Stevens-Johnson Syndrome and Herpes Simplex Virus (type 1) Lindsay Waddington PharmD PGY-1 Pharmacy Resident October 28, 2015

10 Year Old Male Patient Presents with fever, rash, and lip swelling 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 developed a fever of 102 a week ago Monday felt generally fatigued no upper respiratory symptoms Mom gave him acyclovir and ibuprofen – symptoms resolved Feeling better on Friday Saturday coughing and itching eyes (camping trip) fever returned and by Saturday night lips were swelling and eyes were increasingly red with drainage Sunday fever 104 lips continued to swell Initial lab work WBC 12.1 w/ 1.5 bands normal CMP 10/04 1430 Na 135 K 3.9 Cl 99 Co2 26 Glu 96 Bun 12 Scr 0.56 Alk phos Crp 13.0 CRP 13 sed rate 38 blood cultures ng x1 day normal chest x-ray aso titer 28 influenza a pending 10/5 11am 37kg ht 151cm T 98.5 Hr 109 R 21 98/63 10/05 1300 T 98. Hr 117 R 24 97/63 Wt 36.5 Bsa 1.25

Past Medical History Herpes simplex virus starting 2 years ago Similar flare ups not requiring hospitalization July: received lysine and flare resolved September: received oral steroids and flare resolved Has taken acyclovir numerous times since diagnosis without incident Immunizations are up to date immunizations up to date 2 previous episodes FH: grandmother with history of stevens-johnson syndrome Lysine essential amino acid use to prevent recurrent HSV

Home Medications and Allergies Acyclovir 400mg tablet orally TID Ibuprofen 200mg orally 1 tablet 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 Family friend ophthalmologist gave him pazeo and lotomax

Dx: Stevens-Johnson Syndrome Started on Prednisolone 3mg/mL oral 75mg day (2mg/kg) Acyclovir IVPB 370mg every 8 hours (10mg/kg) Intravenous fluids at 76mL/hour

Stevens-johnson syndrome

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.

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) Erythroderma and erythematous drug eruptions – mimic early SJS/TEN Erythroderma and lack mucosal involvement and the prominent skin pain of TEN SSSS- neonates and young children, mucous membranes are not involved upper layers of the epidermis, in contrast with the subepidermal split with full thickness epidermal necrosis observed in SJS/TEN Paraneoplastc - rare disorder that can represent the initial presentation of a malignancy ●Linear IgA bullous dermatosis – Linear IgA bullous dermatosis (LABD) is a rare autoimmune blistering disease that may mimic toxic epidermal necrolysis Drug safety 2002; 25(13):965-972. Ann Pharmacother. 2015, 49(3)335-342.

Spectrum of Bullous Erythema Multiforme <10% BSA PLUS Target lesions Atypical targets (raised) Stevens-Johnson Syndrome Multiple macules (flat) Toxic Epidermal Necrolysis >30% BSA Widespread multiple macules/atypical targets OR epidermal sheets Epidermal detachment BEM – predominantly on the extremities, associated with HSV Annual incidence EM 0.01 and 1% (mortality unknown/doesn’t exist) SJS 0.4-1.2 per million (up to 5%) TEN 1.2-6 per million (30%) SJS/TEN overlap Nikolsky sign is a skin finding in which the top layers of the skin slip away from the lower layers when slightly rubbe Drug safety 2002; 25(13):965-972.

