SEVERE CUTANEOUS ADVERSE REACTIONS TO

DRUGS
STEVENS-JOHNSON SYNDROME,TOXIC EPIDERMAL NECROLYSIS

-DR.SM.SWARNAM
 SCAR:

 It comprises :acute generalized exanthematous pustulosis

Drug reaction with eosinophilia and systemic symptoms

Stevens-Johnson syndrome/Toxic epidermal necrolysis

Drug-induced generalized exfoliative dermatitis

INTRODUCTION:

 STEVENS-JOHNSON SYNDROME(SJS) and TOXIC EPIDERMAL NECROLYSIS

(TEN) are severe mucocutaneous reactions,characterized by blistering and epithelial
sloughing.

 SJS –less extensive

 TEN-more extensive

 Consequence of extensive keratinocyte cell death that results in separation of significant

areas of skin at dermo-epidermal junction,producing the appearance of scalded skin and
mucous membrane detachment.
DEFINITION:

 SJS:epidermal detachment less than 10% BSA plus widespread purpuric macules or flat atypical
targets.

 Overlap SJS-TEN:detachment of 10-30% BSA,widespread purpuric macules or flat atypical

targets.

 TEN with SPOTS: detachment greater than 30% BSA plus widespread purpuric macules or flat
atypical targets.

 TEN without spots: detachment greater than 30% BSA ,with loss of large epidermal sheets
without purpuric macules or flat atypical targets.
RISK FACTORS:
 CYTOTOXIC CD8+ T CELLS-DRUG SPECIFIC

C YTOKINES:TNF-A,IFN-G,IL-6,IL-18,granzyme/perforin

INCREASED EXPRESSION OF FAS ligand on keratinocytes

binds to
Fas death receptor

APOPTOSIS

GRANULYSIN-produced by Cytotoxic t cells ,NKcell,NKT

cells APOPTOSIS

ANNEXIN A1(FROM MONOCYTES)-FORMYL PEPTIDE RECEPTOR 1

NECROPTOSIS
CLINICAL FEATURES:
 LATENCY:1 TO 3 WEEKS
 PRODROME:fever,stinging eyes,pain upon swallowing
 DERMATOSIS:erythematous,dusky or purpuric macules-tendency to coalesce forming
confluent erythema-CUTANEOUS TENDERNESS+,NIKOLSKY SIGN +
 OTHER LESIONS:flat atypical targets
 DISTRIBUTION:face,upper torso,proximal extremities
 MUCOSA:BUCCAL:95%

OCCULAR:76%
GENITAL:63%
ALL 3:66%
PROGRESS:

 Other sites:respiratory tract-25%

gastrointestinal tract-oesophagitis,diarrhea
 SYSTEMIC MANIFESTATIONS:fever,lymphadenopathy,hepatitis,cytopenias and
cholestasis(vanishing bile duct syndrome)
 Necrotic epidermis detaches from underlying epidermis bulla
 Characteristics of blisters:flaccid ,tense blisters-palms & soles
 Skin resembles:wet cigarette paper like with large areas of raw and bleeding dermis -
scalding
MULTI-MUCOSITIS:EROSIVE & HEMORRHAGIC

 EYE:painful and causes visual impairment

 Signs:chemosis,conjunctivitis,pseudomembrane formation,corneal & conjunctival

defects

 Patients with TEN have more frequent ocular involvement.

ORAL MUCOSA:

 Painful mucosal erythema ,blistering ,ulceration

 Vermillion of lips-retention of adherent haemorrhagic crusts

 Extend to :tongue,palate,oropharynx,larynx

 Drinking and eating severely compromised

 UROGENITAL AND PULMONARY INVOLVEMENT:

 Mucosal erythema,blistering,erosion

 Urogenital pain,dysuria,retention

 Pulmonary manifestations:dyspnea,increased respiratory rate,bronchial hypersecretion

 Fibreoptic bronchoscopy:pattern of diffuse loss of bronchial epithelium in the proximal

airways with epithelial detachment caused by epithelial necrosis
COMPLICATIONS:

ACUTE LIFE-THREATENING

HYPOTHERMIA SEPTICAEMIA

TRANSCUTANEOUS FLUID LOSS-2 TO 3L/DAY

END ORGAN HYPOPERFUSION STAPHYLOCOCCUS AUREUS &PSEUDOMONAS

AERUGINOSA
ACUTE KIDNEY INJURY

ANEMIA,LEUCOPENIA MULTIORGAN FAILURE

ABNORMAL LIVER FUNCTION BRONCHIAL-INCREASED SECRETION-

HYPOXAEMIA
HYPOALBUMINEMIA,HYPERGLYCEMIA(INCREAS
ED METABOLIC DEMAND)
 LONG TERM COMPLICATIONS:
DISABLING

POST INFLAMMATORY DYSPIGMENTATION CORNEAL & CONJUNCTIVAL SCARRING-VISUAL IMPAIRMENT

& BLINDNESS

ERUPTIVE MELANOCYTIC NAEVI-RECOVERY PHASE DRY

EYE,DISTICHIASIS,TRICHIASIS,ENTROPION,SYMBLEPHARON,
ANKYLOBLEPHARON

ONYCHOMADESIS-NAIL MATRIX ARREST Loss of limbal corneal stem cells,destruction of conjunctival goblet
cells-impairs tear film

