1. Drug Allergy-urticaria and anaphylaxis
國立成功大學醫學院小兒學科
王志堯

2. Drug related side effects
Potentially dangerous
4th leading cause of death in the USA
Lazaru J. et al. JAMA (1998) 279: )
Altogether frequent – but rare for each drug
Very heterogeneous clinical symptoms
affecting quasi all organs
often mild, sometimes life threatening

3. Adverse Drug Reaction = Drug Allergy
Idosyncratic reaction: due to underline metablictic disorder
Hydralazine and SLE
Chloroquine in G6PD deficiency
Dose-related pharmacological properties:
Theophylline and tachycardia

4. Gell and Coombs Classification of Immune-mediated Allergic Responses
Type
Mechanism
Manifestations I
IgE-dependent
Anaphylaxis, urticaria II
Complement-mediated cytotoxicity
Cytopenias
III
Immune complex deposition
Vasculitis/
nephritis IV
Delayed-type hypersensitivity
Dermatitis or hepatitis

5. Type IV a Type IV b Type IV c
Antibody mediated hypersensitivity reactions (I-III) and delayed type hypersensitivity reactions (IV a-d)
Type I
Type II
Type III
Type IV a Type IV b Type IV c
Type IV d
Immune reactant
IgE
IgG
IFN, TNFα
(TH1 cells)
IL-5, IL-4/IL-13
(TH2 cells)
Perforin/
GranzymeB
(CTL)
CXCL-8.
GM-CSF, IL-17 (?) (T-cells)
Antigen
Soluble antigen
Cell- or matrix-associated antigen
Antigen presented by cells or direct T cell stimulation
Cell-associated antigen or direct T cell stimulation
Effector
Mast-cell activation
FcR+ cells (phagocytes, NK cells)
FcR+ cells Complement
Macrophage activation
Eosinophils
T cells
Neutrophils
Example of hypersen-sitivity reaction
Allergic rhinitis, asthma, systemic anaphylaxis
Some drug allergies (e.g., penicillin)
Serum sickness, Arthus reaction
Tuberculin reaction, contact dermatitis (with IVc)
Chronic asthma, chronic allergic rhinitis, maculo-papular exanthema with eosinophilia
Contact dermatitis,
maculopapular and bullous exanthema,
hepatitis
AGEP,
Behçet disease Ag
platelets
blood vessel
immune complex
TH1
chemokines, cytokines, cytotoxins
cytokines, inflammatory mediators
CTL
IFN-
TH2
IL-4 IL-5
eotaxin
PMN
CXCL8 GM-CSF
Pichler W.J. Delayed drug hypersensitivity reactions, Ann Int Med 2003

6. Drug allergy: Heterogeneous clinical manifestations & pathophysiology
Urticaria, anaphylaxis
Blood cell dyscrasia
Vasculitis
Maculopapular exanthem
Bullous or pustular exanthems (AGEP)
Stevens-Johnson Syndrome (SJS), toxic-epidermal necrolysis (TEN)
Hepatitis, interstitial nephritis, pneumopathy
Drug induced autoimmunity (SLE, pemphigus ...)
Drug induced hypersensitivity syndrome (DiHS/DRESS)

7. Allergic vs non-allergic drug hypersensitivity
Immune reactions (T-cells, IgE,
IgG against a drug/metabolite
with exanthema, urticaria, etc.)
Highly specific
Dependent of structure
Can be dangerous, severe (IgE & T cell reactions!)
Cross-reactions to structurally related compounds
IgE to drug occasionally detectable (skin tests, IgE-serology)
Non-allergic
No immune reaction against the
drug detectable, symptoms can
occur at the first contact
Activation of immunological effector cells (mast-cells, basophil leukocytes, etc)
Cross-reactions due to function of drug, not structure
Skin tests and serology negative
Drug provocation tests can be positive in allergic and non allergic reactions

8. Allergic or Non-allergic drug hypersensitivity
hapten-
carrier MC
Drug-specific IgE with:
penicillin/cephalosporin, pyrazolones*
quinolones*, (recombinant) proteins
Non-immune hypersensitivty reaction with:
NSAID (acetylsalicylic acid, diclofenac*, .…)
radio contrast media*, muscle relaxants*, gelatine-infusions*
Histamine, LT, TNFa,
Tryptase,....
* Both IgE and non-immune mediated mechanisms
possible

