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DRESS AND AGEP

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DRESS AND AGEP

  1. 1. Adverse Cutaneous Drug Reactions – Drug reaction with eosinophilia and systemic symptoms(DRESS) ; Acute generalized exanthematous pustulosis(AGEP). Dr.Rohit Kr. Singh Resident ,Dermatology Base Hospital .Lko
  2. 2.  Introduction  Classification of drug reactions  Risk factors  Mechanism of drug reactions  Drug reaction with eosinophilia and systemic features(DRESS)  Acute generalized exanthematous pustulosis(AGEP)  Comparison b/w DRESS,SJS/TEN ,AGEP  Conclusion  References Contents
  3. 3. Definition of adverse drug reaction: Undesirable clinical manifestations resulting from administration of a particular drug ; this includes reactions due to overdose ,predictable side effects and unanticipated adverse manifestations. Skin is the most common site of drug reactions. Introduction
  4. 4. Adverse cutaneous drug reactions constitute from 24% to 29% of all ADRs . 2 – 3 % of all hospitalized patients experience drug rash. Upto 5 % of all patients on antibiotics experience drug rash. Around 2.5% of the children receiving medication ( 12 % if on antibiotics) Some facts about prevalence of drug reactions .
  5. 5. 1. Non –immunological 2. Immunological Predictable Unpredictable  Overdose Intolerance  Side effects Idiosyncrasy  Cumulation  Delayed toxicity  Facultative effects  Drug interactions  Metabolic alterations  Teratogenicity  Non –immunological activation of effector pathways  Exacerbation of disease  Drug induced chromosomal damage Classification of drug reactions
  6. 6. Immunological 1. IgE-dependent drug reactions 2. Immune-complex –dependent drug reaction 3. Cytotoxicity –induced reactions 4. Cell – mediated reactions.
  7. 7. Women > men Elderly patient (>65 yrs) Obese ( BMI > 30) Inappropriate medications Immunosuppressed patient Patients with Sjogren’s syndrome Antiphospholipid syndrome Dysthyroidism Risk factors for ADRs
  8. 8. Various mechanisms for drug reaction 1. Immune mediated mechanisms 2. Metabolic idiosyncrasies 3. Other mechanisms Mechanisms of drug reactions
  9. 9. Immune mediated Immediate hypersensitivity 1. Urticaria, 2. Angioedema, 3. Anaphylaxis Immune complex disease 1. Cutaneous small vessel vasculitis 2. Serum sickness 3. Lupus erythematosus Delayed hypersensitivity(cell- mediated immunity) 1. Allergic contact dermatitis 2. Systemic allergic contact dermatitis
  10. 10. Drug / Reactive drug metabolite Hapten Acts as antigen for the T-cells activation Drug specific CD4+ and CD8 + T-cells Recognize drugs through their T-cell receptors in an MHC dependent way Immune mediated mechanism
  11. 11. Metabolic idiosyncrasies Epoxide hydroxylase defficiency 1. Anti – convulsant hypersensitivity syndrome Slow acetylators 1.Lupus erythematosus
  12. 12. Other mechanisms Direct mast cell degranulation Aspirin ,NSAIDS,codeine-or radiocontrast –induced urticaria Protein c deficiency (heterozygotes) Warfarin –induced necrosis
  13. 13.  Defination: is a severe cutaneous event characterized by a  Triad of : 1. Skin eruptions , 2. Hematologic abnormalities[hypereosinophilia(80%) and atypical lymphocytes/mononucleosis (40%)], 3. Internal organ involvement( Acute and Late sequelae) . Heterogenesity of the initial presentation leads to it’s misdiagnosis as infection . Drug reaction with eosinophilia and systemic symptoms (DRESS).
  14. 14. Skin lesions can be : 1. Infiltrated papules(follicular or non – follicular) 2. Generalized papulopustular 3. Exanthematous rash 4. Exfoliative dermatitis
  15. 15. organ % of patient involvement Liver 80 Kidney 40 Pulmonary 33 Cardiac(myocarditis) 15 Pancreas 5 Hypothyroidism <5 CNS(encephalitis) <5 Incidence of organ involvment in DRESS Liver damage by eosinophilic infiltration.