PERMANENT ANONYCHIA GINGIVAL SYNECHIAE-food trapping,limitation of oral mobility

“SJOGREN-LIKE SYNDROME”-40%

TELOGEN EFFLUVIUM-20% BRONCHIOLITIS OBLITERANS-3-4months after the acute episode

ABNORMAL PHOTOSENSITIVITY,ABNORMAL OESOPHAGEAL STRICTURE,VANISHING BILE DUCT

SWEATING,HETEROTOPIC OSSIFICATION SYNDROME,DIARRHOEA,MALABSORPTION
OTHER COMPICATIONS:

 UROGENITAL TRACT:vaginal and introital adhesions dyspareunia

 Hematocolpos

 VAGINAL ADENOSIS-replacement of non cornified vaginal epithelium with

metastatic epithelium of endocervical differentiation

 Post traumatic stress disorder

DISEASE COURSE:

EXTENT of skin involvement-5 to 7 days

RE-EPITHELIALISATION-starts once the

disease stops extending

Uncomplicated re-epithelialization-
2to3weeks

DELAYED HEALING:sepsis,systemic
complications,culprit drug not removed
MORTALITY:

 Overall mortality in SJS/TEN-22%

 SJS<10% die from acute illness

 TEN-30%

 CAUSE OF DEATH-SEPTICAEMIA-INDUCED MULTIORGAN FAILURE

PROGNOSTIC SCORING SYSTEM-SCORTEN
 SCORTEN-SCORe of Toxic Epidermal Necrolysis

252mg/dl
INVESTIGATIONS:
A. To substantiate the diagnosis
B. Exclude other blistering dermatoses
C. Identify any systemic complications
*BIOPSY FROM LESIONAL AND
PERI-BLISTER LESIONAL SKIN
FOR HPE AND DIF
*TO RULE OUT
IMMUNOBULLOUS DISORDER
*CHEST X-RAY -MANDATORY
MANAGEMENT:

 Identify culprit drug and stop them as soon as possible

 Supportive care

 Icu or burns unit

 Multi-disciplinary approach
CULPRIT DRUG:

 All medicines taken over the past 2 months

 Latent period between drug initiation and onset of SJS/TEN –typical 7 to 10 days

 Range-5 to 28 days

 Paracetamol ,aspirin,ibuprofen and corticosteroid –unclear association

ALDEN:

 Algorithm of Drug causality in Epidermal Necrolysis-define drug causality in

SJS/TEN

 Tool for RETROSPECTIVE ASSESSMENT of drug causality and not for use in the
acute phase of illness
SKIN HANDLING :

 Careful handling with limited shearing forces and to avoid sources of skin trauma(BP
cuffs,adhesive ECG leads,Adhesive dressing ,identification wrist tags

 Detachable epidermis often peels away leaving zones of denuded dermis

 Detached epidermis left in-situ to act as biological dressing for the underlying dermis

 Blisters-decompressed by fluid aspiration and blister roof retained to cover the

underlying dermis
 TOPICALS AND DRESSINGS:

 Intact skin cleansed each day by gentle irrigation with warmed sterile water or sprayed with a weak
solution of Chlorhexidine(1/5000)

 Greasy emollient-50% white soft paraffin with 50% liquid paraffin(50/50 WSP/LP)

 Topical antibiotic ointment only on sloughy or crusted areas

 Use of silicone dressings on denuded areas will reduce fluid and protein loss,limit microbial
colonization,help pain control and accelerate re-epithelialization

 Absorbent non-adherent dressing as a secondary layer to collect exudate and protect lesional skin
 Eyes:ophthalmological examination
LOCAL THERAPY:

 Ocular lubricant-2 hourly

 Ocular hygiene-to remove inflammatory debris and break down conjunctival adhesions each
day

 A broad spectrum topical antibiotic in presence of corneal ulceration

 Use of topical steroid drops under supervision reduce ocular surface damage in the acute phase
of SJS/TEN

 Amniotic membrane transplantation-in acute phase reduces inflammation,enhanced re-

MOUTH:

 WSP ointment to lips,mucoprotectant mouthwash

 Warm saline mouthwashes or oral sponge

 Anti-inflammatory oral rinse containing benzydamine hydrochloride every 3 hours

and antiseptic mouthwash(chlorhexidine digluconate)twice per day

 In the absence of secondary infection –topical steroid four times per day(Betnosol
mouthwash 0.5mg in 10ml of water a 3-min rinse-and-spit preparation)
UROGENITAL TRACT:

 WSP ointment

 Silicone sheet dressings to eroded areas in the vulva and vagina

 Topical steroid with antimicrobial activity to involved but non-eroded surfaces

 Catheterizing all patients will prevent urethral strictures

FLUID REPLACEMENT & NUTRITION:

