DCH / IPPC LEARNING OUTCOMES 2015

Allergy and Immunology Dr Melanie Wong

1. To understand the basic mechanisms underlying different types of reactions
to antibiotics and their clinical significance
2. To learn an approach to suspected antibiotic allergy.
3. To understand the basic components of immune defence and manifestations
of different types of immunodeficiency.
4. To learn an approach to screening for suspected immunodeficiency and when
to refer for specialist investigation.

These course materials and the works comprising it are protected by copyright which is owned by or
licensed for use by the Childrens Hospital Westmead (the hospital). Apart from any permitted use
under the Copyright Act 1968 (Australia), local or international laws that may apply, no part of these
materials may be reproduced, or any other use made of them, without the express written permission
of the hospital.

Allergy and Immunology

Dr Melanie Wong
Department of Allergy and Immunology

2015 Diploma in Child Health / International Postgraduate Paediatric Certificate

1)
2)

Antibiotic Allergy
Is it Immune Deficiency?

2015 Diploma in Child Health/International Postgraduate Paediatric Certificate

Antibiotic Allergy

More than 90% of adverse drug reactions

are not immunologically mediated
Antibiotics (esp. penicillins and sulphonamides)
account for a large proportion of adverse drug
reactions
Up to 15% of adults believe they are allergic to 1 or
more drugs, but only 5% truly are
unnecessary avoidance

2015 Diploma in Child Health/International Postgraduate Paediatric Certificate

Risk factors for antibiotic allergy

Previous exposure
including non-therapeutic (in utero, food products)

Proximity of onset of therapy to reaction

primary immune reactions take several days to lead to a clinical
reaction
medications in use over long periods less likely to be a problem than
recently introduced agents

Age
Peak 20 - 49 years
Lowest risk in children and the elderly

Route of administration
parenteral > oral
2015 Diploma in Child Health/International Postgraduate Paediatric Certificate

Classification of allergic reactions to antibiotics

based on time of onset
Reaction Type

Onset (hours)

Clinical Reactions

Immediate

01

Accelerated

14

Anaphylaxis
Hypotension
Laryngeal oedema
Urticaria / angioedema
Wheezing
Urticaria / angioedema
Laryngeal oedema
Wheezing

Late

> 72

Morbilliform rash
Interstitial nephritis
Haemolytic anaemia
Neutropenia
Thrombocytopenia
Serum sickness
Drug fever
Stevens-Johnson syndrome
Exfoliative dermatitis

2015 Diploma in Child Health/International Postgraduate Paediatric Certificate

Diagnosis of antibiotic allergy

Almost never clear cut - good history essential
Symptoms due to underlying condition or to the antibiotic?
There is NO single test for antibiotic allergy
Most antibiotics are not complete antigens but haptogenic
metabolites of the parent drug coupled with a carrier protein
except for penicillin, immunoreactive drug metabolites
have rarely been identified

2015 Diploma in Child Health/International Postgraduate Paediatric Certificate

Skin testing for antibiotic allergy

Skin prick and intradermal application
Should only be performed by specialists in place with
appropriate resuscitation equipment
can cause anaphylaxis if significant allergy exists
Only helpful in predicting IgE mediated reactions
Most non-pruritic maculopapular rashes will not be
predicted by skin testing

2015 Diploma in Child Health/International Postgraduate Paediatric Certificate

Specific IgE (RAST) testing for

antibiotic allergy
Are less sensitive than skin testing
if there is a strong history, negative RAST must be
followed up with skin testing
Not routinely available for all antibiotics

Only helpful in predicting IgE mediated reactions

2015 Diploma in Child Health/International Postgraduate Paediatric Certificate

Penicillin allergy
Most common cause of serious allergic drug reactions
A positive skin test indicates a high risk of immediate or accelerated
reaction

Maculopapular rash usually associated with negative skin prick test

A negative skin test indicates risk of life threatening reaction to penicillin
is extremely low
Cautious oral challenge under controlled conditions if skin test negative
If no alternative to penicillin in proven allergy, desensitisation
in hospital by specialist

