Delayed type drug hypersensitivity

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  • rigid separation between immediate and nonimmediate reactions at 1 hour based on the chronology only may be problematic, because there is a considerable overlap of a period of approximately 2 to 6 hours between the reaction period of urticarial and exanthematous eruptions (see Fig. 2, Table 1). The terms immediate and delayed are also commonly used to depict the pathophysiology (ie, type I [IgE mediated]and type IV [T cell mediated]). This is most important with regard to the selection of appropriate diagnostic tests
  • Type IVa reactionscorrespond to Th1 reactions with high IFNg/TNFa secretion, and involve monocyte/macrophageactivation. CD8 cell recruitment (type IVc reaction) often occurs. Type IVb reactionscorrespond to eosinophilic inflammation and to a Th2 response with high IL-4/IL-5/IL-13secretion; they are often associated with an IgE-mediated type I reaction. Type IVc reactions:the cytotoxic reactions (by CD4 and CD8 cells) rely on cytotoxic T cells as effector cells (type IVc). They seem to occur in all drug-related delayed hypersensitivity reactions. Type IVd reactions correspond to a T-cell–dependent, sterile neutrophilic inflammatory reaction. It is distinct from the rapid influx of PMN in bacterial infections. It seems to be related to high CXCL-8/GM-CSF production by T cells
  • Erosive stomatitis; mucositis, especially if affecting more than one mucosa
  • typical dermoepidermal detachment and necrosis beneath the stratum corneum in SJS/TEN
  • Provocation test not well standardized in delayed reactions regarding dose, durationof symptoms, and definition of positivity, and are therefore difficult to perform
  • International Contact Dermatitis Research GroupIrritant reaction Controls show similar response or there was an excited skin responseDoubtful reaction Negative test result. Repeat readings at 3, 4, and 7 days after patch removed. If ACD still suspected, recheck technique or do ROAT1+Light erythema, nonvesicular Equivocal test result. Could either be negative or indicative of waning prior sensitization. False-positive test result or excited skin syndrome must be ruled out by test in control subject. Repeat steps in 3.2+ Edema, erythema, discrete vesicles Positive test result. Indicative of prior or current sensitization. Should correlate with history and physical findings. False-positive test result or excited skin syndrome must be ruled out by test in control subject3+ Coalescing vesiculobullous papules Strongly positive result.
  • (0.5% phenol in 0.9% saline)
  • large prospective study is required to evaluate this test and to determine sensitivity and specificity in drug hypersensitivity diagnosisThis prospective study is currently being performed by the authors’ drug allergy research group in Bern
  • necessary to evaluate anaccurate cutoff for positivity and the exact sensitivity and specificity of these assays
  • Delayed type drug hypersensitivity

    1. 1. Delayed type drug hypersensitivity Boonthorn 2 August 2010
    2. 2. Outline  Pathomechanism  Classification  Clinical feature ◦ MP rash ◦ DRESS/DiHS, SJS/TEN, AGEP  Allergologic workup ◦ In vivo test ◦ In vitro test
    3. 3. How drugs are recognized by the immune system? Pathomechanism
    4. 4. Hapten and prohapten concepts and noncovalent drug presentation to T cells Med Clin N Am 94 (2010) 645–664
    5. 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. Middleton’s allergy. Seventh edition.
    6. 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 Middleton’s allergy. Seventh edition.
    7. 7. The p–i 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. Middleton’s allergy. Seventh edition.
    8. 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) 645–664
    9. 9. ALTEX 24, Special Issue 2007
    10. 10. Classification
    11. 11. Classifying drug hypersensitivity Med Clin N Am 94 (2010) 665–679
    12. 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 manifestations Med Clin N Am 94 (2010) 711–725
    13. 13. Revised Gell and Coombs classification of drug reactions Med Clin N Am 94 (2010) 645–664
    14. 14. T cell orchestrated hypersensitivity reactions (Gell and Coomb's types IVa–d) Middleton’s allergy. Seventh edition.
