GLORIA Module 11:Drug Allergy (Part 1)Definition, Epidemiology and Pathogenesis of Drug

Allergy an educational program of

Updated: June 2011

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GLORIA MODULE 11:Drug Allergy (Part 1)

Definition, Epidemiology and Pathogeneses of

Drug Allergy

AuthorsWerner Pichler, SwitzerlandBernard Thong, Singapore

Learning Objectives

• Understand the difference between– Adverse drug reaction– Drug hypersensitivity– Drug allergy

• Understand the epidemiology and risk factors for drug allergy

• Understand the pathogenesis and immunological mechanisms underlying the different phenotypes of drug allergy

Drug related side effects

• Potentially dangerous– 4th leading cause of death in the USA

Lazaru J. et al. JAMA (1998) 279: 200-205)

• Altogether frequent – but rare for each drug

• Very heterogeneous clinical symptoms – affecting quasi all organs– often mild, sometimes life threatening

Classification of adverse drug reactions

• Type A: predictable; strictly dose dependent – 80% of all side effects – Pharmacological side effects (e.g. gastrointestinal

bleeding under treatment with NSAID)

• Type B: not predictable; usually not dose dependent, and sometimes reactions to very small amounts– 15-20% of all side effects – Immunologic/allergic – Non-immune mediated, “pseudoallergic” – Idiosyncratic

Nomenclature

• Immune mediated drug hypersensitivity (drug allergy)– Clinical symptoms due to different types of specific

immune reactions (T-cell & B-cell/Ig mediated)

• Non immune mediated drug hypersensitivity (non-allergic drug hypersensitivity)– Symptoms and signs similar to immune mediated

hypersensitivity, but failure to demonstrate a specific immune process to the drug

– Older term: “pseudoallergy”

• Idiosyncrasy– symptoms and signs due to some genetic alterations, e.g.

an enzyme deficiency: e.g. hemolytic anaemia due to certain drugs in patients with G-6-P-deficiency

Johansson SGO, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, et al. Revised nomenclaturefor allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization,October 2003. J Allergy Clin Immunol 2004;113:832-6

Nomenclature

Johansson SGO, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, et al. Revised nomenclaturefor allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization,October 2003. J Allergy Clin Immunol 2004;113:832-6

Drug hypersensitivity

Drug allergy Non-allergic hypersensitivity

IgE-mediated Non IgE mediated drug allergy drug allergy

eg: Non-specific histamine release,Arachidonic acid pathway activation,Bradykinin pathway alteration,Complement activation

Epidemiology• Adverse drug reactions (ADRs) have been reported to account for 3 to

6% of all hospital admissions and occur in 10 to 15% of hospitalized patients.

• Drug allergy has been estimated to account for up to a third of all ADRs.

• Most epidemiologic studies have dealt with ADRs or adverse drug events, with few focusing on drug allergy alone.

• In hospitalized patients, the incidence of cutaneous allergic reactions from the rates of hospitalization for ADRs, disclosed an estimated rate of 2.2 per 100 patients and 3 per 1,000 courses of drug therapy.

• The true incidence of drug-induced anaphylaxis is also unknown, as most studies have been based on all causes of anaphylaxis or all causes (both allergic and nonallergic) of ADRs.

• The estimated incidence of Stevens-Johnson Syndrome (SJS), which may occur secondary to ADR, is 0.4 to 1.2 per 1 million people per year; the estimated incidence for TEN is 1.2 to 6 per 1 million people per year.

