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

2. 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/
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/
T 98.
Hr 117
R 24
97/63
Wt 36.5
Bsa 1.25

6. 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

7. 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

8. 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

9. Stevens-johnson syndrome

10. 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): ;
Ann Pharmacother. 2015, 49(3)

11. 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):
Ann Pharmacother. 2015, 49(3)

12. 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 per million (up to 5%)
TEN 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):

13. 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):

14. 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):

15. 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

16. 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

17. 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
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

18. 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

19. 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/ 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/
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

20. 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):

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