DRUG

HYPERSENSITIVITY
BPT teaching 23/11/2015
Outline
• Classification of adverse drug reactions
• Basic immunological concepts
• Hypersensitivity reactions – subtypes
• Management and Investigation
• Conclusions
Adverse Drug Reaction
• ‘a response to a medicine which is noxious and
unintended, and which occurs at doses normally used in
man’ (World Health Organisation)

• Common (Scherer and Bircher 2010)

• Accounts for ~5% of hospital admissions
• Huge contributor to morbidity +/- mortality
• Delayed treatment
• Suboptimal treatment
• Adverse psychological outcomes
• Impact on future treatment options
 80%
Adverse Drug Type A
Reactions Pharmacological
Rawlins and
Thompson 1991

Type B 20% “Non-Specific”

Cytokine imbalance
Idiosyncratic
Enzymatic deficiency
“Hypersensitivity”
Direct mast cell
activation

Immunological
“True Allergy”

Gell and
Type 1
“Immediate” Type 2 Type 3 Type 4 Coombs

4a 4b 4c 4d
Hausmann et al, 2012
Risks for drug allergy
• Epicutaneous application of drug
• ? Greater concentration of dendritic antigen presenting cells
• Atopy (eg asthma, hayfever) is NOT a risk factor for drug
allergy
• Poorly controlled asthma may make reaction harder to treat
• Concomitant disease:
• HIV
• Other infections may also increase risk
• Frequency of exposure:
• Repeated, intermittent exposure likely increases risk
• Female
• Certain HLA Class I subtypes
A. IgE mediated Question
hypersensitivity.
B. Delayed-type Which of the following best
hypersensitivity. describes the toxicological
C. Enhancement
of complement
mechanism of recurrent acute
activation. angioedema related to the use of
D. Disruption of angiotensin converting enzyme
endothelial tight
junctions.
(ACE) inhibitors?
E. Impairment of
bradykinin
catabolism.
A. IgE mediated Question
hypersensitivity.
B. Delayed-type Which of the following best
hypersensitivity. describes the toxicological
C. Enhancement
of complement
mechanism of recurrent acute
activation. angioedema related to the use of
D. Disruption of angiotensin converting enzyme
endothelial tight
junctions.
(ACE) inhibitors?
E. Impairment of
bradykinin
catabolism.
Type A
• ~80% of all ADR
• Predictable
• Related to pharmacological effects of drug
• E.g.
• Bradycardia from b-blockers
• Sedation from morphine
• GI irritation from NSAIDs
Type B
• ~20% of ADR
• Idiosyncratic
• “unpredictable”
• “Dose-independent”

• 1) drug intolerance
• Enzyme deficiency
• G6PD deficiency and dapsone
• TPMT or CP450 polymorphisms
• Cytokine dysregulation
• NSAID and urticaria or asthma exacerbation - COX 1
• ACEI induced angioedema - bradykinin
• Direct mast cell activation
• Opiates
• Vecuronium – red man syndrome
• Iodinated contrast
Type B
• 2) immune mediated
• TRUE Allergy
• Specific allergic response mediated by adaptive immune system
• Requires sensitisation to specific or cross-reactive allergen

• Frequency:
• 0.18-0.4% of hospitalisations due to drug hypersensitivity Thong et al
BJCP 2011

• Cutaneous features 70-95%

• Mortality < 0.001%
T-cell sensitisation
• Dogma - Immune system must be ‘primed’ to an allergen
before reaction can occur
• Required previous sensitisation
• Previous course
• During prolonged course
• Cross reactivity with previously exposed drug
• Sensitisation process
• Antigen presenting cells (eg macrophage) take up allergen
• Broken down allergen irreversibly bound to specific HLA complex
within APC
• HLA/allergen complex moves to surface of APC, presents allergen
to corresponding T- cell receptor
• Binding leads to activation/proliferation of allergen specific T-cells
and subsequent immunoactivation
T-cell sensitisation
• But….drugs too small to be immunogenic on their
own:
• Typical allergens are proteins/peptides >1000Da

• Drug can bind to endogenous peptides:

• Hapten/prohapten concepts

• Can interact pharmacologically with HLA/T-cell

receptor:
• Pi-concept
Hapten
• Small molecules that
covalently bind to
extracellular,
membrane or
intracellular proteins
• Drug-protein
complex then
presented by HLA
complex to T cells
• e.g. penicillin
• All reaction types
Prohapten
• Drug metabolites
become chemically
reactive and bind to
endogenous
proteins
• e.g. co-trimoxazole
• All reaction types
P-i concept
• Drugs directly interacting
with HLA or T cell
receptors (reversible
binding) in a similar way
to receptor-ligand
interaction.
• Processing of antigen
(drug) by APC is not
required
• May account for reaction
on first exposure to drug
• Type IV reactions only:
• activates CD8+ cytotoxic
cells only
 HLA association
• Some drugs interact directly with HLA molecule without
metabolism
• Strong relationship with certain ethnicities
• Often carry extremely high risk of reactivity
• Typically associated with cytotoxic Type IV reactions.

