Delayed type drug hypersensitivity

• 1. Delayed type drug hypersensitivity Boonthorn 2 August 2010

2. Outline Pathomechanism Classification Clinical feature MP rash DRESS/DiHS, SJS/TEN, AGEP Allergologic workup In vivo test In vitro test 3. How drugs are recognized by the immune system?Pathomechanism 4. Hapten and prohapten concepts and noncovalent drug presentation to T cells Med Clin N Am 94 (2010) 645664 5. Acylation of lysine residues in serum or cell surface proteins results in penicilloyl or major antigenic determinant. From its isomer penicillanic acid, other covalent linkages to macromolecules can occur to produce a variety of less common and/or less dominant minor epitopes. Middletons allergy. Seventh edition. 6. Sulfonamide metabolism and haptenation. Sulfonamides are metabolized by N4-oxidation by cytochrome P450 enzymes or by N4-acetylation. N-acetyl sulfonamides and glutathionyl (GSH) sulfonamides are then excreted. Free sulfonamides, N-acetyl sulfonamides, and GSH sulfonamides have the potential to act as univalent inhibitors of antibody-mediated reactions. Carrier haptenation can occur after N-oxidation if the capacity for GSH conjugation is exceeded Middletons allergy. Seventh edition. 7. The pi concept of T lymphocyte activation. The drug happens to fit into some TCR (1) with sufficient affinity to cause a signal. This drug-TCR interaction is supplemented by MHC interaction (2). The T cells react and proliferate. No metabolism of drugs required. The reactive T cell is probably preactivated and has an additional peptide specificity. Middletons allergy. Seventh edition. 8. Evidence for p-i mechanism : Aldehyde-fixed APC are still able to activate specific TCC if incubated together with drug drug binding to proteins more labile than covalent interactions of haptens and can be washed away Calcium influx in TCC happens within seconds ; before drug uptake, metabolism, and processing can occur clinical features of p-i concept are as follows: Positive skin test reactions to inert drugs, although no cutaneous metabolism of this peculiar drug is known Immune reactivity at first encounter, without time of sensitization Higher risk in viral infections, to lower threshold for T cell reactivity Fulminant course (as with superantigen stimulations) reflects abnormal T-cell stimulation with massive/fatal self- destruction as seen in SJS/TEN and DRESS/DiHS Med Clin N Am 94 (2010) 645664 9. ALTEX 24, Special Issue 2007 10. Classification 11. Classifying drug hypersensitivityMed Clin N Am 94 (2010) 665679 12. Characteristic chronology of drug-induced eruptions. separation at 1 hour into immediate or nonimmediate reactions not sufficiently reflect large overlap between pathophysiologically determined immediate- and delayed-type clinical manifestationsMed Clin N Am 94 (2010) 711725 13. Revised Gell and Coombs classification of drug reactions Med Clin N Am 94 (2010) 645664 14. T cell orchestrated hypersensitivity reactions (Gell and Coomb's types IVad) Middletons allergy. Seventh edition. 15. Clinical feature 16. Maculopapular or morbilliform exanthema most common initially with erythematousmacules and infiltrated papules,affecting particularly trunk andproximal ext. (Classic) appear after 7 to 10days DDx : classic infectiousexanthems eg. measles andrubella In more severe reactions,elevated eosinophil counts (~ 50%of pts.) Common elicitors : ATB(aminopenicillins and quinolones),antiepileptic drugs, RCM First signs eg. discrete erythemamay even appear after a fewMed Clin N Am 94 (2010) 665679hours 17. Systemic danger signs for severe delayed-type reactions Fever Malaise Prolonged clinical symptoms after discontinuation of the causative drug Lymphadenopathy Eosinophilia >1.5* 109 cells /liter Liver involvementMed Clin N Am 94 (2010) 665679 18. Cutaneous danger signs for severe delayed-type reactions 19. Central facial erythematous swelling in DRESS syndrome (left), SJS (middle), and TEN (right) (diffuse erythematous swelling)Med Clin N Am 94 (2010) 681689 20. Atypical target lesions( SJS/TEN ) Typical target lesions < 3 cm in diameter with a only 2 zones, are mostly regular round shape,flat, and irregular shape well-defined border, and darker color and 2 concentric rings around sometimes central a central diskblister Med Clin N Am 94 (2010) 681689 21. Positive Nikolsky sign in edematous, erythematous skin indicating necrolytic detachment of epidermis in SJS/TEN Med Clin N Am 94 (2010) 681689 22. Severe mucositis in a patient with TEN, manifesting >1 day before epidermolysis of skin was detectable Med Clin N Am 94 (2010) 681689 23. Cutaneous danger signs for severe delayed- type reactions Involvement of large body surfaces or erythroderma Painful skin, skin tender to touch Hemorrhagic necrotizing lesions PurpuraMed Clin N Am 94 (2010) 681689 24. Clinical symptoms and laboratory findings of DIHS/DRESSMed Clin N Am 94 (2010) 743759 25. Face swelling in early manifestation of DRESS syndrome occurs in 1 in 1,000 -10,000 exposures toantiepileptic drugs 2 -12 weeks afterinitiation of specificdrug therapy Mortality ~ 10% anticonvulsants,dapsone, allopurinol,and minocycline DDx : viral infection( EBV, CMV ),autoimmune Med Clin N Am 94 (2010) 691710 26. Diagnostic criteria for DRESS MP rash developing > 3 weeks after starting with drugs Prolonged clinical symptoms after discontinuation of causative drug Leukocyte abnormalities (at least 1 present): Leukocytosis (>11 * 109 cells / liter) Atypical lymphocytosis (>5%) Eosinophilia (>1.5 * 109 cells / liter) Lymphadenopathy Fever (>38C) Liver abn. (ALT >100 U/L) or other organ involvement HHV 6 reactivation (during 2nd to 3rd week after startMed Clin N Am 94 (2010) 665679 of symptoms) 27. Time interval between onset and visceral involvements during course of DIHS/DRESSMed Clin N Am 94 (2010) 743759 28. Visceral organ involvements in acute stage Hepatitis most common (~70%) If icteric, poorer prognosis Coagulopathy in severe case Steroid benefit in fulminant hepatitis In Europe, 1 mg/kg/d of prednisolone recommended, if ALT >500 IU, Tapering according to clinical course, too early CS reduction tends to transient exacerbations NAC ( case report, 24g/d over 3 d ) Nephritis ~11% kidney biopsy : AIN with lymphocytic infiltrate and ATN ( case SSZ ) Hemophagocytic syndrome (HPS) Rare triggered by viral infection, malignant tumors, or autoimmune diseases Myocarditis Rare Med Clin N Am 94 (2010) 743759 29. Autoimmune diseases after clinical resolution of DIHS/DRESSMed Clin N Am 94 (2010) 743759 30. TOXIC EPIDERMAL NECROLYSIS typical purulent blepharitisMed Clin N Am 94 (2010) 727742 31. SJS and TEN incidence of TEN 1.89 cases per million per year Genetic susceptibility HLA-B*1502, SJS, carbamazepine in Han Chinese ( OR =2504 ), not in Europe HLA-B*5801, SJS and TEN , allopurinol (OR= 80) independent of ethnic background differential diagnoses EM major Autoimmune bullous disorder: Linear IgA bullous dermatosis, BP, paraneoplastic pemphigus SSSSAm J Clin Dermatol 2003. 32. Clinical features that distinguish SJS, SJS-TEN overlap, and TEN Med Clin N Am 94 (2010) 727742 33. Drugs with high risk of inducing SJS/TEN Antibiotics TMP/SMX Aminopenicillin Cephalosporin Quinolone Anticonvulsant Carbamazepine Phenytoin Phenobarbital Nevirapine Oxicam-NSAID Allopurinol(most common in Europe and Israel )Med Clin N Am 94 (2010) 727742 34. Management and Therapy Prompt withdrawal of culprit drugs and supportive care Drug therapy , specific therapy does not exist High-dose IVIg 8 /11 studies may be benefit of IVIG used (>2 g/kg over 3 to 4 days ) on mortality ( TEN ) CsA : insufficient to draw conclusions Systemic steroid : remains controversial prevention of ocular complications Med Clin N Am 94 (2010) 727742 35. SCORTEN severity-of-illness score SCORTEN Parameter IndividualSCORTEN (SumPredicted Score of