    15. 15. Clinical feature
    16. 16. Maculopapular or morbilliform exanthema  most common  initially with erythematous macules and infiltrated papules, affecting particularly trunk and proximal ext.  (Classic) appear after 7 to 10 days  DDx : classic infectious exanthems eg. measles and rubella  In more severe reactions, elevated eosinophil counts (~ 50% of pts.)  Common elicitors : ATB (aminopenicillins and quinolones), antiepileptic drugs, RCM  First signs eg. discrete erythema may even appear after a few Med Clin N Am 94 (2010) 665–679 hours
    17. 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 involvement Med Clin N Am 94 (2010) 665–679
    18. 18. Cutaneous danger signs for severe delayed-type reactions
    19. 19. Central facial erythematous swelling in DRESS syndrome (left), SJS (middle), and TEN (right) (diffuse erythematous swelling) Med Clin N Am 94 (2010) 681–689
    20. 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 disk blister Med Clin N Am 94 (2010) 681–689
    21. 21. Positive Nikolsky sign in edematous, erythematous skin indicating necrolytic detachment of epidermis in SJS/TEN Med Clin N Am 94 (2010) 681–689
    22. 22. Severe mucositis in a patient with TEN, manifesting >1 day before epidermolysis of skin was detectable Med Clin N Am 94 (2010) 681–689
    23. 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  Purpura Med Clin N Am 94 (2010) 681–689
    24. 24. Clinical symptoms and laboratory findings of DIHS/DRESS Med Clin N Am 94 (2010) 743–759
    25. 25. Face swelling in early manifestation of DRESS syndrome  occurs in 1 in 1,000 - 10,000 exposures to antiepileptic drugs  2 -12 weeks after initiation of specific drug therapy  Mortality ~ 10%  anticonvulsants, dapsone, allopurinol, and minocycline  DDx : viral infection ( EBV, CMV ), autoimmune Med Clin N Am 94 (2010) 691–710
    26. 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 (>38ºC)  Liver abn. (ALT >100 U/L) or other organ involvement  HHV 6 reactivation (during 2nd to 3rd week after start Med Clin N Am 94 (2010) 665–679 of symptoms)
    27. 27. Time interval between onset and visceral involvements during course of DIHS/DRESS Med Clin N Am 94 (2010) 743–759
    28. 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) 743–759
    29. 29. Autoimmune diseases after clinical resolution of DIHS/DRESS Med Clin N Am 94 (2010) 743–759
    30. 30. TOXIC EPIDERMAL NECROLYSIS typical purulent blepharitis Med Clin N Am 94 (2010) 727–742
    31. 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 ◦ SSSS Am J Clin Dermatol 2003.
    32. 32. Clinical features that distinguish SJS, SJS-TEN overlap, and TEN Med Clin N Am 94 (2010) 727–742
    33. 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) 727–742
    34. 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) 727–742
    35. 35. SCORTEN severity-of-illness score SCORTEN Parameter Individual SCORTEN (Sum Predicted Score of Individual Mortality Scores) (%) Age>40 years Yes = 1, No = 0 0–1 3.2 malignancy Yes = 1, No = 0 2 12.1 Tachycardia (>120/min) Yes = 1, No = 0 3 35.8 Initial surface of Yes = 1, No = 0 4 58.3 Epidermal detachment >10% Serum urea >10 mmol/L Yes = 1, No = 0 5 90 ( 28 mg/dl ) Serum glucose >14 mmol/L Yes = 1, No = 0 (252 mg/dl ) Bicarbonate <20 mmol/L Yes = 1, No = 0 Med Clin N Am 94 (2010) 727–742 Average mortality : SJS 1- 5%, and TEN 25- 35%
    36. 36. Acute generalized exanthematous pustulosis  5 cases per million annually  females > males  mean age 56 years  Treatment ◦ Exclude infectious dis. ◦ intermediate to high doses of systemic corticosteroids over several days ◦ local corticosteroids of high potency applied for 5 - 10 days Med Clin N Am 94 (2010) 727–742
    37. 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) 727–742
    38. 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) 727–742
    39. 39. Clinical feature SJS/TEN AGEP HSS/DRESS Onset of reaction after taking 1–3 weeks A few days 2–6 weeks medication Typical duration of reaction 1–3 weeks 1 week Several weeks Fever +++ +++ +++ Facial edema - ++ +++ Pustules - +++ + Blisters +++ +* +* Target lesions +++ +/- +/- Mucosal involvement +++ +/- +/- Histological changes in the skin Epidermal necrcrosis Subcorneal pustule Lymphocyte infiltrate Lymph node enlargement - + +++ Lymph node histology - - Lymphoid hyperplasia hepatitis ++ ++ +++ Other organ involvement ++*** + +++** neutrophils ( ) eosinophils - Atypical lymphocytes - - + * Tension blister; ** interstitial pneumonia, interstitial nephritis; *** tracheobrochial necrosis, tubular nephritis
