidence of T1D in youth
increases with age [6], but the predicted incidence trend based on the EURODIAB
population suggests the greatest increase in T1D will be in the youngest age group
(0–4 years of age), with incidence in this age group expected to double by 2020 [5].
The DIAMOND study also found an increase in incidence trend in Europe, Asia,
and North America [7].
Most locations do not have a significant difference in T1D incidence between males
and females, in contrast to the female predominance often seen in other autoimmune
disorders. Evaluation from the EURODIAB study also shows a cyclic pattern to diag-
nosis of T1D, with the peak in winter. This pattern is more evident in countries that
have distinct seasons, with greater temperature variation between the seasons
showing greater variability in the incidence of T1D between seasons of the year [8].
However, the seasonal pattern may also indicate a viral trigger to T1D given that
different viruses have peak incidences at difference times of the year. One such asso-
ciation is between enteroviruses and T1D onset [9,10]. Some studies also show an
association between month of birth and development of T1D. The SEARCH study
[11] found an increased likelihood of being diagnosed with T1D if individuals are born
on or around May in the relatively northern centers (Washington, Ohio, Colorado).
Those born between November and January have the lowest likelihood of being diag-
nosed with T1D. However, this difference did not hold for the more southern centers
of the SEARCH study (southern California, South Carolina, Hawaii, and American
CHILDREN WITH TYPE 1 DIABETES 305
Indian communities of Arizona and New Mexico). The investigators postulate that
this finding could be secondary to environmental variations in climate or exposure
to sunlight [11]. However, a study performed in Europe did not show an association
between season of birth and diagnosis of T1D [12].
CAUSE/PATHOPHYSIOLOGY
Research into the cause of T1D has shown that genes and environment both
play a role in the onset of the disease. A model of the development of T1D
was proposed by George Eisenbarth in the 1980s and remains the paradigm
for development of autoimmune T1D (Fig. 1) [13].
In this model, the first stage involves an individual’s underlying genetic
susceptibility, which varies from population to population. Stage 2 involves
an environmental trigger that leads to the activation of pancreas-specific auto-
immunity. Progression of b-cell destruction occurs in stage 3, with the body
mounting an autoimmune response against b cells. Over stages 4 to 6, insulin
release declines with increasing glucose levels and leads to overt diabetes with
insulin dependence [14].
In the United States, data from the SEARCH study suggest that a child’s risk of
developing T1D is 1.54 per 1000, or 0.154% [4]. The risk of the child developing
T1D is higher if 1 parent has T1D, and 6% risk if a sibling has T1D [15]. The
genetic role in T1D is evident in concordance studies between monozygotic
(MZ) and dizygotic (DZ) twins, which show a strong, but not complete concor-
dance in T1D. A Finnish study, which followed 44 MZ twins and 183 DZ twins
for up to 40 years, showed 42.9% concordance in MZ twins versus 7.4% in DZ
twins. The study also suggested that the risk of T1D in the twin without diabetes
is highest when the twin with T1D was diagnosed at an earlier age (<10 years of
age; P ¼ .06) [16]. In contrast, a US study, which followed 83 MZ twins over
almost 44 years, showed 65% concordance between MZ twins [17]. Other factors
may have played a role in the discrepancy between the 2 studies, including the US
study having almost double the number of MZ twins than the Finland study.
Fig. 1. Stages in development of type 1A diabetes. (Courtesy of George S. Eisenbarth Md,

PhD, Barbara Davis Center for Childhood Diabetes, Aurora CO.)
306 MAJIDI & MAAHS
Multiple genes and autoantibodies have been discovered that are associated
with an increased risk of developing T1D. The HLA genotype presents the
greatest genetic risk for T1D, with HLA DR3 and DR4-DQ8 conferring the high-
est T1D risk [14]. Approximately 30% to 50% of youth with T1D have the DR3/
DR4-DQ2/8 genotype. More than 40 other genetic loci associated with T1D have
been discovered, including INS, PTPN22, ILR1A, and SH2BE [14]. Islet autoan-
tibodies are the autoantibodies detected in most individuals who develop T1D
[14]. The autoantibodies include insulin/proinsulin, GAD65/67, IA-2/IA-2b,
and ZnT8. The risk of T1D increases with increasing number of autoantibodies,
their persistence [18], and with high titers of IA-2A and IAA autoantibodies [19].
Among MZ twins in whom 1 twin has T1D, the risk of developing T1D in the
nonaffected twin who is autoantibody positive is at least 89% [17].
Although genetics play an important role in the development of T1D, twin
studies have shown that other factors such as environmental triggers also
contribute to the development of T1D. There have been a multitude of studies
investigating potential environmental triggers of T1D. The hygiene hypothesis
postulates that decreased exposure to infectious diseases early in life results in
an increase in immune-mediated disorders, such as asthma and diabetes [20].
Some medications have also been known to induce the onset of T1D via trig-
gering the immune system, including interferon therapy, methimazole, penicil-
lamine, and sulfhydryl-containing drugs, although these are rare [14]. Dietary
factors may also be potential triggers. For example, in 1 study, infants breastfed
for shorter periods were more likely to develop T1D compared that those
breastfed for longer periods [21]. One hypothesis states that this situation
may be caused by early exposure to cow’s milk formula, resulting in an
immune response to bovine insulin that is present in formula [21]. Timing of
when cereals, both with gluten and gluten-free, are introduced in an infant’s
diet may also play a role [22]. Vitamin D supplementation in infants is associ-
ated with a decreased risk of T1D [23], and increased intake of vitamin D in
mothers during pregnancy has been associated with decreased presence of islet
autoantibodies [24].
Multiple studies have shown that both genetic and environmental factors
play a role in the development of T1D. Current research is focused on better
elucidating these factors, with a more immediate goal of risk stratification for
early intervention studies to slow or prevent b-cell destruction, with the goal
of prevention of T1D.
MANAGEMENT
Diagnosis
The typical symptoms of T1D include polyuria, nocturia, polydipsia, weight loss,
malaise, nausea, and vomiting. Patients may also have Kussmaul breathing and
fruity breath secondary to ketones. More advanced symptoms include severe
dehydration, drowsiness, altered mental status, and, at late stages, coma.
Diagnosis of T1D requires evaluation of blood glucose levels, and, more
recently, hemoglobin A1c (A1c) has been added as a diagnostic criterion [25].
Fasting blood glucose between 100 and 125 mg/dL is considered glucose intol-
erance, or prediabetes, whereas 126 mg/dL or greater is considered diabetes.
An oral glucose tolerance test is diagnostic if a blood glucose level taken 2
hours after the glucose load is 200 mg/dL or greater. In adults, an A1c of
6.5% or greater is diagnostic of T1D, whereas 5.7% or greater puts the patient
at increased risk for diabetes mellitus. In the absence of unequivocal hypergly-
cemia, repeat testing is required for the above results to be considered accurate.
A random blood glucose of 200 mg/dL or greater with symptoms of hypergly-
cemia is also considered diagnostic for T1D [25]. There is controversy as to
whether A1c is a good diagnostic marker for children and adolescents with
T1D because of limited and inconclusive data [26,27]. However, A1c is an
important marker of glycemic control in youth with T1D after diagnosis,
when intensive and continued management is needed to reduce the risk of
complications. A1c goals are provided for children diagnosed with T1D,
with the goal of preventing macrovascular and microvascular complications.
The American Diabetes Association (ADA) A1c goal is less than 8.5% in
under-6-year-olds, which is higher than other age groups because of greater
vulnerability to hypoglycemia and functional hypoglycemia unawareness in
this age group, with concern for future cognitive impairment after episodes
of severe hypoglycemia. Children in this age group are also unpredictable in
their intake of meals and snacks and physical activity. For 6-year-olds to 12-
year-olds the goal is an A1c less than 8%, because these individuals are still
considered more vulnerable to hypoglycemia and hypoglycemia unawareness,
and is less than 7.5% for 13-year-olds to 19-year-olds [25]. The International
Society for Pediatric and Adolescent Diabetes (ISPAD) recommends a target
A1c of less than 7.5% in all age groups, but comment, as does the ADA,
that the A1c target should be individualized for each patient in order to achieve
the best A1c possible and avoid hypoglycemia [28].
An appropriately focused history and physical examination are key to diag-
nosis of T1D in addition to appropriate laboratory evaluation. Once T1D is
suspected, based on the symptoms and signs discussed earlier, in most clini-
cians’ offices a urinalysis using a dipstick to test for glucose and ketones, or
a glucose meter to evaluate for presence of hyperglycemia, can help to confirm
the suspicion of diabetes. If evidence of hyperglycemia and ketones exists,
a pediatric endocrinologist should be consulted urgently (or emergently,
depending on the patient’s condition) for continued assistance and referral.
DKA
DKA is defined by the ISPAD as blood bicarbonate level less than 15 mmol/L or
venous pH less than 7.3 and hyperglycemia (blood glucose greater than 200 mg/
dL), with related ketonemia or ketonuria [29]. The ADA differs from the ISPAD
with a venous pH cutoff less than 7.25 or arterial/capillary pH less than 7.3. The
severity of DKA is dictated by the degree of acidosis, with mild DKA defined as
a venous pH 7.2 to 7.3 or bicarbonate 10 to 15 mmol/L, moderate DKA defined
as a venous pH 7.1 to 7.2 or bicarbonate 5 to 10 mmol/L, and severe DKA
308 MAJIDI & MAAHS
defined as a pH less than 7.1 or bicarbonate less than 5 mmol/L [29,30]. The
degree of acidosis helps determine the necessary location of treatment. The
frequency of DKA in new-onset diabetes is 15% to 70% in Europe, Australia,
and North America, and 25% in the United States [29,30]. DKA in new-onset
T1D is more common in younger children and those without access to medical
care because of social or economic reasons [29,30]. In youth with established
T1D, risks of DKA recurrence include female sex, longer duration of diabetes,
higher A1c, higher reported insulin dose, presence of psychiatric disorders,
and underinsurance [29–31].
Children presenting with DKA are different from adults in a few funda-
mental ways. First, the younger the child, the more difficult it may be to ascer-
tain the classic symptoms of polyuria, polydipsia, and weight loss, and infants
and toddlers may therefore have delayed diagnosis, which increases the risk of
more severe symptoms at presentation. Also, children have a higher basal
metabolic rate and larger surface area relative to their total body mass, which
makes determination of their dehydration level more difficult. Children, in
contrast to adults, are at risk for cerebral edema, which is the most common
cause of death in pediatric DKA [30]. The risk of cerebral edema in children
and youth younger than 25 years requires that the approach to treatment of
DKA in youth be different from that in adults.
The pathophysiology of DKA involves insulin deficiency as the underlying
cause, whether from progressive b-cell failure in new onsets, or insulin omis-
sion or unrecognized increased insulin needs in the face of medical stress
such as infection in diagnosed patients. Insulin deficiency results in increased
endogenous glucose production via hepatic gluconeogenesis, resulting in hyper-
glycemia. Hyperglycemia then causes an osmotic diuresis, electrolyte loss,
dehydration, and hyperosmolarity. Lipolysis also occurs, and results in an
increase in free fatty acids, which then leads to increased glucose, acetoacetate
and b-hydroxybutyric acid (also known as ketone) production. The production
of these acids, as well as lactic acidosis from poor tissue perfusion, leads to the
metabolic acidosis found in DKA. When patients present with DKA, imme-
diate assessment should include evaluation of level of consciousness, assess-
ment of severity of dehydration, clinical history, and evaluation of blood
chemistries, including sodium, potassium, bicarbonate, blood urea nitrogen
(BUN), creatinine, calcium, phosphorus, magnesium, glucose, venous blood
gas, blood b-hydroxybutyrate, and urine glucose and ketones [29,30]. Appro-
priate initial supportive measures should be taken based on the clinical presen-
tation. An A1c determination is useful for documentation of current metabolic
status in both newly diagnosed T1D as well as in established patients.
Location for management of DKA is dependent on the patient’s condition.
Patients with severe DKA, which includes a prolonged period of symptoms,
hemodynamic instability, altered mental status, or at increased risk for cerebral
edema (patients less than 5 years of age, low pH, or high BUN) should be
treated in an intensive care unit (ICU), preferably a pediatric ICU. Other
patients may be medically managed in an inpatient ward setting if a physician
provider and nursing support with experience in, and knowledge of, pediatric
DKA and diabetes care management are available.
Monitoring of patients with DKA initially includes hourly vital signs, neuro-
logic assessment, accurate input and output, capillary blood glucose and elec-
trolytes every 2 to 4 hours (including sodium, potassium, bicarbonate, BUN,
creatinine, calcium, phosphorus, magnesium), and blood gas [30].
Management includes appropriate treatment of dehydration, acidosis, and
the associated electrolyte imbalance. Initial fluid resuscitation may be needed
in significantly dehydrated patients and can be given as 0.9% saline (normal
saline) or lactated Ringer solution. The volume given should be 10 to 20
mL/kg over an hour. Continued hydration should be given as normal saline
or lactated Ringer solution over the first 4 to 6 hours of treatment as mainte-
nance fluid and replacement of fluid deficits with saline or half-normal saline
with appropriate electrolytes added [30].
Acidosis is corrected both by fluid replacement, which results in improved
tissue perfusion and renal function, and insulin replacement, which reverses
hepatic gluconeogenesis, lipolysis, and allows tissue glucose uptake. Bicarbonate
is not recommended because it can lead to paradoxic central nervous system
(CNS) acidosis and hypokalemia [30]. Intravenous insulin should be started at
0.1 units/kg/h and can be started either once hyperglycemia has been documented
or after the initial fluid resuscitation, to minimize fluid shifts in the severely dehy-
drated child. In children, an insulin bolus may increase the risk of cerebral edema,
does not alter the time to correction of acidosis and is not recommended
[29,30,32]. Similarly, some data suggest that starting insulin at 0.05 units/kg/h
may reduce the risk for rapid fluid shifts and theoretically for cerebral edema
[33]. After initial volume expansion, with intravenous insulin, glucose ideally
decreases at a rate of 54 to 90 mg/dL/h. Once glucose reaches 250 to 300 mg/dL,
according to the ISPAD [29], or less than 300 mg/dL, according to the ADA [30],
5% dextrose should be started to prevent hypoglycemia, whereas continued intra-
venous insulin is required to reverse the underlying pathophysiologic conse-
quences of insulin deficiency. Hourly blood glucose determinations guide the
rate of glucose administration required for maintaining glucose levels of 150 to
250 mg/dL. Insulin should continue until pH is greater than 7.3, and bicarbonate
greater than 15 mEq/L [29]or 18 mEq/L or greater [30].
DKA results in total body potassium deficits, caused by intracellular loss of
potassium and renal excretion. Initial tests may show hyperkalemia despite
total body potassium loss, because acidosis shifts potassium into the extracel-
lular space. Once fluid resuscitation and insulin are started, hyperkalemia
can quickly resolve and hypokalemia may be seen. Therefore, if the patient
has documented urine output, potassium should be started at 40 mmol/L in
replacement fluid after the initial fluid resuscitation if the initial blood potas-
sium level is less than the upper limit of normal. If initial hypokalemia is
seen then 20 mmol/L potassium should be included in initial fluid expansion
or 40 mmol/L immediately after initial fluid expansion [29,30]. Phosphate is
lost because of osmotic diuresis and continues to decrease after treatment
310 MAJIDI & MAAHS
initiation, because insulin also causes intracellular phosphate movement.

Severe hypophosphatemia may result in muscle weakness and should be
treated if symptoms exist or if phosphate levels are less than 1 mg/dL [29,30].
Transition to oral fluids and subcutaneous insulin can take place when bicar-
bonate is greater than 15 to 18 mEq/L and pH greater than 7.3, and plasma
glucose less than 200 mg/dL and oral intake is tolerated [30]. Mealtimes are
convenient for such transitions. If rapid-acting insulin is given, then it should
be given 15 to 20 minutes before stopping the insulin infusion. If regular insulin
is given, then it should be given 1 hour before stopping the insulin infusion. Once
the insulin drip is stopped, the intravenous dextrose should also be stopped to
prevent hyperglycemia. If the patient has preexisting T1D, their usual insulin
regimen can be restarted. If the patient has newly diagnosed T1D, then prepu-
bertal patients should receive 0.75 to 1.0 unit/kg as their total daily dose of insulin
and pubertal patients should receive 1.0 to 1.2 unit/kg as their total daily dose of
insulin [30], although these can be adjusted depending on clinical presentation,
including age, severity of metabolic derangement, and insulin resistance. This
insulin can be divided in different ways depending on the time of day it is given
and whether neutral protamine Hagedorn (NPH) or a long-acting basal insulin is
given in addition to rapid-acting insulin at mealtimes. Basal insulin (glargine or
detemir) is generally preferred instead of NPH because of reduced peak of insulin
action and lower risk of hypoglycemia.
Complications that result in morbidity and mortality from DKA include, most
importantly, cerebral edema, and also hypokalemia, hyperkalemia, hypogly-
cemia, other CNS complications, hematoma, thrombosis, sepsis, aspiration
pneumonia, pulmonary edema, acute respiratory distress syndrome, pneumo-
mediastinum, subcutaneous emphysema, and rhabdomyolysis [29]. Cerebral
edema is discussed in detail because it is the major complication of DKA resulting
in morbidity and mortality. Cerebral edema occurs in 0.5% to 1% of pediatric
patients in DKA. If cerebral edema develops, there is a 21% to 24% mortality
and 15% to 26% morbidity, with permanent neurologic dysfunction [34–36].
Risk factors for cerebral edema include higher BUN, severe hypocapnia, slow
improvements in sodium concentration after treatment initiation, and treatments
including bicarbonate administration [30,34]. Cerebral edema typically is seen 4
to 12 hours after initiation of DKA treatment, but can be seen before initiation of
treatment or up to 24 to 28 hours after treatment initiation [30]. Studies regarding
treatment of cerebral edema are mostly case reports and series. Treatment of
cerebral edema includes 0.25 to 1.0 g/kg mannitol or 5 to 10 mL/kg of 3% hyper-
tonic saline over 30 minutes in addition to supportive measures such as
increasing the head of the patient’s bed and reducing intravenous fluid rate
and, in extreme cases, intubation and hyperventilation [30]. Hyperventilation
(to a PCO2 of less than 22 mm Hg during the first 3 hours after intubation)
has been associated with worse neurologic outcomes and is not recommended
unless absolutely needed to decrease intracranial pressure; it is performed in
consultation with an experienced pediatric critical care team [37]. Because cere-
bral edema in DKA is relatively uncommon, multicenter studies are required to
evaluate which DKA treatment is more efficacious and has fewer side effects.
DKA, with cerebral edema as its most severe accompanying manifestation, is
a significant, and often preventable, complication of T1D seen either at presen-
tation or after diagnosis of T1D. Proper education on symptoms of diabetes, dia-
betes management during infections, and insulin pump use, and home
measurement of blood b-hydroxybutyrate, as well as psychosocial counseling
when necessary, may assist in preventing episodes of DKA [30].
Management of outpatient insulin