Individual Mortality Scores) (%) Age>40 yearsYes = 1, No = 0013.2malignancyYes = 1, No = 0 212.1Tachycardia (>120/min)Yes = 1, No = 0 335.8Initial surface ofYes = 1, No = 0 458.3 Epidermal detachment >10% Serum urea >10 mmol/L Yes = 1, No = 0590 ( 28 mg/dl ) Serum glucose >14 mmol/LYes = 1, No = 0 (252 mg/dl ) Bicarbonate males mean age 56 years Treatment Exclude infectious dis. intermediate to highdoses of systemiccorticosteroids overseveral days local corticosteroids ofhigh potency appliedfor 5 - 10 daysMed Clin N Am 94 (2010) 727742 37. Differential diagnoses of AGEP Generalized pustular psoriasis Subcorneal pustulosis Subcorneal IgA dermatosis Infectious folliculitis Viral exanthema with secondary pustulation Sweet syndrome(neutrophilic dermatosis ) Med Clin N Am 94 (2010) 727742 38. Drugs with high risk for induction of AGEP Ampicillin/amoxicillin Pristinamycin Quinolone Anti-infective sulfonamides Terbinafine Hydroxychloroquine Diltiazem Med Clin N Am 94 (2010) 727742 39. Clinical featureSJS/TENAGEPHSS/DRESS Onset of reaction after taking 13 weeksA few days26 weeks medication Typical duration of reaction 13 weeks1 weekSeveral weeksFever++++++ +++Facial edema -+++++Pustules -+++ +Blisters ++++*+*Target lesions ++++/- +/-Mucosal involvement++++/- +/-Histological changes in the skin Epidermal necrcrosis Subcorneal pustuleLymphocyte infiltrateLymph node enlargement -+ +++Lymph node histology -- Lymphoid hyperplasiahepatitis++ +++++Other organ involvement++***+ +++**neutrophils ( )eosinophils-Atypical lymphocytes -- +* Tension blister; ** interstitial pneumonia, interstitial nephritis; *** tracheobrochial necrosis, tubular nephritis 40. Clinical feature SJS/TENAGEP HSS/DRESS MortalitySJS 1-5% 1 D with pure substances diluted at 10% in pet.& aq. or alcohol (alc.). aciclovir, carbamazepine or pseudoephedrine first diluted at 0.1% and 1,10% ( in severe CADR) Contact Dermatitis, 2001, 45, 321328 45. Drug Patch Testing value in generalized eczema, systemic contact dermatitis, baboon syndrome, MP rash , AGEP , lichenoid rash and fixed drug eruption less value in SJS, TEN, pruritus or vasculitis most frequent reports of positive patch tests Betalactam esp. amoxicillin, Cotrimoxazole corticosteroids , heparin derivatives ,2001, 45, 321328 Contact Dermatitis, 46. Reading of Patch test (ICDRG) criteria 47. Drug Patch Testing Negative results : drug metabolite not formed in skin no immune mechanism No concomitant factors eg. Viral infection Best vehicle not yet been determined steroid hormone (in alcohol) Corticosteroid ( in water& alcohol) Ganciclovir ( in water ) Positive results vary (10-60%) Contact Dermatitis, 2001, 45, 321328 48. Intradermal Tests (IDT) Contraindicated in SJS, TEN or LCV diluted sequentially (10-4, 10-3, 10-2 and 10-1) in phenolated saline or in 0.9% saline performed on extensor surface of arm, with small volume (0.04 ml) produces weal (4-6 mm) Readings performed at 30 min, 6 h and 1 D ( 1 week, if result are negative ) risk of eliciting relapse of initial CADR ( 3 minor incidents/30)Contact Dermatitis, 2001, 45, 321328 49. Intradermal test results positive for Patch test results positive for AX AX and AM and AM Nonimmediate skin test results Med Clin N Am 94 (2010) 805820 50. DrugsPatch test Intradermal test Aminopenicillins 10% in Pet.20-25 mg/ml Cephalosporins 10% in Pet.1/10 of full strength Pristinamycin10% in Pet. Quinolone30% in Pet. Or water 1/100 of full strength Co-trimoxazole 10% in Pet.1/100 of full strength Minocycline10% in Pet.Carbamazepine1%,10% in Pet.NSAIDs (oxicams) 1%,10% in Pet. 51. Lymphocyte Transformation Test most widely used test principle : simple proliferation test with Ag useful in MPE, pustular exanthema, bullous exanthema and DRESS cultured in presence of suspected drug for 6 days measured by incorporation of 3H-thymidine during DNA synthesis stimulation index (SI) >2 ( 3 for betalactam ) not necessarily associated with