1. STEVENS-JOHNSON SYNDROME AND HERPES SIMPLEX VIRUS (TYPE 1) Lindsay Waddington PharmD PGY-1 Pharmacy Resident St. Vincent Hospital-Indianapolis February 16th, 2016

2. Objectives Describe the differences between erythema multiforme, Steven Johnson Syndrome, and Toxic Epidermal Necrolysis Identify causes of erythema multiforme and Steven Johnson Syndrome Recognize treatment options for erythema multiforme and Steven Johnson Syndrome

3. 10 Year Old Male Patient (37kg) Monday – developed a temperature of 102°F, fatigue, no upper respiratory symptoms Tuesday – Temperature still elevated, mom gives acyclovir and ibuprofen, symptoms improve Friday – Still slight fatigue, but overall feeling better (well enough to attend a weekend camping trip) Saturday – starts coughing and complains of itchy eyes, fever returns that night, lips look swollen and eyes are increasingly red with drainage Sunday – Temperature of 104°F and lips continuing to swell Sunday Night - Presents with fever, rash, and lip swelling to Peyton Manning Children’s Hospital

7. Past Medical History Herpes simplex virus type-1 starting 2 years ago 2 Similar flare ups (not requiring hospitalization) July: received lysine and flare resolved September: received oral steroids and flare resolved Immunizations are up to date

8. Home Medications and Allergies Acyclovir 400mg (~10mg/kg) tablet orally TID PRN HSV flare Ibuprofen 200mg orally (~5mg/kg) 1 tablet orally every 6 hours Drug allergies Amoxicillin: dermatologic, sores in mouth, swelling of mouth and gums Sulfamethoxazole/trimethoprim: dermatologic, sores in mouth, and swelling of the mouth and gums Cefdinir: edema/swelling

9. 10 Year Old Male Patient (37kg) Notable labs WBC 12.1 w/ 1.5 bands SCr 0.56 BUN 12 Physical exam conjunctiva inflamed with thick drainage rhinorrhea, sore throat causing poor appetite, productive cough swelling of lips and oropharynx, copious drooling, skin on lips cracking covered in greyish white membrane multiple erythematous macules with purpuric centers on trunk, back, and upper extremities, non-tender to touch, blisters

10. Diagnosis: Stevens-Johnson Syndrome (SJS) Overnight started on Prednisolone 3mg/mL oral 75mg daily (2mg/kg) Acyclovir IVPB 370mg every 8 hours (10mg/kg) Dextrose 5% - 0.45% NS w/ 20mEq K at 76mL/hour Ibuprofen intentionally omitted

11. Team discussion Family centered rounding Mom believes acyclovir caused the reaction Attending is agreeable and wants to discontinue acyclovir

12. STEVENS-JOHNSON SYNDROME

13. What is Stevens-Johnson Syndrome? Early symptoms Fever and general malaise Cough Sore throat Itching or burning eyes Acute phase lasts 8 to 12 days Persistent fever Severe mucous membrane involvement Epidermal sloughing Crit Care Med 2011; 39(6): 1521-1532. Ann Pharmacother. 2015, 49(3)335-342.

14. Differential Diagnosis Erythroderma and erythematous drug eruptions Phototoxic eruptions Staphylococcal scalded skin syndrome Paraneoplastic pemphigus Linear IgA bullous dermatosis Erythema multiforme Stevens-Johnson Syndrome(SJS) Toxic Epidermal Necrolysis (TEN) Drug safety 2002; 25(13):965-972. Ann Pharmacother. 2015, 49(3)335-342.

15. Spectrum of Bullous Erythema Multiforme Bullous Erythema Multiforme <10% BSA PLUS Target lesions Atypical targets (raised) Stevens-Johnson Syndrome <10% BSA PLUS Multiple macules Atypical targets (flat) Toxic Epidermal Necrolysis >30% BSA PLUS Widespread multiple macules/atypical targets OR epidermal sheets Drug safety 2002; 25(13):965-972.