Yun et al, Allergy 2012

Other cells or immune components
• Depending on type of reaction, also:
• B-lymphocytes/Immunoglobulin
• B-cell proliferation with differentiation into plasma cells
• Immunoglobulin production depends on cytokine milieu:
• Th1 (IFNg, TNFa) leads to IgG/A
• Th2 (IL-4, IL-5) leads to IgE
• Mast cells
• Eosinophils
• Neutrophils
• Complement
A. T cells Question
B. IgG
A patient with newly diagnosed
C. Complement
partial epilepsy is commenced on
D. IgE carbamazepine. 2 weeks later, she
E. B cells develops a maculopapular rash.
What is the predominant cell type
involved in this reaction?
A. T cells Question
B. IgG
A patient with newly diagnosed
C. Complement
partial epilepsy is commenced on
D. IgE carbamazepine. 2 weeks later, she
E. B cells develops a maculopapular rash.
What is the predominant cell type
involved in this reaction?
Type I reactions
• Within 1 hr of exposure
• B-cell proliferation with Th2 cytokine (IL-4, IL-5, IL-13)
• Production of allergen specific IgE
• Allergen specific IgE binds to high affinity IgE receptors
on mast cells (FceR1)
• Multivalent allergen cross-links mast cell bound IgE
• Mast cell undergoes degranulation with release of
mediators including histamine, leukotrienes,
prostaglandins, cytokines
• Result:
• Anaphylaxis
• Increased vascular permeability with angioedema, urticaria
• Bronchoconstriction and increased mucous production
• Vasodilation

Hausmann et al 2012
Type II
• > 24hrs
• Modification of cell membranes by the drug or
hapten/carrier complex
• Specific IgG binds to modified cell membrane
• Complement binding leads to removal of cells from
circulation:
• reticuloendothelial system
• phagoytosis or lysis by cytotoxic cells
• Clinically:
• Haemolytic anaemia
• Thombocytopaenia and neutropaenia

Hausmann et al 2012
Type III
• >24 hrs
• B-cell proliferation under Th1 conditions leads to
drug specific IgG antibody production
• IgG/drug immune complexes circulate and lodge in
small blood vessels due to complement activation
• Clinically:
• Drug induced lupus
• Serum sickness
• Vasculitis

Hausmann et al 2012
Type IV
• >24 hrs
• Revised Gell and Coombs based on T-cell subsets and
cytokines
Type IV
• Maculopapular
exanthema, and
delayed urticaria
most common

Hausmann et al 2012
 Type IV
Class Pathophysiology Clinical features/syndrome

IVa IFNg produced by T cells attracts Tuberculin test

macrophages/monocytes with Contact dermatitis
increased cytokine production

IVb T cells produce cytokines (IL-4, IL- DRESS

5) stimulating B cells to produce Maculopapular exanthema
IgE and also attract eosinophils Delayed urticaria

IVc Activation of cytotoxic T-cells leads Bullous exanthema - SJS/TEN

to direct tissue cytolysis through Drug induced hepatitis/nephritis
granzyme and perforin release Contact dermatitis

