KRIZIA JOY BORROMEO-GALVE, MD

Bulacan Medical Center, Department of Pediatrics

March 5, 2018
 HUMAN
HERPES EPSTEIN
VARICELLA CMV ROSEOLA HERPES
SIMPLEX BARR VIRUS
VIRUS 8

Herpes
Simplex Epstein Herpes Human
Varicella Virus 1 Virus 6
Barr Virus Cytomegalo Herpes
Zoster
Herpes (type 1 and virus Herpes Virus 8
Virus
Simplex type 2) Virus and 7 (HHV-8)
Virus II

Chicken Oral Mono Roseola Kaposi

Pox Herpes; Infectious
nuceleosis- infantum \ Sarcoma;
(Primary); Mono-
Genital like or 6th Castleman
Shingles nucleosis
Herpes syndrome disease Disease
(Latent)
Varicella
• Varicella Zoster Virus (VZV) is a neurotropic human
ETIOLOGY herpes virus with similarities to Herpes Simplex Virus

• Most children were infected by 15 years old

EPIDEMIOLOGY • Highly contagious

• Airborne respiratory secretions

TRANSMISSION • Direct contact with fluid of skin lesions

INCUBATION PERIOD • 14-21 days

PERIOD OF • 24-48 hours before the rash until the vesicles are
COMMUNICABILITY encrusted (3-7days)
Varicella
 Varicella: Pathogenesis
Inoculation of
Replicate in the
VZV to Subclinical
local lymphoid Spread to RES
respiratory viremia
tissue
mucosa

Mononuclear
cells carry Widespread
Second viremic Second viremic
infectious virus cutaneous
phase phase
generating new lesions
cops of lesions

Widespread Latency (dorsal

Second viremic HERPES
cutaneous root ganglion of
phase ZOSTER
lesions spinal cord)
Varicella: Clinical Manifestations
 Phases
 Prodromal
 Eruptive

 Prodromes- 24-48 hours before rash

 Fever
 Malaise
 Anorexia
 Headache
 Abdominal pain

 Eruptive- lesions in various stages of evolution

 Fever and other systemic symptoms usually resolve
within 2-4 days after onset of rash
Varicella: Diagnosis
 Diagnosis
 Clinical
 Direct fluorescence assay
 PCR
 Tissue culture
 Serology
Varicella: Treatment
 Varicella
 Varicella
○ Acyclovir- NOT routinely recommended

 Herpes zoster
 Adults- acylclovir
 Children with uncomplicated disease –
NO treatment
Varicella: Complications
 Bacterial infections
 Encephalitis and cerebellar ataxia
 Pneumonia
Varicella: Prevention
 Active immunization
 Post-exposure prophylaxis
○ Immunoglobulin ASAP or within 96hours of
exposure to be given at 125units/10kg (max
625units)
○ Indications
 Immunocompromised children
 Pregnant women
 Newborns
 High risk patient in close contact with herpes zoster
PROGRESSIVE
VARICELLA
 Highest in children with cellular
immunodeficiency
 Clinical manifestation
 Visceral involvement, coagulopathy, severe
hemorrhage, Continued development of
lesions
 Severe abdominal pain
 Hyperkeratotic appearance and
continued new lesion formation for
weeks or months in children with untreated,
late stage HIV
PROGRESSIVE
VARICELLA
PROGRESSIVE VARICELLA
NEONATAL VARICELLA
NEONATAL VARICELLA
 Maternal varicella
• Infant has protective antibody to
>5 days Before ameliorate neonatal infecton
• NO treatment except in preterm
Delivery infants <28 weeks of gestation

5 days before to
2 days after • No protective VZV antibody
• Give VZV immunoglobulin
delivery

PERINATAL • Give acyclovir at 10mg/kg q 8 hr

VARICELLA IV
CONGENITAL
VARICELLA SYNDROME
 Pregnant women with varicella
 25% of infants become infected
 Involves the skin, extremities, eyes and
brain
 2% develop VZV embroyopathy
 Period of greatest risk
CONGENITAL
VARICELLA SYNDROME
Site of involvement Stigmata
Sensory nerves Cicatricial skin lesions, hypopigmentation