 Acute illness:2ml/kg body weight/%BSA epidermal detachment or urine output to

guide fluid replacement

 Enteral nutrition is preferable to reduce peptic ulceration and limit translocation of

gut bacteria

 Naso-gastric feeding with silicone tube when necessary

 During early catabolic phase of SJS/TEN -20-25kcal/kg/day

 Recovery ,anabolic phase increase to 25-30kcal/kg/day
IMPORTANCE OF FLUID CORRECTION:

Peripheral intravenous line can be left in place for a long duration and should not be replaced before 96 h unless
there is evidence of phlebitis, local infection or malfunction.
Patients of toxic epidermal necrolysis lose a significant amount of fluid as blister fluid and insensible fluid loss
and should be assumed to be hypovolemic.
Adult patients having inolvement of 50% of body surface area lose around 3–4 L of fluid every day.
 This is usually accompanied by the loss of electrolytes such as sodium, potassium and chloride in blister fluid
 Hypophosphatemia is a common complication in these patients aggravating insulin resistance and altering the
neurological status and diaphragmatic functions.
 If replacement is not given promptly, the patient may develop dehydration which may adversely affect the
outcome.
 Urine becomes hyperosmolar and urine output decreases. Slowly, the serum urea and creatinine concentration
increases and pre-renal failure may develop.
 The early fluid requirement of TEN patients is two-third to three-fourth of that of a burn
patient with the same extent of skin involvement and should be fulfilled by macromolecules
(Ringer lactate) or saline solutions.
 The fluid requirements of burn patients is calculated by the Parkland formula, as follows:
Fluid requirement = 4 ml/kg body weight × percentage of body surface area involved.

For the first 24 h, half the calculated fluid is administered in the first 8 h and the other half in
the next 16 h.
 Fluid requirements beyond the first 24 h should be managed according to the patient's
condition. Input and output charting is useful to guide fluid administration.
 The maintenance fluid is titrated so as to maintain a urine output between 1000 and 1500 ml.
 It must be noted that overcorrection of hypovolemia may also lead to pulmonary edema.
 Blood transfusion may be useful in some cases and perhaps works by the dilution of drug
metabolites, cytokines, cytotoxic T-cells and autoantibodies, providing immunoglobulins and
nutrition, besides correcting anemia and hypovolemia
ANALGESIA:

 Opiate based analgesia regime using morphine

 Pain associated with patient handling,repositioning,dressing changes and

physiotherapy-a bolus of 0.1mg/kg of morphine iv 10-20 min before commencement
of procedure

 Bolus ketamine analgosedation(0.5mg/kg)-procedural analgesia

 Adjuvants including GABA analogues –opiate-sparing role

ADDITIONAL SUPPORTING MEDICATION:

 Stress related gastric/duodenal ulcer-proton pump inhibitor

 Prophylatic anticoagulation with low-molecular weight heparin unless

contraindicated

 Granulocyte-colony-stimulating factor(G-CSF)-to resist infectious complications

 Also immunomodulatory and enhance re-epithelialization

MONITORING FOR INFECTION:

 Cutaneous infection-impairs re-epithelialization,systemic sepsis

 Swabs for bacterial and candida culture from multiple sites at least 3 particularly
sloughy or crusted areas throughout the acute phase that is at admission and every 48
hours

 Prophylatic systemic antimicrobial therapy increase skin colonization particularly

with Candida albicans ,therefore antibiotics only given if there are clinical signs of
infection
SIGNS OF SYSTEMIC INFECTION:

 Fever
 Confusion
 Hypotension
Monoculture of organisms
 Reduced urine output from swabs taken at
different sites-one strain of
 Reduced oxygen saturation bacteria predominates

 Rise in CRP
 Neutrophilia
INVASIVE INFECTION
 Increase in skin pain
 ANTIBIOTICS:

 Indications of the use of antibiotics in patients with

Stevens-Johnson syndrome/toxic epidermal necrolysis:MARKERS OF
INFECTION:

High bacterial count (single strain) from skin/catheter sample of urine

Sudden hypothermia in a relatively stable patient
Confused mental state, anxiety and excitement
Symptoms of infection pertaining to a particular system, for example,
pneumonia/urinary tract infection
COMPONENTS OF SUPPORTIVE THERAPY:
ACTIVE THERAPY:
 IVIG-interferes with Fas-FasL interaction and apoptosis through anti-Fas activity

 0.5-1g/kg daily for 3-4 consecutive days

 Steroids:1.5mg/kg or 100 mg iv dexamethasone for 3 days

1000mg iv methylprednisolone on 3 consecutive days followed by either a
tapering course of oral prednisolone

 Cyclosporine:inhibition of lymphocyte function,enhance speed of re-epithelialization

OTHER TREATMENT MODALITIES:

 Plasmapheresis

 Anti TNF-A inhibitors

RECOMMENDATIONS:
TAKE HOME POINTS:
THANK YOU