2015 Diploma in Child Health/International Postgraduate Paediatric Certificate

Cross-reactivity in antibiotic allergy

Semi-synthetic penicillins (ticarcillin, piperacillin) contain same nucleus
as penicillin and can be assessed by penicillin skin testing
Carbapenems (imipenem) should also be avoided by penicillin skin test
positive patients, but increasing evidence that meropenam is tolerated
by most penicillin allergic patients
Cephalosporins - beta lactam-ring in common with penicillin but crossreactivity low
3-7% penicillin allergic patients allergic to cephalosporins
Monobactams (aztreonam) safe for penicillin allergic patients

2015 Diploma in Child Health/International Postgraduate Paediatric Certificate

Reactions to ampicillin / amoxicillin

Maculopapular rash common
5-10% of children
Almost 100% if administered to those with infectious
mononucleosis (EBV)
Mechanism unknown
Not IgE mediated
Highly unlikely to develop immediate or intermediate reaction after
subsequent administration penicillin / ampicillin

Urticarial eruptions
More likely to be allergic (DDx infection associated urticaria)
Subsequent administration may induce allergic reaction
Refer for testing
2015 Diploma in Child Health/International Postgraduate Paediatric Certificate

Reactions to Cefaclor
Serum sickness like reaction
rash
joint swelling

Metabolism of cefaclor to a protein-reactive derivative

which can then acetylate proteins to produce
immunogenic complexes
Skin testing to native drug never positive
Sero-assays for drug specific antibodies consistently
negative
Further administration of other cephalosporins or
penicillins NOT contra-indicated
2015 Diploma in Child Health/International Postgraduate Paediatric Certificate

Approach to Suspected
Antibiotic Allergy

2015 Diploma in Child Health/International Postgraduate Paediatric Certificate

Gruchalla et al NEJM 2006

Is it Immune Deficiency?

2015 Diploma in Child Health/International Postgraduate Paediatric Certificate

When to Suspect Immune Deficiency

History and examination
Infections are unusually frequent, severe, chronic
or resistant to therapy
Specific infections indicative of an underlying
immunodeficiency
The family history indicates investigation
Characteristic findings on examination
2015 Diploma in Child Health/International Postgraduate Paediatric Certificate

Frequency of infections in childhood

Age (y)
<1
1-2
3-4
5-9
10-14

Infections/yr
6
6
5
4
3

There is a wide range of normality: up to 12 infections per year

Increased frequency with child care, older siblings, exposure to
tobacco smoke, allergic disease (apparent frequency)
2015 Diploma in Child Health/International Postgraduate Paediatric Certificate

The 10 warning signs of primary immune

deficiency
1) Four or more new ear infections
within 1 year
2) Two or more serious sinus
infections within 1 year
3) Two or more months on
antibiotics with little effect
4) Two or more pneumonias within
1 year
5) Failure of an infant to gain
weight or grow normally

6) Recurrent, deep skin or organ

abscesses
7) Persistent thrush in the mouth or
on the skin, after age 1 year
8) Need for intravenous antibiotics to
clear infections
9) Two or more deep seated
infections such as meningitis,
osteomyelitis, cellulitis or sepsis
10) A family history of immune
deficiency

Patients are advised to seek review if 2 or more apply (Jeffrey Modell Foundation, New York)
2015 Diploma in Child Health/International Postgraduate Paediatric Certificate

Clinical features of immunodeficiency

Usually present

Occasionally present

Recurrent respiratory tract infections

Severe bacterial infections
Persistent infections with incomplete or no response to
therapy

Weight loss, fevers

Chronic conjunctivitis
Periodontitis
Lymphadenopathy
Hepatosplenomegaly
Severe viral disease
Chronic liver disease
Arthralgia or arthritis
Chronic encephalitis
Recurrent meningitis
Pyoderma gangrenosa
Cholangitis and/or hepatitis
Adverse reaction to vaccines
Bronchiectasis
Urinary tract infection
Delayed umbilical cord detachment
Chronic stomatitis

Often present
Failure to thrive or growth retardation
Infection with an unusual organism
Skin lesions (eg. rash, seborrhoea, pyoderma, necrotic
abscesses, alopecia, telangectasia, severe warts)
Recalcitrant thrush
Diarrhoea and malabsorption
Persistent sinusitis, mastoiditis
Recurrent bronchitis, pneumonia
Evidence of auto-immunity
Paucity of lymph nodes and tonsils
Haematologic abnormalities: aplastic anaemia, haemolytic
anaemia, neutropenia, thrombocytopenia