Presumed Causes Infection Drugs Genetics? Herpes Simplex Virus (HSV) Mycoplasma pneumonia Drugs Penicillins Sulfonamides Allopurinol Anticonvulsants NSAIDs Genetics? Exact mechanism unknown Human leukocyte antigen HLA – B12 (HLA-B-1502, HLA-B-5801) asians Patient case gm has hx of SJS Crit Care Med 2011; 39(6): 1521-1532

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

How do we treat? Removal of offending agent (if applicable) No standard consensus Supportive care Pain Nutrition Fluids Steroids IV Immune globulin Previous treatments – cyclosporine, cyclophosphamide, plasmapharesis, NAC, steroids – none accepted as standard of care Since it is so rare, unable to use large randomized controlled trials Potential transfer to burn unit (inhibition of TEN by blockade of CD95) IVIG Managed with acyclovir and prednisone at the onset of herpes simplex virus oropharyngitis

Pediatric Studies Author N Intervention Conclusion Rasmussen 1976 32 17: prednisone 40-80mg/m2/day 15: supportive care Steroid arm: 9 complications, LOS 21 days Supportive care arm: LOS 13 days Kakourou 1997 16 10: methylprednisolone 4mg/kg/day 6: supportive care Shorter period of fever with steroids Morici et al 2000 12 7: IVIG 1.5-2g/kg single infusion on day 3 2: corticosteroids 3: supportive care Average duration of fever and average LOS in favor of IVIG

Schneck et al. Design Case-control Primary outcome Death during hospitalization Population 379 patients with confirmed SJS and/or TEN Intervention 87 received supportive care 35 received IVIG only 40 received IVIG + steroids 119 received steroids only Findings OR 0.4 steroids vs. no steroids 95% CI 0.2-.09 Trend for possible benefit with steroids No statistically significant findings Should be dosed >2g/kg to decrease mortality in patients with SJS or TEN Exact pathophysiology unknown suggested hypothesis is keratinocyte apoptosis is triggered by the upregulation of keratinocyte Fas ligand (FasL) expression IVIG inhibits Fas-mediated keratinocyte apoptosis through naturally occurring FasL blocking antibodies SCORTEN system Largest study of Stevens-Johnson Syndrome Started 2-5 days after admission and continued for 2-12 days 6 countries in Europe (Austria, France, Germany, Israel, Italy, and the Netherlands) J Am Acad Dermatol 2008;58:33-40

Clinical Course for 10yo M Negative chest X-ray Desaturated overnight with worsening respiratory symptoms (required oxygen) Mucositis Continued/increased eye itching and irriatation; no visual deficiencies Mucosal inflammation stable to slightly improved, a few new blisters “10yo male with known HSV presents with mucositis, purulent conjunctivitis and blistering rash. Rash is relatively mild- EM major (associated with HSV) vs. stevens-Johnson syndrome

Clinical Course for 10yo M Managed pain with acetaminophen and morphine Avoided ibuprofen Steroids methylprednisolone 37mg Q12 Maintenance IVF IV acyclovir Ophthalmology consult – no vision changes outpatient follow up Philadelphia mouthwash PRN consider mycoplasma testing and initiating azithromycin or doxycycline if symptoms are not improving 10/5 1100 chest x-ray no active dx Impression: sJS or HSV flare mycoplasma possible cause, Not TEN, stable vitals not concerned currently for sepsis Will start IV steroids, continue acyclovir IV, 10/06 0840 Overnight dsats into mid 80s required 2L of O2 Copious sectretions difficult to clear/cough up due to pain Mucosal inflammation stable to slightly improved no new lesions PERRL, sclera injected, copious purulent discharge, itching not visual field defects or vision changes No nasal discharge, oropharynx inflamed, skin on lips is cracking, diffuse swelling, drooling ad copious thick grey/white secretions Multiple erythematous macules, some blistering on trunk, back and upper extremitis

Stevens Johnson Syndrome and Acyclovir Mom was concerned acyclovir was the cause Lips began to swell in July after being on acyclovir for a week Based on the available literature SJS versus erythema multiforme major More likely response to infection than to drug Case series: acyclovir and steroids at first sign of flare effective management in an adult patient treated with oral steroid and symptoms resolved consider ibuprofen/acyclovir possible cause Arch Intern Med. 1992 Jul;152(7):1513-6.

Stevens-Johnson Syndrome and Herpes Simplex Virus (type 1) Lindsay Waddington PharmD PGY-1 Pharmacy Resident October 28, 2015