In the past 90 years since the discovery of insulin to treat T1D, the medical
community has made significant progress to improving the lives and health
outcomes for people with T1D. Much of modern T1D care is based on the Dia-
betes Control and Complications Trial (DCCT) study [38], which showed an
association between intensive glycemic control and decreased risk of microvas-
cular and macrovascular complications. The use of rapid-acting insulin, long-
acting insulin, insulin pumps, and CGM is all part of intensive glycemic control
and prevention of complications, allowing for more flexibility in the treatment
of T1D.
Rapid-acting insulins
Three forms of rapid-acting insulins, lispro (Humalog), aspart (Novalog), and
glulisine (Apidra), have a faster onset and shorter duration of action than
regular insulin. In adolescents, overall rate of hypoglycemia per patient per
month decreased when using rapid-acting insulin [39].
Intermediate-acting insulin
NPH was introduced in the 1950s and is commonly mixed with regular insulin,
lispro, or aspart in a 70:30 ratio, which provides longer duration of action
compared with rapid-acting insulin alone. This regimen is referred to as a modi-
fied fixed-dose insulin regimen, in which NPH and rapid-acting (or regular-
acting) insulin is given at breakfast, rapid-acting (or regular-acting) insulin is
given before dinner, and then NPH or a long-acting insulin is given at bedtime
[40]. Although once-daily basal insulins are generally used in the United States
instead of twice-daily NPH, it remains a commonly used insulin regimen for
reason of cost, convenience, or for specific situations.
Basal insulins
Glargine (Lantus), the first long-acting insulin, came on the market in 2001.
The onset of action is 2 to 4 hours after injection, with an effective duration
of 20 to 24 hours. There is little or no peak because the insulin forms a depot
in the subcutaneous tissue and the insulin is slowly released over its duration of
action. Determir (Levemir) has a similar onset of action, with a peak action of 6
to 14 hours, and duration of action of 16 to 20 hours. Detemir may need to be
given twice a day in order to provide 24 hours of basal coverage [41]. When
comparing glargine with NPH, there is no consistent difference in A1c or over-
all rates of hypoglycemia [42]. Few studies have compared detemir with NPH
312 MAJIDI & MAAHS
or glargine, with 1 study showing improvement in nocturnal hypoglycemia and

lower body mass index (BMI), calculated as weight in kilograms divided by the
square of height in meters, compared with NPH, but no difference in A1c [43].
Degludec, a new ultralong-acting basal insulin, has been found to have similar
improvement in A1c in type 2 diabetes whether given once per day or 3 times
per week, and similar improvement in A1c compared with daily glargine [44].
Once-daily degludec has been found comparable with glargine in T1D, with
similar A1c and fewer episodes of hypoglycemia [45].
Insulin pump
Continuous subcutaneous insulin infusion, or insulin pump therapy, began in the
1970s. After DCCT results showed benefits with intensive glucose control, there
was increased interest in pump use. Consensus statements from the European
Society for Paediatric Endocrinology and the Lawson Wilkins Pediatric Endo-
crine Society on pump use in pediatrics [46] state that insulin pump use should
be considered in patients who have recurrent severe hypoglycemia, wide fluctu-
ations in blood glucose, suboptimal diabetes control, microvascular complica-
tions, or risk factors for macrovascular complications, or good metabolic
control but an insulin regimen that compromises lifestyle. Insulin pump use in
young children including neonates and infants is also supported [46]. Studies
show that use of insulin pumps can decrease A1c [46,47], although other studies
comparing multiple daily injections with insulin pump therapy show no differ-
ence in A1c between the 2 different regimens [46]. Observational studies show
that insulin pump use results in decreased frequency of severe hypoglycemia,
reduced parental anxiety, and increased satisfaction in adolescents because of
greater sense of control, independence, and increased flexibility in their diet
and daily schedule [46].
Insulin regimens
Multiple insulin regimens exist and should be tailored to each individual to opti-
mize glycemic control, reduce hypoglycemia, and optimize quality of life. Histor-
ically, conventional therapy was based on 1 or 2 daily injections, and can be used
during the honeymoon period after diagnosis; it is also used in some parts of the
world where resources are limited. However, this regimen is no longer generally
recommended because it is less likely to provide optimal glycemic control after
the honeymoon period. Modified fixed-dose insulin therapy involves the use of
rapid-acting (or regular-acting) and NPH insulin in the morning before breakfast,
rapid-acting (or regular-acting) insulin before dinner, and intermediate-acting or
long-acting insulin at bedtime. This regimen can be difficult because consistent
timing and content of meals and insulin doses are needed to be effective. A flexible
insulin regimen involves long-acting basal insulin and bolus insulin doses with
meals and snacks, or the use of continuous subcutaneous insulin infusion (insulin
pump). When a flexible insulin regimen is used, premeal or snack bolus doses can
be based on a sliding scale, adjusting for glucose or, more often, include using an
insulin/carbohydrate ratio for food intake plus a glucose correction factor to
account for blood glucose level [41]. The SEARCH for Diabetes in Youth study
compared insulin regimens in more than 2700 youth with T1D. Insulin pump use
was more common in older children, NHW, higher-income families, children
with higher parental education, and children with private insurance. A1c level
was lowest in those using insulin pumps, even when adjusted for sociodemo-
graphic factors; however, these are not the results of a randomized clinical trial.
There was no difference in frequency of hypoglycemia or frequency of emer-
gency room visits between all the groups, although the number of hospitalizations
was lower in those using insulin pumps [48].
CGM
CGM continuously measures interstitial glucose through a sensor inserted
beneath the skin for up to 7 days per sensor. A meta-analysis of CGM use
showed a decrease in A1c in patients using CGMs, although most of these
studies were in adult patients [49]. One study including patients 7 to 18 years
of age showed a 0.5% reduction in A1c in patients who used sensor-augmented
pump therapy versus multiple daily injections, and those who used the sensors
were more likely to reach ADA-recommended A1c goals [50]. Another study
showed no benefit in A1c in patients younger than 25 years when comparing
CGM with controls who used insulin pumps or multiple daily injections,
primarily because of the inability of youth to consistently use the sensor. In
those who used the sensor consistently, A1c improved similarly as it did in
the adults [51,52]. CGM is being used more and more by patients, and the
devices continue to improve through industry efforts and independent research
for better and safer clinical use.
Multidisciplinary teams
Multidisciplinary teams are recommended as the ideal to provide full support
and resources in all aspects of diabetes care. This team can include, but is not
limited to, a physician, nurse, dietician, and mental-health provider to help
provide support for the medical, nutritional, and psychological needs that are
unique to patients with T1D [25].
Comorbid conditions
T1D is associated with other autoimmune diseases, including celiac disease,
thyroid disease, and Addison disease [53]. Celiac disease is found in 4% to
9%, thyroid disease in 15% to 30%, and Addison disease in 0.5% of T1D
[54]. One study found that, within several months of diagnosis, about 33%
of those with newly diagnosed diabetes have at least 1 other nonislet autoanti-
body, including thyroid peroxidase autoantibody (TPOAb), tissue transgluta-
minase autoantibody (TTGAb), or 21-hydroxylase autoantibody. Of these
autoantibodies, TPOAb is the most likely to be present. In addition, approxi-
mately 19% of patients with new-onset diabetes have another autoimmune clin-
ical disease at diagnosis of T1D [53]. The ADA and ISPAD provide
recommendations for screening of autoimmune diseases given their association
with T1D.
314 MAJIDI & MAAHS
Celiac disease
Patients with celiac disease may develop symptoms including growth failure,
failure to gain weight, weight loss, anemia, gastrointestinal symptoms such as
diarrhea, abdominal pain, flatulence, dyspepsia, and recurrent aphthous ulcers.
In T1D, celiac disease has been associated with an increased number of hypo-
glycemic events and a decrease in insulin requirement before diagnosis [55].
The ADA recommends measuring TTGAb or antiendomysial antibodies
along with IgA levels soon after diagnosis of T1D, which should be repeated
if symptoms develop [25]. The ISPAD recommends antibody testing at the
time of diagnosis, yearly for 5 years, and then every 2 years. If the clinical situ-
ation is suggestive or the patient has a first-degree relative with celiac disease,
more frequent testing is recommended [55].
Hypothyroidism
Patients with hypothyroidism develop symptoms including weight gain, failure
to grow, fatigue, lethargy, cold intolerance, and bradycardia [55]. The ADA
recommends screening TPOAb and thyroglobulin antibodies (TGAb) at diag-
nosis and thyroid-stimulating hormone (TSH) after metabolic control has been
established, which should be repeated every 1 to 2 years and if the patient
becomes symptomatic. Free T4 should be measured if TSH is abnormal [25].
The ISPAD recommends screening TSH, TPOAb, and TGAb at diagnosis
and then every 2 years if results are negative and the patient is asymptomatic [55].
Addison disease
Symptoms and signs of Addison disease include fatigue, weight loss, hypona-
tremia, hyperkalemia, and increased skin pigmentation. In patients with
T1D, frequent and unexplained hypoglycemia and decrease in insulin require-
ment can be seen [55,56]. The ADA and ISPAD do not have guidelines
regarding screening for Addison disease [25,55]. A recent article suggested
that using corticotropin as a screening tool may improve on our current capa-
bilities to diagnose Addison disease [57].
COMPLICATIONS
Hypoglycemia
On average, an adult with T1D has 2 episodes of symptomatic hypoglycemia
per week and 1 or more episodes of severe, temporarily disabling hypogly-
cemia per year [58]. In children, most studies show that the incidence of severe
hypoglycemia is significantly less, with rates of 6 to 20 per 100 patient years,
which may be improving secondary to newer insulin regimens, closer glucose
monitoring, and improved management guidelines [31,59].
Symptoms of hypoglycemia include adrenergic symptoms such as palpitations,
tremor, and anxiety, cholinergic symptoms such as hunger, sweating, and pares-
thesias, and neuroglycopenic symptoms (because of decreased glucose in the
brain) such as difficulty thinking, confusion, seizure, and coma [58,60]. Severe
hypoglycemia involves a hypoglycemic event that the patients themselves are
not able to treat, and thus requires the assistance of another person to treat [60].
Typically in patients with T1D, hypoglycemia is the result of insulin excess

and compromised physiologic defenses against decreasing blood glucose levels
[60]. In patients with T1D, the normal physiologic defense against hypogly-
cemia, which is to decrease insulin and increase glucagon, is not sufficiently
present. There also may be an attenuated adrenergic response, with the glyce-
mic threshold for epinephrine secretion shifted to a lower blood glucose level
[60]. This attenuation can lead to hypoglycemia unawareness, when the typical
symptoms that present with hypoglycemia that help an individual identify that
their glucose level is low, are not present. Data suggest that unawareness can be
reversed if hypoglycemia is avoided for a minimum of 2 to 3 weeks [60].
Risk factors for developing hypoglycemia include deficiency in glucagon
response, the sleep state, recent moderate or intense exercise, previous history
of hypoglycemia, hypoglycemia unawareness, aggressive glycemic therapy
shown by lower glycemic goals or lower A1c levels, and renal failure [60].
Risk of severe hypoglycemia in children has been associated with NHW
ethnicity, longer duration of diabetes, presence of psychiatric disorders, and
underinsurance. Risk of recurrence of severe hypoglycemia is associated with
diabetes duration and underinsurance in older children [31].
Exercise is also associated with hypoglycemia. In 1 study, exercise decreased
glucose levels greater than 25% after a 75-minute exercise session [61]. Exercise
is also associated with more overnight severe hypoglycemic events [62]. Hypo-
glycemia after exercise can be decreased in those who have pumps by tempo-
rarily stopping basal insulin during exercise [63] and decreasing the basal rate
for several hours at the time of sleep [64]; additional carbohydrate before or
during exercise and before sleep can decrease hypoglycemia risk. Given the
importance of exercise for general health, addressing concerns of hypoglycemia
and learning techniques to avoid it are an important clinical area for additional
investigation.
Risk reduction is key to prevention of hypoglycemia. Risk reduction
includes increasing the number of times blood glucose is checked at home
during exercise and, especially before bed, adjusting the patient’s insulin
regimen as necessary, identifying risk factors resulting in recurrent hypogly-
cemia, and working with the patient to reverse hypoglycemia unawareness if
present [58]. Treatment of hypoglycemia includes rapidly absorbed simple
carbohydrates such as glucose tablets, glucose gel, juices, soft drinks, noncho-
colate candy, and other snacks that contain carbohydrates. To treat hypogly-
cemia, 0.3 g/kg of glucose, up to 20 g, is recommended initially. If
hypoglycemia has not resolved after 10 to 15 minutes, oral intake should be
repeated. If the patient is unable to take anything by mouth, then glucagon
should be given subcutaneously or intramuscularly at 0.5 mg for children
younger than 12 years, 1.0 mg for children older than 12 years [65].
Macrovascular and microvascular complications

People with T1D are at risk for several chronic vascular complications that
share many common risk factors. Macrovascular complications include
316 MAJIDI & MAAHS
cardiovascular disease, peripheral vascular disease, and cerebrovascular

disease. Microvascular complications include nephropathy, neuropathy, and
retinopathy.
Macrovascular complications
Cardiovascular disease is the leading cause of death in individuals with T1D
[25,66]. Despite advances in management of T1D, there has been less improve-
ment in cardiovascular disease outcomes compared with microvascular disease
[67]. Intensive glycemic control is associated with decreased risk of cardiovas-
cular disease. The DCCT/Epidemiology of Diabetes Interventions and
Complications study showed a 57% decrease in cardiovascular events,
including nonfatal myocardial infarction or stroke, death caused by cardiovas-
cular disease, subclinical myocardial infarction, angina, or the need for revas-
cularization [68]. Intensive glycemic control is also associated with slower
progression of subclinical atherosclerosis such as intima-media thickness
(IMT) compared with the conventional group in the DCCT trial [69]. Signs
of cardiovascular disease are evident in youth, including subclinical atheroscle-
rosis such as changes in carotid IMT, arterial elasticity, and pulse-wave velocity
[70–72]. Risk factors, such as higher low-density lipoprotein (LDL)-cholesterol,
obesity, hypertension, and smoking are correlated with thicker carotid IMT
during adolescence [73]. Higher LDL-cholesterol, hypertension, low high-
density lipoprotein-cholesterol, and smoking are also associated with decreased
arterial elasticity [74].
The increased mortality in T1D caused by cardiovascular disease, increased
incidence of subclinical atherosclerosis in T1D compared with youth without
diabetes, and the association of cardiovascular risk factors with increased
atherosclerosis markers in youth has led to guidelines focused on
screening and management of cardiovascular risk factors in youth with T1D
[25,75–77]. The benefit of intensive glycemic control on cardiovascular disease
emphasizes the necessity of working with patients to obtain optimal glycemic
control as well as monitoring for healthy blood pressure, lipids, and lifestyle.
Hypertension is defined as a systolic or diastolic blood pressure consistently
greater than or equal to the 95th percentile for age, whereas the 90th to 95th
percentile is considered high-normal [25]. The large DPV epidemiologic study
from Germany and Austria reported that 10% of youth with T1D have increased
systolic or diastolic blood pressures [78]. The ADA recommends treatment of
high-normal blood pressure (defined as between the 90th and 95th percentile
for systolic or diastolic blood pressure), with nutritional changes and exercise
with a goal of weight control and increased physical activity. If target blood pres-
sure, defined as less than the 90th percentile for weight, or less than 130/80, is not
reached within 3 to 6 months, or if blood pressure is greater than the 95th percen-
tile for age or greater than 130/80, then initiation of an angiotensin-converting
enzyme (ACE) inhibitor is recommended. The goal of therapy is to decrease
blood pressure less than the 90th percentile or less than 130/80, whichever is
lower. However, few youth with T1D are treated pharmacologically for
hypertension, with only 1.4% of youth in the SEARCH study [79] and 2.1% of
youth in the DPV study on antihypertensive treatment [78].
Dyslipidemia is defined as LDL level greater than 160 mg/dL or LDL level
greater than 130 mg/dL with 1 or more cardiovascular risk factors [80]. In the
DPV study, 22% of youth with T1D less than 11 years of age and 29% of T1D
youth 12 to 16 years of age had dyslipidemia [78]. Per the ADA, a fasting lipid
profile is recommended in youth with T1D greater than 2 years of age if there
is a family history of hypercholesterolemia or cardiovascular event before age
55 years, or if family history is unknown. If family history is not concerning,
then the first screening is recommended at puberty. If lipid levels are abnormal
(LDL level >100), they should be tested yearly. Otherwise, the ADA recom-
mends screening every 5 years. The ISPAD recommendations are similar [76],
whereas the American Heart Association (AHA) discusses dyslipidemia in the
context of cardiovascular disease (CVD) risk reduction. It categorizes youth
with diabetes into 2 groups. Those with T1D are categorized as the high-risk
group, or tier I. The goals for tier I include BMI less than or equal to 85%, blood
pressure less than or equal to 90% for age/sex, and LDL less than or equal to 100
mg/dL [77].
If dyslipidemia is present, then the ADA recommends obtaining glucose
control as well as recommending the step II AHA diet. The step II AHA
diet restricts saturated fat to 7% of total calories and cholesterol to no more
than 200 mg per day. If this diet does not result in a reduction of LDL level
to less than 160, or less than 130 if the patient has 1 or more CVD risk factors,
then the addition of a statin is recommended. The goal of therapy is to obtain
an LDL less than 100 mg/dL [25]. If treatment is recommended, currently
approved lipid-lowering medications include bile acid sequestrants and statins.
Despite these recommendations, only a small percentage of those with dyslipi-
demia are started on lipid-lowering therapy [75], with 0.4% of patients in the
DPV study on lipid-lowering medication [78].
Cardiovascular disease continues to be a major cause of death, with a diag-
nosis of T1D increasing one’s risk of cardiovascular disease significantly. As
noted earlier, the onset of atherosclerosis begins in youth and physicians
should follow practice guidelines to monitor and attain healthy targets for
A1c, blood pressure, lipids, and weight closely and counsel patients on the risks
of smoking. Additional physician and family education on the importance of
adherence to these recommendations is needed.
Microvascular complications
Diabetic nephropathy is defined as an increased urinary albumin excretion rate
or albumin/creatinine ratio (ACR) in the absence of other potential causes.
Normal ACR is considered less than 30 lg albumin/mg creatinine, microalbu-
minuria 30 to 299 lg/mg, and macroalbuminuria 300 lg/mg or greater [25].
Microalbuminuria, hyperglycemia, duration of diabetes, puberty, age at diag-
nosis, increased blood pressure levels, smoking, hyperlipidemia, and family
history of diabetes complications have all been identified as risk factors for
318 MAJIDI & MAAHS
diabetic nephropathy [81,82]. Intensive glycemic control can reduce the risk of
developing microalbuminuria, as found in the DCCT trial [38], and in the
long-term, can result in more favorable renal outcomes, even if patients have
persistent microalbuminuria [83]. Annual screening for microalbuminuria is
recommended starting at 10 years of age and after 5 years of T1D. If microal-
buminuria or greater is seen on 2 urine samples, an ACE inhibitor is recom-
mended [25]. Management should also include treatment of hypertension
and hyperlipidemia, which can help reduce the risk of developing nephropathy
or worsening nephropathy [84].
Diabetic retinopathy is a significant complication of T1D and is the leading
cause of blindness in young adults. There are 4 stages in the development of
retinopathy. The first stage (mild nonproliferative retinopathy) involves devel-
opment of microaneurysms, which are small areas of balloonlike swelling in the
small blood vessels of the retina. Moderate nonproliferative retinopathy occurs
when blood vessels leading to the retina become blocked. As more blood
vessels are blocked, severe nonproliferative retinopathy develops. The areas
of retina that lack a blood supply then send signals to the body to grow new
blood vessels for nourishment. This development of new blood vessels, which
are thin walled and fragile, is called proliferative retinopathy. When these
fragile blood vessels leak, severe vision loss and blindness can occur [85,86].
Risk factors for diabetic retinopathy include duration of postpubertal dia-
betes [87], poor glycemic control, hypertension, dyslipidemia, and higher
BMI [76]. DCCT data have shown that intensive diabetes treatment leads to
a 74% reduction in the risk for developing retinopathy [38]. The intensive
therapy group also had a reduction of risk for proliferative or severe nonpro-
liferative retinopathy by 47% [38]. New studies have shown that early changes
in retinal vasculature, before development of microaneurysms, are associated
with future retinopathy. These changes can be detected noninvasively and
can be used as a marker for future disease [88].
The ADA recommends annual ophthalmologic examination, including
dilated and comprehensive eye examination, by an ophthalmologist or optom-
etrist in youth with T1D aged 10 years of age or older who have had T1D for 3
to 5 years. Less frequent examinations, up to every 2 to 3 years, may be consid-
ered after 1 or more normal eye examinations, based on the recommendation
of the ophthalmologist or optometrist [25].
Diabetic neuropathy, including diabetic peripheral neuropathy and diabetic
autonomic neuropathy, is typically not seen until adulthood. Diabetic autonomic
neuropathy includes resting tachycardia, exercise intolerance, orthostatic hypo-
tension, constipation, diarrhea, esophageal dysmotility, gastroparesis, neuro-
genic bladder, and erectile dysfunction [25]. Autonomic neuropathy has been
associated with CVD in T1D [25]. Subtle signs of autonomic neuropathy and
distal polyneuropathy can be seen in youth with T1D, and intensive glycemic
control has been shown to slow the progression of neuropathy [38,76,89].
The ADA recommends screening for autonomic neuropathy starting at 5
years after diagnosis by careful history taking, review of systems, review of
vital signs, and physical examination [25]. Testing for distal symmetric poly-
neuropathy should begin at diagnosis and then yearly [25]. Corneal confocal
microscopy (CCM) is a new, noninvasive method proposed for earlier detec-
tion of diabetic neuropathy. Initial studies have shown that CCM can indicate
early small nerve fiber damage in the cornea, and can be accurately associated
with severity of diabetic neuropathy. This procedure is less invasive than other
studies, such as skin and nerve biopsies, that detect neuropathy at the same
early stages as CCM [90].
Manifestations of microvascular complications can develop in youth with
T1D, and intensive diabetes management with as low an A1c as possible
without hypoglycemia should be emphasized as the primary way to prevent
these as well as future microvascular and macrovascular complications.
Psychiatric complications
Development of T1D has been associated with increased risk of psychiatric
disorders, including eating disorders in adolescents [91]. Adjustment disorder
has been seen in the initial period after diagnosis, with 1 study reporting
30% developing clinical adjustment disorder within the first 3 months after
diagnosis. Adjustment disorder typically resolves within a year, but those indi-
viduals are at increased risk for further psychiatric disorders [91]. Anxiety
disorders are seen in up to 9% to 19% of adolescents with T1D and depression
in 10% to 26% of adolescents with diabetes [91]. One study found that depres-
sion is the most common psychiatric disorder to develop in patients with T1D
[92]. Individuals with T1D and comorbid depression are more likely to expe-
rience depressive episodes for longer, and women with T1D are at greater risk
of having recurrent depressive episodes compared with depressed individuals
without T1D [93]. Depression in T1D has been associated with poor glycemic
control, with 1 study showing that patients with persistently high Beck depres-
sion scores have poor glycemic control compared with those who did not have
abnormal Beck depression scores [94].
Eating disorders can also develop in patients with T1D, with an estimate of
up to 10% of adolescent females with T1D meeting criteria for an eating
disorder [95]. Risk factors include female gender, increased body weight,
food preoccupation, presence of eating disorder in parents, presence of other
psychiatric disorders, and problems with family relationships [91] Presence
of an eating disorder is also associated with poor glycemic control [91,96]
and increased frequency of DKA [91]. Given the increased presence of psychi-
atric disorders in patients with T1D, it is important to evaluate for psychiatric
disorders during clinic visits.
CURRENT RESEARCH
Closed-loop system
Intensive insulin therapy has been associated with reduction of risk of com-
plications from T1D [38]. However, intensive management can also lead to
hypoglycemia. Thus, the ability to provide intensive therapy and minimize
320 MAJIDI & MAAHS
hypoglycemic events is the subject of intense investigation. In the research

