Drug Eruptions When to Worry 1. Type of drug reaction 2. Statistics: - PDF document

3/17/2017 Drug reactions: 3 things you need to know Drug Eruptions ‐ When to Worry 1. Type of drug reaction 2. Statistics: – Which drugs are most likely to cause that type of Lindy P. Fox, MD reaction? 3. Timing: Associate Professor Director, Hospital Consultation Service – How long after the drug started did the reaction Department of Dermatology begin? University of California, San Francisco lindy.fox@ucsf.edu I have no conflicts of interest to disclose 1 Drug Eruptions: Common Causes of Cutaneous Drug Degrees of Severity Eruptions • Antibiotics Simple Complex • NSAIDs Morbilliform drug eruption Drug hypersensitivity reaction Stevens-Johnson syndrome • Sulfa (SJS) Toxic epidermal necrolysis • Allopurinol (TEN) Minimal systemic symptoms • Anticonvulsants Systemic involvement Potentially life threatening 1

3/17/2017 Morbilliform (Simple) Drug Eruption Morbilliform (Simple) Drug Eruption Pe r the drug chart, the most likely culprit is: Pe r the drug chart, the most likely culprit is: Day Day Day ‐ > ‐ 8 ‐ 7 ‐ 6 ‐ 5 ‐ 4 ‐ 3 ‐ 2 ‐ 1 0 1 Day ‐ > ‐ 8 ‐ 7 ‐ 6 ‐ 5 ‐ 4 ‐ 3 ‐ 2 ‐ 1 0 1 A vancomycin x x x x A vancomycin x x x x B metronidazole x x B metronidazole x x C ceftriaxone x x x C ceftriaxone x x x D D norepinephrine x x x norepinephrine x x x E omeprazole x x x x E omeprazole x x x x F SQ heparin x x x x F SQ heparin x x x x trimethoprim/ trimethoprim/ G G x x x x x x x x x x x x x x sulfamethoxazole sulfamethoxazole Admit day Rash onset Admit day Rash onset Morbilliform (Simple) Drug Eruption Drug Induced Hypersensitivity Syndrome • Begins 5 ‐ 10 days after drug started • Skin eruption associated with systemic symptoms and • Erythematous macules, papules alteration of internal organ function • Pruritus • “ DRESS ” ‐ Drug reaction w/ eosinophilia and systemic • No systemic symptoms symptoms • Risk factors: EBV, HIV infection • “ DIHS ” = Drug induced hypersensitivity syndrome • Treatment: • Begins 2 ‐ 6 weeks after medication started – D/C medication – time to abnormally metabolize the medication – diphenhydramine, topical steroids • Role for viral reactivation, esp HHV6 • Resolves 7 ‐ 10 days after drug stopped • Mortality 10% – Gets worse before gets better 2

3/17/2017 Hypersensitivity Reactions Drug Induced Hypersensitivity Syndrome Drugs • Aromatic anticonvulsants • Each class of drug causes a slightly different clinical picture – phenobarbital, carbamazepine, phenytoin • Facial edema characteristic of all – THESE CROSS ‐ REACT • Anticonvulsants: • Sulfonamides – 3 weeks • Lamotrigine – Atypical lymphocytosis, hepatic failure • Dapsone: • Dapsone • Allopurinol (HLA ‐ B*5801) – 6 weeks – No eosinophilia • NSAIDs • Allopurinol: • Other – 7 weeks – Abacavir (HLA ‐ B*5701) – Nevirapine (HLA ‐ DRB1*0101) – Elderly patient on thiazide diuretic – Minocycline, metronidazole, azathioprine, gold salts – Renal failure – Requires steroid sparing agent to treat (avoid azathioprine) • Each class of drug causes a slightly different clinical picture DIHS ‐ Clinical Features Hypersensitivity Reactions Treatment • Stop the medication • Rash – FACIAL EDEMA • Follow CBC with diff, LFT ’ s, BUN/Cr • Fever (precedes eruption by day or more) • Avoid cross reacting medications!!!! • Pharyngitis – Aromatic anticonvulsants cross react (70%) • Hepatitis • Phenobarbital, Phenytoin, Carbamazepine • Arthralgias • Valproic acid and Keppra generally safe • Lymphadenopathy • Systemic steroids (Prednisone 1.5 ‐ 2mg/kg) • Hematologic abnormalities – Taper slowly ‐ 1 ‐ 3 months – eosinophilia • Allopurinol hypersensitivity may require steroid – atypical lymphocytosis sparing agent • Other organs involved • NOT azathioprine (also metabolized by xanthine oxidase) – Interstitial pneumonitis, interstitial nephritis, thyroiditis • Completely recover, IF the hepatitis resolves – Myocarditis ‐ acute eosinophilic mycocarditis or acute necrotizing eosinophilic myocarditis • Check TSH monthly for 6 months • EKG, echocardiogram, cardiac enzymes • Watch for later cardiac involvement (low EF) 3