2015 Diploma in Child Health/International Postgraduate Paediatric Certificate

Common infections associated with

immunodeficiency
SPECIFIC IMMUNITY

Antibody

Defence against:

Bacteria + protozoa
(> fungi + viruses)

Usual
microrganisms:

Pyogenic bacteria
Staphylococci
Streptococci
Haemophilus
Some viruses:
Enteroviruses eg:
polio, ECHO virus

Cellular

NON-SPECIFIC IMMUNITY

Complement

Intracellular
microorganisms

Viruses:
Cytomegalovirus
Vaccinia
Herpes
Measles

Bacteria + protozoa
(> fungi + viruses)

Pyogenic bacteria
Staphylococci
Streptococci
Haemophilus
Neisseria

Fungi:
Candida
Aspergillus

Phagocytes

Some viruses

Bacteria:
Mycobacteria
Listeria
Protozoa:
Pneumocystis
2015 Diploma in Child Health/International Postgraduate Paediatric Certificate

Bacteria:
Staphylococci
Gram negative
Fungi:
Candida
Aspergillus

Clinical

Immunodeficiency

Recurrent sinopulmonary infections, chronic diarrhoea

and failure to thrive

Humoral

Less commonly, arthritis, hepatitis, coeliac disease

and inflammatory bowel disease

Humoral

Recurrent fungal, opportunistic infections, chronic

diarrhoea, failure to thrive, neonatal hypocalcaemia

Cellular

Specific clinical syndromes (ataxia telangectasia,

Wiskott-Aldrich syndrome, cartilage hair hypoplasia)

Humoral and
cellular

Recurrent periodontal disease, gingivitis, skin and deep

abscesses, fungal pneumonia, osteomyelitis

Phagocytic

Recurrent bacteraemia, N. meningitidis or disseminated

neisserial infections

Complement

2015 Diploma in Child Health/International Postgraduate Paediatric Certificate

Secondary Immunodeficiency

Production
Malnutrition
Lymphoproliferative diseases
Drugs
Infections

Loss or catabolism
Antibody,
Cell mediated

2015 Diploma in Child Health/International Postgraduate Paediatric Certificate

Secondary immune deficiency

Premature and Newborn
Hereditary and Metabolic Diseases
Chromosomal abnormalities (eg: Downs)
Uraemia
Diabetes mellitis
Malnutrition
Vitamin and mineral deficiencies
Protein losing enteropathies
Nephrotic dystrophy
Myotonic dystrophy
Sickle cell disease

Immunosuppressive agents
Radiation
Immunosuppressive drugs
Corticosteroids
Antilymphocyte or antithymocyte globulin
Anti T-cell monoclonal antibodies

Surgery and trauma

Burns
Splenectomy
Anaesthesia
Head injury

Infectious Diseases
Congenital rubella
Viral exanthema - measles, varicella
HIV infection, AIDS
Cytomegalovirus
Infectious mononucleosis
Bacterial infections
Mycobacterial, fungal or parasitic diseases

Infiltrative and Haematologic Diseases

Histiocytosis
Sarcoidosis
Hodgkins disease and lymphoma
Leukaemia
Myeloma
Agranulocytosis and aplastic anaemia
Lymphoma in immunocompromised transplant
recipients

Miscellaneous
Lupus erythematosis
Chronic active hepatitis
Alcoholic cirrhosis
Aging

2015 Diploma in Child Health/International Postgraduate Paediatric Certificate

Severe Combined Immunodeficiency (SCID)

2015 Diploma in Child Health/International Postgraduate Paediatric Certificate

Pneumocystis Jeroveci

2015 Diploma in Child Health/International Postgraduate Paediatric Certificate

Molluscum

2015 Diploma in Child Health/International Postgraduate Paediatric Certificate

Chronic Mucocutaneous Candidiasis

Specific failure of immune system to respond to
candida
Association with endocrine and autoimmune
disease

2015 Diploma in Child Health/International Postgraduate Paediatric Certificate

Velocardiofacial syndrome (Di George)

Broad nasal root, malar flatness, retrusive mandible, and minor auricular
anomalies are the most common facial abnormalities.