16. Presumed Causes Infection Herpes Simplex Virus (HSV) Mycoplasma pneumonia Drugs Penicillins Sulfonamides Allopurinol Anticonvulsants NSAIDs Genetics? Crit Care Med 2011; 39(6): 1521-1532

17. Complications Fingernail and Toenail loss Vision loss Permanent pigment changes Other infections/Sepsis Altered pulmonary function Pulmonary edema Epithelial necrosis of bronchial epithelium Crit Care Med 2011; 39(6): 1521-1532

18. How do we treat EM/SJS? Removal of offending agent (if applicable) No standard consensus Supportive care Pain Nutrition Fluids Steroids Acyclovir if infection mediated IV Immune globulin (consider for SJS/TEN) J Am Acad Dermatol. 1988; 18(1): 197-199. J Am Acad Dermatol. 1986; 15(1): 50-54. Allergy Asthma Proc. 1996 Mar-Apr;17(2):71-3. Allergy Proc. 1995 Jul-Aug;16(4):157-61. Pediatrics. 2003 Dec;112(6 Pt 1):1430-6.

19. Tatnall et al. Acyclovir in REM Design Double-blind, placebo controlled RCT Primary outcome Efficacy of acyclovir in recurrent erythema multiforme Population >18yo adult patients who suffered at least 4 episodes of EM/year (excluding pregnancy Intervention 11 received 6 months of acyclovir 400mg BID 9 received 6 months of placebo Findings 15 patients had clinical evidence of HSV precipitated episodes 6 in placebo and 9 in acyclovir EM attacks placebo 3 acyclovir 0 p <0.0005 HSV attacks placebo 1 acyclovir 0 p=0.04 3 patients in the acyclovir group did not respond to therapy Brit J Dermatol 1955;132:267-270

20. Schneck et al. IVIG in SJS and TEN DesignCase-control Primary outcome Death during hospitalization Population379 patients with confirmed SJS and/or TEN Intervention87 received supportive care 35 received IVIG only 40 received IVIG + steroids 119 received steroids only FindingsOR 0.4 steroids vs. no steroids 95% CI 0.2-0.9 Trend for possible benefit with steroids No statistically significant findings J Am Acad Dermatol 2008;58:33-40

21. ADVERSE DRUG REACTION?

22. Naranjo Algorithm CriteriaScore Previous reports of this reaction?DON’T KNOW +0 AMR after drug administered?YES +2 AMR worsened with dose increase or decrease with discontinuation NO +0 Reappear when drug re-administeredN/A +0 Potential alternative causesYES -1 Toxic levels of drugDON’T KNOW +0 Similar reaction previouslyYES +1 Objective evidence confirming AMR?NO +0 TOTAL2 1-4 POSSIBLE Adverse Medication Reaction

23. RECOMMENDATION

24. Recommendation Continue on acyclovir, steroids, and fluids Acyclovir most likely a confounder RCT and case reports of acyclovir treating REM Received acyclovir previously with no reported issues Case reports of HSV induced REM Potential alternatives to acyclovir Avoid IVIG unless develops into SJS or TEN then reevaluate Monotherapy with steroids

25. Clinical Course Managed pain with acetaminophen and morphine Avoided ibuprofen Steroids methylprednisolone IV 37mg (1mg/kg) Q12 Maintenance IVF (D5-1/2NS +20meq K) Acyclovir IVPB 370mg every 8 hours (10mg/kg) Ophthalmology consult – no acute vision changes follow up outpatient Philadelphia mouthwash 5mL swish and swallow PRN

26. Clinical Course Diagnosis changed from SJS to Erythema Multiforme Desaturated overnight with respiratory symptoms (required oxygen), negative chest X-ray Rash began blistering, no new lesions appeared Continued/increased eye itching and irritation; no visual deficiencies Mucosal inflammation stable to slightly improved Discharghed home

27. Take Aways Erythema multiforme, Stevens Johnson Syndrome, and Toxic Epidermal Necrolysis have similar presentations with increasing severity Drugs most likely to cause SJS are sulfa antibiotics, NSAIDs, anticonvulsants, penicillin antibiotics, and allopurinol Treatment of SJS consists of steroids +/- IVIG Herpes simplex virus has been associated with recurrent erythema multiforme

28. STEVENS-JOHNSON SYNDROME AND HERPES SIMPLEX VIRUS (TYPE 1) Lindsay Waddington PharmD PGY-1 Pharmacy Resident St. Vincent Hospital-Indianapolis February 16th, 2016