Epidemiology

• Limitations of current epidemiological data– Includes all ADR– Does not differentiate immunologically and non-

immunologically mediated drug hypersensitivity– Different study populations

• Inpatients or outpatients

– Different methodologies– Different methods of assessing drug imputability– Different methods of data analyses

Gomes ER, et al. Curr Opin Allergy Clin Immunol 2005;5:309-16

Risk factors

• Drug-related factors– Nature of the drug– Degree of exposure (dose, duration, frequency) – Route of administration – Cross-sensitization

• Host-related factors– Age – Sex – Genetic factors (HLA type, Acetylator status) – Concurrent medical illness (e.g. Ebstein-Barr Virus

(EBV), human immunodeficiency virus (HIV), asthma) – Previous drug reaction – Multiple allergy syndrome

Drug-related risk factors• Nature of the drug

– Hapten concept (intrinsically reactive) – Pro-hapten concept (requires conversion to reactive

intermediates)– Danger concept (drug related cytotoxicity enhancing

immune response)– Pharmacological interaction concept (direct non-covalent

binding to immune receptors, T-cell receptors, MHC)• Degree of exposure

– Dose, duration, frequency, intermittent repeated administration

• Route– Topical, oral, parenteral

• Cross-sensitization– Reactivity either to drugs with a close structural chemical

relationship or to immunochemically similar metabolites.

Host-related risk factors• Age

– Most of the studies among children and adults not comparable • Sex

– No evidence, with the possible exception of cutaneous reactions, that allergic drug reactions are more common in females than in males. 

• Genetic factors (HLA type, Acetylator status) • Concurrent medical illness (e.g. Ebstein-Barr Virus (EBV), human

immunodeficiency virus (HIV), asthma) • Previous drug reaction • Multiple allergy syndrome

– May have a predilection to more than one non-cross-reacting medication, but the existence of this condition is controversial.

Genetic risk factors

Immunogenetic disposition together with race:

1. HLA-B*1502: Carbamazepine: SJS/TEN, DRESS; Han Chinese but not Caucasians

2. HLA-B*5801: Allopurinol: DHS/DRESS like, Han Chinese

3. HLA-B*5701: Abacavir: DRESS like, Caucasians, but not Hispanics or Africans

Viral infections & autoimmunity

Viral infections & autoimmunity:

Generalized immune stimulation in the frame of

• Acute EBV infections: maculopapular exanthem with aminopenicillins

• HIV infections:

– Sulfonamides: MPE, SJS/TEN, DRESS

– SJS/TEN to various drugs is 500 fold more frequent

– Nevirapine and abacavir: frequent side effects

• Drug induced autoimmunity:

– Drug-induced Lupus

– Drug-induced vasculitis

Pathophysiology of drug reactions

• Antigenicity of drugs– Hapten concept– Prohapten concept– p-i (pharmacological interaction with immune receptors)

concept

• Classification of drug reactions – Type I– Type II– Type III– Type IV

• a, b, c, d reactions

Hapten, prohapten and p-i concept

• Hapten– chemically reactive drug– able to bind covalently to proteins

• Prohapten– chemically non reactive drug– becomes reactive upon metabolism (transformation of

prohapten hapten)

• p-i concept– parent, chemically non reactive drug– unable to bind covalently to proteins– can nevertheless interact with “immune receptors” like

T-cell receptors for antigen and elicit an immune response

How can drugs stimulate the immune system (I)?

• Hapten/prohapten concept – The hapten-carrier complex (e.g. penicillin

covalently bound to albumin) leads to formation of neoantigens: these will be recognized by the immune system (hapten-specific Ig on B-cells and by T-cells)

– The binding of haptens to cellular structures may be associated with stimulation of the innate immune system. This provides “danger signals”, e.g. leading to upregulation of CD40/CD86 on Dendritic Cells

Hapten concept: Possible reactive sites of benzylpenicillin

Benzylpenicillin (PenG)

PenG is a hapten like drug, as it can rapidly form covalent bonds to other proteins. 1) via the b-lactam ring (1), which opens and tends to form a bridge to lysin: „major determinant“. 2) via the thiazolidin moiety (2) of the penicillin: forming „minor determinant“

