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 PUSTULE FORMATION.
• 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 1 mg/kg/day is recommended as initial treatment, with a tapering‐off
period varying from 1 to 3 months.
• 1 g/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)
• Plasmapharesis has 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 JOHNSON SYNDROME/ 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 Fas ligand, perforin and granzyme have all been
implicated in triggering keratinocyte death however current evidence favours granulysin as 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 sulfa antibiotics • 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 pain accompany 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,
dyspnoea or 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 2–3 L/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 oesophageal stricture 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 lesional skin.
• 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 mucoprotectant mouthwash.
• In the absence of secondary infection, consider using a
topical corticosteroid four times per day (e.g. Betnesol
mouthwash 0.5 mg in 10 mL 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