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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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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
Authors
Werner Pichler, Switzerland
Bernard 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-6P-deficiency
Johansson SGO, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, et al. Revised nomenclature
for 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
Drug hypersensitivity
Drug allergy
IgE-mediated
drug allergy
Non-allergic hypersensitivity
Non IgE mediated
drug allergy
eg: Non-specific histamine release,
Arachidonic acid pathway activation,
Bradykinin pathway alteration,
Complement activation
Johansson SGO, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, et al. Revised nomenclature
for 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
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 nonimmunologically 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
Hapten, prohapten and
p-i concept
– 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 (haptenspecific 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)
S
2
O
C
H2
H
N
O
1
N
H
CH3
S
CH3
N
ONa
O
Penicilloyl-
O
C
H2
S
H
N
H
S
N
CH3
CH3
O
Penicilloate-
ONa
O
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“
Hapten concept
O
C
H2
penicillin
H
N
H
S
N
CH3
CH3
O
ONa
O
Ig
processing
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
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 R
NH
R
NH
SO
SO
GSH
NH2
sulfamethoxazole
R= N
O
Cribb & Spielberg, 1992
Gill et al., 1997
R
NH
R
NH
SO
SO
NO
NH S
GSH
NHOH
O
sulfamethoxazole
hydroxylamine
nitroso
sulfamethoxazole
sulfamethoxazole
protein conjugate
ANTIGEN
PROCESSING
CH3
HYPERSENSITIVITY
IMMUNE
RESPONSE
Prohapten concept
sulfamethoxazole
(SMX)
NH2
NO
NH2
O S O
O S O
N
O
NH
R
O S O
SMX-NO
R
metabolism
inert
reactive
H3C
Metabolism is required to generate reactive compounds, which then behave like haptens and
bind to soluble and cell bound proteins.
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 (pi 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.
The p-i-concept:
Pharmacological interaction of
drugs with immune receptors*
peptide
*) elaborated for T-cell receptors (TCR) only
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)
T-cell recognition of hapten like drugs:
covalent drug binding to MHC-peptide
NO
Covalent binding
(SMX-NO)
N
O S O
NH
O
H3C
T-cell
TCR
APC (e.g. activated
keratinocyte, DC,...)
MHC+ peptide
„Classical“ immune response to hapten carrier compound
Direct stimulation of T-cells by nonhapten like drugs:
direct interaction with the TCR
NH2
Sulfamethoxalole (SMX)
1
T-cell
TCR
N
O S O
NH
O
APC (e.g. activated
keratinocyte)
H3C
2
MHC+ peptide
Labile, non covalent binding of SMX itself to TCR; This initial stimulation is
supplemented by TCR-MHC interaction
SUMMARY:
“Antigenicity” of drugs
NH2
O S O
HAPTEN
N
P-I CONCEPT
NH
O
•
•
•
•
•
Chemical (hapten)
H3C
Stable protein/peptide modification
(covalent)
MHC-APC directed
(processing and metabolism)
Very heterogeneous and often
combined immune responses (Ig, Tcells.....)
•
•
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.....)
Gell & Coombs Classification of
Hypersensitivity reactions
Immune reactant
Antigen
Type I
Type II
Type III
Type IV
IgE
IgG
IgG
T cell
Soluble antigen
Cell- or matrixassociated
antigen
Soluble antigen
Mast-cell activation
FcR+ cells
(phagocytes, NK
cells)
FcR+ cells
Complement
Effector
MHC-presented antigen
T-cells, via cytokines recrutement of monocytes, eosinophils,
neutrophils(?)
blood
platelets vessel
Ab - platelet
immune
complex
Ag
Example of
hypersen-sitivity
reaction
Allergic rhinitis,
asthma, systemic
anaphylaxis
Some drug
allergies (e.g.
penicillin)
Serum sickness,
Arthus reaction
Cytokines
cytotoxicity
Many different diseases:
Different forms of exanthems, eczema, contact dermatitis
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
Bullous
Exanthem
Maculopapular exanthem
(MPE)
Acute generalized
exanthematous
pustulosis (AGEP)
MPE: infiltration of T cells in
dermis and epidermis
CD4+
CD8 +
Perforin and Granzyme B
• Are important for cellmediated 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.
keratinocytes
or hepatocytes
Perforin+ and Granzyme B+
cells infiltrate into the epidermis
Perforin
Granzyme B
In MPE infiltrating T cells are killing keratinocytes and
orchestrate an inflammatory process, which is often
eosinophil rich
keratinocyte
keratinocyte
cell necrosis
ICD541
hydropic
degeneration
eosinophils
mononuclear
cell infiltrate
MHC II
perforin
granzymeB
TCR
LFA-1
-
Drug specific CD4+ T cell
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
MHC I
CD4
Activated,
MHC II+
CD8 T cells can kill all cells, not only activated MHC II+ cells
T-cells recognize the drug and exert, depending
on their function, a specific pathology
Bullous
exanthem
MHC-I (+ MHC-II)
CD8+ > CD4+
cytotoxicity (CD8+)
IFN ; IL-5
Amoxicillin
MPE
MHC-II
CD4+
cytotoxicity (CD4+)
IL-5; IFN 
AGEP
MHC-II + I
CD4+ & CD8+
cytotoxicity
IL-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 Secretariat
555 East Wells Street, Suite 1100
Milwaukee, WI 53202
United States
Tel: +1 414 276 1791
Fax: +1 414 276 3349
Email: [email protected]