  16. 16.  Other features include: 1. Fever(>38 ºcelcius). 2. Lymphadenopathy(benign lymphoid hyperplasia) . 3. Malaise 4. Pharyngitis and mucosal involvement 5. Facial oedema ( anticonvulsant induced reactions) Periorbital edema
  17. 17. Can occur with 1st exposure to drug. In case of previous exposure – symptoms develop within 1 day . Onset : b/w 3 wks and 2 months. Probability ranges : 1:1000 to 1:10,000. Genetic predisposition Progress to SJS or TEN. Mortality is about 10%
  18. 18. Progression of the DRESS Clinical symptoms can worsen even after withdrawal of the offending drug. Step by step development of several organ failure. Late sequel-Encephalitis ,type 1 DM and delayed hypothyroidism ,SIADH, long after discontinuation of the drug.
  19. 19. Dysfunction in drug metabolism and detoxification  Slow acetylators  Related to Epoxide Hydroxylase defficiency Leads to accumulation of toxic metabolite ARENE OXIDES Trigger immunological response Pathophysiology of DRESS
  20. 20. Generation of drug specific T-cell recognition Endothelial damage Reactivation of HHV-6,7; EBV, CMV, Hepatitis C virus A multiorgan T cell response ( TNF-α ,INF -γ ,IL-2) Increase in IL-5 Eosinophilia
  21. 21.  During the acute phase of DRESS ,regulatory Tcells (T-regs) are expanded and functionally more robust.  In late phase T-regs become functionally defficient as DRESS resolves ,perhaps allowing for the development of autoimmune disease. Cont…
  22. 22.  Intercurrent infection (URTI or UTI) in cases of maculopapular eruption in 58 % of cases. Mechanism  Transient drug induced hypogammaglobinemia is susceptible individuals creates an immunological environment that permits viral reactivation. Compications of the viral reactivation 1. The sequential reactivation of these virus may be responsible for the delayed onset ,paradoxical worsening of clinical features ,long after discontinuation of drug. 2. Sodium valproate directly induce HHV-6 replication. Viral reactivation theory
  23. 23.  Most common drugs causing DRESS Anti-convulsants Sulphonamides Phenytoin Anti-microbial agents Carbamazepine Dapsone Phenobarbital Sulfasalazine
  24. 24. Anticonvulsants Sulphonamides and related drugs Cabamazepine Dapsone Lamotrigine Sulfasalazine Phenobarbital Sulfonamide antibiotics Phenytoin Antiretroviral agents Miscellaneous drugs Indinavir Allopurinol Nevirapine Valdecoxib Other antibacterial agents Traditional chinese medicines Minocycline Nitrofurantoin vancomycin Other Drugs causing DRESS
  25. 25.  Cutaneous drug eruption  Hematologic abnormalities Eosinophilia > 1500/dl or Presence of atypical lymphocytes  Systemic involvement Adenopathies > 2 cm in a diameter Hepatitis (transaminases > 2N) or Interstitial pneumonitis or Interstitial nephritis or Carditis Proposed criteria of a diagnosis for drug rash with DRESS(Bocquet et al)
  26. 26. RegiSCAR inclusion criteria for DRESS( 3 required) 1 Hospitalization 2 Reaction suspected to be drug related 3 Acute rash 4 Fever > 38 celcius 5 Lymphadenopathy ( at 2 sites) 6 Internal organ involvement ( at least one ) 7 Blood counts abnormality (lymphopenia or lymphocytosis ,eosinophilia , thrombocytopenia)
  27. 27. Japanese consensus group diagnostic criteria for DRESS(7 needed or first 5 required) 1 Maculo-papular rash after >3 wks of starting of the drug 2 Prolonged clinical symptom 2wk after stopping suspected drug 3 Fever > 38 celcius 4 ALT > 100 U/L (liver or any other organ involvement ) 5 Leukocyte abnormality 6 Leukocytosis 7 Atypical leukocytosis ( > 5%) 8 Lymphadenopathy 9 HHV-6 reactivation
  28. 28. 1. Drug induced pseudolymphoma . 2. Other cutaneous drug reactions with systemic features. 3. Idiopathic hypereosinophilic syndrome 4. Lymphoma. 5. Acute viral infections( EBV,CMV,Hepatitis virus, influenza virus). Differential diagnosis
  29. 29. At present :  CBC with differential .  LFT.  S.creatinine  Other like – chest x rays etc for systemic investigation.  Baseline thyroid function tests (eg..TSH). At < 3 weeks  Repeat abnormal tests. At 3 weeks  Repeat blood work /investigation as clinically warranted. At 3 months  TSH.  Review warnings about cross-reacting drugs. Skin biopsy: if blistering or pustular eruption. Patch test : specially in case anticonvulsant-induced drug rash. Investigations for DRESS