setting, CGM (discussed earlier) can be combined with insulin pump therapy
to create a closed-loop system, in which the data collected from the CGM
are transmitted to a computer, which then, via an insulin delivery algorithm,
signals the pump to deliver appropriate insulin doses [97]. A current partial
closed-loop system includes an insulin pump containing programming that
suspends insulin delivery when the associated CGM detects that the patient
is hypoglycemic. This feature is called ‘low glucose suspend’, and insulin
delivery is suspended for up to 2 hours when the user does not make a response
to a low glucose level alarm [98]. Other closed-loop systems being developed
include stopping or attenuating insulin delivery based on a glucose trend con-
cerning for hypoglycemia before the occurrence of hypoglycemia (called
a predictive algorithm) [99], another that adjusts insulin delivery to increase
the rate of delivery based on evaluation of glucose rate of change during meals,
and a system that is activated only when glucose levels increase above or
decrease below predetermined glucose levels [100]. In a hospital research
setting using a recently developed program in an overnight closed-loop system,
Hovorka and colleagues [97] reported that the closed-loop system maintained
glucose levels in the target range and with a similar, or lower, incidence of
hypoglycemia when compared with the currently available insulin pump use.
If the current pace of development continues, the successful development of
an overnight closed-loop system could provide real benefit in decreasing the
risk of nocturnal hypoglycemia [97]. Limitations remain in the development
of a closed-loop system, including issues with sensor accuracy and reliability,
delay between interstitial glucose and blood glucose, and the lack of ultrarapid
action of delivered insulin, and inadequate algorithms to allow rapid increases
and decreases in delivered insulin [100]. Research is ongoing to overcome these
problems and create a practical closed-loop system.
Prevention of T1D
There has been extensive research into prevention of diabetes at all levels,
including primary, secondary, and tertiary prevention.
Primary prevention
Current investigation into primary prevention includes dietary modifications
and antigen-specific vaccinations. Current research studies into dietary modifi-
cations include TRIGR, evaluating the effect of cow’s milk formula versus
hydrolyzed formula, BABY DIET, which is investigating whether avoiding
gluten until age 1 year has an effect on development of T1D, NIP, investigating
use of docosahexaenoic acid in pregnant women in their last trimester or
infants less than 6 months who have a family member with T1D, and use of
vitamin D in infants [101]. Antigen-specific vaccines are being investigated in
the Pre-POINT trial, using human insulin to investigate whether regulatory
T cells can become tolerant to insulin and therefore provide protection against
development of T1D [101].
Secondary prevention
Secondary prevention can be investigated for patients who have islet cell auto-
antibodies, but have not yet developed T1D. Secondary prevention research
includes the use of oral insulin and intranasal insulin as used in DPT-1
[101]. The DPT-1 trial results suggest that oral insulin may result in a delay
in T1D in patients who have high levels of insulin autoantibodies. However,
this delay was not maintained once oral insulin treatment was stopped [102].
Tertiary prevention
Tertiary prevention refers to prevention for patients who have already been
diagnosed with T1D with the aim for preserving remaining b cells, thus pro-
longing remaining endogenous insulin secretion [101]. Research is being con-
ducted using antigen-specific vaccines, systemic immunomodulators,
metabolic control, and b-cell rest. Antigen-specific vaccines include using
altered insulin or insulin peptides to induce immune tolerance [101]. A vaccine
based on the recombinant human GAD65 molecule when given twice is asso-
ciated with smaller decreases in C-peptide after 30 months [103]. Many immu-
nomodulators are being investigated, including cyclosporine A, antithymocyte
globulin, monoclonal anti-CD3 antibody, anti-CTLA-4 immunoglobulin, ritux-
imab, and cell therapies such as T cells and dendritic cells [101].
Transplantation
Two forms of transplantations have emerged with the potential of restoring
b-cell function and insulin independence. Pancreas transplantation, often per-
formed simultaneously with kidney transplantation, has been used for more
than 40 years, whereas islet transplantation has been used for about 20 years.
Pancreas transplantation
Forms of pancreatic transplantation include simultaneous pancreas and kidney
(SPK), pancreas after kidney transplantation, and pancreas alone transplanta-
tion. SPK is more commonly used and results in an 85% graft survival rate
at 1 year after transplantation [104]. Successful pancreatic transplantation
may result in return to normoglycemia and restore hypoglycemic awareness
[105]. Transplantation has also been associated with improved kidney function,
particularly when kidney transplant is included, stabilization of neuropathies,
improvement in retinopathy 3 or more years after transplant, and stabilization
of macrovascular disease. However, limitations in transplantation include side
effects from immunosuppressive therapies, including significant infections and
b-cell damage from immunosuppressive medications [105].
Islet transplantation
There has been investigation into islet transplantation with the goal to restore
insulin independence and avoid significant hypoglycemia, particularly in those
patients with severe hypoglycemia and labile glucose levels despite maximal
therapeutic attempts. The Edmonton group study in 2000 [106] initially had
a 100% success rate of islet cell transplantation in 7 patients at 1 year, defined
as having no need for exogenous insulin. The Edmonton group aimed to
322 MAJIDI & MAAHS
decrease failure rates by increasing the number of islet cells transplanted and
using glucocorticoid-free immunosuppressants, and was successful in dramati-
cally increasing success rates compared with previously documented rates of
8% at 1 year [106]. However, in a second trial using the same protocol with
a larger number of study sites and greater number of participants (36 patients)
[107], complete insulin independence was reached in 44% of patients by 1 year,
which decreased to 14% by 2 years. Twenty-eight percent of participants had
partial function by 1 year, and these patients were also completely protected
from severe hypoglycemic episodes. Partial function, defined as C-peptide level
0.3 ng/mL or greater and requirement for insulin or inadequate glycemic
control, was also associated with reduction in insulin doses, reduced fasting
glucose and A1c, and improvement in basal C-peptide levels compared with
those with complete failure. Adverse effects from transplantation include neu-
tropenia, pneumonia, gastrointestinal complications, decline in renal function,
and pericardial effusion. More common adverse effects included mouth ulcer-
ations, anemia, leukopenia, and neutropenia [107]. Overall, although initial
success was reported with islet cell transplantations in the Edmonton protocol,
continued investigation and research are required to improve this treatment of
T1D.
Despite multiple advances in the past decade, T1D continues to be a chronic,
lifelong disease requiring intensive daily management with the potential for
significant complications. The past 90 years since the discovery of insulin
have seen tremendous advances in the care of T1D and improvements in
the quality of life for people with T1D. Extensive and diverse research
continues regarding pathogenesis, management, complications, and prevention
and cure of T1D, with the goal of preventing T1D. The past decade since the
last update on diabetes in youth has shown significant advances, and the next
decade promises even greater improvements in quality of life and improved
clinical outcomes for people with T1D.
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Recent Advances in the Understanding

and Treatment of Pediatric Leukemias
Kelly W. Maloney, MD*, Roger Giller, MD,
Stephen P. Hunger, MD
Children’s Hospital of Colorado and The Department of Pediatrics, University of Colorado
Denver School of Medicine, Aurora, CO, USA
Keywords
Pediatric leukemia Treatment Hematopoietic Stem cell transplant
Key Points
Acute Lymphoblastic Leukemia: significant progress made in all groups, genomic
technologies increasing understanding and identifying new potential therapeutic
targets.
Acute Myeloid Leukemia: Risk group classification now applies to pediatric AML
to help guide therapy and choice of hematopoietic stem cell transplantation
(HSCT).
Chronic Myelogenous Leukemia: therapy now with tyrosine kinase inhibitors,
unclear role now for HSCT.
HSCT: 1. improving morbidity risks, increasing use of unrelated adult and cord
blood stem cell donors, current transplant approaches and current indications for
transplant in pediatric leukemia.
INTRODUCTION AND OVERVIEW

Leukemia is the most common pediatric cancer accounting for 31% of cancers
that occur before 15 years of age and 25% that occur before 20 years of age [1].
The proportion of the 3 major types of leukemia changes considerably during
childhood. The annual incidence of acute lymphoblastic leukemia (ALL) reaches
a maximum of 80 to 90 cases per million at 2 to 3 years of age, starts to decrease
significantly at 5 to 6 years of age, drops to about 20 cases per million at 8 to 11
years of age, and decreases gradually to about 10 cases per million at 20 years of
age. In contract, the incidence of acute myeloid leukemia (AML) is about 5 to 10
S.P.H. is the Ergen Family Chair in Pediatric Cancer.
*Corresponding author. Center for Cancer and Blood Disorders, Children’s Hospital Colorado,
13123 East 16th Avenue, Box B115, Aurora, CO 80045. E-mail address: Kelly.Maloney@
childrenscolorado.org

330 MALONEY, GILLER, & HUNGER
cases per million throughout the first 20 years of life, and the incidence of chronic
myeloid leukemia (CML) is only about 2 cases per million until 15 years of age
and then doubles to about 4 cases per million by 20 years of age. Thus, for chil-
dren younger than 5 years, ALL accounts for about 80% of leukemias, AML 15%,
and CML 2% to 3%. In contrast, the distribution is approximately 50% ALL, 35%
AML, and 10% CML for adolescents aged 15 to 19 years. In the early 20s, the
incidence of AML passes that of ALL and remains higher throughout adulthood.
Even though cure rates have increased considerably over the past few decades for
all subtypes of disease, leukemia accounts for 30% of pediatric cancer deaths and
remains the most common cause of death from cancer during childhood. This
predominance extends until about 35 years of age [2].
The most recent National Cancer Institute Surveillance, Epidemiology, and
End Results (SEER) program estimates show 5-year survival rates in the 2000-
2004 era for children less than 15 years of age being 87.5% for ALL and 59.9%
for AML, with projected increases to 90.6% for ALL and 64.8% for AML in the
2005-2009 era [3]. The SEER survival estimates in the 2000-2004 era were
much lower for adolescents aged 15.0 to 19.99 years: 61.1% for ALL and
47.2% AML [4,5]. Because of the rarity of CML, it is difficult to obtain good
population-based estimates of survival rates among younger children. The
SEER data showed an estimated 82.3% 5-year survival rate for persons
with CML 15 to 24 years of age during 2000-2004 [4]. As discussed later,
the survival for CML has increased significantly since the development of
BCR-ABL1 tyrosine kinase inhibitors (TKI).
During recent years, there have been significant advances in understanding the
molecular pathogenesis of different subtypes of leukemia and improvements in
therapy. In particular, advances in genomic medicine are leading to rapid changes
in knowledge of the genomic landscape for leukemias; it is hoped that this will
translate to further improvements in cure rates during the next 5 to 10 years.
ALL
Overview of chemotherapy used to treat ALL
Several different individual institutions and cooperative groups have shown
steady improvements in event-free (EFS) and overall survival (OS) for children
with ALL over the past 10 to 15 years, leading to predictions that 85% to 90%
of children and adolescents diagnosed with ALL in the current era will be long-
term survivors [6]. Almost all of these improvements have occurred through
optimizing the use of about 10 different chemotherapy drugs that have been
used to treat childhood ALL since the 1970s [7–12]. Imatinib and related
TKIs are the only new drugs introduced successfully into treatment regimens
for children newly diagnosed with ALL over the past 4 decades and these
agents are only relevant for the 3% to 5% of children with Philadelphia chro-
mosome positive (Phþ) ALL. The basic outline of ALL treatment regimens has
been stable since the early 1980s and includes 4 phases: induction, central
nervous system (CNS) preventative therapy, consolidation or intensification,
and maintenance or continuation. The first 3 more intensive phases of
PEDIATRIC LEUKEMIAS 331
therapy typically last 6 to 8 months, and maintenance therapy continues until 2

to 3 years from the date of the initial diagnosis.
Induction therapy
The treatment regimens used by the various major centers and cooperative
groups differ modestly from one another but they all share common features.
The first 4 to 6 weeks of therapy are designed to induce remission and are,
therefore, termed induction. Remission is defined by fewer than 5% lympho-
blasts in a normocellular bone marrow (BM), with normal peripheral blood
counts and the resolution of any extramedullary evidence of leukemia. Induc-
tion chemotherapy regimens have changed little over the past 30 years and
typically include either 3 or 4 systemic agents and daily administration of corti-
costeroids for 4 weeks, weekly intravenous (IV) injections of vincristine,
and variable doses of an asparaginase (ASNase) preparation without (3-drug
induction) or with (4-drug induction) an anthracycline given weekly for 3 to
4 doses. More than 98% of children with ALL enter remission following induc-
tion, and the toxic mortality rate during induction is less than 2% in industri-
alized countries [13].
For many years, ALL induction regimens used prednisone or a prednisone-
derivative at a dosage of 40 to 60 mg/m2/d. Several, but not all, studies have
shown that dexamethasone use during induction, as compared with doses of
prednisone thought to be equally toxic, improved EFS [14–16]. However,
dexamethasone is much better tolerated in 3-drug induction regimens than it
is in 4-drug regimens because of the higher early mortality when dexametha-
sone is used in conjunction with anthracyclines, which causes both myelosup-
pression and mucositis. Until recently, the Children’s Oncology Group (COG)
ALL protocols, on which about 70% of US children with ALL are treated, used
dexamethasone (6 mg/m2/d) in 3-drug induction regimens given to children
with standard-risk (SR) ALL (aged 1.0–9.99 years and initial white blood cell
count [WBC] <50,000/lL) but used prednisone (60 mg/m2/d) in 4-drug induc-
tion regimens given to children with high-risk (HR) ALL (aged 10 years or
initial WBC 50,000/microliter). Recently, the COG AALL0232 trial showed
that 14 days of dexamethasone during induction produced better results than
28 days of prednisone for children less than 10 years of age with HR ALL,
which changed clinical practice [17].
There are also differences in the ASNase preparations used in various treat-
ment regimens. Native Escherichia coli asparaginase is typically administered 2 to
3 times per week intramuscularly (IM) for 6 to 9 doses to maintain the depletion
of plasma asparagine during induction therapy. Because it is a foreign protein,
clinical or subclinical allergy develops in more than 25% of patients treated
with native ASNase. In addition to causing potentially life-threatening symptoms,
allergy leads to the rapid destruction of ASNase and, hence, loss of efficacy. A pe-
gylated form of ASNase was developed and is associated with a lower incidence of
allergy and a greatly prolonged half-life. Based on these factors, Pegaspargase
(PEG ASNase) is now the most common form of the drug used in ALL treatment
regimens in the United States and it is often given only once during induction.
Until recently, PEG ASNase was almost always administered via IM injection,
but recent studies have shown that IV injection is safe and COG protocols
now use IV PEG ASNase [18]. Allergy to PEG ASNase occurs in up to about
20% of patients treated intensively with this agent. When allergy occurs to
PEG ASNase, treatment with the native product is not possible. There is another
non–cross-reactive ASNase product that uses an enzyme derived from Erwinia
chrysanthemi, which was recently approved by the US Food and Drug Administra-
tion for clinical use in the United States [19].
Presymptomatic CNS therapy
In the mid 1960s, a high proportion of children with ALL attained remission but
most relapsed within 6 to 12 months; many of these relapses involved only the
cerebrospinal fluid, which led to the recognition that the CNS served as a sanc-
tuary site for lymphoblasts. Presymptomatic irradiation of the brain and spinal
cord was added to childhood ALL treatment regimens in the late 1960s and early
1970s, which led to substantial increases in survival [20]. Over the ensuing
decades, it has been shown that CNS irradiation can be eliminated in most chil-
dren with ALL when more effective systemic therapy is administered in conjunc-
tion with periodic administration of intrathecal (IT) chemotherapy, typically
methotrexate (MTX), but sometimes combined with cytarabine and hydrocorti-
sone in triple IT therapy. Most contemporary ALL therapies use CNS irradiation
for only 15% to 25% of children [21]. Recent small studies have shown excellent
results in regimens with no cranial irradiation [22,23]. These findings challenge all
centers and groups to carefully reconsider which patients can be treated without
irradiation.
Consolidation or intensification
After remission is achieved, children with ALL receive 6 to 8 months of intensive
therapy. Treatments are typically delivered in 1- to 2-month phases that use
a variety of non–cross-resistant chemotherapy agents. Most ALL treatment regi-
mens stratify the intensity of therapy based on the risk of relapse. Thus, the
consolidation phase of treatment can vary significantly for different risk groups.
In COG trials, the first 1 to 2 months of consolidation therapy that follows induc-
tion is different for SR and HR patients. The SR patients receive 4 weeks of oral
chemotherapy combined with weekly IT MTX. In contrast, along with weekly
IT MTX, HR patients receive 8 weeks of multiagent chemotherapy that produces
significant periods of myelosuppression associated with high rates of infection.
The recently completed COG AALL0331 study randomized children with SR
ALL to receive either the usual SR consolidation phase or the multiagent HR
consolidation; results of that study will become available in the next several years.
Following 1 to 2 months of consolidation, almost all groups administer a block of
MTX-based therapy. The COG has typically given lower-dose (100–250 mg/m2/
dose) MTX given IV over 5 to 15 minutes every 10 days without leucovorin rescue,
whereas the Berlin-Frankfurt-Muenster (BFM) group and other groups have used
high-dose MTX (5 mg/m2/dose) administered IV over 24 hours followed by
leucovorin rescue. The COG has recently completed a trial (AALL0232) for chil-
dren and adolescents with HR ALL that compared these two modes of MTX
administration and found that high-dose MTX was better for HR ALL [24].
After this, most ALL treatment regimens include a reinduction/reconsolida-
tion phase termed protocol II by the BFM group that developed it in the early
1970s and delayed intensification (DI) by the COG [25]. Many groups repeat
the protocol II/DI phase for some or all patients, but the COG has recently
shown that 1 or 2 DI phases produce nearly identical outcomes for most
patients that have a good early response to therapy [26,27].
Maintenance
After postinduction consolidation/intensification is completed, patients receive
maintenance therapy with daily oral 6-mercaptopurine and weekly oral MTX,
with variable administration of IT chemotherapy and periodic doses of vincris-
tine and corticosteroid pulses that last 5 to 7 days. These pulses are not necessary
in the context of BFM-based therapy but are still used by the COG, which is now
studying whether outstanding cure rates can be maintained in SR-ALL if pulses
are given every 12 weeks rather than every 4 weeks [28].
Recent developments in treatment of newly diagnosed childhood ALL

Although the overall cure rate for children with ALL is high, patient subsets
can be identified using clinical or biologic features (see later discussion) that
are at an increased risk of relapse. Important recent developments in the treat-
ment of several of these HR subsets are considered next.
T-cell ALL
Approximately 85% of childhood ALL cases have an immature B-cell immuno-
phenotype (B-precursor ALL), whereas about 15% express surface markers asso-
ciated with T-cell lineage (T-ALL). Historically, T-ALL was associated with
lower cure rates, but it is now clear that similar cure rates can be attained for
both groups as long as patients with T-ALL receive intensive therapy similar to
that given for children with B-precursor ALL and HR age/WBC features. There
are some unique factors that must be considered in the treatment of children with
T-ALL. Epidemiologically, T-ALL occurs more frequently in adolescents and in
African Americans and is frequently associated with a high initial WBC and
a mediastinal (thymic) mass [13]. Management of the first few days of induction
therapy can be challenging, particularly if there is airway obstruction from a medi-
astinal mass or problems with acute tumor lysis syndrome caused by hyperleuko-
cytosis. Children with T-ALL have a higher rate of CNS failure and remain the
group that most commonly receives cranial irradiation.
One new chemotherapy agent that has shown great promise in T-ALL is ne-
larabine, a nucleoside analogue of araG (9-B-arabinofuranosylguanine) that is
selectively cytotoxic to T-lymphoblasts [29]. Nelarabine was used initially as
monotherapy for children and adults with refractory T-ALL with excellent
response rates but significant neurotoxicity in some patients that included
severe ataxia, coma, and death [30]. A subsequent phase II trial of nelarabine
in T-ALL showed a complete response rate of approximately 50% for those in

the first relapse, but significant neurotoxicity occurred in 10% to 15% of
patients. Based on the extremely promising activity observed in phase I/II trials,
and the occurrence of major neurotoxicity in some patients, nelarabine has
been introduced cautiously into regimens for newly diagnosed T-ALL. The
COG AALL00P2 pilot study showed that 5-day courses of nelarabine could
be integrated safely into multiagent chemotherapy regimens used to treat chil-
dren with newly diagnosed T-ALL with much lower rates of serious neurotox-
icity than observed in children with relapsed T-ALL [31]. Encouraging results
were again seen in this trial, leading the COG to develop the AALL0434
randomized trial of chemotherapy nelarabine that is currently being con-
ducted for children with newly diagnosed T-ALL.
Recently, a unique subset of patients with an early T-cell precursor (ETP)
immunophenotype has been identified that has been reported in one study
to have a poor outcome [32]. Further study is needed to determine if other
groups also find an adverse outcome for patients with the ETP phenotype
and whether alternative treatment strategies might improve outcome.
Phþ ALL
One of the strongest adverse prognostic factors in childhood ALL has always been
the presence of the Philadelphia chromosome, a reciprocal t(9;22)(q34;q11.2), that
results in the production of a BCR-ABL1 fusion protein with constitutive tyrosine
kinase (TK) activity. The Phþ is present in only about 3% of children with ALL, but
until recently fewer than half of children with Phþ ALL have been cured despite the
use of intensive chemotherapy and the frequent use of hematopoietic stem cell
transplant (HSCT) [33,34]. A recent retrospective review of more than 600 patients
with Phþ ALL treated by 14 cooperative groups from 1995 to 2005 without TKI
therapy showed that HSCT was the best form of postremission treatment, but
the 7-year EFS and OS in this study were only 31% and 44% [34].
However, the development of imatinib, which inhibits the BCR-ABL1 TK
activity, has revolutionized the treatment of CML (see later discussion) and
serves as a paradigm for the potential benefit of molecularly targeted therapy
in ALL. Single-agent imatinib therapy was active in patients with refractory
Phþ ALL but responses were transient [35]. However, exciting early results
were attained when imatinib was added to multiagent chemotherapy regimens.
The COG conducted a clinical trial (AALL0031) between 2002 and 2006 that
added imatinib to an intensive chemotherapy regimen starting after the induction
was completed [36]. This trial was done in a stepwise fashion with patients in the
last cohort (number 5) receiving continuous imatinib treatment (340 mg/m2/d)
from the start of consolidation, with the drug given on a 2-week-on-2-week-off
schedule for the last year of maintenance. Several important findings derived
from this study. First, the addition of imatinib to intensive chemotherapy was
well tolerated and did not increase toxicity. Second, this strategy produced
outstanding early results; patients treated in cohort 5 had a 3-year EFS of 80%,
which was more than double that of historical controls (35%). There was no
advantage for HSCT, with 3-year EFS similar for patients in cohort 5 treated with
chemotherapy plus imatinib or sibling-donor HSCT. Although a longer follow-
up of this study is necessary and additional studies are needed to clearly define
the role of HSCT in Phþ ALL, these results establish that molecularly targeted
agents can dramatically improve the outcome of patients with ALL with specific
sentinel chromosome lesions. In Phþ ALL, there is great interest in testing chemo-
therapy combined with second-generation TKIs, such as dasatinib. One can
anticipate that this paradigm will be extended to other patient subgroups in the
next 5 to 10 years as new HR genetic lesions are identified and new targeted ther-
apies are developed [37].
Infant ALL
ALL that occurs in infants less than 1 year old is uncommon, with only about
100 cases per year in the United States, but this is a biologically distinct subset
of ALL with a poor outcome. Infants account for only about 2% of patients
with childhood ALL, but 8% of deaths occur in this subgroup [6]. Chromo-
some translocations involving the 11q23 mixed lineage leukemia (MLL) gene
occur in 70% to 80% of infant ALLs versus only 2% to 3% of older children
[38,39]. The Interfant-99 trial (1999–2005), which was the largest infant ALL
study ever conducted, achieved a 4-year EFS of only 47% overall and only
38% in those with MLL rearrangements [39,40]. Controversy exists regarding
the role of HSCT for infants with ALL and MLL rearrangements, with the
COG finding no benefit but Interfant showing a modest benefit confined to
those with additional HR clinical features [40,41]. Because infant ALL with
MLL rearrangements overexpress the wild-type FLT3 receptor, both COG
and Interfant are now investigating the addition of FLT3 inhibitors to intensive
chemotherapy [42].
Adolescents and young adults with ALL