9. Sub-classification of drug allergy
According to
Timing of onset
Symptoms start <1hr after administration (immediate) vs
>1hr (often 6hr) after application (delayed)
- Immune mechanism
Gell & Coombs classification, type I-IVa-d
- Combined
Immediate and IgE mediated
Delayed and T-cell mediated (rarely IgG)
Correlating the clinical manifestations with the immununological mechanisms

10. Timing of onset
Within 1(-2)* hrs: immediate reactions, mainly IgE mediated;
Urticaria, angioedema, bronchospasm, anaphylaxis, and anaphylaxis related symptoms
After 1(-2)** hr (often > 6hrs - weeks): delayed reactions, mainly T cell, occasionally IgG mediated: often, but not always skin symptoms
*) the onset of IgE mediated reactions can occasionally occur later, particularly with oral drugs
**) the onset of T-cell mediated reactions can occasionally occur early, particularly with previous exposure to the drug

11. Appearance of symptoms in immediate or delayed type drug allergy
Immediate type:
“silent” sensitization,
well tolerated;
at re-exposure quick development of symptoms
(urticaria, anaphylaxis)
Delayed type:
Sensitization and symptoms often at 8th – 10th day of therapy (exanthema)
         () ()
    
 

12. Clinical Symptoms and Signs
Type I (IgE mediated)
Allergy or non-immune hypersensitivity reaction
rapidly appearing urticaria
rapidly appearing angioedema, mostly periorbital, oral, genital
swellings, with moderate pruritus, in association with generalized urticaria
gastrointestinal symptoms: cramps, diarrhoea, vomiting
anaphylaxis and anaphylactic shock

13. Anaphylaxis and anaphylactic shock

15. Delayed reactions Due to drug specific T cells
T-cells secrete different cytokines
The cytokines activate and recruit distinct effector cells
Cytotoxic mechanisms 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)

16. Drug-induced exanthems
Fig. 1. A typical drug-induced maculo-papular exanthem (a). Note the presence of some irregularly shaped annular lesions on the thigh (b).
A vacuolar interface dermatitis is shown in (c). In maculopapular exanthems, CD4+ T cells dominate and are able to kill activated, major
histocompatibility complex (MHC)-class II expressing keratinocytes in a perforin/granzyme B dependent manner.

17. Maculopapular exanthem
Exanthems
T-cells recognize the drug and exert, depending on their function, a specific pathology
Maculopapular exanthem
(MPE)
Acute generalized
exanthematous
pustulosis (AGEP)
Bullous
Exanthem

18. Acute Generalized Exanthematous Pustulosis (AGEP)
Clinical manifestations
Generalized, sterile pustules
Fever (>38°C)
Leukocytosis
Aetiology
Mainly drugs (~90%)
Rapid onset (3-4d)
Mercury (~10%)
Acute enteroviral infection

19. Acute Generalized Heterogeneous Exanthematous Pustulosis (AGEP) - Patch Tests
Patch tests are frequently positive
The patch test reaction at 48 hrs
imitates the early phase of the
disease with T-cell infiltration
After 96 hrs, pustule formation
can be observed

23. Acute generalized exanthematous pustulosis (AGEP)
AGEP. Dozens of non-follicular pustules arising on disseminated erythema
1.3.
AGEP is characterized by fever and a pustular rash (Beylot et al., 1980). Numerous, small, mostly non-follicular pustules arise on a widespread edematous erythema (Fig. 1). Edema of the face and the hands, purpura, vesicles, blisters, erythema multiforme-like lesions and mucous membrane involvement, has also been associated. The pustules are mainly localized on the mainfolds (neck, axillae, groins, etc.) trunk and upper extremities.

24. Persistent exfoliative dermatitis
The acronym of DRESS for drug reaction with eosinophilia and systemic symptoms has been proposed as more specific than “hypersensitivity” which would be an appropriate denomination for most types of drug reactions. DRESS points to two important characteristics: multi-systemic involvement and frequent eosinophilia

25. Overlap SJS/TEN
Fixed drug eruption

26. Delayed reactions: danger symptoms and signs
Extensive, confluent infiltrated exanthema
Bullae, pustules
Nikolsky sign
Erythrodermia
Painful skin
Mucosal affection
Facial oedema
Lymphadenopathy
Constitutional symptoms (higher fever, malaise, fatigue): Look carefully if any of these signs is present. Stop all ongoing drugs. Do liver, renal and blood tests.

