Drug hypersensitivity syndrome

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1. drug hypersensitivity syndrome

2. drug hypersensitivity syndrome
3. drug hypersensitivity syndrome
(adverse drug reactions, ADR)
ADR
5-15%
(WHO) ADR

ADR 2 ( 1)
1. Type A reactions

80% ADR
1.1 Pharmacologic side effects antihistamine
1.2 Toxic effects hepatotoxicity methotrexate
1.3 Secondary effects broad spectrum antibiotic oral thrush
1.4 Drug interactions theophylline erythromycin theophylline
overdose
2. Type B reactions (hypersensitivity reaction)
15 - 20% ADR

2.1 Immune mediated (allergic) 5-10% ADR 3

a. IgE-mediated ADR urticaria, anaphylaxis
b. T cell-mediated ADR maculopapular rash, erythema multiforme
c. Other drug-induced lupus-like,
anticonvulsant hypersensitivity syndrome, drug reaction with eosinophilia
and systemic symptoms (DRESS)
2.2 Non-immune-mediated (non-allergic) 5-10% ADR

a. Idiosyncratic reaction
(pharmacokinetics)
hemolytic anemia G-6-PD deficiency primaquine
b. Drug intolerance toxicity side effect
c. Pseudoallergic reaction - mast cell
mediators IgE-mediated hypersensitivity reaction

opiates, vancomycin radiocontrast media

1 adverse drug reaction (from Thien FC. Med J Aust. 2006)

immune-mediated hypersensitivity syndrome

Drug hypersensitivity syndrome (Immune-mediated hypersensitivity
syndrome)
clinical diagnosis
iatrogenic illness
skin testing
drug hypersensitivity syndrome
1. 4 Gell and Coomb classification
2. hepatotoxic drug reaction, cutaneous drug reaction
3. phenobarbital

 2 immune-mediated
drug hypersensitivity syndrome
1. hypersensitivity

2. metabolite
(drug-protein conjugate),
(drug-cell conjugate)
hapten
antigen
tissue damage

drug hypersensitivity syndrome

1.
I. Type I ( IgE mediated) IgE mast cell mediators
urticaria, angioedema, bronchospasm anaphylaxis 1
-lactam
II. Type II antigen
complement life threatening
immune hemolytic anemia penicillin, immune thrombocytopenia
quinidine immune neutropenia thiouracils
III. Type III - antibody immune complex tissue
complement activation inflammation
1-3 serum sickness anti-thymocyte globulin, penicillin,
sulfonamides, phentytoin
IV. Type IV - present antigen presenting cell cell-mediated
reaction cytokine activation of macrophage

maculopapular morbiliform, bullous reaction, contact dermatitis

2. reactive metabolites metabolite non-toxic metabolites

metabolite HIV glutathione deficiency sulfa
epoxide hydrolase deficiency phenobarbital

 drug hypersensitivity syndrome

1. Host SLE beta-blocker
HIV, human herpes virus type 6

2. immunogenicity , (<1,000
dalton) immunogenicity protein (hapten)
3. topical, intramuscular, intravenous

drug hypersensitivity syndrome
anaphylaxis, urticaria, angioedema, asthma (IgEmediated), serum sickness, , hepatitis, interstitial nephritis, lupuslike syndromes (
3)
1

anaphylaxis
mucous membrane lesions, lymphadenopathy, joint tenderness, abnormal
pulmonary examination

biological immunologic marker

drug hypersensitivity syndrome
1. Type I hypersensitivity reaction
1.1 specific IgE 2
a. Skin testing 2 skin prick test intradermal skin test

penicillin, muscle relaxants, insulin,

biological agents gelofusine, streptokinase
b. Blood for specific IgE test radioallergosorbent test (RAST)
non-radioactive enzyme-linked immunosorbent assay (ELISA) specificity
sensitivity penicilin
1.2 mast cell activation serum histamine ( 5
30 ), serum tryptase ( 1
2-4)
2. Type II hypersensitivity reaction hemolytic anemia direct indirect
Coombs test

3. Type III hypersensitivity reaction nonspecific inflammatory marker

erythrocyte sedimentation rate, C-reactive protein complement level

(CH50, C3, C4) circulating immune complex specificity
4. Type IV hypersensitivity reaction skin patch test
5. Others
5.1 Lymphocyte transformation test T- lymphocyte mediated hypersensitivity
syndrome
5.2 Cytokine measurement IL-5 DRESS
6.Drug provocation test gold standard
- Severe life-threatening immunocytologic reaction
- Vasculitis syndrome
- Exfoliative dermatitis
- Erythema multiforme major (Steven-Johnson syndrome (SJS)) / Toxic epidermal
necrolysis (TEN)
- Drug reaction with eosinophilia and systemic symptoms (DRESS)

drug hypersensitivity syndrome

1. Specific treatment
1 2
2. Supportive and symptomatic treatment
2.1 Systemic steroid controversy SJS, Type II
hypersensitivity reaction
2.2 Topical steroid
2.3 Antihistamine
3. desensitization

drug hypersensitivity syndrome

1. (HIV sulfonamide, EBV aminopenicillin) phenobarbital
2. cross-reactivity phenobarbital phenytoin
carbamazepine, penicillins
3. skin tests penicillins
4.