The adolescents and young adults (AYA) population, generally considered to be
those aged 16 to 21 years at ALL diagnosis, has historically had a significantly poor-
er outcome than that of younger children [4]. The reasons for these differences are
likely multifactorial, but a series of recent studies have shown remarkably similar
findings regarding the treatment setting [43]. Because adolescents can be treated
in either pediatric or adult centers, these retrospective studies compared outcomes
for AYA patients with ALL treated during the same era in either adult or pediatric
cancer units. Although it is important to remember that these were not randomized
trials, the outcome differences were remarkable with AYA patients with ALL
treated on pediatric cooperative group trials typically having EFS and OS rates
that were 20% to 30% higher than those obtained in contemporaneous adult coop-
erative group trials. The largest study compared the outcomes of patients with ALL
aged 16 to 20 years treated in North America on pediatric (Children’s Cancer
Group [CCG]) or adult (Cancer and Leukemia Group B [CALGB]) trials between
1988 and 2001 [44]. The outcome was dramatically better for AYA patients treated
on the pediatric trial: 7-year EFS 63% versus 34% on the CALGB trial.
Recent studies have shown continued improvements in outcomes for AYA

patients with ALL. The CCG 1961 study is the largest published trial [45].
The 262 AYA patients enrolled in this trial between 1996 and 2002 had 5-year
EFS and OS of 71.5% and 77.5%, respectively. Thus, it is now clear, whatever
the reasons, that AYA patients with ALL treated in pediatric centers can obtain
outstanding cure rates, which suggests that the optimal approach for patients of
this age range with ALL is referral at the time of the diagnosis to a pediatric cancer
center experienced in the care of older adolescents. These results call into ques-
tion the policy of some children’s hospitals to cap the patient age at 18 years
and challenge pediatric oncologists to educate potential referring internists,
family practitioners, and emergency room physicians about these data.
Treatment of relapsed ALL
Unfortunately, the outcome for children with ALL who relapse is much worse
than at the initial diagnosis. For example, a retrospective study examined the
OS of 1961 patients (of 9585 originally enrolled) that relapsed following treat-
ment on a COG ALL clinical trial between 1988 and 2002 [46]. A variety of
clinical factors impact outcomes after relapse with an increased risk of death
associated with older age at diagnosis and HR versus SR characteristics at diag-
nosis. The two strongest predictors of outcome were site of relapse (isolated
BM worse than combined BM and extramedullary, which was worse than
isolated extramedullary) and shorter time to relapse. Most patients (57.3%)
had an isolated BM relapse and their outcome was poor with a 5-year OS
rate 24.1%. For patients with early (<18 months from diagnosis) or interme-
diate (18–36 months) time to relapse, the OS rates were only 11.5% and
18.4%, respectively. These results suggest that improvements in survival
require the identification of patients at HR of relapse early during the initial
therapy and the application of novel treatments before relapse because the
chance of salvage is poor once relapse occurs. In addition, new treatments
are needed to treat patients who have relapsed, particularly those with BM
relapses or those that occur within 3 years of the initial diagnosis.
To attempt to improve the outcome of children with early and intermediate
isolated BM relapse, the COG developed a treatment platform that includes
three 4-week blocks of non–cross-resistant intensive chemotherapy and is
now testing whether adding new agents, such as epratuzumab, a monoclonal
antibody targeted at CD22, or bortezomib (a proteosome inhibitor), to this
backbone will improve remission rates and early EFS [47].
New prognostic factors and potential therapeutic targets in childhood
ALL
ALL is a clinically and biologically heterogeneous disorder, and different treat-
ment approaches may be warranted for different patient subsets. As discussed
earlier, age and initial WBC are strong prognostic factors that are used to clas-
sify patients as SR or HR and stratify treatment intensity [48]. Two of the most
important biologic factors that influence outcome and are often used in risk
stratification are the acquired (somatic) genomic lesions involved in the
pathogenesis of ALL and early response to therapy. The latter is a clinical inte-
gration of several different leukemia- and host-specific factors.
Until recently, most studies of the genetics of ALL have focused on the
visible cytogenetic changes present in most cases of childhood ALL, which
are generally categorized as structural or numerical alterations. Chromosome
translocations, the most common structural alterations, activate proto-
oncogenes by bringing them under control of one of the immunoglobulin or
T-cell receptor loci leading to the dysregulated expression of an intact protein
or by creating fusion genes that encode novel fusion proteins [49]. The most
common chromosome translocations in childhood ALL are associated with
different treatment outcomes, including the t(9;22) and BCR-ABL1 fusion
(poor), translocations of the 11q23 gene MLL (poor), t(1;19) and TCF3-PBX1
fusion (intermediate), and the cryptic t(12;21) and ETV6-RUNX1 (TEL-
AML1) fusion (good) [49]. Numerical alterations are also associated with the
treatment outcome. About 2% of childhood ALL cases are classified as hypo-
diploid, with fewer than 44 chromosomes in the leukemia cells, and these
patients have a poor treatment outcome, with a long-term OS less than 50%
[48,50]. In contrast, 25% to 30% of childhood ALL cases have a hyperdiploid
DNA content with excess chromosomes and those with greater than or equal to
53 chromosomes or specific chromosome trisomes (4 and 10) have been re-
ported to have an outstanding treatment outcome [48].
In the past few years, high throughput genomic technologies have increasingly
been used to analyze childhood ALL, leading to major new insights into the
genomic landscape of this disease. These technologies include gene expression
profiling, use of high-density single nucleotide polymorphism arrays to determine
copy number alterations between leukemia and germline DNA, and increasingly
new sequencing technologies [51]. The COG High Risk ALL TARGET (therapeu-
tically applicable research to generate effective treatments; see http://target.cancer.
gov/) serves as a paradigm for this approach. One major discovery of the ALL
TARGET project was that genomic alterations of IKZF1, which encodes the critical
lymphoid transcription factor IKAROS, occur in about 30% of HR ALL cases and
is associated with poor outcomes [52]. A second discovery is that mutations of Janus
family kinase genes (especially JAK2 but also JAK1 and JAK3) occur in 5% to 10%
of childhood ALLs, almost always associated with genomic alterations that lead to
the overexpression of the cytokine receptor CRLF2, and are linked to poor
outcomes [53,54]. The latter finding is particularly intriguing because JAK kinase
inhibitors have been developed to treat adult myeloproliferative disorders associ-
ated with somatic JAK2 mutations with encouraging early results [55]. Based on
these findings, the COG has developed a phase I trial of JAK2 inhibitor therapy
with plans to move forward with combination therapy for JAK-mutant ALL, which
is analogous to imatinib combined with chemotherapy for Phþ ALL [36].
One of the strongest prognostic factors in childhood ALL is the early response to
therapy measured either morphologically or now more commonly by quantifying
the level of minimal residual disease (MRD) present after 4 to 12 weeks of therapy.
The COG now incorporates end induction MRD burden into risk stratification
schemes and has shown that an MRD level of less than 0.01% at end induction is the
most robust prognostic factor [56]. The MRD burden can be integrated with
genomic characteristics to further enhance risk stratification. For example, an
ultra–low-risk group of patients, defined as those with SR age/WBC features,
ETV6-RUNX1 fusion or trisomies of both chromosomes 4 and 10, and induction
day 8 peripheral blood and day 29 BM MRD less than 0.01%, had a 97% 5-year
EFS with limited therapy that included no alkylating agents or anthracyclines [56].
AML
Approximately 500 new cases of AML occur per year in children and adoles-
cents in the United States. Although AML accounts for only 25% of all leuke-
mias in this age group, it is responsible for at least one-third of the deaths from
leukemia in children and teenagers. Congenital conditions associated with an
increased risk of AML include anemia; neurofibromatosis; Down syndrome;
Wiskott-Aldrich, Kostmann, and Li-Fraumeni syndromes; and chromosomal
instability syndromes, such as Fanconi anemia. Acquired risk factors include
exposure to ionizing radiation, cytotoxic chemotherapeutic agents, and
benzenes. Historically, the diagnosis of AML was based almost exclusively
on morphology and immunohistochemical staining of the leukemic cells.
This practice combined with a few limited disease and host factors determined
the prognosis of AML. Over the past 10 to 15 years, major advances have been
made in identifying molecular and cytogenetic risk factors in AML.
Treatment of AML
Induction and consolidation therapy
As with ALL, multiple cooperative groups have trialed different combinations of
chemotherapy for AML, leading to marked improvement in complete remission
and OS over the last 15 to 20 years. Therapy for AML consists of sequential
chemotherapy combinations designed to obtain initial remission (induction
therapy) followed by postremission therapy (consolidation) because it has been
demonstrated that initial remission without consolidation does not result in pro-
longed remission. However, similarities in these combinations exist because they
all use intensive chemotherapy, which causes prolonged BM aplasia [57,58].
The most favorable outcomes are achieved with the use of high cumulative
doses of anthracyclines and cytarabine, with the addition of other agents, eto-
poside being commonly used. In addition, the ability to deliver few but inten-
sive courses of combination chemotherapy helps to explain the improved
prognosis of children with AML. Most of the large cooperative groups use
this strategy with variations in risk groups, chemotherapeutic agents, and
time to stem cell transplant. Despite the differences, outcomes in the modern
area of children with AML are similar [59].
The United Kingdom Medical Research Council (MRC) recruited 1966
patients with AML from May 1988 to April 1995 for AML10 [60,61]. This trial
was the first MRC trial to include children and infants with AML and was
a sentinel trial for childhood AML. This trial compared the standard therapy
at the time (daunorubicin, cytarabine, and thioguanine) with cytarabine,

daunorubicin, and etoposide. Patients received 2 cycles of chemotherapy and
then continued with 2 further consolidation cycles if in remission. This trial
also evaluated stem cell transplantation following remission induction. The
remission induction rate for the children/infants was 92% with a disease-free
survival of 52% at 7 years and an OS of 56% at 7 years. The results of this trial
were superior to the prior MRC trials and were better than or comparable with
other cooperative groups at the time. An important outcome from this trial was
the identification of 3 risk groups that incorporated the biology of the AML
rather than only the presenting features of the patients. The large cooperative
groups now use risk classification using cytogenetic and molecular risk factors.
Consolidation strategies for different AML risk groups
Favorable-risk AML is defined by the core binding factor leukemias t(8;21) and
inv (16) as well at the t(15;17) (which is discussed later). This group of patients
with AML was first shown to have an excellent 7-year EFS of 78% with chemo-
therapy alone [61]. The possible benefit of BM transplant (BMT) in terms of
reduced relapse risk is likely to be outweighed by the toxicities of transplant,
both acute and long term. The favorable prognosis of this group has now
been verified by multiple large studies [57,62,63].
Unfavorable-risk AML include cases with complex cytogenetics (3 or more
distinct cytogenetic abnormalities in a leukemic clone), monosomy 7, mono-
somy 5, del(5q), and abnormal chromosome 3. This group also includes
FLT3 internal tandem duplications (ITD, discussed later) [64,65]. This group
has a much poorer outcome, with a 3-year survival rate of 42% [61]. Initial
therapy is begun with intensive combination chemotherapy as previously dis-
cussed. Most investigators think that the best treatment available for this group
of patients is stem cell transplantation (SCT) in the first remission, with EFS
rates of greater than 50% [66]. Many of the ongoing cooperative group studies
include SCT for HR patients with outcomes unknown at this time [57].
The intermediate-risk group for pediatric AML includes all remaining chromo-
somal abnormalities seen in AML, such as þ8, þ21, and 11q23 abnormalities, and
patients with AML with a normal karyotype [64,65]. The approach to this group of
patients is more variable than for those with favorable-risk and HR-risk AML.
CCG’s 2891 trial showed a significant survival advantage for patients who under-
went allogeneic SCT versus autologous SCT or chemotherapy [67]. The current
COG trial incorporates intensive chemotherapy as described previously. For the
intermediate-risk group in this trial, if patients have a matched sibling donor,
then SCT is recommended. However, the approach in other cooperative trials is
to continue with intensive chemotherapy [57,66]. The OS for this group ranges
from 29% to 59% depending somewhat on the specific cytogenetic group [64].
Special subgroups of AML
Acute promyelocytic leukemia
Acute promyelocytic leukemia (APL) is a rare malignancy and even more
uncommon in children less than 10 years of age [68]. However, the EFS of
APL is higher than other AMLs at 70% to 80% [69,70]. This subtype of AML
has a unique t(15;17) that produces PML-RARA fusion (or variant RARA trans-
locations) that must be demonstrated either cytogenetically or molecularly to
confirm the diagnosis. Induction therapy consists of treatment with all trans-ret-
inoic acid (ATRA) combined with chemotherapy. ATRA therapy causes differ-
entiation of promyelocytic leukemia cells and can induce remission by itself,
but single-agent ATRA therapy is not curative. This combination results in
extremely high antileukemic efficacy, leading to clinical remission (CR) in
90% to 95% of patients [69,71,72]. Unlike other AML subtypes, maintenance
therapy similar to that used for ALL is thought to be beneficial for APL
[73]. Recently, arsenic trioxide (ATO) has been shown to be active in APL
[74]. The current COG APL trial, AAML0631, incorporates ATO in consoli-
dation in parallel with the International Pediatric APL protocol. Several studies
have shown that some patients with APL can be cured with ATRA plus ATO
without cytotoxic chemotherapy, but more study is needed to identify which
patients will or will not benefit from this approach.
Acute myeloid leukemia in children who have Down syndrome
Another biologically distinct subtype of AML occurs in children with Down
syndrome (DS), who have a greatly increased risk of developing AML, partic-
ularly the megakaryocytic subtype. Children with DS who develop AML typi-
cally do so between the ages of 1 and 4 years. Using less intensive treatment,
remission induction rate and overall survival of these children are superior to
non–Down syndrome children with AML. Therapy in the last decade has a re-
ported EFS of 83% with relapse rates as low as 3% [75,76]. The high EFS rate
of DS patients is partly due to increased sensitivity to Ara-C and daunorubicin
[77,78]. Newer protocols for DS AML concentrate on optimizing their therapy
to minimize the toxicities and morbidity.
Newly identified molecular subtypes of AML
More recently, molecular techniques have been used to understand the devel-
opment of AML in patient’s without detectable sentinel cytogenetic abnormal-
ities. Mutations in several genes have been shown to have some impact on the
prognosis of childhood AML: Fms-like TK 3 (FLT3) gene, the nucleophosmin
(NPM) gene, and the CCAAT/enhancer-binding protein-alpha (CEPBA) gene.
FLT3 is a receptor TK expressed on hematopoietic progenitors. FLT3 ITDs
are present in 10% to 15% of cases of pediatric AML [79,80]. FLT3 ITD is asso-
ciated with a poorer outcome, mainly associated with an increased risk of relapse
[80,81]. Contemporary CCG trials also confirmed the poor outcome associated
with FLT3 ITD and showed that survival decreased with an increasing allelic
ratio of FLT3 ITD to wild-type FLT3. This study found that a ratio greater
than 0.4 was associated with a significantly worse progression-free survival
(PFS) than a lower ratio (16% vs 72%) [80]. In addition, the poor prognostic
impact on PFS could be overcome with SCT.
Other potentially important molecular markers include CEBPA mutations
and NPM mutations. CEBPA mutations confer a favorable prognosis in
patients with cytogenetically normal AML regardless of the age at presentation.

In one of the largest studies of pediatric AML, CEBPA mutation was an inde-
pendent risk factor for outcomes with a 5-year EFS of 70% versus 38%, with
a lower incidence of relapse for those with CEBPA mutations [82]. NPM muta-
tions have been detected in up to 50% of adult AML but a lower percentage of
pediatric AML [83,84]. In patients with wild-type FLT3, NPM mutations are
associated with an improved outcome. The EFS and OS in one study of pedi-
atric AML with NPM mutations was found to be 80% and 85% compared with
39% and 60% in those without the mutations, respectively [85]. However, the
investigations of these 2 mutations are ongoing and have not been completely
incorporated in AML risk classification in pediatric AML.
CML
Overview
CML is diagnosed rarely in children less than 18 years of age, accounting for
only 3% of leukemias with an annual incidence of 1 case per million children in
Western countries [1]. Generally, children are diagnosed at a median age of 11
to 12 years, with approximately 10% presenting in advanced phases [86]. No
significant racial or sexual predilection exists and there has been no hereditary
component demonstrated. Ionizing radiation exposure is the only recognized
environmental factor; however, this is rarely implicated in pediatric patients.
The natural history of CML is divided into chronic (CP) and accelerated (AP)
phases and blast crisis (BC). Most children and adults present with CML-CP,
which is characterized by the expansion of the hematopoietic pools, with morpho-
logically mature blood cell elements with no or a low number of blasts. CP typi-
cally lasts approximately 3 years. AP is a more aggressive phase with similarities
to acute leukemia; however, according to the World Health Organization classi-
fication, it has less than 20% blasts. The patients may also have progressive
systemic symptoms. BC is analogous to acute leukemia, with anemia, thrombo-
cytopenia, and increased blasts (>20%). The cells have now lost their ability to
differentiate. There may also be an evolution of the karyotype.
Children with CML usually present with nonspecific complaints, including
fever, night sweats, weakness, left upper quadrant pain or fullness, and bone
pain. However, patients can also be asymptomatic, CML only being found
on blood work done for other causes. Physical examination, however, usually
reveals splenomegaly, with spleens that often extend into the pelvis.
Biology of CML
The cytogenetic hallmark of CML is the Philadelphia chromosome, which
results in the fusion of the BCR gene on chromosome 22 and the ABL gene
on chromosome 9. The resulting fusion protein is a constitutively active TK
that interacts with a variety of effector proteins and allows for deregulated
cellular proliferation, decreased adherence of cells to the BM extracellular
matrix, and resistance to apoptosis. BCR-ABL can be the sole oncogenic event,
inducing CML-CP [87,88].
The disease usually progresses within 3 to 6 years to an AP and then to a BC. It

is generally accepted that Phþ cells have an increased susceptibility to the acqui-
sition of additional molecular changes. The accumulation of molecular abnormal-
ities leads to a loss of the capacity for terminal differentiation of the leukemic clone
[89]. In the past, the progression usually led to a fatal leukemia [90].
CML treatment and prognosis
Treatment options in the preimatinib era
Historically, busulfan, hydroxyurea, and interferon-a were used to reduce or
eliminate Phþ cells, thus prolonging the CP. However, these therapies were
not curative. HSCT was the only consistently curative intervention and is
most effective with a matched sibling donor done during the CP of CML
[91,92]. Reported survival rates for patients younger than 20 years transplanted
in the CP from matched related donors are 70% to 80%. Unrelated SCTs result
in survival rates of 60% to 65% [93]. HSCT remains the treatment of choice for
children/adolescents who have progressed beyond the CP, have failed to
achieve a complete cytogenetic response (CCyR), or those with the persistence
of the Phþ on standard karyotype analysis at 12 months. Further details
regarding HSCT are provided later.
TKI therapy
The understanding of the molecular mechanisms involved in the pathogenesis
of CML has led to the rational design of molecularly targeted therapy. Imatinib
mesylate is a TKI that has had dramatic success in the treatment of CML,
initially introduced in the phase 1 trial in 1998 [90]. In the phase III randomized
trial of imatinib (International Randomized Study of Interferon vs STI571 trial)
previously untreated patients with CML-CP were randomized to imatinib or
interferon-a plus cytarabine. The 6-year follow-up of this study reported
a cumulative best CCyR of 82% [94]. The 3-year EFS was 83%, with an OS
of 88% and the estimated rate of freedom from progression to AP/BC was
93%. The level of cytogenetic response (CyR) at 6 months remains a prognostic
factor, those with a CCyR at 6 months had an EFS of 91% versus 85% with
a partial cytogenetic response versus 58% in those with minor or minimal CyR.
More recently, second- and third-generation and more potent TKIs have
been introduced for the treatment of CML. Dasatinib, a second-generation
TKI, is 325 times as potent as imatinib in inhibiting unmutated BCR-ABL
kinase in vitro [95]. A randomized trial of dasatinib versus imatinib showed
that the CCyR rate at 12 months was higher with dasatinib than with imatinib
(83% vs 72% [96]). In addition, patients who received dasatinib had a higher
major molecular response rate at 12 months and this was achieved faster.
The side-effect profile between the two drugs was similar. Nilotinib, another
second-generation TKI, has also been compared with imatinib in randomized
trials. Nilotinib also has a superior CCyR and molecular response compared
with imatinib at 1 year, with more equivalent results to dasatinib [97]. All of
these trials have been done in adults. As of early 2012, nilotinib is in only being
tested in phase I trials in children.
Imatinib and dasatinib are currently the first-line therapy for newly diag-
nosed children with CML. However, the question remains unanswered as to
whether TKI therapy is curative in children. No long-term trial results are
available. As children have been on TKI therapy longer, significant longitu-
dinal growth retardation has been reported as well as hyperparathyroidism
and a decline in bone resorption markers [98–100]. Careful monitoring of
the linear growth of children with CML on TKI therapy is critical.
HEMATOPOIETIC STEM CELL TRANSPLANTATION