clinical severity Sensitivity 60- 70% (depends on drug tested,Immunol Allergy Clin N Am 29 (2009) 537554 > skin test ) 52. Lymphocyte Transformation Test Specificity ~ 85% Perform in 1-6 mo. After event ( bullous dis., positive in first week of dis.) False positive :vancomycin, possibly paracetamol, and RCM False negative :abacavir disadvantages: requires sterile cell cultures takes a long time and cumbersome depends on quality of culture medium involves radioactivity, and expensive equipment Immunol Allergy Clin N Am 29 (2009) 537554 53. CD69 UP-REGULATION CD69 : membrane type II C-type lectin, transiently expressed on activated lymphocytes up-regulated in T cells from patients who had drug-induced MPE, erythema multiforme, SJS, and DRESS when assessed by flow cytometry comparable to LTT Advantage : not require radioactive substances and less time-consuming Disadvantage : flow cytometry-based test, difficult to standardizeImmunol Allergy Clin N Am 29 (2009) 537554 54. Immunol Allergy Clin N Am 29 (2009) 537554 55. Measurement Of Drug-induced Cytokine Production From Ex Vivo PBMC measurement of IL-2, IL-5, IL-13, and IFN- cytokines might be promising tool for detecting drug sensitization in delayed-type reactions ELISA or ELISPOT assay, or multiplexed bead- based flow cytometric assays, mRNA by RT- PCR IFN- ELISPOT assay exhibited high sensitivity and specificity since specific T cells were detected in 20/22 ( 91%) of amox-DTH patients only 1/26 nonDTH allergic patient had unexpected but weak reactivity to unrelated control antibioticImmunol Allergy Clin N Am 29 (2009) 537554Allergy 2009: 64: 534542 56. ELISA ELISPOT Immunol Allergy Clin N Am 29 (2009) 537554 57. Cytotoxicity: Granzyme B Enzyme Immunospot Assay gives results 48 to 72 hours after stimulation and not involve radioactivity Once cytotoxic T cells get activated, lytic granules reach plasma membrane, granzymes and perforin released into immunologic synapses, and cumulative exposure of granular membrane proteins (CD107a) can be measured on surface of responding cytotoxic cells, providing positive marker for degranulation seems to be most sensitive and robust method to detect cytotoxic cells in peripheral blood of drug-allergic patients Immunol Allergy Clin N Am 29 (2009) 537554 58. Cytotoxicity: Granzyme B Enzyme Immunospot AssayImmunol Allergy Clin N Am 29 (2009) 537554 59. When Should Diagnostic Tests Be Performed? recommend performing LTT within 1 week after onset of skin rashes in MP eruptions and SJS or TEN and > 5 to 8 weeks after event in DRESS some patients lose reactivity within 1 to 3 years after reaction many groups carry out tests after of 3 weeks- 6 months after acute event In vitro tests offer advantage of safety, simultaneous assessment of T-cell responses to multiple drugs, lack of risk for resensitization, and insight into pathomechanismImmunol Allergy Clin N Am 29 (2009) 537554 60. Conclusion Delayed type drug hypersensitivity classified by pathomechanism (type IVa- d) MP rash : most common SJS/TEN : most severe, treatment is supportive care ( may be try IVIg ) Skin test ( patch test, ID test ): low sensitivity In vitro test : LTT ( gold standard ), other test remained study 61. conclusionSJS/TENAGEPHSS/DRESS Onset of reaction after taking 13 weeksA few days26 weeks medication Typical duration of reaction 13 weeks1 weekSeveral weeksFever++++++ +++Facial edema -+++++Pustules -+++ +Blisters ++++*+*Target lesions ++++/- +/-Mucosal involvement++++/- +/-Histological changes in the skin Epidermal necrcrosis Subcorneal pustuleLymphocyte infiltrateLymph node enlargement -+ +++Lymph node histology -- Lymphoid hyperplasiahepatitis++ +++++Other organ involvement++***+ +++**neutrophils ( )eosinophils-Atypical lymphocytes -- +* Tension blister; ** interstitial pneumonia, interstitial nephritis; *** tracheobrochial necrosis, tubular nephritis 62. ConclusionSJS/TENAGEP HSS/DRESS Mortality SJS 1-5%