SEVERE CUTANEOUS ADVERSE REACTION TO DRUGS

SEVERE CUTANEOUS ADVERSE REACTION TO DRUGS

1. SEVERE CUTANOEUS
ADVERSE REACTIONS TO
DRUGS
DR PRIYANKA DAYALANI
JUNIOR RESIDENT ,DERMATOLOGY

2. INDEX
❖ACUTE GENERALISED EXANTHEMATOUS PUSTULOSIS (AGEP)
❖DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC
SYMPTOMS (DRESS)
❖DRUG INDUCED EXFOLIATIVE DERMATITIS
❖SJS/ TEN SYNDROME

3. ACUTE GENERALISED EXANTHEMATOUS PUSTULOSIS
•AGE-ADULT> CHILDREN
•SEX-MALE : FEMALE INCIDENCE RATIO –0.8
•DRUGS CAUSING AGEP-
• PRISTINAMYCIN
• AMINOPENICILLINS
• QUINOLONES
• CHLOROQUINE AND HYDROXYCHLOROQUINE
• SULPHONAMIDES
• TERBINAFINE
• DILTIAZEM

4. AGEP
•DRUGS WHICH PREDISPOSE TO (SJS/TEN) DO NOT APPEAR TO TRIGGER AGEP.
•THIS INCLUDED PARACETAMOL, BENZODIAZEPINES, ANGIOTENSIN‐CONVERTING ENZYME (ACE)
INHIBITORS, Β‐BLOCKERS, ASPIRIN, CALCIUM‐CHANNEL BLOCKERS, THIAZIDE DIURETICS, SARTANS,
ALLOPURINOL AND CEPHALOSPORINS .
•HISTOLOGY-

5. CLINICAL FEATURES -
•EXPOSURE to the culprit drug typically occurs between 2 and 5 days prior to the onset of the eruption( short latency is
typical of AGEP. )
•Sheets of hundreds of sterile non‐follicular pustules are seen arising most commonly in the major flexures such as the
neck, axillae and inframammary and inguinal folds.
•Involvement of internal organs may be present in up to 18% of patients with AGEP, including hepatic, renal and pulmonary
dysfunction .
•Agranulocytosis has also been seen in a few cases
•Systemic involvement is self‐limiting and resolves spontaneously

6. DIAGNOSTIC CRITERIA
•1. APPEARANCE OF HUNDREDS OF STERILE NON‐FOLLICULAR PUSTULES AT FLEXURAL SITES.
•2. HISTOPATHOLOGICAL CHANGES OF SPONGIOSIS AND EPIDERMAL PUSTULEFORMATION.
•3 .FEVER >38°C.
•4 .BLOOD NEUTROPHIL COUNT >7 ×109/L.
•5. ACUTE EVOLUTION.

7. DIFFERENTIAL DIAGNOSIS
•SUB CORNEAL PUSTULAR DERMATOSIS
•DRESS
•CANDIDIAL INFECTION
•PSORIASIS

8. INVESTIGATION AND TREATMENT
•SKIN BIOPSY (IN EARLY STAGE TO DISTINGUISH IT FROM PUSTULAR PSORIASIS .
•CBC( TO CHECK FOR NEUTROPHILIA AND EOSINOPHILIA )
•SEPTIC SCREEN IF SUSPICION OF INFECTION IS HIGH .
•TREATMENT –TOPICAL CORTICOSTEROIDS (MILD CASES )
•EXTENSIVE INVOLVEMENT WITH SYSTEMIC FEATURES –ORAL CORTICOSTEROIDS MAY BE
NEEDED ,

9. DRESS
(DRUG REACTION WITH EOSINOPHILIA AND
SYSTEMIC SYMPTOMS )
•DRESS is an idiosyncratic multisystem drug hypersensitivity disorder, characterized by cutaneous features,
namely a rash, which may be of variable morphology, and systemic involvement like haematological
disturbance, with eosinophilia being the most consistent finding. Leucocytosis, lymphopenia, lymphocytosis,
thrombocytosis and thrombocytopenia can also be seen
•Atypical lymphocytes are a common finding on blood film in DRESS patients, the presence of which is used as a component of
the diagnostic criteria.
•Lymphadenopathy is found in more than 75% of patients, with involvement of two nodal basins required to meet diagnostic
criteria

10. PATHOPHYSIOLOGY
•DRUG INTERACTS WITH MHC COMPLEX and thus leading to t-cell response .
•Virus reactivation appears to occur in a sequential fashion, with HHV‐6 and EBV being detected earlier in
the course of the disease, followed by HHV‐7 and CMV.
•Drug‐induced immunosuppressed state, characterized by hypogammaglobulinaemia, facilitates the initial
reactivation of latent herpesvirus .
•The sequential nature of viral reactivation suggests a correlation with the clinical phases of DRESS.
•Rash and fever are often the first presenting features, followed by lymphadenopathy and internal organ
dysfunction.
•Fluctuation of viral loads gives rise to these ‘waves’ of disease in DRESS.