  30. 30. Atypical lymphocyte 63 % Eosinophilia (>1500/dl) 52 % Lymphocytopenia 45 % Thrombocytopenia 25 % Lymphocytosis 25 % Incidence of hemtologic abnormality in DRESS syndrome
  31. 31. 1. Dyskeratosis 2. Basal vacuolation 3. Lymphocyte exocytosis 4. Dermal oedema 5. Superficial perivascular inflammation Histopathology of DRESS
  32. 32. Stop the offending drug . General management – hypothermia and fluid loss Prednisone at dose of 1-2 mg/kg daily if symptoms are severe ,with a slow taper , often over wks to months. IVIg dose = 0.4g/kg/day . Plamapheresis in combination with Rituximab. Cyclosporine dose = 3-5 mg/kg per day p.o or IV . Topical steroid. Antihistamines. Management of DRESS
  33. 33. Continuing management for systemic symptoms  Eye care  Oral care  Pulmonary care  And other organs involved
  34. 34.  Def: is characterized by a fever (>38 celcius) and a cutaneous eruption with non-follicular sterile pustules on an edematous erythematous background.  Onset of symptoms : within 2days to 2-3 weeks.  Abrupt onset. Acute generalized exanthematous pustulosis(AGEP)
  35. 35.  Scarletiniform eruptions starting from intertriginous areas, or face then spread to trunk and lower limbs.  Burning and itching sensation present.  Multiple small pinhead sized , 5mm non – follicular sterile pustules arise at the site of the rash.  Mucous membrane is involvement ( 20%) usually mild limited to oral mucosa.  After 2 weeks – generalized desquamation occurs after pustules subside. Clinical features of AGEP
  36. 36.  Additional skin lesion : 1.Petechial purpura 2.Erythema multiforme like target lesion 3.Vesicles or blister Fever. Malaise. Lymphadenopathy. No internal organ involvement .
  37. 37. Risk of superinfection can be life threatening in old and immunocompromised patient. Lethality is about 1%. Over all good prognosis. Progression of AGEP
  38. 38. 1.T-cell mediated reaction. 2.Drug – specific CD-4+ T-cells. IL-8 (CXCL8) produced by keratinocytes Infiltration of the neutrophils Other cytokines involved are IL-4,5 ;IFN-γ ;GM-CSF. 3.Viral infections(CMV,EBV) can also trigger the disease. Pathogenesis of AGEP
  39. 39. Most common offending drugs include 1. Amoxicillin 2. Ampicillin 3. Fluoroquinolones 4. Hyroxychloroquine 5. Terbinafine 6. Sulfonamides Drugs causing AGEP
  40. 40. Anticonvulsants Beta-lactam antibiotics other antibiotics CARBAMAZEPINE AMOXYCILLIN/AMPICILLIN CIPROFLOXACIN PHEYTOIN CEFACLOR DOXYCYCLINE Antifungal CEFUROXIME ISONIAZIDE ITRACONAZOLE CEPHALEXIN STREPTOMYCIN TERBINAFINE PENICILLIN SULPHONAMIDES Antimalarial agents MACROLIDE other drugs HYDROXYCHLOROQUINE AZITHROMYCIN ACETAMINOPHEN CALCIUM CHANNEL BLOCKERS ERYTHROMYCIN ALLOPURINOL DILTIAZEM SPIRAMYCIN DICLOFENAC NIFEDIPINE PRISTINAMYCIN MERCURY Other Drugs causing AGEP
  41. 41. 1. Pustular psoriasis 2. Bacterial folliculitis 3. Localized pustular contact dermatitis 4. Dermatophyte infection 5. Pyoderma vegetans 6. Varicella 7. Kaposi’s varicelliform eruption 8. Sweet’s syndrome 9. Behcet’s syndrome 10. Infantile chronic acropustulosis Differential diagnosis of AGEP
  42. 42. AGEP Pustular psoriasis History of psoriasis Possible Mostly Duration pattern Predominant in the folds More generalized Duration of pustules Shorter Longer Duration of fever Shorter Longer H/O drug reaction Usual Uncommon Recent drug administration Very frequent Less frequent Arthritis Rare 30% Histology Subcorneal or intraepidermal pustules,papillary edema,lymphohisti ocytic infiltrate Subcorneal and /or intraepiderma pustules,papillomatosis, acanthosis
  43. 43. Hematological investigations – Leukocytosis Neutrophilic(90%) Eosinophilia in 30% cases LFT and KFT can be abnormal. Patch test Lymphocyte transformation tests- suggest involvement of T cells in AGEP. Re-administration (re-challange) is not advised. Skin biopsy Lab. Diagnosis of AGEP
  44. 44.  Subcorneal or Intraepidermal pustules  Papillary oedema  Lymphohistiocytic infiltrate with some eosinophils and neutrophils Histopathology of AGEP
  45. 45. Contd… Subcorneal pustule Diffuse spongiosis Neutrophilic infiltration
  46. 46. MORPHOLOGY 1.PUSTULES Typical 2 Compatible 1 Insufficient 0 2.ERYTHEMA Typical 2 Compatible 1 insufficient 0 3.DISTRIBUTION Typical 2 Compatible 1 Insufficient 0 Validation Scoring system in AGEP by EuroSCAR study group A.