Optic stalk and lens vesicles Microphthalmia, cataracts, chorioretinitis,

optic atrophy

Brain Microcephaly, hydrocephaly,

calcifications, aplasia of brain

Cervical or lumbosacral cord Hypoplasia of an extremity, motor and

sensory deficits, absent deep tendon
reflexes, anisocoria, horner syndrome,
anal/urinary sphincter dysfunction
Herpes Zoster
 Occurs in older age group
 by 85 years of age 50% of the population should have
experienced the disease
 Clinical manifestations
Herpes Zoster
 Occurs in older age group
 by 85 years of age 50% of the population should have
experienced the disease
 Clinical manifestations

In adults
The vesicular lesions
clustered within one or two
adjacent dermatomes
In children
Localized pain,
hyperesthesias, pruritus and
low grade fever are
infrequent

Burning pain Rash is mild

Complete resolution- 1-2

Postherpetic neuralgia
weeks
Herpes Simplex Infection
Herpes Simplex Infection
• HERPES SIMPLEX VIRUS 1
ETIOLOGY (HSV-1) AND HERPES
SIMPLEX VIRUS 2 (HSV-2)

• Spread is by close contact and

EPIDEMIOLOGY trauma

CLINICAL • Usually involve the skin, eye, oral

MANIFESTATIONS cavity and genital tract
Herpes Simplex Infection
PRIMARY • Individuals who have not been infected
previously with HSV-1 or HSV-2
INFECTION • Infection can be severe

NON • Occurs in individuals previously infected with 1

type of HSV who have become infected for the
PRIMARY first time with the other type of HSV
FIRST • Immunity to one HSV type provides cross-
protection against disease
INFECTION • Tend to be less severe than primary infection

RECURRENT • Virus is maintained at latent stage and is

INFECTION activated
Herpes Simplex Virus Infection
 Perinatal infections
 75% are due to HSV 2
○ Maternal primary infection- 33-50%
○ Recurrent maternal infection- 1-3%
 Manifests in the first month
 9% in the first day
 40% in the first week
 Major manifestations
 Localized skin, eye, mouth- 30-43%
○ If not treated, 70% will progress to CNS or disseminated diseases
 CNS infection- 48-79%
 6% mortality
 Disseminated infection
 31% mortality
CONGENITAL HERPES
CONGENITAL HERPES
 Clinical manifestations
 Congenital infection syndrome
○ Primary genital herpes- 44% risk
○ Recurrent genital herpes- 3% risk
HERPES SIMPLEX
INFECTIONS
 Clinical manifestations
 Congenital infection syndrome
○ Skin- vesicles or scars
○ Eyes- chorioretinitis, microphthalmia
○ Brain- microcephaly, atrophy, intracerebral
calcifications

 Kaposi Varicelliform Erruption;

juliusberg pustulosis vaciniformis
acuta
HSV Infection: Diagnosis
 Any two of the following
○ Clinical pattern
○ Isolation of the virus
○ Specific antibodies
○ Demonstration of characteristics cells,
histologic changes, viral antigen, of HSV DNA
in scrapings, CSF, or biopsy material
HSV Infection: Treatment
 Treatment
 Skin and mucous membranes
○ Oral acyclovir

 Genital herpes
 Oral acyclovir, famciclovir or valacyclovir
 CNS (encephalitis)
 IV acyclovir
HSV Infection: Prevention
 Prevention
 Chemoprophylaxis with acyclovir
 Standard methods of infection control
 Prevent contact with active lesions
Epstein Barr Virus: Infectious
Mononucleosis: EPIDEMIOLOGY
Low
• Infancy and childhood
socioeconomic
strata

Industrialized • Adolescents and young adults

countries

• Oral secretions >6 months after acute

infection then intermittently for life
Viral shedding • Male and female secretions
Epstein Barr Virus: Infectious
Mononucleosis: TRANSMISSION
Adults and adolescents

Penetrative sexual intercourse

“Deep kissing”

Children: Exchange of saliva

Epstein Barr Virus: Infectious
Mononucleosis: TRANSMISSION
Incubation period – 30-50 days