IVd T cells produce chemokines which AGEP

attract neutrophils Behcets
Pustular psoriasis
Images from: http://www.regiscar.org/, http://www.aocd.org/?page=erythemamultiforme, http://oncologypro.esmo.org/Guidelines-Practice/Multikinase-Inhibitor-Related-Skin-
Toxicity/Healthcare-Professionals/Symptoms-and-Grading/Skin-Changes/Maculopapular-Rash
Management and Investigation
A. Haemolytic Question
anaemia.
B. Laryngeal Desensitisation is most likely to be
oedema. effective in individuals who have
C. Stevens- had which of the following
Johnson
Syndrome. reactions to penicillin?
D. Toxic
epidermal
necrolysis.
E. Immune
complex
reactions
A. Haemolytic Question
anaemia.
B. Laryngeal Desensitisation is most likely to be
oedema. effective in individuals who have
C. Stevens- had which of the following
Johnson
Syndrome. reactions to penicillin?
D. Toxic
epidermal
necrolysis.
E. Immune
complex
reactions
A. Desensitisation
Question
with contrast
media. A patient is at high risk for repeat
B. Change to use of radiographic contrast media
non-ionic contrast
media. reactions. Which of the following is
C. Premedication least likely to be effective?
with oral
diphenhydramine.
D. Premedication
with oral
prednis(ol)one.
E. Premedication
with intramuscular
adrenaline.
A. Desensitisation
Question
with contrast
media. A patient is at high risk for repeat
B. Change to use of radiographic contrast media
non-ionic contrast
media. reactions. Which of the following is
C. Premedication least likely to be effective?
with oral
diphenhydramine.
D. Premedication
with oral
prednis(ol)one.
E. Premedication
with intramuscular
adrenaline.
A. Total IgE Question
B. Penicillin RAST
C. Oral trial of
A 50 yo male presents with right
graded doses of foot cellulitis due to Strep. He has
flucloxacillin a vague history of childhood
D. Skin prick and
intradermal
allergy to penicillin, but cannot
injection of remember the type of reaction.
cephalosporin Which test would be the best way
E. Skin prick and
intradermal
to clarify the type of reaction?
injection of
penicillin
allergen
A. Total IgE Question
B. Penicillin RAST
C. Oral trial of
A 50 yo male presents with right
graded doses of foot cellulitis due to Strep. He has
flucloxacillin a vague history of childhood
D. Skin prick and
intradermal
allergy to penicillin, but cannot
injection of remember the type of reaction.
cephalosporin Which test would be the best way
E. Skin prick and
intradermal
to clarify the type of reaction?
injection of
penicillin
allergen
F. Other
A. Total IgE Question
B. Penicillin RAST
C. Oral trial of
A 50 yo male presents with right
graded doses of foot cellulitis due to Strep. He has
flucloxacillin a vague history of childhood
D. Skin prick and
intradermal
allergy to penicillin, but cannot
injection of remember the type of reaction.
cephalosporin Which test would be the best way
E. Skin prick and
intradermal
to clarify the type of reaction?
injection of
penicillin
allergen
Investigation
• Diagnosis largely dependent on clinical features:
• Exposure to likely drug at appropriate time
• Timing of symptom onset
• Co-existent features
• Symptoms:
• Immediate-type features including:
• Classical urticaria, angioedema, cardiovascular or respiratory symptoms
• Delayed-type features:
• Maculopapular, pustular or blistering rash, especially mucous membranes
• Lymphadenopathy
• Systemic features
• Fever
• Hepatitis
• Nephritis
• Cytopaenias
• Eosinophilia
Baldo and Pham, Drug Allergy 2014
Investigation
• In vitro
• Specific IgE testing:
• Only useful for Type 1 reactions
• Easy to obtain, objective
• Few drugs available:
• Penicillins, cefaclor, neuromuscular blocking agents
• Sensitivity may be poor, especially if distant history
• May be false positive

• Serum tryptase
• Only useful for Type 1 reactions
• Peaks at 1-4 hrs after systemic reaction
• Sensitivity greatest with IV drug reactions
• Normal tryptase does not exclude mast cell degranulation
Investigation
• Basophil activation test:
• Good specificity, moderate to low sensitivity
• Not routinely available outside research labs

• HLA testing
• Only helpful for small number of drugs
• Helpful PRIOR to exposure to prevent reaction in high risk ethnic groups
Investigation
• In vivo:
• Skin testing – skin prick, intradermal, patch
• Well validated for some drugs, e.g. beta-lactams, neuromuscular
blocking agents
• Uncertain utility for other drugs
• Of little use for hapten/prohapten drugs

• Drug provocation testing

• Very rarely used as first-line investigation
• Gold standard to prove drug allergy
• May be high risk depending on incident reaction
• Usually in form of graded challenge
• Culprit drug if low likelihood of reaction
• Alternative agent to assess cross-reactivity
• Contraindicated for severe Type IV reactions (SJS/TEN/DRESS/AGEP)
• Potentially life threatening reactions
Management
• Acute management:
• Main tenet: cease offending drug
• Depends on clinical scenario:
• If anaphylaxis, adrenaline +/- antihistamines +/- corticosteroids
• Others: corticosteroids, antihistamines, intravenous immunoglobulin as
appropriate

• If can’t avoid, desensitisation can be considered:

• Type 1 reactions
• Some Type IV – maculopapular
• Desensitisation is contraindicated in:
• Type II, III and most Type IV (SJS/TEN/DRESS/AGEP
• Desensitisation of unknown benefit in non-allergic hypersensitivity
(direct mast cell activation)
Management
• Mechanism of desensitisation:
• Poorly understood
• ? Small concentration of allergen binds to IgE but is insufficient to cross-
link IgE
• ? Internalisation of IgE on mast cell it unresponsive

• Aims to produce temporary tolerance

• Lose tolerance when drug ceased (different to Immunotherapy for
aeroallergens)
References
• Hausmann et al, Adverse Drug Reactions, Chem Immunol
Allergy 2012;97:32-46
• Thong et al, British Journal of Clinical Pharmacology
2011;71(5);684-700
• Pichler et al, Med Clin N Am 2010;94:645-664
• Cernadas et al, Allergy 2010;65:1357-1366
• Baldo and Pham, Drug Allergy: Clinical Aspects,
Diagnosis, Mechanisms, Structure-Activity Relationships,
Springer 2013