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Transcript of GLORIA Module 11: Drug Allergy (Part 1) Definition, Epidemiology and Pathogenesis of Drug Allergy an...
GLORIA Module 11:Drug Allergy (Part 1)Definition, Epidemiology and Pathogenesis of Drug
Allergy an educational program of
Updated: June 2011
Global Resources in Allergy (GLORIA™)
Global Resources In Allergy (GLORIA™) is the flagship program of the World
Allergy Organization (WAO). Its curriculum educates medical
professionals worldwide through regional and national presentations and
local training programs. GLORIA modules are created from established guidelines and recommendations to address different aspects of allergy-
related patient care.
US GLORIA ProgramIn conjunction with the American College of Allergy, Asthma and
Immunology (ACAAI), GLORIA is now presented for CME Credit in the US to
Regional, State and Local Societies.The GLORIA educational materials are
available for download on WAO’s website www.worldallergy.org/gloria
World Allergy Organization (WAO)
The World Allergy Organization is an international coalition of
89 regional and national allergy and clinical
immunology societies.
WAO’s Mission
WAO’s mission is to be a global resource and advocate in the
field of allergy, advancing excellence in clinical care,
education, research and training through a world-wide alliance of allergy and clinical immunology
societies
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 (?)
World Allergy Organization (WAO)
For more information on the World Allergy Organization (WAO), please visit www.worldallery.org or contact the:
WAO Secretariat555 East Wells Street, Suite 1100
Milwaukee, WI 53202United States
Tel: +1 414 276 1791Fax: +1 414 276 3349
Email: [email protected]