 3 adverse drug reaction (from Riedl MA. Am Fam Physician. 2003)


3 generalized tonic seizure
diazepam phenobarbital ER acute otitis
media, status epilepticus phenobarbital, cefotaxime 10
generalized maculopapular rash source
of infection CBC: WBC 4,940/mcL N 49%, L 39%,
M 5%, E 7%, Hct 37%, Plt. 414,000/mcL, LFT: AST 212 IU/L, ALT 197 IU/L,
ALP 221 IU/L, GGT 109 IU/L, Alb 44 mg/dL, TB 0.4 mg/dL DB 0.1 mg/dL
Diagnosis : Drug reaction with eosinophilia and systemic symptoms (DRESS)
Treatment : phenobarbital, systemic steroid

Drug reaction with eosinophilia and systemic symptoms (DRESS)

Type B ADR immune-mediated hypersensitivity reaction
1:1,000 - 1:10,000 3 (triads)
hepatitis, pneumonitis, interstitial nephritis 1 4
3
DRESS
1. 90 100% 38-40oC
2. (rash) 90%
- Exanthema with or without pruritus
- Periorbital or facial edema ( 25%)
- Exudative tonsillitis, pharyngitis ( 10%), oral ulceration, and
conjunctivitis
- Exfoliative dermatitis or erythroderma, erythema multiforme, StevensJohnson syndrome, or toxic epidermal necrolysis
skin biopsy perivascular lymphocytic infiltrates
3. 60% generalized localized
4. Liver abnormalities 30 60% transaminases, alkaline
phosphatase, prothrombin time bilirubin severe hepatitis

liver biopsy periportal inflammation with or without necrosis

5. Hematologic abnormalities > 50%

- Lymphocytosis ( 65%) with atypical lymphocytes
- Leukocytosis
- Marked eosinophilia ( 30%)
- Anemia
- Others - leukopenia, thrombocytopenia, and aplastic anemia
6. myalgias, arthralgia, rhabdomyolysis, renal dysfunction,
pneumonitis, thyroiditis

 DRESS
1.
2.
3.
4.
5.
6.
7.
8.

Anticonvulsants: Phenytoin, carbamazepine, phenobarbital, lamotrigine

Antiviral drugs: Nevirapine, abacavir
Antibiotics: Trimethoprim, sulphonamides, dapsone, minocycline
Antituberculosis: Isoniazid
NSAIDs, Oxicams
Antihypertensive: Diltiazem, atenolol, captopril
Immunosuppressive: Azathioprine,
Others: Allopurinol, gold salts, sulphasalazine, mexiletine

acetylation metabolite Human herpes
virus 6
(triads) lymphocyte toxicity testing

supportive treatment corticosteroids

1. Gomes ER, Demoly P. Epidemiology of hypersensitivity drug reactions. Curr Opin

Allergy Clin Immunol 2005;5:309-16.
2. Thien FC. Drug hypersensitivity. Med J Aust 2006;185:333-8.
3. Greenberger PA. Drug allergy. J Allergy Clin Immunol 2006;117:S464-70.
4. Syn WK, Naisbitt DJ, Holt AP, Pirmohamed M, Mutimer DJ. Carbamazepineinduced acute liver failure as part of the DRESS syndrome. Int J Clin Pract
2005;59:988-91.
5. Naisbitt DJ. Drug hypersensitivity reactions in skin: understanding mechanisms and
the development of diagnostic and predictive tests.
Toxicology. 2004;194:179-96.
6. Morkunas AR, Miller MS. Anticonvulsant hypersensitivity syndrome. Crit Care Clin.
1997;13:727-39.
7. Riedl MA., Casillas Am. Adverse drug reactions: types and treatment options.
Am Fam Physician. 2003;68:1781-90.

1. 2 amoxicillin, paracetamol 1

generalized urticaria
A. Type I immune response
B. Type II immune response
C. Type III immune response
D. Type IV immune response
2. 5 penicillin .. 3
high fever, tonsil enlarge 3+ with exudate, cervical LN
enlargement with tender

A. amoxicillin

B. erythromycin

C. antibiotics

D. challenge test penicillin penicillin

3. 3 generalized tonic clonic seizure

phenobarbital 3 elevation of liver enzyme

A. phenobarbital
B. phenytoin
C. sodium valproate
D.
4. drug provacation test
A. Exfoliative dermatitis
B. Steven-Johnson syndrome
C. Vasculitis syndrome
D. Urticaria and angioedema
5. 5 amoxicillin 1
investigation
A. serum IgE
B. Skin prick test
C. coombs test
D. Complement level

1. A

2. B

3. D

4. B

5. D