2

1

N

SCH2

ONH

O

H CH3CH3

ONaON

N

SCH2

ONH

O

H CH3CH3

ONaO

S

Penicilloyl- Penicilloate-

S

Hapten concept

Binding of a chemically reactive

structure to

1) soluble proteins (IgE, IgG)or

2) membrane bound proteins ( IgG + T-cell reactions)

or 3/4) the MHC-peptide

complexes (I & II) directly ( only T-cells)

Distinct clinical consequences of hapten carrier formation

depending on binding to soluble or cell bound proteins

penicillinN

SCH2

O

NH

O

H CH3

CH3

ONa

O

processing

Ig

Drug (hapten) presentation to immune system (B & T

cells) • Potentially highly immunogenic• Immunostimulatory properties (activation of dendritic cells)• B and T cell response

• Clinical : “everything” binding to cell-bound and soluble proteins

Ig: anaphylaxis, hemolytic anemia, thrombocytopenia... T-cell: contact dermatitis, hepatitis, interstitial lung disease,

MPE, AGEP, TEN, ....

MPE: maculopapular drug exanthema, AGEP: acute generalized exanthematous pustulosis, TEN: Toxic epidermal necrolysis

Prohapten - Metabolism required

- e.g. Sulfamethoxazole

Hypersensitivity -

Cribb & Spielberg, 1992Gill et al., 1997

sulfamethoxazole sulfamethoxaz

ole hydroxylamine

SO

NH

NHOH

R

nitroso sulfamethoxazo

le

SO

NH

NO

R

sulfamethoxazole protein conjugate

SO

NH

NH S

O

R

HYPERSENSITIVITY

ANTIGEN PROCESSING

IMMUNE RESPONSE

SO

NH

NH2

R

GSH GSH

R =NO CH3

Metabolism is required to generate reactive compounds, which then behave like haptens and bind to soluble and cell bound proteins.

Prohapten conceptsulfamethoxazole

(SMX)

ON

CH3

S OO

NH

NH2

S OO

NO

RS OO

NH2

R

metabolism inert reactive

SMX-NO

Drug (prohapten) presentation to immune

system (B & T cells) • Many drugs are potentially highly immunogenic as they are

transformed to chemically active intermediates• Potent and rapid intracellular detoxification mechanism

(i.e. GSH) may prevent immunogenicity of the generated reactive metabolites

• It is possible that the liver may play a role as a tolerogenic organ

----------------------------------------------------------------------------------------Clinical: potentially immunogenic for B- and T-cells; • Immunogenicity and clinical manifestation might be restricted

to the organ where metabolism (generation of hapten and stimulation of innate immunity) takes place, namely the liver (hepatitis) or kidney (interstitial nephritis)

How can drugs stimulate the immune system (II) ?

• Pharmacological interaction with immune receptors (p-i concept)

– direct stimulation of T-cells by drugs binding to the T-cell receptors for antigen

– no involvement of the innate immune system, and no generation of an own immune response to the drug

– stimulation of preactivated T-cells with additional specificity

The p-i concept:Pharmacological Interaction of drugs with immune Receptors

A chemically inert drug, unable to covalently bind to some proteins, „happens“ to bind to some of the 1012-1015 distinct immune receptors (as it does to

other proteins/receptors).

This drug-receptor interaction can under certain circumstances activate specific immune cells.

The subsequent reaction imitates a specific immune response.

a) Binding of the drug to TCR, providing an initial signal

b) Additional MHC- TCR interaction, supplementing the signal

c) Readiness of the T cell to react (low threshold level of activation)

peptide

*) elaborated for T-cell receptors (TCR) only

The p-i-concept: Pharmacological interaction of

drugs with immune receptors*

T-cell recognition of hapten like drugs: covalent drug binding to MHC-peptide

T-cell TCR

ON

CH3

S OONH

NO

Covalent binding (SMX-NO)

MHC+ peptide

APC (e.g. activated keratinocyte, DC,...)