Prodromal period – 1-2 weeks

• Fever
• Headache
• Abdominal pain
• Malaise
• Myalgia
• Severe sore throat
EBV: Infectious Mononucleosis:
MANIFESTATIONS: Physical Exam
EBV: Infectious Mononucleosis:
MANIFESTATIONS: Physical Exam
Generalized lymphadenopathy – 90%

• Anterior and posterior cervical

• Submandibular
• Axillary and inguinal
• Epitrochlear

Splenomegaly – 50%

Hepatomegaly – 10%

Rashes – 3-15%
EBV: Infectious Mononucleosis:
DIAGNOSIS

• Leukocytosis • IgM antibodies • VCA (viral capsid antigen) –

IgM and IgG
(10,000-20,000 • Antibodies that • EA (early antigen);
cell/cm3) agglutinate sheep or • EA-D – diffuse-staining
• 20-40% of horse RBC component
leukocytes are • EA-R – cytoplasmic
• Titers of >1:28 or restricted component
atypical 1:40 are positive • EBNA (nucleic acid antigen)
lymphocytes
• Thrombocytopenia
Heterophile Specific EBV
CBC
antibody test antibody test
EBV: Infectious Mononucleosis
DIAGNOSIS
AB APPEARANCE DURATION SIGNIFICANCE
VCA: IgM At Presentation 1-3 months Best indicator of primary
infection
VCA: IgG Peaks late in the Lifelong Marker for prior or current
acute phase infection
EA-D Peaks 3-4 wks 3-6 months Indicator of acute phase
High titer of IgA anti EA-D is
found in NPC

EA-R Several wks Months to years Indicator of reactivation

Present in high titers in EBV-
associated Burkitt’s
lymphoma
EBNA 3-4 months Lifelong Marker for primary infection
EBV: Infectious Mononucleosis
DIAGNOSIS
EBV: Infectious Mononucleosis:
COMPLICATIONS
 Subcapsular splenic hemorrhage or splenic rupture
 Airway obstruction
 Headache, seizures and ataxia
 Alice in wonderland syndrome (metamorphopsia)
 Meningitis
 Facial nerve palsy
 Transverse myelitis
 Encephalitis
 Guillain-Barre syndrome
 Hemolytic anemia
 Burkitt’s lymphoma
 Nasopharyngeal carcinoma
Cytomegalovirus: Overview
Human Cytomegalovirus
• Ubiquitous in the population
• Once infected, individuals remain persistently
infected FOR LIFE
• Intermittent excretion of Excretion Virus

Congenital CMV
• Remains a well-recognized cause of disease in the
newborn infant following intrauterine infection

CMV in Immunocompromised host

• Most common opportunistic infection in
HIV/AIDS patients prior to the advent of HAART
• Invasive CMV infections in patients under
immunosuppresive drugs
Cytomegalovirus: Overview
Cytomegalovirus
• High levels of viral replication
• End-organ Disease
• Robust inflammatory response

CMV Diseases
• CARDIAC: Associated with Coronary Artery
diseases; Cardiac Allograft Loss
• Transplant vasculopathy
• RENAL: Tubular Sclerosis, Renal Allograft Loss
• GIT: Exacerbations of inflammatory bowel
disease
• CNS: Glioblastoma
Cytomegalovirus: Host Interaction

CMV
•Largest of the Human
herpesvirus
Cytomegalovirus: Host Interaction
CMV
• Largest of the Human herpesvirus

50% Larger than the herpes simplex virus genome and encodes
more than 100 unique virion proteins

Tegument Layer:highly immunogenic; induces strong

adaptive immune responses (CMV-specific CD8 cytotoxic
lymphocytes): with pivotal role in CMV replication
Protein components:
• protective antibody response

Replicate in nearly ALL tissues and cell types

Thought to express IMMUNE EVASION: remain hidden from

protective host immunity over years with stable viral load
Cytomegalovirus: Epidemiology
Community Nosocomial Intrauterine
Exposure: Transmission Infection