12. INVESTIGATIONS
•Haematological-Full blood count to include white cell differential
•Hepatic-Liver function tests , Lactate dehydrogenase (LDH) ,Ferritin, Coagulation screen (prothrombin
time/international normalized ratio) Hepatitis B, C Epstein–Barr virus, cytomegalovirus, HHV‐6, HHV‐7 titres
•Cardiac –Electrocardiogram, Echocardiogram ,Cardiac enzymes (creatine kinase, troponin)
•Pulmonary -Chest X‐ray ,Pulmonary function tests
•Autoimmune-Antinuclear antibody ,Extractable nuclear antigens ,Complement ,Antineutrophil cytoplasmic
antibody
•Renal -Urea and creatinine ,Calcium Urinalysis ,Renal ultrasound
•Neurological-Microscopy, culture and sensitivity of cerebrospinal fluid ,CT/MRI ,head
Electroencephalogram
•Endocrine -Thyroid‐stimulating hormone T3/T4 ,Blood glucose
•Infection-Blood cultures, Mycoplasma serology ,PCR for herpes simplex virus
•Gastrointestinal Amylase ,Lipase ,Triglycerides, Colonoscopy

13. TREATMENT
•Oral prednisolone of 1mg/kg/day is recommended as initial treatment, with a tapering‐off
period varying from 1 to 3 months.
•1g/day methylprednisolone for 3 days demonstrated safety and improved clinical outcome with
this dose ( In cases where oral therapy has failed to produce satisfactory response )
•Ciclosporin has been used in this capacity, and is useful in patients where a protracted course of
illness (e.g. with persistent liver dysfunction or a chronic exfoliative dermatitis)
•Plasmapharesishas been used, as has ECMO . Alternative immunosuppressants such as
cyclophosphamide , may be used for their steroid‐sparing effect.
•Rituximab ,Valganciclovir
•In cases of severe liver involvement, N‐acetylcysteine has been used as an adjunct to other
treatments

14. DRUG INDUCED EXFOLIATIVE DERMATITIS
•Generalized exfoliative dermatitis (GED) is an adverse drug reaction characterized by erythema
and scaling affecting more than 90% of the body surface area.
•Drug‐induced GED accounts for between 5 and 40% of all erythroderma.
•GED is characterized by increased epidermal turnover, decreased transit time and increased
mitotic activity.
•Patients present with generalized scaling and erythema associated with pruritus.
•Constitutional symptoms such as malaise, hypothermia or fever may be present as well as signs of
lymphadenopathy, organomegaly and high‐output cardiac failure.

15. DRUGS ASSOCIATED WITH GENERALIZED EXFOLIATIVE
DERMATITIS (GED)
•• CARBAMAZEPINE
•• PHENYTOIN
•PHENOBARBITAL
•ALLOPURINOL
•CO‐TRIMOXAZOLE
•PENICILLINS
•• CEPHALOSPORINS
•• VANCOMYCIN
•• ANTITUBERCULOSIS MEDICATIONS
•• ANTI‐HIV THERAPY • NON‐STEROIDAL ANTI‐INFLAMMATORY DRUGS • ACITRETIN • OMEPRAZOLE • LANSOPRAZOLE •
CALCIUM‐CHANNEL BLOCKERS • LITHIUM • CHLORPROMAZINE • TRAZEPAM• IMATINIB • INTERFERON‐Α• HEAVY METALS
• COMPLEMENTARY MEDICATIONS

16. COMPLICATIONS ,INVESTIGATIONS,TREATMENT
•Complications of exfoliative dermatitis include hypothermia, fluid and electrolyte imbalances,
high‐output cardiac failure and sepsis from the impaired skin barrier. Long‐term sequelae of post‐
inflammatory dyspigmentation may also occur.
•Patch testing has been found to be of value in determining drug causality in GED.
•TREATMENT-
•1.Identification and withdrawal of the offending drug is key.
•2. Topical and systemic corticosteroids are often indicated.

17. STEVEN JOHNSONSYNDROME/ TOXIC EPIDERMAL
NECROLYSIS
•SJS/TEN presents as an acute eruption characterized by epidermal loss and multisite mucositis, accompanied by systemic
disturbance.
•The incidence of SJS/TEN is approximately one to two cases per million per year .
•There is an increased incidence in women, the female to male ratio being 2:1
•PATHOPHYSIOLOGY -
MHC class I‐restricted drug presentation leads to clonal expansion of CD8+ CTLs which infiltrate the skin, while soluble factors
induce keratinocyte apoptosis .
Pro‐apoptotic molecules, including tumour necrosis factor‐α, interferon‐γ, and inducible nitric oxide synthase, may link
drug‐induced immune responses to keratinocyte damage . Soluble Fasligand, perforin and granzyme have all been
implicated in triggering keratinocyte death however current evidence favours granulysinas the key mediator of apoptosis in
SJS/ TEN.

