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Acute Drug ReactionAcute Drug ReactionSJS/TENSJS/TEN
Dr B Dr B ParagParag
History
45 yr old female – RVD postive CD4 238, clin. stage 1Pulmonary TB on treatment for 2/52
p/w ‐ sore throat‐ septic mucocutaneous lesions‐ pustules involving the
upper and lower lips, purulent eye discharge, blisters over the feet, diffuse hyperpigmentation of the skin
‐ fever ‐ generalised body pains
HxPC: initially diagnosed with PTB in February 2007.commenced on TB treatment and subsequently developed a rash a month later. Rx was stopped and not re‐challenged(4 sputum samples taken were negative).
She then presented in Manzini with constitutional symptoms of TB 5mths later. Sputum was + and treatment was commenced.INH was given for 3 days and thereafter full TB treatment wasgiven together with streptomycin. 2/52 she had developed SJSand sent to greys hospital.
PmedHx: Hypertensive on Hctz 12.5 mg dailyDrug hx: also on bactrim prophylaxisNo other significant hx of note
O/E general‐ septic oral lesions involving both the upper and lower lip, purulent eye discharge, diffuse hyperpigmentation ofthe skin, blisters over the feet. Swelling of the ankles and knees.Pyrexial.
No lymphadenopathy, no pallorRESP: chest clear, CVS: s1 s2 normal, no murmursABD: SNT, no organomegalyCNS: fully orientated to person,place,time
no focal signsENT: purulent otitis media
Assesment:Stevens Johnson syndrome secondary to TB treatment/ bactrim induced.
NaNa 138138 HbHb 8.28.2 AlpAlp 4646 CaCa 2.402.40
KK 4.864.86 WCCWCC 5.65.6 TbilTbil 88 MgMg 0.800.80
ClCl 109109 PltPlt 358358 AlbAlb 2020 PO4PO4 0.900.90
HCO3HCO3 22.922.9 GGTGGT 4747
UreaUrea 6.46.4 ALTALT 2020
CreatCreat 8181
GlucGluc 5.15.1
INRINR 0.980.98
Sputum : TB auramine stain positive.,CXR‐ NAD, sensitivity: INH resistant.HSV serology‐ neg
ManagementDermatology: Hydocortisone 200mg TDS for 3 days
wait for lesions to completely healskin lesions treated with flamazine dressings
Rechallenge TB treatment
Acute Drug Eruption
Steven Johnson syndrome
Toxic Epidermal Necrolysis
SJS/TEN overlap syndrome
Epidemiology
Incidence: 2 cases per million people per yearSJS: TEN‐ 3:1
Mean age: 25‐47 ( SJS), 46‐63( TEN)Sex‐M=FFemales: 33‐ 62%(SJS), 60%(TEN)
Pathogenesis
‐Incompletely understood‐Immunological process‐ T‐ lymphocyte (cell mediated cytotoxicreaction against epidermal cells). ‐Role for reactive drug metabolites‐ slow N acetylation‐other: mixed drug‐induced, immune‐mediated phenomenon,
role of fas and fas ligand in apoptosis of keratinocytes(absence of substantial dermal inflammation): Perforin,TNF‐a, granzyme B‐ non apoptotic cell death
Stevens‐ Johnson Syndrome
‐Less severe‐ prodrome‐ fever and malaise, influenza like sympt( 1‐3 days)‐ rapid onset of erythematous/purpuric macules and plaques‐ epidermal necrosis and sloughing‐< 10% body surface‐mucosal involvement: 92‐100%, 2‐3 distinct sites( ocular , oral,genital)
Stevens Johnson syndrome
Toxic Epidermal Necrosis
‐prodrome: fever( temp higher than in SJS‐ >39C), malaise 1‐3 days
‐Skin lesions: widely distributed erythematous macules and patches, 50% may begin with diffuse erethema‐early stages: skin pain‐Full thickness epidermal necrosis ‐>30% body surface (“ extensive thermal injury”‐mucous membrane involvement‐ almost all cases
Toxic Epidermal Necrolysis
SJS/TEN Overlap Syndrome
‐>10% by < 30 % body surface
Erythema Multiforme
‐ Previously used to describe SJS‐Typical “target” lesions , distal extremities incl. palms & soles‐ reaction to infection, most commonly herpes simplex virus/mycoplasma
‐benign clinical course
Erythema Multiforme
Presentation
‐All three –SJS, TENS, SJS/TENS‐ acute onset( 1‐3 weeks, avg 14 days), re‐exposure – <48hrs‐Skin tenderness, photophobia, conjuctival itching/burning ‐ early symptoms‐Painful(burning )skin lesions‐ begin on the face and thorax, scalp spared, palms and soles less involved‐Fever ‐Sore throat‐Visual impairment( mucous membrane and ocular involvement)‐Transcutaneous fluid loss‐ prerenal failure
Skin lesions‐ill defined erythematous macules with purpuric centres‐Occasional target lesions on SJS‐Symmetrically distributed‐Vesicles flacid bullae‐Sloughing
Mucous membrane: painful crusts and erosions, includesGenitalia, GI tract and respiratory tract
Ophthalmic: conjuctival lesions‐ 85%‐ simple hyperaemiaand congestion of vessels, scarringLong term: photophobia, visual impairment, trichiasis,neovascularization of the cornea, keratitis, corneal scarringleading to blindness
SevereTEN“burns”
Mucosal lesion- oral
Ocular involvement- presence of pseudomembranein the lower cul de sac
Late stage: cornea -symblepharon formation
Early signs of potentially serious reaction
Confluent erythemaFacial oedema/ central facial involvementSkin painPalpable purpuraSkin necrosisBlisters/epidermal detachmentMucous membrane erosions and crustingUrticariaSwelling of the tongue
Differential Diagnosis