„Classical“ immune response to hapten carrier compound

Labile, non covalent binding of SMX itself to TCR; This initial stimulation is

supplemented by TCR-MHC interaction

Direct stimulation of T-cells by non- hapten like drugs: direct interaction with the

TCR

T-cell TCR

MHC+ peptide

APC (e.g. activated

keratinocyte)

2

1

Sulfamethoxalole (SMX)

ON

CH3

S OO

NH

NH2

SUMMARY: “Antigenicity” of drugs

• Chemical (hapten)• Stable protein/peptide

modification (covalent)• MHC-APC directed• (processing and metabolism)• Very heterogeneous and

often combined immune responses (Ig, T-cells.....)

• Structural (fitting into TCR)• No covalent binding

• TCR – T cell directed

• No processing/no metabolism• Only T-cell reactions of different

types (exanthema, DRESS, AGEP.....)

ON

CH3

S OO

NH

NH2

HAPTEN P-I CONCEPT

Gell & Coombs Classification ofHypersensitivity reactions

Type I Type II Type III

Immune reactant

IgE IgG IgG

Antigen Soluble antigen

Cell- or matrix-

associated antigen

Soluble antigen

EffectorMast-cell activation

FcR+ cells (phagocytes,

NK cells)

FcR+ cellsComplement

Example of hypersen-sitivity reaction

Allergic rhinitis, asthma, systemic anaphylaxis

Some drug allergies (e.g. penicillin)

Serum sickness, Arthus reaction

Ag

platelets

blood vessel

immune complexAb - platelet

Type IV

T cell

MHC-presented antigen

T-cells, via cytokines recrutement of monocytes, eosinophils, neutrophils(?)

Many different diseases: Different forms of exanthems, eczema, contact dermatitis

Cytokinescytotoxicity

Delayed reactions

• Due to drug specific T cells• T-cells secrete different cytokines• The cytokines activate and recruit distinct

effector cells• Cytotoxic mechanism are always involved, in

some severe reactions (SJS/TEN) even dominating the clinical symptoms

• Similar mechanism in skin as in internal organs (e.g. interstitial nephritis)

Mechanism of immune mediated exanthems

T-cells recognize the drug and exert, depending on their function, a specific pathology

BullousExanthem

Acute generalized exanthematous pustulosis (AGEP)

Maculopapular exanthem(MPE)

MPE: infiltration of T cells in dermis and epidermis

CD4+ CD8 +

Perforin and Granzyme B

• Are important for cell- mediated cytotoxicity

• Are preformed in granules of cytotoxic T-cells (CTLs, NK)

• Are released during exocytosis of granules and form pores in the cell membrane of the target cell with subsequent fragmentation of DNA.

CTL

Killing of e.g. keratinocytesor hepatocytes

Perforin+ and Granzyme B+

cells infiltrate into the epidermis

Perforin Granzyme B

hydropic degeneration

eosinophils

keratinocytecell necrosis

mononuclear cell infiltrate

ICD541

LFA-1

keratinocyte

MHC II

TCR

Drug specific CD4+ T cell-

granzymeBperforin

In MPE infiltrating T cells are killing keratinocytes and orchestrate an

inflammatory process, which is often eosinophil rich

Comparison of MPE and Bullous Exanthem

• Higher activation of circulating T-cells (CD4 and CD8) in bullous exanthem

• Higher activation of CD8+ T-cells in the skin of patients with bullous exanthem

Bullous exanthem: CD8 MPE: CD4

Why are cytotoxic CD8+ T cells more dangerous than

CD4+ T cells ?

CD8 T cells can kill all cells, not only activated MHC II+ cells

CD8 CD4

Activated, MHC II+

MHC I

T-cells recognize the drug and exert, depending on their function, a

specific pathologyAmoxicillinBullous

exanthem

MHC-I (+ MHC-II)CD8+ > CD4+

cytotoxicity (CD8+)IFN ; IL-5

MPEMHC-II CD4+

cytotoxicity (CD4+)IL-5; IFN

AGEP

MHC-II + ICD4+ & CD8+

cytotoxicityIL-8; IL-5, IL-17 (?)

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