3/17/2017 Consult: 2 days of redness, pustules, Acute generalized exanthematous pustulosis Clinical Features neutrophilia on azithromycin for bronchitis • Acute onset • Fever, neutrophilia • Edema (face, hands) • Additional morphologies – purpura, vesicles, bullae, erythema multiforme ‐ like lesions • Mucous membrane lesions! • May mimic pustular psoriasis • Typically resolves within 2 weeks of stopping medication, but may require systemic steroids Acute Generalized Exanthematous Consult: 5 days of painful red lesion Pustulosis = Pustular Drug Eruption after taking tylenol for headache • EuroSCAR (97 cases of AGEP, 1009 controls): – Macrolides BJD 2007 Nov;157(5):989-96. – Ampicillin/amoxicillin – Quinolones – (hydroxy)chloroquine – Sulphonamides – Terbinafine – Diltiazem – No infections found – Not associated with personal or family history of psoriasis • Mercury • Enterovirus infection Amantadine 4

3/17/2017 Consult: Blisters after starting Fixed Drug Eruption vancomycin • Morphology – Annular red plaque – Can have central bulla – Heals with marked hyperpigmentation • Pain is the major symptom • Limited number of lesions • “ Fixed ” is a curious phenomenon – if patient takes the same medication again, the same spots light up • Spontaneously resolves Drug-Induced Linear IgA Disease Drug-Induced Linear IgA Disease • Immune-mediated subepidermal blistering disease • Others Common causes – Vancomycin – Amiodarone – Antigen: 97 kDa of BPAG2 (BP180) – Penicillins – Sulfamethoxazole – DIF: band-like (linear) IgA deposition at DEJ – Cephalosporins – Diclofenac • Clinical features – Captopril – Furosemide – Subepidermal blisters accentuated in flexural areas – Glyburide – Morphology: herpetiform or rosette-like – GCSF • Can be caused by medications – IFN – Lithium – Vancomycin most common – Phenytoin • Spontaneously resolves after stopping medication in – Piroxicam most cases – Rifampin 5

3/17/2017 Consult: My skin hurts and is blistering Severe Bullous Reactions • Stevens ‐ Johnson Syndrome • Toxic Epidermal Necrolysis (TEN) Stevens-Johnson (SJS) versus Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) Toxic Epidermal Necrolysis (TEN) • Medications Disease BSA – Sulfonamides – Aromatic anticonvulsants (carbamazapine [HLA ‐ SJS < 10% B*1502], phenobarbital, phenytoin) – Allopurinol (HLA ‐ B*5801) SJS/TEN overlap 10-30% – NSAIDs (esp Oxicams) – Nevirapine (HLA ‐ DRB1*0101) TEN with spots > 30% – Lamotrigine – Weaker link: Sertraline, Pantoprazole, Tramadol TEN without spots Sheets of epidermal loss > 10% J Invest Dermatol. 2008 Jan;128(1):35 ‐ 44 6

3/17/2017 Stevens-Johnson (SJS) versus Question 2 Toxic Epidermal Necrolysis (TEN) SJS TEN What is the most important consult besides dermatology to get in a patient with Atypical targets Erythema, bullae Mucosal Skin pain SJS/TEN? membranes ≥ 2 Mucosal A. Renal membranes ≥ 2 B. Ophthalmology C. Allergy/immunology Causes: Causes: D. Wound care Drugs Drugs E. GI/liver Mycoplasma HSV Question 2 SJS/TEN: Emergency Management • Stop all unnecessary medications What is the most important consult besides – The major predictor of survival and severity of disease dermatology to get in a patient with • Ophthalmology consult SJS/TEN? • Check for Mycoplasma ‐ 25% of SJS in pediatric patients A. Renal • Treat like a burn patient B. Ophthalmology – Monitor fluid and electrolyte status (but don ’ t overhydrate) C. Allergy/immunology – Nutritional support – Warm environment D. Wound care – Respiratory care E. GI/liver • Death (up to 25% of patients with more than 30% skin loss, age dependent) 7

3/17/2017 SJS/TEN: Treatment • Topical – Protect exposed skin, prevent secondary infection – Aquaphor and Vaseline gauze • Systemic ‐ controversial – No role for empiric antibiotics • Surveillance cultures • Treat secondary infection (septicemia) – Consider antivirals, treat Mycoplasma if present – SJS: high dose corticosteroids ‐ 1.5 ‐ 2 mg/kg prednisone (no RCT) – TEN: IVIG 1g/kg/d x 4d – TNF blockade, cyclosporine 8