18. DRUGS CAUSING SJS /TEN -
•Allopurinol •
•Carbamazepine •
•Lamotrigine • Nevirapine • Oxicam non‐steroidal anti‐inflammatory drugs • Phenobarbital •
Phenytoin •
•Sulfamethoxazole and other sulfaantibiotics • Sulfasalazine

19. HISTOPATHOLOGY

20. CLINICAL FEATURES
•The latent period is typically 7–10 days, but ranges from 5 to 28 day.
•History of malaise ,fever ,upper respiratory tract symptoms often precedes the
onset of the dermatosis by a few days (the prodrome).
•The rash of SJS/TEN commonly develops on the face and chest initially and
disseminates widely over the ensuing days.
•Pruritus and cutaneous painaccompany the skin signs. Involvement of mucosal sites
may occur before, after or simultaneously with the dermatosis.
•SJS/TEN involvement of the respiratory tract presents with cough, chest pain,
dyspnoeaor haemoptysis; involvement of the bowel is characterized by
diarrhoea.

21. CLINICAL FEATURES

22. CLINICAL FEATURES

23. CLASSIFICATION
•Extent of maximal epidermal detachment
SJS is defined as: epidermal detachment less than 10% BSA, plus widespread
purpuric macules or flat atypical targets
• Overlap SJS-TEN: detachment of 10–30% BSA, plus 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 target lesions.

24. COMPLICATIONS
1.Epidermal detachment of 50% BSA will lead to a water loss of 2–3L/day from exudation and
evaporation. Fluid depletion can cause end‐organ hypoperfusion leading to acute kidney injury.
2.Epithelial necrolysis may occur in the bronchi during the acute phase of SJS/TEN resulting in
bronchial erosions and airway obstruction by sloughed epithelium. This occurs in up to 25% of
patients and causes dyspnoea, haemoptysis, increased bronchial secretion and hypoxaemia.
3.Commonest life threatening complication is SEPTICAEMIA.

25. COMPLICATIONS
•corneal and conjunctival ulceration and scarring, dry eye, distichiasis, entropion, trichiasis and ocular
surface failure .
•Oral mucosal scarring can cause gingival synechiae resulting in food trapping and limitation of oral
mobility [40].
•A Sjögren‐like syndrome has been reported (ANA/Ro/ La‐negative) and is believed to occur in up
to 40% of survivors.
•The most important late complication of pulmonary involvement is bronchiolitis obliterans, in which
airway epithelial injury is followed by regeneration and scarring .
•Long‐term complications in the gastrointestinal tract are rare but oesophagealstricture is reported.

26. DIFFERENTIAL DIAGNOSIS

27. INVESTIGATIONS

28. SCORE -TEN

29. TREATMENT
•SKIN HANDLING, TOPICAL THERAPY AND DRESSINGS-
•Silicone dressings are recommended for areas of exposed dermis, while an absorbent non‐adherent
dressing should be applied as a secondary layer to collect exudate and protect lesionalskin.
•The intact skin should be cleansed each day by gentle irrigation with warmed sterile water or sprayed
with a weak solution of chlorhexidine (1/5000). If mobility permits, the patient may be bathed in a
weak solution of chlorhexidine (1/5000).
•In cases where bullae are prominent, blisters can be decompressed by fluid aspiration and the blister
roof retained to cover the underlying dermis.

30. EYES
•An ocular lubricant must be applied 2‐hourly.
•Ocular hygiene, to remove inflammatory debris and break down conjunctival adhesions
•. A broad spectrum topical antibiotic should be used in the presence of corneal fluorescein staining
or frank ulceration.
•The use of topical corticosteroid drops, supervised by an ophthalmologist, may reduce ocular
surface damage in the acute phase of SJS/TEN. For patients in whom there is extensive loss of
ocular surface epithelia which is unresponsive to conservative measures, then amniotic membrane
transplantation (AMT) can be considered.
•The proposed benefits of AMT in the acute phase include reduced inflammation, enhanced
re‐epithelialization, and reduction of scarring and symblepharon formation.

31. MOUTH
•Apply WSP ointment frequently to the lips; protect ulcerated
intra‐oral surfaces with a mucoprotectantmouthwash.
•In the absence of secondary infection, consider using a
topical corticosteroid four times per day (e.g. Betnesol
mouthwash 0.5mg in 10mL of water as a 3‐min rinse‐and‐
spit preparation).

32. UROGENITAL TRACT
•Use WSP ointment as an emollient frequently.
•Use silicone sheet dressings to eroded areas in the vulva and vagina.
•Consider applying a topical corticosteroid cream with additional
antimicrobial activity to the involved but non‐eroded surfaces.
•Catheterizing all patients will prevent urethral strictures.

34. •THANKYOU