• occurs throuhgout • Blood products • Perinatal exposure

life and is linked by containing CMV to infected genital
exposure to CMV • Allograft secretions during
present in SALIVA transplantation: birth
and URINE. Less common • Breastmilk: most
common route of
• Peak in exposure: CMV infection in
CHILDHOOD & early childhood
ADOLESCENTS (60-70% infection
and YOUNG in seropositive
ADULTS women)
(Sexually) • Once infected,
infants can readily
transmit virus to
their parents or
siblings
Cytomegalovirus: Mechanism of Disease
Mechanisms of disease associated with
CMV infections remains undefined for
most clinical syndromes that follow CMV
infections

Overall Lack of Understanding of

Pathogenesis of CMV

• 1. Asymptomatic Nature of infections in almost all

individuals
• 2. Complexity of the underlying disease processes in
the immunocompromised host
• 3. Limitations of observational studies in humans
• 4. Species-Specific Tropism of Human CMV
Cytomegalovirus: Clinical Manifestations

Acute CMV Infections: No specific manifestations or clinical findings

In symptomatic patients: consistent with Mononucleosis-like syndrome

• Fatigue
• Occasionally cervical adenopathy
• Heterophile antibody negative
• Mild elevation of ALT, AST
• Decreased platelet
Congenital Cytomegalovirus

Occurs following
intrauterine Transmission
Congenital CMV
transmission of rate: 0.5 to1.0%
CMV

Transmission Hematogenous
Transferred to
rate to fetus: spread of virus to
developing fetus
30% placenta
Cytomegalovirus: Congenital Infections

CMV can present

with symptomatic
infections in approx
10% of infected
newborns

90% of infected
infants will have no
clinical
manifestations in the
newborn period
Blue berry muffin rash microcephaly
Infants with Symptomatic CMV
11% HEARING LOSS will
Manifestation Laboratory develop in of CMV infected
infants

Chorioretinisitis (<10%) Hyperbilirubinemia

Hearing Loss:common
long term sequelae Elevated ALT, AST Suspect CMV infection in
hearing loss in older infant
Hepatosplenomegaly and young child
Thrombocytopenia
Petechial Rashes
Anemia
Jaundice
Abnormal findings on Approx 50% of infants with
Microcephaly Cranial UTZ hearing loss is associated
with Congenital CMV
will pass an initial exam
IUGR Increased CSF Protein
BUT develop hearing loss in
infancy and early childhood
Cytomegalovirus: Treatment
 Diagnosis requires evidence of primary Infection

 CMV IgG: Serologic activity for CMV in lifelong

following primary infection; therefore the PRESENCE of
Immunoglobulin (IgG) antibody to CMV does not
provide evidence of infection

 CMV IgM: IgM reactivity for CMV can be detected for

prolonged periods after acute infection; cannot be used
reliably to estimate duration of infection

 Polymerase Chain Reaction: viral load

measurements in blood

 Tissue Biopsy: detection of CMV DNA

Cytomegalovirus: Treatment
 Treatment of Congenitally infected
infants: Symptomatic and asymptomatic
but at risk for hearing loss
 Ganciclovir: 6 weeks treatment could limit
hearing loss and possibly improve
developmental outcome in symptomatically
infected infants
 Valganciclovir: Used also for infants with
CMV Infections following breastmilk ingestion
and symptomatic infants : 6months of oral
valganciclovir
End
HHV-8: Kaposi Sarcoma
• HHV-8 is a gamma-human herpesvirus similar to Epstein Barr
ETIOLOGY virus

• HHV-8 infection is Endemic in Africa and parts of South Africa 30-

EPIDEMIOLOGY 60% by adolescence: >20% in Mediterranean; <5% in North
America, Central Europe and Asia

• Varies with risk behavior

PREVALENCE • Rates of 30-75% being found in med having sex with men in North
America and Europe

• Saliva: Major mode of transmission

• Blood Transfusion
TRANSMISSION • Bone marrow transmission
• Solid Organ Transplantation
HHV-8: Pathogenesis

HHV-8 contain
Viral proteins Induce expression of
multiple genes that
interfere with p53 Proangiogenesis
impact cell-cycle
and Rb protein factors, vEGF A
regulation

upregulation of
Serves as host cell Encodes IL-6: bind rapamycin pathway:
autocrine growth and activate cytokine instrumental in the
factor receptors control of cell growth
and metabolism
HHV-8: Kaposi Sarcoma
Symptomatic Primary HHV-8