    40. 40. Clinical feature SJS/TEN AGEP HSS/DRESS Mortality SJS 1-5% <5% 10% TEN 25-35% Drug Nevirapine Aminopenicillins Carbamazepine Allopurinol Cephalosporins Phenytoin Phenytoin Pristinamycin Lamotrigine Carbamazepine Quinolone Minocycline Lamotrigine Macrolides Allopurinol Co-trimoxazole Terbinafine Dapsone Barbiturate Celecoxib Sulfasalazine NSAIDs (oxicams) Diltiazem Co-trimoxazole
    41. 41. Allergologic Work Up
    42. 42. Tests for detection of drug-specific T cells in patients with delayed-type drug hypersensitivity Immunol Allergy Clin N Am 29 (2009) 537–554
    43. 43. Guidelines in drug skin testing  performed 6 weeks to 6 months after complete healing of CADR  at least 1 month after discontinuation of systemic corticosteroid or immunosuppressive therapy  not to test during pregnancy Contact Dermatitis, 2001, 45, 321–328
    44. 44. Drug Patch Testing  performed on upper back using Finn Chambers  read at 20 min, D2 and D4 ,D7 (if negative on D4)  In FDE, should be performed both on normal skin and on residual pigmented site of FDE  with commercialized drug ◦ Incorporated at 30% in pet. and aq. ◦ made for only 1 patient and kept no > 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, 321–328
    45. 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, 321–328 Contact Dermatitis,
    46. 46. Reading of Patch test (ICDRG) criteria
    47. 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, 321–328
    48. 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, 321–328
    49. 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) 805–820
    50. 50. Drugs Patch test Intradermal test Aminopenicillins 10% in Pet. 20-25 mg/ml Cephalosporins 10% in Pet. 1/10 of full strength Pristinamycin 10% in Pet. Quinolone 30% in Pet. Or water 1/100 of full strength Co-trimoxazole 10% in Pet. 1/100 of full strength Minocycline 10% in Pet. Carbamazepine 1%,10% in Pet. NSAIDs (oxicams) 1%,10% in Pet.
    51. 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) 537–554 > skin test )
    52. 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) 537–554
    53. 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 standardize Immunol Allergy Clin N Am 29 (2009) 537–554
    54. 54. Immunol Allergy Clin N Am 29 (2009) 537–554
    55. 55. Measurement Of Drug-induced Cytokine Production From Ex Vivo PBMC  measurement of IL-2, IL-5, IL-13, and IFN-γ 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-γ 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 antibiotic Immunol Allergy Clin N Am 29 (2009) 537–554 Allergy 2009: 64: 534–542
    56. 56. ELISA ELISPOT Immunol Allergy Clin N Am 29 (2009) 537–554
    57. 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) 537–554
    58. 58. Cytotoxicity: Granzyme B Enzyme Immunospot Assay Immunol Allergy Clin N Am 29 (2009) 537–554
    59. 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 pathomechanism Immunol Allergy Clin N Am 29 (2009) 537–554
    60. 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. 61. conclusion SJS/TEN AGEP HSS/DRESS Onset of reaction after taking 1–3 weeks A few days 2–6 weeks medication Typical duration of reaction 1–3 weeks 1 week Several weeks Fever +++ +++ +++ Facial edema - ++ +++ Pustules - +++ + Blisters +++ +* +* Target lesions +++ +/- +/- Mucosal involvement +++ +/- +/- Histological changes in the skin Epidermal necrcrosis Subcorneal pustule Lymphocyte infiltrate Lymph node enlargement - + +++ Lymph node histology - - Lymphoid hyperplasia hepatitis ++ ++ +++ Other organ involvement ++*** + +++** neutrophils ( ) eosinophils - Atypical lymphocytes - - + * Tension blister; ** interstitial pneumonia, interstitial nephritis; *** tracheobrochial necrosis, tubular nephritis
    62. 62. Conclusion SJS/TEN AGEP HSS/DRESS Mortality SJS 1-5% <5% 10% TEN 25-35% Drug Nevirapine Aminopenicillins Carbamazepine Allopurinol Cephalosporins Phenytoin Phenytoin Pristinamycin Lamotrigine Carbamazepine Quinolone Minocycline Lamotrigine Macrolides Allopurinol Co-trimoxazole Terbinafine Dapsone Barbiturate Celecoxib Sulfasalazine NSAIDs (oxicams) Diltiazem Co-trimoxazole

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