Vesicular and bullous rash

Vesicles are fluid filled lesions under 1 cm and bullae are over 1 cm. The main clinical point is to separate the rare emergencies (necrotising infection, toxic epidermal necrolysis, staphylococcal scalded skin syndrome, extensive pemphigus, eczema herpeticum, disseminated zoster) from the many benign causes.

Classification by level of split

• Intraepidermal (flaccid, fragile): pemphigus, staphylococcal scalded skin syndrome, bullous impetigo.
• Subepidermal (tense): pemphigoid, dermatitis herpetiformis, epidermolysis bullosa acquisita, bullous lupus, porphyria cutanea tarda.
• Full thickness epidermal necrosis: Stevens-Johnson syndrome and toxic epidermal necrolysis.
• Spongiotic: eczema and contact dermatitis.

Classification by cause. Infective, immune bullous, drug related, physical and chemical, metabolic, genetic.

Clinical sign. The Nikolsky sign (epidermal detachment on lateral pressure) is positive in pemphigus, scalded skin syndrome and toxic epidermal necrolysis.

Distribution clues. A dermatomal unilateral pattern suggests zoster. Grouped vesicles on an erythematous base suggest herpes simplex. Linear vesicles on exposed skin suggest plant or beetle contact. Sun exposed dorsal hands suggest porphyria. Symmetrical extensor surface lesions suggest dermatitis herpetiformis.

History

• Tempo of onset, prodrome, pain versus itch, mucosal symptoms, fever.
• Drugs in the preceding 1 to 4 weeks (Stevens-Johnson syndrome and toxic epidermal necrolysis start 4 to 28 days after a drug). Naproxen, furosemide, tetracyclines and amiodarone cause pseudoporphyria.
• Exposures: plants, chemicals, sunlight, insects (especially Paederus beetles), freshwater or seawater, burns, friction.
• Contacts with varicella, zoster, hand foot and mouth disease or mpox; sexual history.
• Immunosuppression, diabetes, HIV, hepatitis C, alcohol use, iron overload, pregnancy, family history of blistering.
• Vaccination status for varicella.

Examination

• Vital signs, perfusion and pain.
• Tense or flaccid blisters, haemorrhagic contents, erosions, target lesions, grouped lesions, dermatomal pattern.
• Nikolsky sign and Asboe-Hansen sign (bulla extension on pressure).
• Oral, ocular and genital mucosa.
• Body surface area detached or involved.
• Eye examination when periocular or nasal tip lesions.
• Lymph nodes and neurological signs.
• Bedside tests: unroof a vesicle and scrape the base for Tzanck smear (multinucleated giant cells; cannot separate herpes simplex from varicella zoster, and sensitivity is low), swab for PCR, urine dipstick.

Red flags

• Pain out of proportion, rapid spread, haemorrhagic bullae, crepitus, hypotension (necrotising infection).
• Erosions at 2 or more mucosal sites with epidermal detachment (Stevens-Johnson syndrome or toxic epidermal necrolysis).
• Widespread erosions with oral involvement (pemphigus).
• Zoster involving the ophthalmic division (nasal tip lesions, Hutchinson sign), the ear (Ramsay Hunt syndrome), multiple dermatomes, or in an immunocompromised patient.
• Vesicles or punched out erosions on eczema with fever (eczema herpeticum).
• Varicella in an adult, pregnant woman, neonate or immunocompromised patient.
• Bullae in a cirrhotic patient after seafood or seawater exposure (Vibrio vulnificus).
• Bruising and burn patterns suggesting child maltreatment.

Special groups

• Pregnancy: pemphigoid gestationis (periumbilical onset in the second or third trimester), varicella and primary genital herpes near term.
• Children: bullous impetigo, scalded skin syndrome, hand foot and mouth disease, papular urticaria, epidermolysis bullosa.
• Older adults: bullous pemphigoid is the commonest immune bullous disease.
• Kidney disease and dialysis: pseudoporphyria.
• Region specific: Paederus (Nairobi fly) dermatitis, mpox, and post herpetic neuralgia in HIV.

