111 immunology com.pdf

These course materials and the works comprising it are protected by copyright which is owned by or licensed for use by the Children’s 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.

1

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.

Allergy and Immunology

Dr Melanie Wong

Department of Allergy and Immunology

© 2015 Diploma in Child Health / International Postgraduate Paediatric Certificate

© 2015 Diploma in Child Health/International Postgraduate Paediatric Certificate

1) Antibiotic Allergy

2) Is it Immune Deficiency?

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


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


Classification of allergic reactions to antibiotics

based on time of onset

Reaction Type Onset (hours) Clinical Reactions

Immediate 0 – 1 Anaphylaxis

Hypotension

Laryngeal oedema

Urticaria / angioedema

Wheezing

Accelerated 1 – 4 Urticaria / angioedema

Laryngeal oedema

Wheezing

Late > 72 Morbilliform rash

Interstitial nephritis

Haemolytic anaemia

Neutropenia

Thrombocytopenia

Serum sickness

Drug fever

Stevens-Johnson syndrome

Exfoliative dermatitis


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


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


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


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


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 cross-

reactivity low

– 3-7% penicillin allergic patients allergic to cephalosporins

• Monobactams (aztreonam) safe for penicillin allergic patients


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


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


Approach to Suspected Antibiotic Allergy

Gruchalla et al NEJM 2006


Is it Immune Deficiency?


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


Frequency of infections in childhood

Age (y) Infections/yr

<1 6

1-2 6

3-4 5

5-9 4

10-14 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)


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)


Clinical features of immunodeficiency

Usually present

Recurrent respiratory tract infections

Severe bacterial infections

Persistent infections with incomplete or no response to

therapy

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

Occasionally present

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


SPECIFIC IMMUNITY NON-SPECIFIC IMMUNITY

Antibody Cellular Complement Phagocytes

Defence against: Bacteria + protozoa

(> fungi + viruses) Intracellular

microorganisms

Bacteria + protozoa

(> fungi + viruses)

Usual microrganisms:

Pyogenic bacteria : Staphylococci Streptococci Haemophilus

Some viruses: Enteroviruses eg: polio, ECHO virus

Viruses: Cytomegalovirus Vaccinia

Herpes

Measles

Fungi: Candida Aspergillus

Bacteria: Mycobacteria

Listeria

Protozoa: Pneumocystis

Pyogenic bacteria : Staphylococci Streptococci Haemophilus

Neisseria

Some viruses

Bacteria: Staphylococci Gram negative

Fungi: Candida

Aspergillus

Common infections associated with immunodeficiency


Clinical Immunodeficiency

Recurrent sinopulmonary infections, chronic diarrhoea Humoral

and failure to thrive

Less commonly, arthritis, hepatitis, coeliac disease Humoral

and inflammatory bowel disease

Recurrent fungal, opportunistic infections, chronic Cellular

diarrhoea, failure to thrive, neonatal hypocalcaemia

Specific clinical syndromes (ataxia telangectasia, Humoral and

Wiskott-Aldrich syndrome, cartilage hair hypoplasia) cellular

Recurrent periodontal disease, gingivitis, skin and deep Phagocytic

abscesses, fungal pneumonia, osteomyelitis

Recurrent bacteraemia, N. meningitidis or disseminated Complement

neisserial infections


Production Loss or catabolism

Malnutrition Antibody,

Lymphoproliferative diseases Cell mediated

Drugs

Infections

Secondary Immunodeficiency


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

Hodgkin’s disease and lymphoma

Leukaemia

Myeloma

Agranulocytosis and aplastic anaemia

Lymphoma in immunocompromised transplant recipients

Miscellaneous

Lupus erythematosis

Chronic active hepatitis

Alcoholic cirrhosis

Aging


Severe Combined Immunodeficiency (SCID)


Pneumocystis Jeroveci


Molluscum


Chronic Mucocutaneous Candidiasis

• Specific failure of immune system to respond to candida

• Association with endocrine and autoimmune disease


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 mid-face +/- cleft palate,


Neutrophil

dysfunction


Hyper-IgE Syndrome

Cold abscesses,

pneumatoceles,

typical facies, rash

(DDx in early

childhood: severe

eczema)

NEJM


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

Cystic fibrosis

Immotile cilia

Asthma

Foreign body

Bronchial malformation

Ear Adenoidal hypertrophy

Meninges Fistula

Urinary tract Malformations


Screening investigations

• FBC and film

• IgGAM

• Lymphopenia and reduced Ig’s 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

These course materials and the works comprising it are protected by copyright which is owned by or licensed for use by The

Children’s 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.


1

Self Assessment Questions

Allergy and Immunology Dr Melanie Wong - 2015

Question 1 Which of the following statements are true regarding antibiotic allergy?

A. Penicillin is the most common cause of serious allergic drug reaction. B. Peak age for antibiotic allergy is 5 to 10 years. C. A good history is essential in helping to diagnose antibiotic allergy. D. 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


2

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.

111 immunology com.pdf

Documents

suspected antibiotic

antibiotic allergy skin

different types of reactions

parent drug

mediated antibiotics

permitted use

clinical reaction medications

clinical significance