Overview
HSCT, often referred to as BMT, involves the IV infusion of stem cells to rees-
tablish normal blood cell production following high doses of chemotherapy or
radiation therapy that destroy normal BM function. Transplants can be autolo-
gous (infusion of the patient’s own hematopoietic stem cells) or allogeneic (infu-
sion of another individual’s stem cells). Different stem cell sources also are
available for transplantation. These sources include BM, peripheral blood, and
umbilical cord blood. Registries of BM and umbilical cord blood from unrelated
individuals catalog more than 12 million potential donors worldwide for patients
who lack suitably matched allogeneic family member donors.
HSCT is now considered standard therapy for a variety of cancers (leukemias,
solid tumors), severe nonmalignant blood disorders (aplastic anemia, sickle cell
disease, thalassemia), and certain life-threatening genetic diseases (storage
diseases, severe immunodeficiencies). In general, HSCT is recommended for
the treatment of pediatric leukemias in only the initial treatment of HR situations
or after conventional treatment fails. For example, in some cases of newly diag-
nosed ALL and AML, the cure rate expected with conventional chemotherapy
approaches can be predicted to be poor based on biologic features of the
leukemic blasts or inadequate response to initial treatment. In circumstances
when a poor response to conventional chemotherapy is anticipated, transplanta-
tion in the first remission, before relapse occurs, may lead to better overall
outcomes. When acute leukemia relapses during or after the initial conventional
chemotherapy regimens, HSCT is frequently the treatment of choice to best
attain long-term remission. In juvenile myelomonocytic leukemia (JMML) and
myelodysplastic syndromes (MDS), a rare childhood malignancy and an
uncommon preleukemic disorder, respectively, HSCT is used as the primary
therapy because no other curative treatment exists. The commonly accepted
indications for HSCT in pediatric leukemias are summarized in Table 1.
Details of HSCT therapy

Rationale for HSCT
HSCT can be helpful in treating more resistant forms of leukemia because
higher-dose chemotherapy, often in combination with total body irradiation
(TBI), may overcome cancer cell resistance and achieve additional tumor cell
kill that is not possible with standard-dose treatments. This strategy is only
feasible when marrow toxicity from high-dose chemotherapy and TBI can
Table 1
Common indications for allogeneic HSCT in childhood leukemias
Disorder Disease state Comments
ALL CR1: hypodiploid karyotype
CR1: following primary induction failure
CR1: infant ALL (HR subgroup) <3 mo old at dx; WBC>300 k/mm3,
MLL+
CR1: increased MRD after induction?
CR2: T-cell ALL Relapse in marrow or any other site; any
timing
CR2: Ph+ ALL Relapse in marrow or any other site; any
Timing
CR2: precursor B-cell ALL Marrow relapse while on or within 1 y
of completing primary therapy
CR2: precursor B-cell ALL Extramedullary (CNS, testis, eye)
relapse within 18 mo of initial
diagnosis
AML CR1: unfavorable risk disease variants Karyotype ¼ monosomy 7, monosomy
5, del(5q), complex FLT3/ITD (high
allelic ratio)
CR2
Early relapse, limited disease 5%–25% marrow blasts
CML Accelerated phase
BC Ideally, reinduced into second CP
CP1: absence of CCR to TKI therapy
CP1: TKI intolerance
JMML
MDS Early HSCT Monosomy 7, del(7q), complex
karyotype (3 abnormalities)
t-MDS
MDS from IBMFS
Abbreviations: CCR, complete cytogenetic response; dk, diagnosis; IBMFS, inherited BM failure syndrome;
t-MDS, therapy-associated MDS.
be circumvented by hematopoietic rescue. In allogeneic BMT, the additional

benefit of graft versus leukemia (GVL) effect may occur [101]. In GVL, donor
lymphocytes attack the malignant cells of the recipient, producing additional
tumor cell kill. Although chemotherapy agents and radiation are typically
most damaging to actively dividing cancer cell populations, GVL has the poten-
tial to recognize and eliminate resting cancer cells over time, thus complement-
ing the other treatment modalities.
Donor options and selection
One of the critical issues in allogeneic HSCT is finding a closely matched family
member (most often a sibling) or unrelated donor. Donor/recipient matching is
determined by testing for each individual’s human leukocyte antigen (HLA)
profile, coded for by genes of the major histocompatibility complex located on
the short arm of chromosome 6. The HLA-A, B, C, DR, and DQ antigens are
typically considered in assessing donor/recipient matching. A full sibling has
a 25% chance of being a suitable HLA-matched donor, whereas a parent has only
a 3% to 5% chance. Thus, most children that require an allogeneic HSCT will not
have an available matched family member to serve as their donor. Because of
this, there has been great interest in developing other potential donor sources,
including matched unrelated adult volunteer donors, banked unrelated umbilical
cord blood units, and partially matched family members that can be used for
HSCT. Currently, most Caucasian patients will have a suitably matched related
or unrelated donor stem cell source. However, the chances of finding a suitable
unrelated donor are smaller for some racial and ethnic minority groups [102].
Immune suppression and graft versus host disease
Before allogeneic transplantation, sufficient recipient immune suppression must
be achieved to prevent graft rejection by surviving host lymphoid elements and
to allow the recipient to recover normal donor-derived blood counts and
immune function posttransplant. Immune suppression after allografting also
serves to decrease the risk and severity of graft versus host disease (GVHD),
an immune attack against normal recipient tissues by donor lymphoid elements.
Autologous transplantation
Sometimes, the patients’ own cells can be collected and used as the stem cell source
for transplantation. The primary obstacle in these autologous transplants is the
ability to collect sufficient hematopoietic progenitor cells that are not contaminated
by leukemia cells. Although malignant cells can be purged from autologous stem
cells by treating the cell graft with chemotherapy or antibodies, trials comparing
allogeneic and autologous HSCT in pediatric acute leukemia have generally
demonstrated superior outcomes with allografting [67,103]. These studies and
others demonstrating higher leukemia relapse rates with syngeneic identical
twin donors and successful remission induction by infusion of allogeneic donor
lymphocytes support both the existence and potency of GVL in HSCT [101,104].
Components of transplant care

Preparative therapy and stem cell rescue
The preparative phase is designed to produce both host immune suppression and
antileukemia effect. Preparative regimens use 1 or more chemotherapy drugs,
typically in high myeloablative doses and often in combination with total body
irradiation. Stem cell rescue is then accomplished by the IV infusion of BM,
peripheral blood stem cells, or umbilical cord blood. Supportive care in the initial
months after the transplant includes transfusions of red blood cells and platelets,
infection prevention and treatment, and therapy to prevent GVHD. Successful
engraftment typically occurs about 10 to 28 days following the transplant. Periph-
eral blood SCT patients usually recover neutrophil counts earlier than patients
receiving BM or cord blood transplants. Platelet recovery generally occurs 6 or
more weeks after HSCT. Hematopoietic growth factors, such as granulocyte
colony-stimulating factor or granulocyte-macrophage colony-stimulating factor,
may be used to speed neutrophil recovery but also seem to carry an added risk
for GVH in allogeneic HSCT recipients [105].
Prevention and treatment of infectious complications

The posttransplant period can be complicated by bacterial, viral, and fungal
infections. Certain infections are typically seen at different time intervals
after the transplant. The posttransplant period can be divided into an early
phase (0–1 month), an intermediate phase (1–6 months), and a late phase
(6–12 months) with respect to infectious risks. During the early phase, when
the patients’ white count is extremely low and chemotherapy and radiation
may have disrupted the mouth and gastrointestinal tract lining, bacteria from
the patients’ own respiratory and digestive tracts are common causes of inva-
sive infection. Antibacterial and antifungal prophylaxis can decrease the risk
for posttransplant bacterial and fungal infections. In addition, because many
fungi are transmitted as airborne spores, patients with BMTs are usually hospi-
talized in a special unit with high-efficiency particulate arresting air filtration
and positive pressure ventilation until neutrophil recovery, wear high-
filtration masks when outdoors, and need to live in clean outpatient environ-
ments during the initial months after the transplant [106].
In the intermediate post-BMT phase (1–6 months after transplant), patients
continue to have reduced lymphocyte numbers and function. This milieu
creates heightened susceptibility to and more severe and prolonged course of
viral infections, which reactivate endogenously (herpes simplex virus [HSV],
cytomegalovirus [CMV], varicella zoster virus [VZV], Epstein-Barr virus,
human herpesvirus 6) or are acquired through community exposures (adeno-
virus, respiratory syncytial virus, parainfluenza) [107,108]. The preventive
administration of acyclovir or ganciclovir helps reduce CMV and other herpes
virus infections (shingles/VZV, cold sores/HSV) in the posttransplant period.
The avoidance of crowds and ill contacts reduces the risk of exposure to respi-
ratory or gastroenteritis viruses. Other infections, such as Pneumocystis jirove-
ci (formerly carinii) pneumonia, are also a risk in this intermediate phase.
Patients receive trimethoprim-sulfamethoxazole or pentamidine for the preven-
tion of pneumocystis infection.
The late phase, 6 to 12 months posttransplant, may be associated with infec-
tions from encapsulated bacteria, such as pneumococcus caused by reduced
function of the spleen. Reactivation of VZV causing shingles is also common.
Patients on prolonged immunosuppressive treatment of chronic GVHD have
a particularly increased and prolonged risk of all forms of infection.
Prevention and treatment of GVHD

Approximately 20% to 70% of patients with allogeneic BMT experience some
degree of acute GVHD. Factors influencing GVHD risk include the degree of
HLA match, stem cell source, patient age, and donor sex. Acute GVHD typically
occurs within the first 100 days after the transplant. Manifestations include
erythematous rash, secretory diarrhea, and cholestatic jaundice. Biopsies of
affected tissues show areas of apoptosis or programmed cell death. Chronic
GVHD occurs after day 100 and may also involve multiple organ systems.
Skin rash, sometimes with sclerodermalike changes, weight loss, dry eyes, mouth
sores, lung disease, and abnormal liver function are common manifestations.
Biopsies of tissues affected by chronic GVH often show sclerotic changes. Treat-
ment of GVHD consists of the further use of immunosuppressive drugs [109].
Long-term follow-up
Allogeneic HSCT for pediatric hematologic malignancies typically result in
stable EFS curves by approximately 2 years posttransplant. Thereafter, post-
HSCT care shifts attention to the potential late side effects of pretransplant
leukemia chemotherapies and subsequent transplant therapies. Prominent
among the side effects occurring in this patient population are ocular cataracts;
pulmonary dysfunction; cardiomyopathy; iron overload; renal damage; ortho-
pedic issues, such as osteoporosis and avascular necrosis of articular cartilage;
neuropsychological deficits and school problems; endocrinopathies, such as
growth hormone deficiency, hypothyroidism, and metabolic syndrome; and
second malignancies. Investigating and eliminating these so-called costs of
cure remains one of the central challenges in pediatric oncology and transplant
care. Many pediatric oncology and transplant programs have special multidis-
ciplinary clinics designed to monitor patients and study the late effects of
therapy. In addition to assessing the scope and frequency of late effects and
their relationship to specific chemotherapy and radiation exposures, newer
efforts are exploring possible genetic predispositions to certain organ toxicities
and potential interventions to slow the evolution of sequelae, such as anthracy-
cline cardiomyopathy, renal injury, and osteoporosis [110].
The role of HSCT in ALL treatment

As reviewed previously, current chemotherapy approaches cure in 80% to 85%
of children with ALL. HSCT is used either to treat patients with ALL in first
remission that have an HR of treatment failure with conventional chemo-
therapy treatment alone or to treat patients in second or later remission
following relapse. Based on earlier trials, autologous HSCT seems to have little
or no role in ALL therapy and all current approaches to HSCT in pediatric
ALL focus on allogeneic transplant [103].
HSCT indications for ALL in first remission
With current improvements in chemotherapy approaches, there are only a few
subgroups of patients with ALL for whom HSCT in the first remission is the
preferred treatment approach. The 2 generally accepted subgroups are patients
with hypodiploidy with a modal chromosome number less than 44 in the
leukemia cells and those patients with conventional induction failure, defined
as more than 25% BM blasts at the end of the first month of therapy [50].
New data suggest that this latter group is more heterogeneous that assumed
previously and that HSCT may not be needed for all patients with induction
failure [111]. Until recently, HSCT was considered the preferred treatment
during first remission for children with Phþ ALL, but, as discussed earlier,
the introduction of TKI therapy has changed the approach to this patient
subset. Another group in whom HSCT is often used are infants less than
1 year of age, particularly the 70% to 75% of cases with MLL rearrangements.
Although not without some controversy, younger infants less than 3 months of
age at diagnosis with MLL rearrangements and initial white counts of greater
than 300,000/mm3 have the poorest outcomes with chemotherapy approaches
and seem to benefit from allogeneic HSCT. The role of HSCT in other subsets
of infants with MLL-rearranged ALL in the first remission is less clear [39,41].
HSCT indications for ALL following relapse

Once relapse occurs, only a minority of patients with ALL will be long-term
survivors [46]. The major factors that are predictive of long-term survival
following relapse are time to relapse, shorter being worse, and immunopheno-
type, T-cell ALL having worse outcomes than precursor B-cell ALL. Based on
this, HSCT following achievement of a second remission is the preferred ther-
apy for patients with an early first BM relapse that occurs less than 36 months
from the initial diagnosis and for those who relapse at any point with Phþ ALL
or T-cell ALL. Likewise, patients who suffer a second or subsequent relapse of
their ALL in either the marrow or an extramedullary site (CNS, testes, among
others) after a second attempt at chemotherapy treatment are considered HR
and seem best managed by allogeneic HSCT.
A summary of current indications for transplant in childhood ALL is pre-
sented in Table 1. Additional measures that may define higher-risk subsets
of patients with ALL who might be best managed by HSCT are currently
under study. The parameters being assessed include elevated levels of MRD
at early treatment time points, patterns of gene expression, and newly identified
sentinel genetic lesions.
Transplant factors and outcome after HSCT for ALL

Various approaches to allogeneic transplant in ALL have been analyzed with
respect to their impact on long-term survival. In this regard, myeloablative
approaches to allogeneic HSCT seem superior to approaches in which the
intensity of transplant preparative therapy is reduced (ie, nonmyeloablative
or reduced intensity conditioning). In addition, the inclusion of TBI in myeloa-
blative HSCT preparative therapy produces superior outcomes to what is
achieved with myeloablation by chemotherapy alone [112]. TBI doses typically
total 1200 to 1400 cGy and are fractionated over 3 to 4 days to reduce acute
and chronic toxicities to normal tissues. TBI is generally coupled with 1 or 2
chemotherapy agents administered in high doses, such as cyclophosphamide,
melphalan, cytarabine, etoposide, fludarabine, or thiotepa. Related and unre-
lated donor sources, including marrow, peripheral blood stem cells, and cord
blood, have all been evaluated as to their impact on survival outcomes for
HSCT in ALL. Although the relapse risk seems to be higher with matched
related-donor HSCT and complications are higher with unrelated donor sour-
ces, the net impact of donor type on overall survival seems to be minimal.
Achieving acceptable rates of long-term survival with allogeneic HSCT in
relapsed ALL requires successful induction of second or subsequent remission
by conventional chemotherapy before embarking on transplantation. Effective

care coordination between the treating oncology and transplant teams is essen-
tial to optimizing patient outcomes in these circumstances. Reported survival
for ALL transplanted in CR1, CR2, CR3, or greater and active relapse is
approximately 55% to 65%, 45% to 55%, 20% to 25% and 3% to 10%, respec-
tively [113] (Center for International Blood and Marrow Transplant Research
[CIBMTR] summary slides 2011, http://www.cibmtr.org). More limited data
also indicate an incremental influence of detectable pre-HSCT MRD using
flow cytometric or molecular genetic methods on post-HSCT relapse risk,
even for patients whose pre-HSCT marrows are in morphologic remission.
When patient comorbidities, such as infection or pulmonary or cardiac
dysfunction, are present, reduced intensity preparative therapy can be used
with some potential for success albeit with lower EFS than in more-fit patients
approached with TBI-based myeloablative conditioning. These less-aggressive
approaches trade reduced rates of treatment-related mortality for higher relapse
rates [114].
New approaches presently under investigation in randomized prospective
clinical trials to control post-HSCT relapse risk include use of cord blood
from 2 donors instead of 1 and the addition of the mammalian target of rapa-
mycin pathway inhibitor, sirolimus, to post-HSCT care as a measure to inhibit
malignant lymphoid proliferation [115,116].
The role of HSCT in AML treatment

HSCT plays a much more prominent role in the treatment of pediatric AML
than it does in ALL. As discussed previously, children with newly diagnosed
AML are separated into 3 different risk groups with varying prognoses for
successful treatment by conventional chemotherapy alone. As reviewed previ-
ously, these risk groupings are primarily based on cytogenetic and molecular
genetic features of the patients’ AML cells. The risk categories, in turn, trans-
late into differing HSCT recommendations. In the first remission, children
with SR AML are not considered candidates for HSCT, those with
intermediate-risk AML are candidates for matched sibling but not unrelated
donor HSCT, and those with HR AML are candidates for HSCT using either
a related or unrelated donor. Children with AML that relapse following
chemotherapy treatment alone are rarely cured if retreated with chemotherapy
alone, even using different agents than initially used. Hence, essentially all
patients with relapsed AML should move on to allogeneic HSCT if they
can re-achieve control on their leukemia with reinduction chemotherapy,
have a suitably matched related or unrelated donor, and are in adequate
medical condition [117].
Reported 5-year post-HSCT survival for pediatric AML in CR1, CR2, and
CR3 or later remission are approximately 70%, 55%, and 30%, respectively.
Unlike ALL, AML in relapse, particularly cases with limited disease burden
(eg, 5%–25% marrow blasts), can sometimes be cured with allogeneic HSCT
[118] (CIBMTR summary slides 2011, http://www.cibmtr.org).
The role of HSCT in CML treatment

In the preimatinib era, HSCT was considered the treatment of choice for chil-
dren with CML. However, nearly all adults with newly diagnosed CP CML
are now managed with long-term TKI therapy, and allogeneic HSCT is now
largely reserved for those who present in AP or BC or who have a poor
response to or relapse while receiving TKI therapy. Children with CML are
generally treated with the same approach as adults. Thus, patients are started
on TKI therapy and continue this treatment indefinitely unless patients present
with more advanced phase disease, demonstrate resistance or progression on
therapy, or show intolerable medication toxicity. That said, there is less
consensus about this approach than there is concerning the treatment of adults
with CML because current recommendations are for indefinite and potentially
lifelong treatment with TKIs. The long-term consequences of this approach are
not known at this time, and some pediatric hematologists think that HSCT
following 6 to 12 months of TKI therapy is the preferred treatment of pediatric
CML, particularly if a matched sibling donor is available.
When transplant is chosen for pediatric CML management, the best-
established approach uses myeloablative doses of busulfan and cyclophospha-
mide in the preparative regimen. The European Group for Blood and Marrow
Tranplantation reported outcomes in 314 children who received allogeneic
HSCT in the preimatinib era. In this cohort, the best results were achieved
among children in CP who received a matched sibling donor transplant
(75% 3-year OS, 63% EFS). Among patients who received an unrelated donor
HSCT, procedural mortality reached 35% versus 20% with an MSD. Severe
GVHD (grades 2–3) occurred in 52% of unrelated donor HSCT recipients
compared with 37% of recipients with a matched sibling donor [119]. Using
more contemporary approaches, such as IV versus oral busulfan and dosing
guided by pharmacokinetic monitoring, the Seattle program has reported
78% EFS in a cohort of younger adults transplanted in first CP with matched
sibling donors [120]. Survival decreases considerably for patients transplanted
in the accelerated phase (AC), BC, or second CP (disease controlled following
progression to AC or BC). Reported 5-year survival for these CML categories
in largely adult populations are approximately 45%, 20%, and 45%, respec-
tively [119] (CIBMTR summary slides 2011, http://www.cibmtr.org).
The role of HSCT in treatment of JMML and MDS

JMML and MDS are rare disorders in children. Hence, randomized trials
directly comparing available treatment strategies have not been undertaken.
Nonetheless, registry surveys retrospectively assessing transplant and other
treatment outcomes have been done. In addition, several single-arm prospec-
tive treatment trials for JMML and MDS have been reported.
JMML historically has been fatal in more than 90% of patients despite the
use of chemotherapy. Allogeneic HSCT is the only intervention thus far shown
to provide long-term disease control. In a European study of 100 patients with
JMML using an aggressive preparative chemotherapy regimen with busulfan,
cyclophosphamide, and melphalan, survival of 64% was reported at 5 years

following allogeneic HSCT. Among patients who had disease recurrence, 7
of 15 who underwent a second allogeneic HSCT survived free of disease
[121]. Analyses of preparative therapy efficacy have suggested that busulfan-
based myeloablative regimens achieve higher survival outcomes compared
with TBI-based conditioning because of the superior leukemia control.
Childhood MDS is an entity distinct from that seem in adults. MDS is clini-
cally important because the cytopenias associated with the disorder may prove
life threatening and because MDS often progresses to acute leukemia. Childhood
MDS may arise as a de novo BM disorder, secondary to toxic marrow insults
from chemotherapy or radiation (therapy-associated MDS), or as a consequence
of an inherited BM failure syndrome (IBMFS), such as Fanconi anemia, dysker-
atosis congenita, Shwachman-Diamond syndrome, or amegakaryocytic throm-
bocytopenia. Recently, a unique MDS classification scheme has been
developed for pediatric patients. Clinically, these patients tend to present with
symptoms of pancytopenia, such as anemia, infection, or bleeding. Compared
with adults, whereby anemia is the predominant cytopenia at presentation, in
children, neutropenia and thrombocytopenia are the most common findings,
leading to the coining of the diagnostic category refractory cytopenia of child-
hood. The differential diagnosis of MDS in children includes hypoplastic presen-
tations of ALL, IBMFS, and idiopathic severe aplastic anemia. These distinctions
are critical because management approaches may differ considerably [122,123].
In MDS, marrow morphology most commonly shows overall hypoplasia and
dyspoietic changes with altered maturation of affected hematopoietic lineages.
Cytogenetic abnormalities are common and help to establish the diagnosis and
prognosis of MDS. Complete or partial deletions of chromosome 7 are the
most common findings and typically herald a more rapid evolution to severe
pancytopenia or acute leukemia. Likewise, complex karyotypes, whereby 3 or
more cytogenetic abnormalities are found, are markers for more aggressive forms
of childhood MDS. Other karyotypic variants of childhood MDS (normal karyo-
type, trisomy 8) may follow more indolent courses and are sometimes ap-
proached with a watch-and-wait strategy or even immunosuppressive therapy
as used in severe aplastic anemia. MDS arising secondary to prior cancer treat-
ment or related to an IBMFS have more challenging courses and merit prompt
consideration of aggressive treatment by allogeneic HSCT.
For patients with childhood MDS with severe transfusion-dependent cytope-
nias, severe neutropenia with risk for overwhelming infection, and those with
monosomy 7, partial deletion of chromosome 7, or complex karyotypic abnor-
malities, early allogeneic HSCT is recommended. Recent reports suggest that
most patients with de novo MDS treated in this fashion can be long-term
MDS-free survivors [124]. Patients with IBMFS who develop MDS are also
best approached with allogeneic HSCT; however, their underlying genetic
defects typically impart greater sensitivity of all tissues to the cytotoxic effects
of chemotherapy and radiation, necessitating modified approaches to pre-
HSCT preparative therapy.
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Pediatric Overuse Injuries in Sports