27. Serious drug allergies
Both immediate and delayed reactions may be potentially life-threatening
Anaphylaxis (immediate reaction) is not the only life-threatening reaction

28. Drugs with potential for serious allergies
Immediate reactions (anaphylaxis)
-lactam-antibiotics, pyrazolone, neuromuscular blocking agents, radiocontrast media
Delayed reactions (drug-induced hypersensitivity syndromes)
Antiepileptics: carbamazepine, lamotrigine, phenobarbital
Allopurinol
Sulfonamide/Sulfasalazine
Nevirapine, Abacavir
Certain quinolones
Minocyclin, diltiazem

29. 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

30. Risk factors Drug-related factors Host-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

31. 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

32. Immunogenetic disposition together with race:
Genetic risk factors
Immunogenetic disposition together with race:
HLA-B*1502: Carbamazepine: SJS/TEN, DRESS; Han Chinese but not Caucasians
HLA-B*5801: Allopurinol: DHS/DRESS like, Han Chinese
HLA-B*5701: Abacavir: DRESS like, Caucasians, but not Hispanics or Africans

34. Pathogenesis of drug reaction
Hapten-carriers complex
“Complete Ag”: insulin, chymopapain
Haptenation or covalently binding to serum or cell surface proteins
Epitopes of immune response: drugs (hapten); the hapten-carrier complex (neo Ag); or the carrier protein ( self Ag.)
Generation of Penicillin Ags
Penicillin Ag + protein = minor Ag determinants( via covalent linkage) + major Ag determinants ( penicilloyl determinant)

35. 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

36. Hapten concept Binding of a chemically reactive structure to
penicillin
processing
Binding of a chemically reactive
structure to
soluble proteins (IgE, IgG) or
2) membrane bound proteins ( IgG + T-cell reactions)
3/4) the MHC-peptide complexes (I & II) directly ( only T-cells) Ig
Distinct clinical consequences of hapten carrier formation
depending on binding to soluble or cell bound proteins

37. Prohapten - Metabolism required - e. g
Prohapten - Metabolism required - e.g. Sulfamethoxazole Hypersensitivity -
sulfamethoxazole
sulfamethoxazole hydroxylamine
nitroso sulfamethoxazole
sulfamethoxazole protein conjugate
HYPERSENSITIVITY
ANTIGEN PROCESSING
IMMUNE RESPONSE
GSH
R = N O C H 3
To form an antigen, sulfamethoxazole is metabolised to via CYP P450 to a hydroxylamine metabolite. SMX NHOH circulates in blood and tissue and is excreatred unchanged in human urine. Further – autoxidation yeilds an unstable nitroso intermediate that can haptenate proteins, including the surface of viable lymphocytes and keratinocytes. The degree of tissue exposure to SMX NO is determined by the balance between oxidation of SMX and reduction of SMX-NO BY GSH. GSH is thought to be of particular importance in patients with HIV infection where GSH levels are lower tthan in healthy controls.
Cribb & Spielberg, 1992
Gill et al., 1997

38. sulfamethoxazole (SMX) metabolism inert reactive
Prohapten concept
sulfamethoxazole (SMX)
metabolism inert reactive
SMX-NO
Metabolism is required to generate reactive compounds, which then behave like haptens and bind to soluble and cell bound proteins.

39. The p-i-concept: Pharmacological interaction of drugs with immune receptors*
Binding of the drug to TCR, providing an initial signal
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

40. Diagnosis of drug allergy
Can it be a drug hypersensitivity ? If so, allergic or non-allergic?
Documentation of acute stage:
Documentation of the case (semiology, chronology, all drugs taken)
Documentation of the severity of symptoms, including laboratory analysis (suspected serious reactions)
Establish temporal relationship of drug intake to appearance of symptoms
Risk factors (underlying disease)
Rule out possible differential diagnosis
Identifying the responsible drug

41. Identifying the responsible drug
History
Experience with the drug: books indicating specific side effects of drugs
Definition of presumed pathomechanism (IgE, T-cell, IgG)
Skin tests with non toxic preparations of the drug
Skin prick test (SPT); Intradermal test (IDT)
Late reading IDT and patch tests
Serology/specific IgE
Drug specific IgE (available for few drugs only)
Basophil activation tests (in theory available for many drugs)
Coombs-test in the presence of drug in hemolytic anaemia
Lymphocyte transformation/activation test
Drug provocation tests (where 4-6 not available/ not validated)
The responsible drug is identified by a combination of history, clinical experience of
drug imputability and targeted tests
Skin and laboratory tests are performed 6 weeks after the acute stage
Type of test depending on whether diagnosing immediate or delayed reactions