  47. 47. 4.POST –PUSTULAR DESQUAMATION Yes 1 No 0
  48. 48. COURSE 1.MUCOSAL INVOLVEMENT Yes 2 No 0 2.ACUTE ONSET (10 days) Yes 0 no 2 3.RESOLUTION(15 days) Yes 0 No 4 4.FEVER ( 38ºcelcius) Yes 1 No 0 5.PMNs (7000/mm3) Yes 1 No 0 B.
  49. 49. HISTOLOGY 1.Other disease 0 2.Exocytosis of PMNs 1 3.Subcorneal and/or intraepidermal non-spongioform or NOS pustules(s) with papillary edema or Subcorneal and/or intraepidermal spongiform or NOS Pustules with papillary edema 2 4.Spongiform subcorneal and/or intraepidermal pustules with papillary edema 3 C.
  50. 50. INTERPRETATION 0 No AGEP 1 – 4 Possible 5 – 7 Probable 8 - 12 Definite chance of AGEP Interpretation of the validation score
  51. 51. Stop the offending drug Supportive treatment Topical steroid Antihistamines Systemic steroid can also be given Severe cases – Infliximab ; etanercept Cyclosporine dose = 3-5 mg/kg/day. Management of the AGEP
  52. 52. Clinical sign’s DRESS SJS/TEN AGEP Onset of eruption 2-6 wks 1-3wks 48 hrs Duration of eruption Several wks 1-3 wks < 1 wks Fever +++ +++ +++ Infiltrated papules +++ - ++ Facial edema +++ - ++ Pustules + - +++ Blisters + +++ + Atypical targets Chelitis +++ Rarely Mucous membranes +++ +++ Rarely Lymphadenopathy +++ - + Other organ involvement +++ +++ +
  53. 53. Histological pattern DRESS SJS/TEN AGEP Histological pattern of the skin Lymphocytic infiltrate Epidermal necrolysis Subcorneal pustules Histology of lymphnode Lymphoid hyperplasia ,pseudolymphoma NA NA
  54. 54. LAB. values DRESS SJS/TEN AGEP Hepatitis +++ + + Neutrophils Normal or increase Decrease +++ Eosinophil +++ Normal + Atypical lymphocytes ++ - +
  55. 55. The identification of the responsible drug presents as a major challenge. Absence of any definitive diagnostic test. Unpredictable outcome due to some cases due to non-pharmacological additives. More focus on immune – mediated cutaneous drug reaction that can cause systemic complications. Conclusion
  56. 56. 1. FITZPATRICK’S DERMATOLOGY IN GENERAL MEDICINE 2. ROOK’S TEXTBOOK OF DERMATOLOGY 3. IADVAL TEXTBOOK AND ATLAS OF DERMATOLOGY BY R.G AND AMEET VALIA 4. DERMATOLOGICAL SIGNS OF INTERNAL DISEASE BY JEAN L BOLOGNIA 5. COMPREHENSIVE DERMATOLOGIC DRUG THERAPY BY STEPHEN E . WOLVERTON 6. JOURNAL IN CUTANEOUS PATHOLOGY( EUROPIAN JOURNAL) 7. ARCHIVES JOURNAL( JAMA) References
  57. 57. THANKYOU

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