Quynh B. Hoang, MDa,*, Mohammed Mortazavi, MDb
a
Sports Medicine Program, Department of Orthopedics, Children’s Hospital Colorado, University
of Colorado Denver Health Sciences Center, 13123 East 16th Avenue, B060, Aurora, CO 80045,
USA; bChildren’s Hospital Colorado, University of Colorado Denver Health Sciences Center,
13123 East 16th Avenue, B060, Aurora, CO 80045, USA
Keywords
Overuse injuries Apophysitis Sports Pediatric
Key Points
Overuse injuries in youth sports are increasingly common as more children and
adolescents participate in some form of athletics.
Overuse injuries are chronic injuries that occur when repetitive stress is placed on
bone, muscle or tendon without adequate time for healing and recovery.
Familiarity and basic knowledge of common sports-related overuse injuries is
important so that proper diagnosis can be made. This allows timely treatment to
minimize time loss from participation and ensures a safe return to sports.
Although management of overuse injuries are centered around relative rest and
activity modifications, identifying youths at risk of these injuries is key so that
education, prevention, and early diagnosis and treatment can occur.
INTRODUCTION
As more children participate in recreational or organized athletics, pediatricians
are evaluating more sports-related injuries in their practice. Each year an esti-
mated 30 million children in the United States participate in some form of orga-
nized athletics [1] and this number likely will continue to grow. Moreover,
many children today are playing on multiple teams during a given season or
are playing different sports throughout the year. Some children have no
such thing as an ‘‘off season.’’ Consequently, an increase in the incidence of
acute injuries and in chronic injuries related to overuse has been seen.
When repetitive stress is placed on bone, muscle, or tendon without adequate
time for healing and recovery, microtrauma occur in these structures, resulting in
an overuse injury. Physiologically, growing cartilage in pediatric bone is vulner-
able to stress. These cartilaginous growth plates and apophyses lend to unique
injury patterns that are specific to children. During times of rapid growth,
*Corresponding author. E-mail address: Quynh.Hoang@childrenscolorado.org

360 HOANG & MORTAZAVI
apophysitis is a common overuse injury. An apophysis is a secondary ossification

center that gives contour to bone and is also the site of attachment of the muscle
tendon. In a growing child, the muscles attached to these apophyses are overly
tight, and when overworked, repetitive traction forces are placed on these vulner-
able growth centers. The result is chronic irritation, inflammation, and microa-
vulsions at the bone-cartilage junction. Common locations of apophysitis
include the heel (Sever disease), elbow (little league elbow), and knee (Osgood-
Schlatter disease). Overuse injuries to the physis and epiphysis are also common
in children, particularly in the overhead athlete or the gymnast. Examples include
little league shoulder and gymnast’s wrist. Repetitive stress and microtrauma can
also lead to overuse tendon injury (tendinitis), which is another major subset of
overuse injuries in children. Some of the more common tendinitis in children
that are discussed in this article include patellar tendinitis and iliotibial band tendi-
nitis (IT syndrome), although foot and ankle tendinitis and shoulder (rotator cuff)
tendinitis can also occur in young athletes. Finally, stress fractures are another
example of an overuse injury. Repetitive compressive or tensile forces weaken
the bone through a continuum of bone marrow edema without a visible fracture
line (stress reaction) and can lead to a complete fracture (stress fracture). Once
a rare phenomenon, stress fractures are being reported at a much higher inci-
dence today with the advent of organized youth sports [2,3]. Although this article
reviews only spondylolysis (stress fracture of the pars interarticularis of the verte-
bral body), predominant sites of stress fractures in young athletes also include the
tibia, fibula, femur, metatarsals, and navicular bone in the foot [2,3]. Regardless,
they all have a common denominator with a multifactorial phenomenon: training
errors, biomechanics, diet, and, in girls, menstrual function.
As primary care providers, familiarity and basic knowledge of some
common sports-related overuse injuries become important as increasingly
more children participate in sports. That way, proper diagnosis can be made
and timely treatment or referral to a sports medicine specialist can commence
to minimize the time lost from participation.
UPPER EXTREMITY INJURIES

Little league shoulder (proximal humerus epiphysitis)
Little league shoulder refers to an overuse injury of the proximal humerus in over-
head athletes with open growth plates. It is believed to result from repetitive
microtrauma to the proximal humeral epiphysis and physis from constant trac-
tion and rotational torque stresses during throwing and overhead activities
[4,5]. Although most commonly seen in male baseball players, little league
shoulder (or proximal humeral epiphysitis) can affect all overhead athletes,
including tennis players, swimmers, volleyball players and even gymnasts
[6,7]. It commonly occurs between 11 and 16 years of age [4,8], when the prox-
imal humeral physis growth is at its peak, leaving it vulnerable to stress injury.
In baseball players, risk factors that contribute to the development of little
league shoulder include improper pitching mechanics and frequent pitching
without rest periods [4].
PEDIATRIC OVERUSE INJURIES IN SPORTS 361
The typical patient presents with progressive pain over the lateral aspect of
the proximal humerus that occurs with throwing and overhead activities [4,8].
Physical examination shows tenderness over the proximal and lateral aspect of
the humerus in approximately 70% of the patients [8]. Thus, a normal exami-
nation does not preclude the diagnosis, and a classic history of pain with
throwing or overhead activity is key.
Radiographs should be ordered to confirm the diagnosis and also help rule
out other causes of shoulder pain. Findings on radiographs include widening,
sclerosis, and irregularity of the humeral physis, which can best be appreciated
on anteroposterior view of the shoulder in external rotation (Fig. 1).
Obtaining comparison views of the unaffected shoulder is often helpful to
confirm the diagnosis if radiograph findings are subtle. If radiograph findings
are negative and clinical suspicion remains high, further imaging with either
MRI or bone scan may be considered.
Treatment of little league shoulder includes rest from throwing and over-
head activities until pain is significantly decreased. On average this takes
approximately 3 months before symptoms resolve and the athlete is able to re-
turn to play. Evidence of radiographic healing typically lags behind the clinical
course, and therefore normal radiographs are not necessarily required to allow
an athlete to return to activities. During this period of relative rest, physical
therapy should also be initiated for strengthening exercises, and if the athlete
is a baseball player, evaluation of throwing mechanics and progression through
an interval throwing program when the patient is pain-free is also crucial. The
most important factor in the management of little league shoulder, however, is
education and prevention. One should ensure adherence to youth baseball
pitching guidelines set forth by the USA Baseball Medical & Safety Advisory
Committee and the American Academy of Pediatrics (AAP) as they pertain
to pitch count, pitch types, and adequate rest period.
Fig. 1. Radiograph of right shoulder proximal humerus epiphysitis. Notice the widened and
sclerotic proximal humerus physis compared with normal left shoulder.
Multidirectional shoulder instability

Shoulder instability in the young athlete can be caused by an acute traumatic
injury (shoulder dislocation) or can be atraumatic secondary to underlying
capsular laxity. Multidirectional instability (MDI) is a well-known cause of
chronic shoulder pain and is generally a bilateral, atraumatic condition
affecting shoulder function. MDI refers to laxity within the glenohumeral joint
in all planes of motion, leading to hypermobility and decreased stability. It is
caused by generalized capsular laxity and insufficiency of the labrum, liga-
ments, and muscles that stabilize the shoulder joint [9–11].
The presenting symptoms of multidirectional instability often have an insid-
ious onset and are usually associated with increases in duration, frequency, or
intensity of overhead activities, such as swimming, baseball, racquet sports, and
volleyball [9,12]. Athletes complain of activity-related generalized shoulder
pain, usually worse in the dominant arm. Symptoms typically wax and wane
with changes in activity level and overhead motions. Patients usually have
no history of frank shoulder dislocation, but recurrent shoulder subluxations
may be noted even with activities of daily living [9,11–13]. MDI may also
present with pain from related conditions, such as shoulder impingement or
labral tears.
Examination findings for MDI should be expected in both shoulders. With
adequate relaxation, shoulder laxity in multiple planes can be evaluated. The
humerus can be passively translated anteriorly and posteriorly, and the classic
feature of MDI is demonstration of the sulcus sign. For the sulcus sign, the
arm is pulled inferiorly and the presence of a dimple below the acromion
signifies the presence of inferior instability. According to early studies by
Neer and Foster [14], the combination of posterior and inferior laxity is classic
for MDI [9,15,16]. For symptomatic anterior instability, the apprehension test
can be applied. With the patient’s arm in the abducted and externally rotated
position, passive stressing of the shoulder into further external rotation will
cause a sensation of the shoulder wanting to dislocate (Fig. 2). This reaction
results in patient guarding and apprehension and is considered a positive test.
The apprehension test can then be followed by the relocation test, which also
tests for symptomatic anterior instability. For this test, the arm is again ab-
ducted and externally rotated, but this time with the patient lying supine.
While in this position, the arm and humeral head is then pulled forward
toward the examiner. This movement will cause pain and apprehension,
which can then be relieved by applying posterior force to the shoulder to
stabilize it (Fig. 3). If this improves the pain and apprehension, it is considered
a positive test.
Workup with imaging is usually not indicated for MDI without associated
injury, because MDI is a clinical diagnosis [9,12,15]. Radiographs of the
shoulder are usually normal, although inferior and superior translation can
be noted and misinterpreted for frank dislocation without knowledge of the
patient history. If concern exists about rotator cuff or labral disease, MRI
with arthrogram of the shoulder can help identify these lesions.
Fig. 2. Apprehension test.
Treatment of MDI without known associated labral or rotator cuff disease is

usually conservative, with relative rest from offending activities and physical
therapy. After an initial period of rest and antiinflammatories to improve
pain, physical therapy should begin with strengthening exercises for the
dynamic rotator cuff and scapular stabilizer muscles [9,15,17]. An endurance
Fig. 3. Relocation test.

program should also be added to strengthening exercises to prevent fatigue-

induced injury on return to activities. When the athlete has regained pain-
free full strength and range of motion, gradual return to play through
increasing sport-specific activities can be initiated.
Medial epicondyle apophysitis (little league elbow)

Little league elbow is intended to refer specifically to medial epicondyle apo-
physitis. It is a traction injury to the medial epicondylar physis and can be
best understood by considering how throwing forces are applied to the medial
elbow. Important anatomic considerations of the medial elbow include the
medial epicondyle, medial epicondyle apophysis, and ulnar collateral ligament.
Injury to this area is caused by repetitive valgus stress to the medial elbow seen
in overhead sports [18,19]. Force mechanisms include both compression to the
lateral elbow involving the radiocapitellar joint and traction to the medial
elbow created by repetitive dynamic valgus stress involved in throwing
motions [19,20].
The incidence of medial epicondyle apophysitis is increasing as the numbers
and intensity of organized youth sport have increased [21–23]. This condition
most commonly presents between 9 and 12 years of age before closure of the
medial epicondyle apophysis [18,21,24]. Once the medial epicondylar physis
closes, valgus forces are transmitted to other medial elbow structures, and
injuries such as flexor-pronator tendonitis or ulnar collateral ligament sprains
occur instead. Medial epicondyle apophysitis is most common in baseball
pitchers, but is also seen in infielders, catchers, outfielders, and athletes partici-
pating in other overhead activities, such as football quarterbacks and tennis
players [21–23].
Typically, patients have no history of acute injury. Athletes will complain of
insidious onset of medial elbow pain with throwing, but in severe cases pain
may also occur with nonthrowing activities. Often athletes report a history
of weaker or less-accurate throws. Inquiring about what position they play,
the number of teams and seasons per year, throwing history (including pitch
count, number of practices and games), and any recent changes in throwing
techniques becomes important. Physical examination will reveal tenderness
localized over the medial epicondyle, and pain can be reproduced with valgus
stressing. Having the patient flex the wrist or pronate the forearm against resis-
tance can also elicit pain. Range of motion may also be limited and strength
decreased because of pain.
Workup generally involves imaging that starts with plain radiographs of the
elbow. Radiographs are useful for ruling out other abnormalities such as frac-
tures, osteochondral defects, loose bodies, growth plate irregularities, tumors,
and infections. In medial epicondyle apophysitis, radiographs are typically
normal, but widening of the apophysis and even an avulsion are not
uncommon. A comparison view of the opposite elbow may be helpful when
clinical suspicion is high, because radiographs show a large degree of variation
in normal growth centers. MRI is rarely necessary to confirm the diagnosis.
Treatment of medial epicondyle apophysitis consists of complete throwing

restriction and symptom control with ice and antiinflammatories. Based on
severity and duration of symptoms, the timeline for recovery will be different
for every individual. An initial period of immobilization with a brace or cast
may be necessary for the most severe cases in patients experiencing persistent
pain at rest. Most will benefit greatly from initiating physical therapy early, and
this is highly recommended [18,20,21]. The initial treatment phase involves
initiation of range-of-motion exercises and joint mobilizations as necessary to
prevent joint contractures. General conditioning is encouraged and core
strengthening is usually started right away [18,21]. When tolerated, gradual
strengthening is then used. Physical therapy should also address the athlete’s
throwing mechanics to decrease load forces on the elbow. When athletes are
pain-free with full range of motion and near full strength, an interval throwing
program should be initiated, which will gradually progress them through stages
of increased throwing velocity and repetitions [18,21,22,24]. One critical
component of rehabilitation is that return to play is gradual, because potential
complications include worsening symptoms, abnormal bone development, or
an avulsion injury.
AS with little league shoulder, education and prevention are key in the
management of little league elbow. Proper throwing mechanics should be
taught and pitching guidelines should be followed. Current AAP recommenda-
tions along with those of Little League Baseball specify age-specific maximum
pitch counts, required rest days, and recommended pitch types; maximum
pitch counts are 50 to 105 pitches per game depending on age [25]. USA Base-
ball Medical & Safety Advisory Committee recommends no more than 75 to
125 pitches per week depending on age [26].
Gymnast’s wrist (distal radius epiphysitis)

Gymnast’s wrist is a well-known overuse phenomenon that affects 25% to 40%
of all gymnasts, and up to 80% in the most elite groups [27–29]. This injury
involves a stress reaction of the distal radius physis and epiphysis and is caused
by repetitive forces across the wrist joint, particularly with axial loading of the
wrist in hyperextension [30–33]. Other forces experienced at the wrist by
gymnasts, such as rotational and distraction forces, also have been noted to
play a significant role in causing injury to the distal radius epiphysis [30,34].
Gymnasts are often involved in activities requiring weight-bearing with their
wrist in hyperextension, such as the beam, tumbling, vault, and floor routines.
These activities create direct axial and rotational forces onto the distal radius
physis, which over time results in microtraumatic changes to the epiphysis
and the vulnerable cartilaginous growth plate.
Obtaining a sports-specific history is vital, because gymnasts commonly
present with recent increases in activity level with wrist-loading routines
[28,30,31,35]. A history should be obtained of the athlete’s level, hours per
week, and types of routines causing the most wrist pain. The most common
complaint is wrist pain that begins at the onset of the offending activity,
worsens during the activity, and improves with rest. The physical examination
shows tenderness along the radial physis and pain with wrist hyperextension
and axial loading [29,30,35], as in the table push-off test, which usually repro-
duces the wrist pain (Fig. 4).
Decreased range of motion, especially with extension, and swelling are also
seen in more advanced cases [30,31,35], and the athlete’s grip strength is
usually decreased on the symptomatic side.
Radiographs are obtained to evaluate for radiographic evidence of stress
injury to the distal radial physis. Comparison views of the unaffected wrist
are often very helpful. These radiographic findings include widening, sclerosis,
and calcification of the radial physis consistent with repetitive microtrauma
[27,30,36]. The origin of these changes has been postulated to occur from
blood supply compromise, leading to abnormal endochondral ossification of
the physis [30,34,37]. More-advanced disease may lead to radial physis growth
arrest and a positive ulnar variance (greater relative length of distal ulna with
respect to the distal radius) [30,34,38]. Follow-up radiographs are critical to
document healing or progression of physeal injury [30,34,39].
Gymnast’s wrist can be separated into three different stages [30,34,39]. Stage
one presents with clinical symptoms without any radiographic changes. Stage
two exhibits radiographic changes as noted earlier (Fig. 5). Stage 3 has radio-
graphic findings of a positive ulnar variance. MRI of the wrist is usually unneces-
sary for this diagnosis and is only obtained when other possible abnormality is
suspected [30,39].
The mainstay of treatment of gymnast’s wrist involves rest from wrist-loading
activities. Ice, antiinflammatories, and immobilization in a wrist brace as needed
for pain control can be used. Physical therapy is usually helpful and a graded re-
turn to activity is essential. Physical therapy during the rest and rehabilitation
phase should include focused assessment of limb alignment, laxity, strength-
ening, and proprioception [28,30]. A wrist brace or taping to reduce wrist
Fig. 4. Table push-off test.

Fig. 5. (A) Left wrist with subtle widening of radial physis and sclerosis through radial meta-
physis. (B) Right wrist normal comparison view.
hyperextension on return to gymnastics is often helpful in reducing loads over the

radial physis [30]. Gymnasts with stage one injuries can gradually return to
activity once pain has resolved, which usually takes 3 to 6 weeks. Stage two
injuries may take much longer, sometimes even up to 3 months, to heal, and
require both clinical and radiographic confirmation of resolving injury before
the patient can return to gymnastics [28,30,37]. Stage three injuries usually will
require a period of immobilization with bracing and orthopedic consultation
and close follow-up with serial radiographs to assess for premature closure of
the distal radial physis [28,30,37]. Participation should be abruptly stopped and
the wrist reevaluated on any recurrence of pain.
LOWER EXTREMITY INJURIES

Iselin disease (fifth metatarsal apophysitis)
Iselin disease, first described in 1912 by Dr Iselin, is another chronic overuse
injury seen in young athletes that involves the apophysis of the fifth metatarsal
[40,41]. It results from repetitive traction on the apophysis at the base of the
fifth metatarsal, where the peroneal brevis tendon attaches. The apophysis
typically appears at 8 to 9 years of age and fuses between 12 and 15 years
of age, making ages 8 to 15 years most common for presentation of Iselin
disease [42–44].
Although it occurs with running and jumping activities, Iselin disease is more
commonly associated with cutting sports that create inversion stress on the
ankle, which requires repetitive activation of the peroneal muscles [44–46]. A
history of trauma is usually absent. However, acute inversion injuries have
been reported as both initiating and exacerbating events [43,45,46]. Presenting
symptoms include pain and tenderness at the base of the fifth metatarsal. It is
typically insidious in onset, aggravated with activity, and gradually worsens
over time without rest from activity.
On examination, a prominence of the fifth metatarsal base may be present,
sometimes with soft tissue swelling and mild erythema. Focal tenderness is
found at the base of the fifth metatarsal, and resisted eversion can illicit pain
in this area. Full dorsiflexion and plantar-flexion with inversion also may
produce discomfort in the same location. In some patients with longstanding
Iselin disease, gait may be altered, with patients attempting to weight-bear on
the medial side of the foot to avoid lateral foot pain. Like other apophyseal
overuse injuries, Iselin disease is a clinical diagnosis. Radiographs can be ob-
tained to confirm the presence of an apophysis at the base of the fifth metatarsal
and to rule out other boney abnormalities. The oblique view of the foot usually
produces the best view of a small shell-shaped fleck of bone oblique to the fifth
metatarsal shaft (Fig. 6) [43–45]. The apophysis may appear widened, frag-
mented, and thickened.
Treatment of Iselin disease is centered around activity modification, icing,
antiinflammatories, and peroneal stretching and strengthening. For more symp-
tomatic or recalcitrant cases, physical therapy should focus on ankle flexibility,
particularly of the evertors and plantar-flexors; ankle strengthening; and
proprioceptive exercises [41,43,45,47]. These exercises can improve dynamic
ankle stabilization, which can minimize repetitive traction forces on the fifth
metatarsal apophysis from ankle instability. With mild to moderate cases,
symptoms typically improve with conservative treatment and one can antici-
pate return to play in 3 to 6 weeks. More severe cases may require an
Fig. 6. Fifth metatarsal apophysis.

immobilization period with a walking boot or cast followed by physical therapy

for 2 to 4 weeks before return to play [43–46]. In almost all cases, this condition
resolves by the time of closure of the apophysis, typically by 15 years of age.
Rarely, a nonunion of the apophysis causing symptoms into late adolescence
can occur with Iselin disease, which may warrant orthopedic consultation to
discuss surgical excision or fixation if conservative treatment fails [41,45,46].
Sever disease (calcaneal apophysitis)
Calcaneal apophysitis, or Sever disease, is the most common cause of heel pain
in young athletes and accounts for 8% of all pediatric overuse injuries [42,43].
Sever disease is a chronic traction injury that occurs at the calcaneal apophysis
with repetitive tension forces applied by the calf muscles through the Achilles
tendon. Radiographically, the calcaneal apophysis appears at 8 to 9 years of age
and typically fuses between 12 and 15 years of age (Fig. 7) [48,49].
Calcaneal apophysitis is most commonly seen in athletes participating in
sports requiring running, jumping, and plantar-flexion activation. Common
sports include soccer, basketball, track, gymnastics, and dance [42,45,48,49].
Athletes present with pain in one or both heels, although bilateral involve-
ment is typical. The most common age group affected is 10 to 12 years of
age, with the condition being two to three times more common and occurring
1 to 2 years later in boys because of later skeletal maturity [42,45,49]. Pain is
activity-related and reported to be along the heel or at the posterior aspect of
the heel where the Achilles tendon inserts onto the apophysis. Patients will
often limp or walk on toes to prevent painful walking. Examination reveals
tenderness along the calcaneal apophysis, either medial or lateral, and can be
elicited through medial and lateral compression of the calcaneus along the
apophysis (Fig. 8).
Fig. 7. Calcaneal apophysis.