Erythematous drugs eruptionsPustular drug eruptionsPhototoxic eruptionsStaphylococcal scalded skin syndromeToxic shock syndromeAcute generalized exanthematous pustulosis
(skin biopsy to exclude above causes)
Staphtlococcal TSS
Staphylococcal scaleded skin syndrome
Aetiology
Medication( 30‐ 50%SJS, 80%TENS): Antibiotics: penicillins , sulphonamides, cephalosporinNSAIDSTB medication‐ Rifampicin and EthambutolCough cold remediesAntipsychoyticslamotrigineAromatic anticonvulsants‐ carbamazepineOxicamAnti‐ gout agents‐allopurinol
Aetiology
Infection( 15 % SJS, rare TEN)‐ Herpes Simplex, MycoplasmaRare causes: vaccinations, systemic disease, chemical exposure,herbal medication, foods
Risk Factors
Certain HLA typesLower N‐ acetylation capacity ( slow acetylators)Immunosuppression‐malignancyViral infections Physical stimuli‐ UV light and radiation therapy
Laboratory Abnormalities
Anaemia(TEN)Lymphopaenia(TEN)Neutropaenia( 1/3 )Mild inc ALT, AST (2‐3 times normal) 50% TENHepatitis‐ 10% TEN
Management( KEH Protocol)-Stop TB treatment-Supportive management-Topical agents: avoid soap, use aqueous cream to bath, topicalsteroid- Advantan, emoliants
-IV fluids and correct electrolyte imbalance-monitor for sepsis- avoid urinary catheter,CVP,NG tube-do not use sulphur containing antibiotics -wound management: flamazine dressing, bactroban, salinewash, glycothymol mouth wash-Multidisciplinary: ophthalmology, dietician, psychologist-Desensitization: 1/3 dose IRPE for 3 days (monitor for
2/3 dose IRPE 3 days rash,pyrexia)full dose
Steroids: 1mg/kg for 3 days only- prevent dissemination of TBand other oppurtunistic infections
Treatment
‐stop offending medication‐burn unit, sterile handling‐fluid management‐ocular care‐ ophthalmology consult‐temperature management and environmental support‐monitor for superimposed infection‐ staph aureus‐routine cultures of skin, blood , catheters, gastric tubes‐no benefit from prophylactic oral antibiotics‐topical antibiotics‐ 0.5% silver nitrate( avoid topical sulphur agent)‐corticosteroids‐IV gammaglobulin
Treatment
PlasmapheresisThalidomide‐ increase mortality in TENS –not usedPatient education
TreatmentTreatment Observations in SJSObservations in SJS Observations in TENObservations in TEN
Systemic Systemic corticosteroids (short corticosteroids (short term, high dose)term, high dose)
Results mixed: Results mixed: possible benefit, possible benefit, possible harmpossible harm
Possible harm due to Possible harm due to increased rates of increased rates of sepsis and impaired sepsis and impaired rere--epithelializationepithelialization
Intravenous Intravenous immunoglobulinimmunoglobulin
Possible benefitPossible benefit
No significant evidence No significant evidence of harmof harm
Possible benefitPossible benefit
PlasmapheresisPlasmapheresis No dataNo data Possible benefitPossible benefit
No evidence of harmNo evidence of harm
ThalidomideThalidomide No dataNo data HarmfulHarmful
ContraindicatedContraindicated
Summary of reported treatments for SJS and TEN
Resolution
‐2‐4 weeks in the absence of complicaitons‐re‐ epithelialization ‐ several days after onset, usually 2‐3wks‐Remaining skin may peel, nails may detach
Long term sequele
‐scarring, irregular pigmentation, eruptive naevi , abnormal regrowth of nails, alopecia.
Prognosis
Poor: intestinal and pulmonary involvementolder ageneutropaeniaincreased % denuded skinDrug withdrawn late
Mortality
SJS: 5%TEN: 30%
Independent prognosis factorsIndependent prognosis factors WeightWeight
AgeAge 40 years40 years 11
Malignancy*Malignancy* YesYes 11
Body surface area Body surface area detacheddetached
10%10% 11
TachycardiaTachycardia 120/min120/min 11
Serum ureaSerum urea > 10 > 10 mmol/lmmol/l 11
Serum glucoseSerum glucose > 14 > 14 mmol/lmmol/l 11
Serum Serum bicarbonatebicarbonate
< 20 < 20 mmol/lmmol/l 11
SCORTEN#SCORTEN# 77
SCORTEN schema
HIV Infected Patients
‐3 times increased risk for SJS/TEN‐40 fold increased risk for SJS/TEN due to Bactrim( benefit outweighs risk)‐related to the degree of immunosuppression‐? Exposure to multiple medications, including sulphonamides, “slow acetylation” status, immune dysregulation, presence of concomitant infections‐Bactrim , sulfadiazine, dapsone, amino penicillins‐Abacavir, Efavirenz, nevirapine, ‐strong association between herpes virus infections and EM, SJS is more associated with exogenous agents(drugs)
Case‐Recommenced on modified TB treatment ‐INH commenced for 3 days, stopped due to temp spike and re‐occurrance of mucosal lesions‐1/52 later pyrazinamide and rifampicin commenced at full dose, Rifampicin stopped‐ itchy skin and pyrexia‐Pyrazinamide continued‐11 days later Ethambutol commenced at low dose and increased after 3 day interval to maximum dosage according to weight.‐sensitivity – INH resistant‐7 days later ciprobay commenced at ½ full dose, increased to full dosage after 3 days‐repeat auramine negative ‐currently due to commence on HAART
THE END