Infective

• Herpes simplex (orolabial, genital, eczema herpeticum).
• Varicella (chickenpox).
• Herpes zoster, including ophthalmicus.
• Hand, foot and mouth disease.
• Mpox.
• Bullous impetigo.
• Staphylococcal scalded skin syndrome.
• Bullous cellulitis and necrotising fasciitis.
• Vibrio vulnificus infection.
• Cutaneous anthrax.
• Scabies in infants (vesicles on palms and soles).

Immune mediated

• Bullous pemphigoid.
• Mucous membrane pemphigoid.
• Pemphigoid gestationis.
• Pemphigus vulgaris and pemphigus foliaceus.
• Dermatitis herpetiformis.
• Linear IgA bullous dermatosis (including vancomycin induced).
• Epidermolysis bullosa acquisita.
• Bullous lupus erythematosus.
• Erythema multiforme major.

Drug related

• Stevens-Johnson syndrome and toxic epidermal necrolysis.
• Fixed drug eruption, bullous.
• Pseudoporphyria.

Contact, physical and environmental

• Allergic and irritant contact dermatitis.
• Paederus dermatitis.
• Phytophotodermatitis (plant sap and sunlight).
• Burns and scalds, sunburn, frostbite, friction blisters.
• Insect bites and papular urticaria.
• Dyshidrotic eczema.

Metabolic and genetic

• Porphyria cutanea tarda.
• Bullosis diabeticorum.
• Coma blisters.
• Epidermolysis bullosa.

Step 1. Identify emergencies. Look for sepsis, necrotising infection, severe cutaneous drug reaction, scalded skin syndrome, eczema herpeticum and disseminated zoster. Surgical exploration is the diagnostic test for necrotising fasciitis. Scoring tools have limited sensitivity and must never delay surgery.

Step 2. Tense or flaccid, Nikolsky sign, mucosal involvement and distribution.

Step 3. Tests

• PCR of vesicle base swabs for herpes simplex, varicella zoster and mpox (use viral transport medium and appropriate precautions).
• Bacterial swab and blood cultures for bullous impetigo, scalded skin syndrome and necrotising infection.
• Full blood count (eosinophilia in pemphigoid), urea, creatinine, electrolytes, glucose, liver tests, CRP, lactate, creatine kinase, and blood cultures if unwell.
• Skin biopsy: one 4 mm punch from the edge of a fresh blister (including intact skin) for histology, and one from uninvolved perilesional skin (within 1 cm) for direct immunofluorescence, placed in Michel medium or saline and not formalin.
• Serum indirect immunofluorescence and ELISA: anti BP180 and BP230 for pemphigoid; desmoglein 1 and 3 for pemphigus.
• Tissue transglutaminase IgA with total IgA for dermatitis herpetiformis; perilesional biopsy shows granular IgA at the dermal papillae.
• Porphyria: plasma or spot urine porphyrins (plasma fluorescence peak near 620 nm), ferritin, hepatitis C, HIV, glucose.
• Antinuclear antibodies and anti Ro for bullous lupus.
• HIV and syphilis serology; pregnancy test.

Severity in toxic epidermal necrolysis. Definition by detached body surface area: under 10% (Stevens-Johnson syndrome), 10 to 30% (overlap), over 30% (toxic epidermal necrolysis).

The SCORTEN score gives 1 point each for age over 40, malignancy, heart rate over 120, detached area over 10%, urea over 10 mmol/L, glucose over 14 mmol/L and bicarbonate under 20 mmol/L. It predicts mortality, with approximately 3% at 0 to 1 point, 12% at 2, 35% at 3, 58% at 4 and over 90% at 5 or more.

Limits. Tzanck smears have limited sensitivity. Biopsy placed in formalin makes immunofluorescence impossible. Treat before serology when emergencies are suspected.

Immediate. Airway, breathing and circulation; analgesia; warmth; fluid resuscitation directed by haemodynamics. Stop suspected drugs. Isolate suspected varicella or disseminated zoster.

Stevens-Johnson syndrome and toxic epidermal necrolysis. Admit to intensive care or a burns unit. Fluid need is about two thirds of that for burns (roughly 2 mL/kg for each percent of body surface area detached over 24 hours), titrated to urine output of 0.5 to 1 mL/kg/h.

Supportive care: nonadherent dressings, daily ophthalmology review, nutritional support, temperature control.