Fig. 8. Calcaneal squeeze test.
Tenderness can also be found at the Achilles insertion site on the calcaneus.
Athletes will also often have tight calf muscles and Achilles tendon, with weak-
ness on dorsiflexion because of pain. Radiographs typically appear normal or
may reveal a fragmented hyperdense sclerotic apophysis [43,49]. Radiographs
of the calcaneus are not necessary to confirm the diagnosis if the history and
clinical findings are consistent, but can be obtained to rule out other bony
disease. Studies have found that up to 5% of radiographs in patients with
heel pain reveal pathologic conditions, making radiographic evaluation worth-
while even in light of a clear clinical picture for Sever disease [50].
Treatment consists of relative rest and activity modification, coupled with ice
and antiinflammatories as needed for pain. Rehabilitative exercises focused on
calf and Achilles stretching and eccentric strengthening of the Achilles can help
decrease traction forces applied to the apophysis. Although high-level evidence
supporting the use of orthotics is still lacking, heel cups, lifts, and pads have
been reported to reduce traction forces and axial loads on the calcaneal apoph-
ysis, helping to decrease symptoms [42,49,51]. When pain and flexibility
improve, the athlete may gradually return to sports as symptoms permit,
because it is a self-limited process that will resolve when the calcaneal apoph-
ysis closes [43,48,49]. More severe symptoms of persistent pain and limping
may benefit from a short period of immobilization with a walking boot or
casting before gradual return to sports [43,45,49]. With early diagnosis and
appropriate treatment, immobilization is rarely required and only reported in
1% to 3% of patients [48]. In fewer than 1% of cases, neglected Sever disease
can progress to calcaneal avulsion injury [52].
Osgood-Schlatter disease (tibial tubercle apophysitis)

Osgood-Schlatter disease is a tibial tubercle apophysitis that commonly causes
anterior knee pain in children and adolescents. It results from repetitive traction
of the patella tendon on the tibial tubercle apophysis, leading to microtrauma,
inflammation, and pain. It frequently presents between the ages of 10 and 15

years in children who participate in jumping and running sports, such as
basketball, volleyball, gymnastics, and soccer [53,54]. Approximately 30% of
patients have bilateral knee involvement [55,56].
The typical clinical presentation is aching pain and swelling over the tibial
tubercle that is exacerbated by jumping and running activities, and with direct
pressure such as kneeling. On examination, patients experience point tender-
ness, and associated swelling or prominence over the tibial tubercle may be
present. Resisted knee extension, which activates eccentric quadriceps muscle
movement, may also reproduce the pain. Evaluation with radiographs is often
not necessary because it is a clinical diagnosis, but these should be obtained to
rule out other abnormalities, such as fractures or tumors, if the clinical presen-
tation is atypical. Radiograph findings of Osgood-Schlatter disease include
overlying soft tissue swelling and fragmentation or irregularity of the tibial
tubercle ossification center.
Management of Osgood-Schlatter disease is conservative, aimed at symptom
control. Treatment involves relative rest and activity modification, along with
icing and analgesics with nonsteroidal antiinflammatory drugs (NSAIDs). Use
of an infrapatellar strap, which helps to decrease traction forces on the tibial
tubercle, may be used for symptomatic relief during activity. Physical therapy
focusing on quadriceps and hamstring flexibility can also help reduce symptoms.
Osgood-Schlatter disease is typically a self-limited process, with symptoms
resolving spontaneously when the child or adolescent reaches skeletal maturity.
However, some individuals develop persistent symptoms that remain into
adulthood. One retrospective study reported that 60% of patients with child-
hood Osgood-Schlatter disease described pain with kneeling as adults, although
76% of them did not have any pain or limitations with activity [57]. For the few
who experience complications, such as persistent painful ossicles in the distal
patellar tendon and painful kneeling, and those for whom conservative
management fails, surgical treatment to shave the tibial tubercle can be per-
formed in skeletally mature patients [58,59].
Sinding-Larsen-Johansson disease (apophysitis of the inferior pole of the

patella)
Sinding-Larsen-Johansson disease is another common overuse injury that causes
anterior knee pain. It is similar to Osgood-Schlatter disease, except that it is a trac-
tion apophysitis that occurs at the inferior pole of the patella where the proximal
patella tendon attaches. Presentation typically occurs between 9 and 12 years,
which is slightly younger than in Osgood-Schlatter disease. Patients present
with activity-related anterior knee pain localized to the inferior pole of the patella.
Like Osgood-Schlatter disease, symptoms are aggravated by jumping and
running. On examination, the pain can be reproduced with direct palpation of
the inferior pole of the patella. Diagnosis is made clinically, although radiographs
can be helpful to rule out other abnormalities. Radiograph findings may show
fragmentation of the distal pole of the patella.
Like Osgood-Schlatter disease, it is a self-limited process that responds well

to conservative treatment involving relative rest and activity modification. Pain
control with NSAIDS and stretching exercises to improve quadriceps and
hamstring flexibility can also improve symptoms.
Patellar tendinopathy (‘‘jumper’s knee’’)
Repetitive loading of the quadriceps muscle during jumping and running
activities can lead to patellar tendinopathy, an overuse injury resulting in
partial-thickness tears in the deep layers of the patella tendon. Although the
condition is seen commonly in jumping sports, such as basketball, volleyball,
and track and field (high and long jump), athletes in other sports such as soccer
and football are also affected [60,61]. Once thought to be an inflammatory
tendinitis, histopathologic and biochemical studies have now shown that it is
a degenerative tendinosis. The pathogenesis is tendon overload from strain
that is applied to the patella tendon, resulting in tissue microtrauma [62].
Consequently, management of patellar tendinopathy should be aimed at reha-
bilitation rather than antiinflammatory strategies.
Patients present with insidious onset of anterior knee pain that is aggravated
with activity or even with prolonged sitting. Generally, these patients have
a history of recent increase in intensity, frequency, or duration of sport activity
participation. The pain is well localized and examination reveals tenderness
over the patellar tendon. Although primarily a clinical diagnosis, radiographs
may sometimes reveal calcification in the tendon, and they can also be helpful
to rule out other associated conditions such as Osgood-Schlatter or Sinding-
Larsen-Johansson disease. Ultrasound has also become a popular imaging
modality for diagnosis because the patella tendon lies superficial and can be
visualized easily.
Because patellar tendinopathy is an overuse injury from mechanical over-
load, treatment includes relative rest and refraining from the aggravating activ-
ities while still symptomatic. The role of NSAIDs remains controversial,
because patellar tendinopathy is a noninflammatory condition. The literature
contains no conclusive evidence showing that NSAIDs have an effect on the
treatment outcome of patellar tendinopathy [63], although patients with acute
pain may benefit from the analgesic effects. Conservative management through
physical therapy remains the mainstay of treatment. Although scientific
evidence on the efficiency of nonoperative treatment is still lacking, manage-
ment of patellar tendinopathy continues to focus largely on eccentric strength-
ening of the tendon [64]. Improving quadriceps and hamstring flexibility can
also be beneficial in prevention and treatment of patellar tendinopathy [65].
In some patients for whom conservative management fails after 6 months of
therapy, surgical options can be explored.
Patellofemoral pain syndrome
Patellofemoral pain syndrome refers to anterior knee pain originating from the
patellofemoral joint and the surrounding supporting structures. It is the most
common cause of all knee overuse injuries. Other terms that have been used
to refer to this condition include anterior knee pain, runner’s knee, and chondromalacia
patella. The cause of patellofemoral pain is multifactorial and includes biome-
chanical problems, dysfunction of muscles, and overuse. Anatomically, the
patella articulates with the trochlear groove of the femoral condyles in the distal
femur. Proper tracking of the patella in this groove is dependent on multiple
forces such as strength of the quadriceps muscles, supporting soft tissue struc-
tures, patellar stabilizing mechanisms, and biomechanics of the patient. Biome-
chanical problems include lower extremity malalignment, patellar
hypermobility, strength imbalances, and muscle inflexibility. Examples of ma-
lalignment of the lower extremity include femoral anteversion, genu valgum,
excessive lateral insertion of the patellar tendon (increased Q angle), tibial
torsion, and foot hyperpronation from pes planus (flat feet). Increases in activ-
ities and these predisposing factors causes overload stress on the patellofemoral
joint. The result is pain.
Patients complain of a dull aching pain underneath or around the patella that
occurs with activity. Prolonged sitting or going up and down stairs typically also
aggravates the pain. Mild swelling or a sense of crepitation may also be reported.
Symptoms are commonly bilateral, although presentation in one knee is not
unusual. Physical examination requires assessment from hips to feet, because ma-
lalignment problems can contribute to patellofemoral pain. Abnormal tracking of
the patella can be evaluated by extending the patient’s knee while in the seated
position. If abrupt or excessive lateral tracking of the patella occurs as the knee
extends, this is considered positive J tracking. On palpation, tenderness may be
present under the patellar facets. Compressing down on the patient’s patella while
displacing it inferiorly can also elicit pain as the patient is asked to contract the
quadriceps; this is a positive patellar grind test (Fig. 9).
Functional deficiencies such as core and pelvic weakness, quadriceps and
hamstring tightness, and IT band tightness should also be assessed. Radio-
graphs are not necessary for diagnosing patellofemoral pain, but they can
Fig. 9. Patellar grind test.

help confirm abnormalities in patellar alignment (ie, patella alta, femoral

trochlea hypoplasia, lateral patella tilt) or rule out other bony abnormalities.
Like many overuse injuries, relative rest and modifying activities based on
subjective pain is part of the treatment. Because the origin of patellofemoral
pain is multifactorial, management should also address the various predisposing
factors, with correction of biomechanical problems being the primary focus.
Physical therapy for core and hip strengthening has thus become a mainstay of
treatment for this condition. Part of the rehabilitation also addresses any strength
imbalances, hamstring and quadriceps inflexibility, and IT band tightness. Use of
over-the-counter or customized orthotics may be necessary to correct hyperpro-
nation from pes planus. Patellar stabilizing braces can also be helpful to minimize
patellar hypermobility and lateral tracking. For patients who do not respond to
conservative management, consultation with an orthopedic surgeon for consider-
ation of a lateral release or patellar realignment surgery is reasonable, although no
evidence shows that surgical intervention is effective.
HIP INJURIES
Pelvic apophysitis
Pediatric overuse injuries commonly involve the pelvis during times of rapid
growth when bone growth exceeds muscle ability to stretch sufficiently, leading
to increased inflexibility and traction forces on the pelvic apophyses. Knowl-
edge of the bony anatomy, muscular attachments, and its actions are key for
understanding and diagnosing pelvic apophysitis.
The pelvis has multiple apophyses that may be involved in overuse injuries
depending on the type of activity and age, because these secondary ossification
centers appear and close at different ages (Table 1).
Table 1
Pelvic apophyses- muscle attachments and ages at time of their ossification
Originating Age of Age of
Apophysis muscle Inserting muscle appearance (y) closure (y)
Greater trochanter None Gluteus maximus 9–10 14–16
and medius,
external hip
rotators
Lesser trochanter None Iliopsoas 9–10 14–16
Anterior superior Sartorius None 12–14 14–16
iliac spine
Anterior inferior Rectus femoris None 12–14 14–16
iliac spine
Iliac crest Tensor fascia latae Internal and 13–15 16–18
external
obliques,
transversus
abdominis
Ischial tuberosity Biceps femoris, hip None 15–17 21–25
extensors
The muscles originating or attaching at each apophysis create traction forces

with activity as the muscle-tendon group repetitively pulls against the
apophysis, producing microavulsion, inflammation, and cellular breakdown
[66–68]. Eventually the cartilaginous apophysis weakens and leads to widening
of the apophysis, putting the athlete at high risk for an acute avulsion injury
[49,69–71]. The most commonly injured apophyses of the pelvis include the
ischial tuberosity, anterior inferior iliac spine (AIIS), and anterior superior iliac
spine (ASIS), followed less commonly by the lesser trochanter, iliac crest, and
rarely the greater trochanter [67,69]. The actions of the muscles involved at the
injured apophysis are often repetitive motions common to specific types of
sports. For example, sprinters will often experience ischial tuberosity apophy-
sitis from recurrent ballistic hamstring use during explosive sprints, and figure
skaters will experience iliac apophysitis from explosive jumping and twisting
that engages their oblique muscles. Pelvic apophysitis occurs commonly in
a variety of sports, including soccer, running, gymnastics, skating, football,
and dance, but may occur in any sport [49,66,67].
Athletes present with well-localized activity-related pain at the site of the
involved apophysis. In contrast to acute avulsion injuries, the athlete’s pain
is insidious in nature and is usually described as aching or throbbing. Without
appropriate rest, the pain will progress and athletes may develop limp with
activities and pain with walking or standing. With continued activity despite
worsening pain, athletes are at risk for avulsion fracture at the apophysis,
and may describe a sudden painful event in which a pop is felt followed by
intense pain and disability of the involved muscle [42,49,68,70,71].
Physical examination will reveal significant localized pain directly over the
involved apophysis on palpation. Some local swelling may be present, but
erythema, bruising, and deformity are usually not appreciated unless an avul-
sion fracture has occurred. The pain is worsened by resisted activation or
passive stretching of the involved muscle group. Muscle tightness is often
appreciated bilaterally, and range of motion is usually decreased on the affected
side. With more advanced apophysitis, mild contractures may be noted.
Workup involves radiographs of the pelvis and hip to visualize the apophysis
of concern. However, radiographs typically appear normal, making this a clinical
diagnosis. In moderate to severe cases, radiographs may show an apophysis with
widening and sclerosis. Radiographs should be obtained in the presence of
concerns for constitutional symptoms, tumors, infection, or persistent symptoms
not responding to therapy. Avulsion fractures should be ruled out with radio-
graphs if the history is concerning for such. On MRI, edema of the apophysis
can be appreciated in its early stages before widening and sclerosis [69–71].
However, MRI is unnecessary for the diagnosis and should only be obtained
when other concerns exist, such as infections, tumors, or stress fractures.
The mainstay of treatment for pelvic apophysitis is rest and activity modifica-
tion to prevent further injury from the insulting activity. Ice and ibuprofen can be
used for pain as needed. Weight-bearing is allowed as tolerated. However, pro-
tected weight-bearing on crutches may be necessary initially if the athlete has
pain with walking and standing. If needed, physical therapy can usually be initi-
ated by 1 to 2 weeks, with a focus on flexibility and range of motion, and progress-
ing to core and pelvic strengthening and lower extremity strengthening. When
symptom-free, it is important to engage the athlete in a graded return to sports-
specific activities before full participation. In general, most can expect to return
to full participation at 4 to 6 weeks [49,68].
IT band syndrome (IT band tendinitis)

IT band syndrome is a very common cause of lateral hip pain and lateral knee
pain, and is found especially in runners. Anatomically, the IT band is a large
connective tissue structure that runs from the iliac crest down to the lateral
tibia. With hip flexion and extension, the IT band glides anteriorly over the
greater trochanter in the femur and then glides back posterior to the trochanter,
respectively. The friction that is created by the IT band sliding back and forth
results in pain. A trochanteric bursa allows for smooth gliding of the IT band
through reducing friction, but when this bursa becomes inflamed, an associated
trochanteric bursitis can also develop, resulting in painful movement. Running
downhill causes the worst pain because symptoms typically occur when the hip
is flexed at 30 . This reduced foot strike angle on downhill running is a risk
factor for developing IT band syndrome, because track athletes who run on
level surfaces, and thus have greater foot strike angle, have been found to
have a lower incidence of this condition.
Clinically, patients present with achy pain over the lateral upper thigh and
knee with running. On examination, they may have tenderness over the
greater trochanter if a bursitis has developed, or they may have tenderness
in the knee over the lateral femoral condyle. Symptomatic patients generally
have findings of a tight IT band on examination, as indicated by a positive
Ober test. For this test, the patient is in a side-lying position, with the affected
side up. The examiner then extends the symptomatic hip while supporting the
leg. With IT band inflexibility, the knee and leg will remain suspended off the
table once the examiner no longer supports the leg up (Fig. 10).
Physical examination also will often reveal biomechanical abnormalities.
Varus alignment of the lower extremity (bowlegged), overpronation from
high arches, or lateral tilt of the pelvis can all place strain on the IT band, pre-
disposing individuals to this condition [72].
Treatment aims at reducing stress on the IT band, both through physical
therapy and correction of any biomechanical problems. In addition to stretch-
ing the IT band and hamstrings to decrease friction, physical therapy should
also strengthen gluteal and hip abductors to minimize pelvic tilt. Ice and
NSAIDs for symptomatic control can be helpful. More importantly, addressing
training errors, such as excessive downhill running or rapid increases in
activity, can help prevent recurrences. For those who fail conservative manage-
ment, consultation with a surgeon for surgical release of the IT band is an
option. Most athletes are generally able to gradually return to sport activities
within 2 to 6 weeks once they are asymptomatic [73].
Fig. 10. Ober test.
BACK INJURIES
Spondylolysis
Spondylolysis is a stress fracture of the pars interarticularis, the bony connec-
tion between the inferior and superior articulating facets of the vertebral
complex. Estimates show that spondylolysis may contribute to nearly 50% of
cases of back pain in young athletes, and physicians should always maintain
a high index of suspicion for this diagnosis [53]. The cause of the defect in
the pars interarticularis is stress to the posterior elements of the spine from
repetitive flexion and hyperextension motion, combined with truncal rotation.
Gymnastics, football (lineman), weight lifting, dance, and volleyball are
common sports requiring repetitive hyperextension that may lead to spondylol-
ysis [3,53]. The stress fracture occurs most commonly at the L5 vertebral level,
followed by the L4 level [74–76], and can be unilateral or bilateral. If the stress
fracture at the pars interarticularis occurs bilaterally, then spondylolisthesis can
develop, which is a forward slippage of one vertebral body on the vertebral
body below it. Diagnosis and grading of spondylolisthesis can be made on
lateral radiographs based on percentage of anterior displacement.
Patients with spondylolysis typically present with insidious onset of activity-
related low back pain that worsens with spine hyperextension. The
prototypical patient falls into one of three categories: (1) the female athlete
with a hyperlordotic spine with increased motion and flexibility, (2) the male
athlete with poor flexibility, particularly of the paraspinal musculature, and
who has recently undergone a growth spurt, and (3) the deconditioned athlete
with poor core and pelvic strength who recently started a new sport. On phys-
ical examination tenderness to palpation may be present at the affected verte-
bral level. Findings may also show increased lordosis of the lumbar spine,
poor hamstring flexibility, and weak core and pelvic strength. The pain is
reproducible when the patient extends the back or with single-leg hyperexten-
sion during the Stork test (Fig. 11).
Fig. 11. Stork test.
Diagnostic workup should begin with plain radiographs, including antero-

posterior and lateral views of the lumbar spine. Obtaining oblique views to
look for the ‘‘Scotty dog’’ sign in the pediatric patient remains debatable
because of the increase in radiation exposure and uncertainty regarding
whether it improves diagnostic accuracy. In general, plain radiographs have
been shown to have poor sensitivity in demonstrating pars defects [77] but
can helpful to assess for other gross bony abnormalities.
Further imaging with single-photon emission CT (SPECT) scan, CT scan,
and/or MRI is generally necessary to confirm the diagnosis. Which imaging
modality is most sensitive and specific for detecting a pars stress fracture
remains controversial. Each has its own advantages and disadvantages. The
SPECT scan has increased sensitivity of up to 68% over radiographs [78,79]
and can be helpful in distinguishing symptomatic pars stress fractures from
asymptomatic lesions based on whether increased uptake is seen on the scan.
However, it has poor specificity and cannot rule out other pathologies that
also demonstrate increased uptake, such as infections or tumors. CT, on the
other hand, provides excellent visualization of bony anatomy and can identify
the exact location of the stress fracture. It can also be used on follow-up to
assess bony healing. The downfall is the amount of radiation exposure.
More recently, use of MRI for diagnosing spondylolysis has become more
popular because of the lack of radiation exposure in pediatric patients and
the ability to detect bone marrow edema (stress reaction) and soft tissues.
With improvements in magnetic field and strength and fat saturation tech-
niques, high-resolution MRI images have increased diagnostic accuracy.
However, the efficacy is still being studied [80–83].
No gold standard for management of spondylolysis currently exists. Its

clinical outcome has little correlation with radiographic evidence of healing
status [84]. That is, patients with healed stress fractures or with bony
nonunions can be asymptomatic. Thus, treatment consists primarily of a period
of high-impact and extension-based activity restrictions to alleviate pain and
allow for bony healing and/or progression to fibrous nonunion. No universal
guideline exists for the duration of activity restriction, although most authors
would agree that a period of relative rest of approximately 3 months is reason-
able. During this time physical therapy is started once pain is improved, with
rehabilitation emphasizing core and back stabilization and hamstring flexibility.
The use of bracing in the treatment of spondylolysis remains controversial;
some still advocate for bracing until the patient is asymptomatic, which may
take up to 9 to 12 months [53,85]. Outcome studies show similar results
with return to sports and bony healing regardless of whether bracing was
used. Given the lack of evidence supporting therapeutic bracing, many will
reserve bracing for severe cases in which pain is experienced at rest and with
daily activities. Most patients with symptomatic spondylolysis respond well
to nonoperative management. Once symptom-free, the athlete may gradually
return to sport activities without restrictions. For recalcitrant cases for which
conservative measures fail after 9 to 12 months, surgical options may be consid-
ered, with posterolateral fusion having a success rate of close to 90% [84].
SUMMARY
Overuse injuries in the pediatric and adolescent population are a growing
problem in the United States as more children participate in recreational and
organized sports. It is not uncommon for children and adolescents to play
on multiple teams simultaneously or to be involved in sports year-round.
Without adequate rest, the demands of exercise can exceed the body’s ability
to repair tissues, leading to repetitive microtrauma and overuse injury. Unlike
in adults, the consequences of overuse injury in the pediatric and adolescent
athlete are far more serious because the growing bones are vulnerable to stress.
The ability to identify individuals who are at risk of overuse injuries is key so
that education, prevention, and early diagnosis and treatment can occur.
Preventive measures of modifying training factors (ie, magnitude, intensity,
and frequency of sports participation) and correcting improper biomechanics
(alignment, laxity, inflexibility, and muscle imbalance) should always be part
of the management plan.
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INDEX
A Attention deficit hyperactivity disorder,
management of, 39–40
Acetaminophen, concerns regarding,
30, 31–32 Autism, in Down syndrome, 146–147
Adamantanes, in influenza, 83–84 Aztreonam, 33
Addison disease, glucose monitoring in, 314 B
Adrenal hyperplasia, congenital,
Back injuries, 377–379
21-hydroxylase deficiency, 269–272
treatment guidelines for, Bed sharing, and cultural and socioeconomic
275–279 considerations, 200
17a-hydroxylase/17, 20-lyase Best Pharmaceuticals for Children Act, 28–29
deficiency, 273
11ß-hydroxylase deficiency, 273 Biopterin metabolism, disorders of, 213
3ß-hydroxysteroid dehydrogenase Biotinidase deficiency, 215–216
deficiency, 273–274
genetic testing/counseling in, 279 C
growth and development in,
CACT deficiency, 227
277–278
lipoid, 274 Calcaneal apophysitis, 369–370
maintenance medical treatment of, Calcaneal squeeze test, 370
275–277 Cancer, children with, immunization for,
NC 21-hydroxylase deficiency, 104–107
treatment of, 277
newborn screening for, 27 Carbohydrate disorders, 210–211
P450 oxioreductase deficiency, Cardiology, pediatric, 41
274 Cardiovascular disease, in type 1 diabetes,
pregnancy and fertility in, 279 316
prenatal treatment of, 275
psychosexual health and, 278 Celiac disease, glucose monitoring in, 314
surgical intervention in, 278 Channelopathies, sudden infant death
transition adult care in, 279 syndrome and, 192–193
treatment outcomes in, 269–281 Chondromalacia patella, 372–374
types of, 271
Citrin deficiency, 218
Amino acid disorders, 212–218
Citrullinemia, 217–218
Analgesic-antipyretics, 29–30
Cobalamin A/B/C/D1, 220–221
Antipsychotic medications, 40
Comparative effectiveness research, 27
Antiretroviral medications, currently
Corticosteroids, children on, immunization
available, 18
for, 118
Antiviral medications, in influenza, 85, 86
Cough and cold preparations, 30–31
Apgar, Virginia, 1–7
CPT-I deficiency, 227
Apprehension test, 362, 363
CPT-II deficiency, 227
Argininosuccinate lyase deficiency, 218
CTD deficiency, 228
Asthma, treatment of, 31–33
Cystic fibrosis, treatment of, 33
Note: Page numbers of article titles are in boldface type.