• Fever
• Maculopapular ash
• Mononucleiosis-like sydrome

Immunocompromised Patients

• Fever
• Rash
• Splenomegaly
• Pancytopenia
• Lymphoid hyperplasia
HHV-8: Kaposi Sarcoma Clinical Forms
Classic Kaposi Sarcoma

• Indolent Disorder
• Seen in Elderly men
• Limited involvement of skin of the lower extremities

Endemic Kaposi Sarcoma

• Aggressive form
• Occuring in children and young people
• Primarily in Africa
• Include visceral involvement
• Widespread cutaneous lesions (patches, plaques or nodules)

Posttransplantation and AIDS-related Kaposi

• Most severe forms

• Disseminated lesions
• Usually involves Gastrointestinal and lungs in addition to skin
HHV-8: Kaposi Sarcoma Clinical Forms
Primary-Effusion Based Lymphoma

• Rare disease caused by HHV-8 that is seen most

commonly in HIV-infected individuals
• Lymphomatous invasion of the serosal surfaces of
pleura, pericardium, peritonuem

Multicentric Castleman Disease

• Unusual lymphoproliferative disorder

• characterized by anemia, thrombocytopenia
• Generalized lymphadenopathy
• Constitutional symptoms
• High degree of viral replication
HHV-8: Kaposi Sarcoma Diagnosis
Serologic Assays

• Immunoflorescence and Enzyme-linked

immunosorbent assay: limited sensitivity and
speciificity

Seroversion

• Loss of antibodies over time, has been described

Immunohistochemistry

• For detection of HHV-8 in tissue samples: Utilized for

dx of Kaposi, PEL and multicentric Castleman disease
HHV-8: Kaposi Sarcoma Treatment

Multicentric

• Include attempts to control malignant proliferation

Traditional Chemotherapuetic Agents

HAART (Highly Active Anti retroviral Treatment)

Thank You
Roseola
Rosoela
infantum
(Rose rash)

Exanthem
subitum
(sudden rash)
Roseola: Epidemiology
Most adults • Excrete HHV-6 and HHV-7 in saliva

Women • excrete HHV-6 and HHV-7 in the genital tracts

• HHV-6: more common infants & younger

HHV6 children
• Peaks at 6-15 months

• More common in older children and adults

HHV-7: • By 2years of age – 45-75% have been infected
• By 7-10 years of age – 90% have been infected
Roseola: Clinical Manifestations
Pre-
Eruptive
Prodrome eruptive
phase
phase
Usually symptomatic Appears within 12-24
High grade fever of 3-5
hours of fever
days
May have mild resolution
respiratory signs

Rhinorrhea Seizures – 5-10% of Macular (measles like)-

children 40%
Pharyngeal
inflammation Infrequent complaints
Mild conjunctival – rhinorrhea, sore Papular (rubella like)-
redness throat, abdominal pain, 55%
vomiting, diarrhea
Cervical or occipital
lymphadenopathy Ulcers at the
uvulopalatoglossal Location: Neck, face,
Mild palpebral edema junction – Nagayama proximal extremities
spots (enanthem)
Roseola: Clinical Manifestations
 Nonspecific febrile illness – 15%
 Febrile seizures – 10-20% (HHV6)
 Mononucleosis-like illness
 Rash without fever
 Hemophagocytic syndrome
 Phagocytes ingest RBC

 *benign, febrile seizure: Most
common from HHV6
Roseola: Clinical Manifestations
Manifestations %
Occipital or cervical LN 30-35
Respiratory signs and symptoms 50-55
Mild diarrhea 55-70
Seizures 5-35
Bulging anterior fontanelle 26-30
Edematous eyelids 0-30
Popular pharyngitis 65
Roseola: Diagnosis
 Diagnosis of Roseola
 Clinical
 Serology
 Viral culture
 PCR
Roseola: Treatment
 Treatment of Roseola
 Symptomatic and supportive
 Severe diseases
 HHV6 – ganciclovir, cidofodir, foscarnet
 HHV7 – cidofodir

 No vaccine available for roseola
Thank you