42. Laboratory tests for serious reactions
Immediate reactions
Serum tryptase
Serum histamine
Delayed reactions
Complete blood count: eosinophilia and lymphocytosis, leukocytosis
Liver function tests:  ALT, AST, GT, ALP
 Serum creatinine
Urine microscopy and dipstick: nephritis, proteinuria
( CRP )
In late reactions certain laboratory tests are recommended to assess severity

43. Immediate reactions Serum tryptase
Plasma histamine
Serum tryptase
24-hr Urinary histamine metabolite
An elevated level supports a diagnosis of anaphylaxis.
Normal levels do not exclude anaphylaxis.

44. Delayed reactions Patch tests
Drug patch tests are positive in 32–50% of patients who have developed a cutaneous drug eruption
Advantages
Usually positive in AGEP, maculopapular rash, photodermatoses, lichenoid rash, fixed drug eruption
Frequently positive for betalactam antibiotics, especially amoxicillin, cotrimoxazole, corticosteroids, heparin derivatives, pristinamycin, carbamazepine, diltiazem, diazepam, hydroxyzine, pseudoephedrine, tetrazepam
Disadvantages
Low sensitivity (at best 50%)
Lack of standardized test reagents.
Barbaud A, et al. Contact Dermatitis, 2001, 45, 321–328
Barbaud A. Toxicology 2005; 209:209–216

45. Acute Generalized Exanthematous Pustulosis (AGEP) - Patch Tests
Patch tests are frequently positive
The patch test reaction at 48 hrs
imitates the early phase of the
disease with T-cell infiltration
After 96 hrs, pustule formation
can be observed.
Courtesy: Pichler WJ

46. Drug Provocation Tests (DPT)
Risks/benefits explained to patient
Informed consent
Cessation of antihistamine
short-acting (chlorpheniramine, hydroxyzine) days
long-acting (cetirizine, loratidine, fexofenadine) days
Fasted overnight
Careful observation with resuscitation equipment.
Aberer W, et al. ENDA, the EAACI interest group on drug hypersensitivity. Drug provocation testing in the diagnosis of drug hypersensitivity reactions: general considerations.
Allergy 2003; 58:854-63

47. Treatment Stop the suspected drug/ drugs
Resuscitation in serious reactions
ABC (airway, breathing, circulation) in anaphylaxis
Drugs:
Antihistamine: i/v, oral.
i/m epinephrine: anaphylaxis
Systemic corticosteroids: for DiHS, SJS
High dose IVIG 1g/kg/d x 2 days : for early TEN/SJS overlap, TEN
Emollients & Skin care
Hydration and prevention of skin superinfection (TEN)

48. Treatment Inpatient: observation, i/v, skin care, allergist referral
Angioedema (oropharyngeal/laryngeal), anaphylaxis
Severe skin: bullous drug eruption, EM/SJS/TEN
Systemic symptoms: fever, lymphadenopathy, organomegaly
possibly > 1 implicated drug
Outpatient
Urticaria/ maculopapular rash
Fixed drug eruption
Drug allergy without systemic symptoms
When to refer to allergist
Uncertain whether the reaction was drug allergy
Uncertain which drug: need for re-evaluation and specific testing
Desensitization

49. Desensitization
Making a patient tolerant to a drug he/she is allergic to
When there are no reasonable alternatives
Contraindicated: SJS/TEN
Not contraindicated: anaphylaxis
Patient still considered allergic to the drug
Rapid desensitization
immediate hypersensitivity: penicillin G, insulin
Slow desensitization
delayed hypersensitivity: allopurinol, sulphasalazine, TB drugs, SMX

50. Desensitization Possible mechanisms (IgE-mediated reactions)
Consumption of IgE in immune complexes
Hapten inhibition
Mediator depletion from mast cells and basophils
Antigen specific mast cell desensitization
Recent research models
Cross-linking of inhibitory receptors on mast cells
In-vitro desensitization of human mast cells depletes syk, an upstream signal transducing molecule necessary for IgE signalling
Mechanism in delayed reactions unknown

51. Prevention Patient Education Potentially cross-reacting drugs
Medic Alert cards/bracelets
Pharmacovigilance
Notify local drug regulatory agencies
Electronic Medical Records