doi:10.1016/S0065-3101(12)00027-8 ª 2012 Elsevier Inc. All rights reserved.
386 INDEX
D Drug shortages, yearly since 2004, 28

Dermatology, pediatric, 38 DTaP, for children with rheumatologic
diseases, 121
Diabetes mellitus, in Down syndrome,
for hematopoietic stem cell transplant
152–153
type 1, care of children with, 303–327 recipients, 108
cause/pathophysiology of, for pediatric travelers, 125
305–306 DTaP, Hib, and IPV vaccines, 97
closed-loop system in, 319–320
diagnosis of, 306–307 E
incidence and prevalence of,
304–305 Electronic health records, case studies of,
management of, 306–314 implementation of new, and barriers to
outpatient insulin in, complications use of, 167–168
of, 314–319 in asthmatic child, 164
management of, 311–313 in sexually active teenage girl, 165
prevention of, 320–321 in teenage boy with seizure
stages in development of, 305 disorder, 166–167
transplantation in, 321–322 clinical content of, development of,
treatment of, 38–39 170–177
developmental screening and, 176
Diabetic ketoacidosis, 307–311 documenting of information, 175
complications of, 310–311 history of, 161–162
definition of, 307–308 pediatric norms for, 176
management of, 308–309 pediatric update of, content barriers to,
pathophysiology of, 308 159–181
potassium deficits of, 309 referral tracking in, 176–177
Diabetic neuropathy, 318–319 required fields for, 169–170
sample for asthma care plan, 174
Diabetic retinopathy, 318 sensitive health information and, 177
Distal radius epiphysitis, 365–367 social history (education) in, 172–173
Down syndrome, acute myeloid leukemia in, status of, for use in pediatric practice,
143, 340 162–163
anesthesia in, 149, 150 structured data for, 168–169
autism in, 146–147 transition from paper records, 160
behavior problems in, 145–146 units of measurement used in, 175–176
cardiovascular problems in, 141 unstructured data for, 169
clinical assessment of, in childhood, use by pediatricians, 160
139–140
Endocrinology, pediatric, 38–39
in newborn period, 138–139
cognitive impairment in, 143–144 Epilepsy, pediatric, treatment of, 39
communication of diagnosis of, 139 Ethylmalonic encephalopathy, 224
dental problems in, 154
diabetes mellitus in, 152–153 F
early intervention in, 144
endocrine disorders in, 152 Fabry disease, 230–231
epidemiology, genetics, and prenatal Fatty acid oxidation, disorders of, 225–229
diagnosis of, 137–138
gastrointestinal problems in, 149–152 Fifth metatarsal apophysitis, 367–369
hematologic and oncologic problems in,
143 G
immune deficits in, 147–148
medical update for children with, GA-II/multiple acyl-CoA dehydrogenase
137–157 deficiency, 229
musculoskeletal conditions in, 153–154 Galactosemia, 210–211
otolaryngologic problems in, 141–142 Gastrointestinal reflux disease, treatment of,
pulmonary dysfunction in, 148–149 36
seizures in, 144–145
Gene polymorphisms, sudden infant death
Drug allergy, in use of antibiotics, 33–34 syndrome and, 191
INDEX 387
Glucose monitoring, continuous, in diabetes Hypothyroidism, continuous glucose

type 1, 313–314 monitoring in, 314
Glutaric aciduria type I, 223
I
Gymnast’s wrist, 365–367
stages of, 366, 367 Immune deficiencies, primary, immunization
treatment of, 366–367 in, 99–100
Immunization, for children on corticosteroids,
H 118
Head lice, management of, 38 for children with cancer, 104–107
for children with hyposplenia/asplenia,
Hematopoietic stem cell transplant recipients, 118–119
immunization for, 107–110 for children with rheumatologic
Hematopoietic stem cell transplantation, in diseases, 120–122
pediatric leukemias, 343–351 for hematopoietic stem cell transplant
Hepatitis A vaccine, for pediatric travelers, recipients, 107–110
124 for HIV-infected children, 110–118
for solid organ transplant recipients,
Hepatitis B vaccine, 96–97 109–104
for pediatric travelers, 124 in immunocompromised patients, 95–96
in rheumatologic diseases, 121 in pregnancy, 98–99
Herpes simplex virus infections, treatment of, in preterm and low-birth weight infants,
36–37 96–98
in primary immune deficiencies, 99–100
Hib, for pediatric travelers, 125 in special populations, 95–136
Hib vaccine, for children with hyposplenia/ of internationally adopted children,
asplenia, 120 122–123
for hematopoietic stem cell transplant of pediatric travelers, 124–126
recipients, 110
Inborn errors of metabolism, expanded
Hip injuries, 374–376 newborn screening for, 209–245
HIV-1, evolution of, 10, 11 ethical issues in, 231–232
HIV-1 infection, immunopathogenesis of, Infectious diseases, antibiotics in, 34–36
10–15 Influenza, biology of, 76–77
HIV disease, in children and adolescents, Influenza infection, antigenic drift and
management of, 17–19 antigenic shift, 78
HIV-exposed infant, management of, 19–20 chemoprophylaxis of, 89
HIV-infected children, immunization for, clinical manifestations of, 80–81
110–118 complications of, 82–83
persons at risk for, 84
HIV infection, pediatric, 9–26 diagnosis of, 81–82
focus on mother-to-child immunity to, 77
transmission, 16–17 impact and epidemiology of, in children,
immune dysfunction and, 15–16 78–80
prevention efforts in US, 21–23 prophylaxis of, 87–89
HIV-positive mother, neonatal care of infents seasonal and pandemic, 75–93
born to, 20 treatment of, 83–86
HMG-CoA-lyase deficiency, 221 Influenza vaccine(s), 87–89, 98
Holocarboxylase synthetase deficiency, for children with rheumatologic
221–222 diseases, 122
for hematopoietic stem cell transplant
Homocystinuria, 214–215 recipients, 109–110
Hyperphenylalaninemia, 212–213 for pregnant women, 98–99
Hypertension, in type 1 diabetes, 316–317 Influenza virus, life cycle of, 77
Hypoglycemia, in type 1 diabetes, 314–315 structure of, 76–77
Hyposplenia/asplenia, children with, Insulin, outpatient, in diabetes mellitus type 1
immunization for, 118–119 management, 311–313
388 INDEX
International Society for Pediatric and hematopoietic stem cell

Adolescent Diabetes, 307 transplantation in, 350
Internationally adopted children, natural history of, 341
immunization of, 122–123 treatment and prognosis in, 342
tyrosine kinase inhibitors in,
IPV vaccine, for pediatric travelers, 124 342–343
Iselin disease, 367–369 juvenile myelomonocytic, hematopoietic
Isobutyrylglycinuria, 223–224 stem cell transplantation in,
350–351
Isovaleric acidemia, 220 pediatric, hematopoietic stem cell
IT band syndrome, 376 transplantation in, 343–351
IT band tendinitis, 376 details of, 343–345
graft versus host disease in,
J treatment of, 346–347
prevention and treatment of
Japanese encephalitis vaccine, for pediatric infection in, 346
travelers, 126 transplant care in, 345–346
‘‘Jumper’s knee,’’ 372 incidence of, 329–330
understanding and treatment of,
K 329–358
ß-Ketothiolase deficiency, 223 Life-threatening event, apparent, 186–188
Krabbe disease, 230 Little league elbow, 364–365
Little league shoulder, 360–361
L Lower extremity injuries, 367–374
LCHAD and TFP deficiency, 228 Lysosomal storage diseases, 229–231
Leukemia(s), acute lymphoblastic,
chemotherapy in, 330–333 M
and central nervous system
therapy, 332 M/SCHAD deficiency, 228–229
consolidation or Macrovascular complications, in type 1
intensification, 332–333 diabetes, 316–317
induction regimens for, Malonic aciduria, 224
331–332
maintenance, 333 Maple syrup urine disease, 216–217
childhood, prognostic factors and Mass spectrometry, tandem, 209–210
therapeutic factors in, MCAD deficiency, 226
336–338
hematopoietic stem cell Measles, mumps, and rubella vaccine, for
transplantation in, 347–349 hematopoietic stem cell transplant
in adolescents and young adults, recipients, 108–109
treatment of, 335–336 Measles vaccine, for pediatric travelers, 124
in infants, treatment of, 335 Medial epicondyle apophysitis, 364–365
newly diagnosed, treatment of,
333–336 Meningococcal vaccine, for children with
Ph+, treatment of, 334–335 hyposplenia/asplenia, 120
relapsed, treatment of, 336 for children with rheumatologic
T-cell, treatment of, 333–334 diseases, 122
acute myeloid, hematopoietic stem cell for pediatric travelers, 125
transplantation in, 349 Metformin, 39
in Down syndrome, 143, 340
induction and consolidation Methicillin-resistant Staphylococcus aureus, 35–36
therapy in, 338–339 Methionine adenosyltransferase, 215
molecular subtypes of, 340–341 2-Methyl-3OH butyryl-CoA dehydrogenase
risk groups for, consolidation deficiency, 222
therapy in, 339
subgroups of, 339–341 2-Methylbutyrylglycinuria, 222
acute promyelocytic, 339–340 3-Methylcrotonyl-CoA-carboxylase
chronic myeloid, biology of, 341–342 deficiency, 221
INDEX 389
3-Methylglutaconic aciduria, 224 Pneumonia, diagnosis and management of, 35

Methylmalonic acidemia types Poliovirus vaccine, for hematopoietic stem
mut0/mut-, 220 cell transplant recipients, 108
Microvascular complications, in type 1 Pompe disease, 230
diabetes, 317–319 Pramlintide, 39
Myelodysplastic syndromes, hematopoietic Pregnancy, immunization in, 98–99
stem cell transplantation in, 351 medications taken during, fetal and
neonatal effects of, 37–38
N
Propionic acidemia, 219
NA inhibitors, in influenza, 83–84
Proximal humerus epiphysitis, 360–361
Neurology, pediatric, 39
Psychiatric complications, in type 1 diabetes,
Newborn screening, expanded, for inborn 319
errors of metabolism, 209–245
Psychiatry, pediatric, 39–40
ethical issues in, 231–232
R
O
Rabies vaccine, for pediatric travelers, 126
Ober test, 376, 377
Relocation test, 362, 363
Obesity, management of, 39
Retinopathy of prematurity, treatment of, 37
Omalizumab, 33
Rheumatologic diseases, children with,
Organ transplant recipients, immunization
immunization for, 120–122
for, 100–104
Rotavirus infection, 47–74
Organic acid disorders, 218–224
adjunctive therapy in, 53
Ornithine transcarbamylase deficiency, 217 changing seasonality of, after vaccine
Osgood-Schlatter disease, 370–371 introduction, 66
Otitis media, antibiotics in, 34 clinical illness due to, 50–52
control and prevention of, 49
Overuse injuries, pediatric, in sports, 359–383 deaths due to, 47
diagnosis and management of, 52
P epidemiology and transmission of,
48–49
Patella, apophysitis of inferior pole of, incidence of, 47–48
371–372 natural protection against, 54–55
Patellar grind test, 373 pathophysiology of, 49–50
surveillance in US, 63–64
Patellar tendinopathy, 372
Rotavirus vaccination, effect on rotavirus
Patellofemoral pain syndrome, 372–374 strain circulation, 66–67
Pediatric Research Equity Act, 28–29 herd immunity after, 65–66
Pelvic apophysitis, 374–376 Rotavirus vaccine program, implementation
Pharmacology, neonatal, 36–38 in US, 62–67
pediatric, in symptomatic care, 29–31 Rotavirus vaccine(s), currently licensed,
pulmonary and allergy, concerns 56–58
regarding, 31–34 development of, 55–56
therapeutics, and toxicology, effectiveness of, 64–65
advances in, 27–45 goals for, 55
Phenylketonuria, 212–213 impact on health burden of rotavirus
disease, 65
Pneumococcal conjugate vaccine, 97–98 live, attentuated human, 58
Pneumococcal vaccine, for children with postlicensure safety-monitoring data
hyposplenia/asplenia, 119 and, 63
for children with rheumatologic reassortant, human-bovine, 56
diseases, 121 human-rhesus, 55–56
for hematopoietic stem cell transplant use in US, recommendations for, 59–62
recipients, 110 worldwide implementation of, 59
390 INDEX
Rotaviruses, structure and classification of, intrinsic risk factors for, 193
53–54 neurotransmitters and, 193–194
Runner’s knee, 372–374 prolonged QT syndrome and, 192–193
sleep positions and, 188–189
S sudden unexpected infant death, and
apparent life-threatening events,
SCAD deficiency, 225–226 183–208
Sever disease, 369–370 Sudden unexpected infant death, 190
Sexual development, disorders of, categories bed-sharing risks, 198
of, 284–288 breastfeeding and bed-sharing risks,
diagnostic evaluation in, 288–289 199–200
ethical issues in, 289–291 death scene investigation in, 194–197,
female, 284–286 198
gender identity and, 284 educating grandparents about, 200
gonadal ambiguities in, 287–288 environmental factors and, 194
incidence of, 283 extrinsic risk factors and, 194
informed consent and pediatric inborn errors of metabolism and,
consent in, 290–291 190–191
initial presentation in, 289–290 recommendations to reduce risk of,
male, 286–287 200–202
surgical and ethical challenges in, unsafe sleep environments and, 198
283–302
treatment of, and patient T
outcomes, 299–300
treatment options in, in Table push-off test, 366
abnormality after bladder Tdap, for pregnant women, 98
exstrophy repair, 293, 294
Teething products, 31
in CAH and inadequate
vagina, 299 Tibial tubercle apophysitis, 370–371
in CAIS, 292 Transient tachypnea of newborn, treatment
in mixed gonadal dysgenesis, of, 36
293, 295, 296–298 Travelers, pediatric, immunization of,
in Müllerian agenesis,
124–126
292–293
in ovotesticular DSD, Typhoid vaccine, for pediatric travelers, 126
298–299 Tyrosinemia type I, 213–214
in vaginal atresia, 295, 296 Tyrosinemia type II, 214
Shoulder instability, multidirectional, Tyrosinemia type III, 214
362–364
Sinding-Larsen-Johansson disease, 371–372 U
Sleep, safe, for infants, recommendations to
Upper extremity injuries, sports-related,
promote, 200–202
360–367
Spondylolysis, 377–379
Urea cycle disorders, 217
Sports, participation in, by children, 359
Urinary tract infections, antibiotics in, 34–35
pediatric overuse injuries in, 359–383
Steroid hormone synthesis, 270 V
Stork test, 377, 378
Vaccine(s), inactivated, for children with
Stress fractures, in pediatric sports, 360 cancer, 105–107
Sudden infant death syndrome, apnea and, for HIV-infected children,
185–186 111–116
changing picture of, 188–190 for solid organ tranplant
channelopathies and, 192–193 recipients, 101
child abuse and, 191–192 in primary immune deficiencies,
definition of, 184 100
epidemiology of, 184–185 live, for children with rheumatologic
gene polymorphisms and, 191 diseases, 122
INDEX 391
for HIV-infected children, evaluation in, 251–252

117–118 genetics of, 248–251
for pregnant women, 99 late effects of, 263–264
for solid organ tranplant metastasis of, surgery in, 262–263
recipients, 101 National Wilms Tumor Study Group
in primary immune deficiencies, and, 247–248, 252–253
100 pathology of, 248
live attenuated, for children with cancer, presentation of, 251
105 recurrent, treatment of, 262
staging of patients with, 252, 253
Varicella vaccine, for pediatric travelers, 125
surgery for, 258–263
VLCAD deficiency, 226 explorative, 259–261
timing of, 258–259
W
Wilms tumor, 247–267
bilateral, intravascular extension of, Y
surgery in, 262
surgery in, 261–262 Yellow fever vaccine, for pediatric travelers,
current protocols in, 254–258 125–126

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ADVANCES IN

PERRY M. BUTTERFIELD, MA, Retired, Senior Research Associate, Department of

SILVANA CARR, MD, Division of Infectious Diseases, Department of Pediatrics,

TINA Q. CHENG, DO, Fellow, Division of Pediatric Endocrinology, Cohen Children’s

ANDREW M. DAVIDOFF, MD, Chairman, Member, Department of Surgery, St. Jude

PENELOPE H. DENNEHY, MD, Division of Pediatric Infectious Diseases, Hasbro

ROGER GILLER, MD, Department of Pediatrics, Children’s Hospital Colorado,

PAIGE HERTWECK, MD, Chief of Gynecology, Director of Pediatric and Adolescent

FRAN HICKEY, MD, Medical Director, Associate Professor, Department of Pediatrics,

QUYNH B. HOANG, MD, Pediatrics Sports Medicine Program; Assistant Professor,

STEPHEN P. HUNGER, MD, Department of Pediatrics, Children’s Hospital Colorado,

MICHAEL S. KAPPY, MD, PhD, FAAP, Department of Pediatrics, Children’s Hospital

CHRISTINA LAM, MD, Division of Medical Genetics, Department of Pediatrics, David

DAVID M. MAAHS, MD, PhD, Department of Pediatrics, Children’s Hospital

SHIDEH MAJIDI, MD, Department of Pediatrics, Children’s Hospital Colorado;

KELLY W. MALONEY, MD, Department of Pediatrics, Children’s Hospital Colorado,

MICHAEL A. MILLER, MD, Assistant Professor of Pediatrics, Pediatric Infectious

AYESHA MIRZA, MD, FAAP, Assistant Professor, Department of Pediatrics, Division

MOHAMMED MORTAZAVI, MD, Pediatric Primary Care Sports Medicine Fellow,

JENNIFER PRUITT, Director, Clinical Information Systems, Children’s Health Fund,

STEVEN J. RALSTON, MD, MPH, Instructor in Obstetrics and Gynecology, Harvard

KAREN L. SUMMAR, MD, MS, Assistant Professor, Department of Pediatrics George

ANGELA SUN, MD, Medical Genetics Institute, Cedars-Sinai Medical Center,

DEREK A. WONG, MD, Division of Medical Genetics, Department of Pediatrics,

CONTENTS VOLUME 59  2012

Foundations of Pediatrics: Virginia Apgar

Pediatric HIV Infection

Advances in Pediatric Pharmacology, Therapeutics,

Rotavirus Infection: An Update on Management

The impact of rotavirus vaccination on the health burden of

Seasonal and Pandemic Influenza: An Overview

Immunization in Special Populations

Live vaccines 101

Medical Update for Children With Down Syndrome

The newborn period 138

Content Barriers to Pediatric Uptake of Electronic

Sudden Infant Death Syndrome, Sudden

A changing picture of SIDS 188

Expanded Newborn Screening for Inborn Errors of

HMG-CoA-lyase deficiency 221

Surgery for Wilms tumor 258

Treatment Outcomes in Congenital Adrenal Hyperplasia

Surgical and Ethical Challenges in Disorders of

Case 1: CAIS 292

Update on Care of Children with Type 1 Diabetes

Recent Advances in the Understanding and

Treatment of AML 338

Pediatric Overuse Injuries in Sports

Michael S. Kappy, MD, PhD

0065-3101/12/$ – see front matter

Virginia Apgar, MD (1909–1974). (Courtesy of Augustus C. Long Health Sciences Library,

E-mail address: perry.butterfield@gmail.com

0065-3101/12/$ – see front matter

In 1962, the American Journal of Diseases of Children requested permission to

Pediatric HIV Infection

PEDIATRIC HIV INFECTION: 30 YEARS AND MOVING

0065-3101/12/$ – see front matter

IMMUNOPATHOGENESIS OF HIV-1 INFECTION

dendritic cells, and macrophages, in addition to CD4þ T cells, all facilitate

IMMUNE DYSFUNCTION AND HIV INFECTION

PEDIATRIC HIV INFECTION WITH A FOCUS

MANAGEMENT OF HIV DISEASE IN CHILDREN AND

Box 1: List of currently available antiretroviral medications

issues, such as societal discrimination and stigma. These are in addition to

CONTENTS VOLUME 59 2012