Plus: Congenital heart disease, hypoparathyroidism (hypocalcaemia),

recurrent ENT infections and speech problems associated with small midface +/- cleft palate,
2015 Diploma in Child Health/International Postgraduate Paediatric Certificate

Neutrophil
dysfunction

2015 Diploma in Child Health/International Postgraduate Paediatric Certificate

Hyper-IgE Syndrome

Cold abscesses,
pneumatoceles,
typical facies, rash
(DDx in early
childhood: severe
eczema)
NEJM

2015 Diploma in Child Health/International Postgraduate Paediatric Certificate

Recurrent infections limited to one site are more likely to

be secondary to a local anatomic problem than systemic
immunodeficiency
Infection Site

Possible Causes

Skin

Eczema
Burns

Respiratory Tract

Ear

Cystic fibrosis
Immotile cilia
Asthma
Foreign body
Bronchial malformation
Adenoidal hypertrophy

Meninges

Fistula

Urinary tract

Malformations

2015 Diploma in Child Health/International Postgraduate Paediatric Certificate

Screening investigations
FBC and film
IgGAM
Lymphopenia and reduced Igs require further investigation
Suspicious clinical picture and normal screening tests should not prevent
specialist referral as levels may fluctuate with time
Abnormal levels may be temporary and will usually be repeated
Secondary assessment: (IgG subclasses), functional antibodies (tetanus,
diphtheria, HiB, pneumococcus), T and B cell subsets, complement
and neutrophil function tests, IgE, HIV
GP may be asked to give additional boosters or Pneumovax to
assess functional antibody status
2015 Diploma in Child Health/International Postgraduate Paediatric Certificate

These course materials and the works comprising it are protected

by copyright which is owned by or licensed for use by The
Childrens Hospital at Westmead (the Hospital). Apart from any
permitted use under the Copyright Act 1968 (Australia), local or
international laws that may apply, no part of these materials may
be reproduced, or any other use made of them, without the
express written permission of the Hospital.

Self Assessment Questions

Allergy and Immunology
Dr Melanie Wong - 2015

Question 1
Which of the following statements are true regarding antibiotic allergy?
A.
B.
C.
D.

Penicillin is the most common cause of serious allergic drug reaction.

Peak age for antibiotic allergy is 5 to 10 years.
A good history is essential in helping to diagnose antibiotic allergy.
Antibiotic allergy occurs in around 15% of adults.

Answer:
True: A and C
A
Penicillin is the most common cause of serious allergic drug reaction.
C
A good history is an essential factor in diagnosis.
False: B and D
B
Peak age for antibiotic allergy is 20 to 49 years. Lowest risk is in children and elderly.
D
Up to 15% of adults believe they are allergic to 1 or more drugs, but only around 5%
are actually allergic.
Question 2
Give 4 examples of late onset (usually non-IgE mediated) allergic reactions to
antibiotics.
Answer:

Morbilliform rash (non urticarial)

Interstitial nephritis
Haemolytic anaemia
Neutropenia
Thrombocytopenia
Serum sickness
Drug fever
Stevens-Johnson Syndrome
Exfoliative dermatitis

Questions 3
What important information must you give to parents in relation to an asplenic
patient?
Answer:
A. Risk of infection with encapsulated organisms
These course materials and the works comprising it are protected by copyright which is owned by or
licensed for use by the Childrens Hospital Westmead (the hospital). Apart from any permitted use
under the Copyright Act 1968 (Australia), local or international laws that may apply, no part of these
materials may be reproduced, or any other use made of them, without the express written permission
of the hospital.

B. Need for antibiotic prophylaxis prior to surgical procedures; also note

recommendations for immunization.
C. Long term Penicillin prophylaxis
D. In case of febrile illness to seek medical attention early.

These course materials and the works comprising it are protected by copyright which is owned by or
licensed for use by the Childrens Hospital Westmead (the hospital). Apart from any permitted use
under the Copyright Act 1968 (Australia), local or international laws that may apply, no part of these
materials may be reproduced, or any other use made of them, without the express written permission
of the hospital.