Ciclosporin 3 to 5 mg/kg orally daily in 2 doses for 7 to 10 days then taper is used by specialists; evidence is limited. Intravenous immunoglobulin and systemic corticosteroids are not routinely advised.

Necrotising infection. Immediate surgical exploration and debridement with antibiotics:

• piperacillin with tazobactam 4.5 g intravenously every 6 hours (or meropenem 1 g every 8 hours)
• plus clindamycin 600 to 900 mg intravenously every 8 hours
• plus vancomycin 15 to 20 mg/kg intravenously every 8 to 12 hours if MRSA is likely

Adjust for kidney function (piperacillin with tazobactam: creatinine clearance 20 to 40 mL/min, 3.375 g every 6 hours; under 20 mL/min, 2.25 g every 6 hours).

Vibrio vulnificus: doxycycline 100 mg twice daily plus ceftriaxone 2 g intravenously once daily.

Bacterial.

• Bullous impetigo: mupirocin 2% three times daily for 5 days, or fusidic acid 2% three times daily for 5 to 7 days.
• Extensive disease: flucloxacillin 500 mg orally four times daily for 5 to 7 days (clarithromycin 250 to 500 mg twice daily if penicillin allergic).
• Scalded skin syndrome: admit; flucloxacillin 1 to 2 g intravenously every 6 hours in adults (children 12.5 to 25 mg/kg every 6 hours), with fluids and analgesia.

Viral

• Herpes simplex: aciclovir 400 mg orally three times daily for 7 to 10 days for primary genital disease, or for 3 to 5 days for recurrences.
• Eczema herpeticum or immunocompromise: aciclovir 5 to 10 mg/kg intravenously every 8 hours, changing to oral when improving. Adjust intravenous dose for creatinine clearance 25 to 50 mL/min (every 12 hours), 10 to 25 mL/min (every 24 hours), under 10 mL/min (half dose every 24 hours). Maintain hydration to reduce crystal nephropathy.
• Herpes zoster, within 72 hours of the rash (later if new lesions, ophthalmic, or immunocompromised): aciclovir 800 mg orally five times daily for 7 days, or valaciclovir 1 g three times daily for 7 days.
• Valaciclovir by creatinine clearance: 30 to 49 mL/min, 1 g every 12 hours; 10 to 29 mL/min, 1 g once daily; under 10 mL/min, 500 mg once daily.
• Urgent ophthalmology for ophthalmic zoster.
• Analgesia stepwise; gabapentin 300 mg orally at night, increased over 1 to 2 weeks to 300 mg three times daily. Titrate to a usual maximum of 3.6 g daily in divided doses (halve or reduce the dose when creatinine clearance is under 60 mL/min; monitor sedation and dizziness).
• Varicella in adults: aciclovir 800 mg orally five times daily for 7 days, started within 24 hours of rash.
• Pregnant women after 20 weeks: same dose; varicella zoster immunoglobulin for exposed susceptible pregnant women within 10 days.
• Hand, foot and mouth disease: fluids and analgesia. Mpox: supportive care and isolation; tecovirimat for severe or high risk disease under specialist direction, with limited evidence.

Immune bullous disease. Start after biopsy unless the patient is deteriorating.

• Bullous pemphigoid: clobetasol propionate 0.05% cream 20 to 40 g daily applied to the whole body (excluding face if mild), tapered over months, or prednisolone 0.5 mg/kg orally daily. Monitor glucose, blood pressure, bone health and infection. Consider adding doxycycline as a steroid sparing agent.
• Pemphigus vulgaris: prednisolone 0.5 to 1 mg/kg orally daily with rituximab 1000 mg intravenously on days 1 and 15; azathioprine 1 to 2.5 mg/kg daily (after TPMT or NUDT15 testing) is an alternative adjunct. Give bone protection and Pneumocystis prophylaxis during high dose steroids.
• Dermatitis herpetiformis: dapsone 25 to 50 mg orally once daily, increased to 100 mg daily, usual maximum 200 mg daily. Check G6PD before starting. Monitor full blood count (haemolysis, methaemoglobinaemia) and liver tests. Lifelong gluten free diet.
• Porphyria cutanea tarda: avoid alcohol, oestrogens and iron; sun protection; venesection of 450 mL every 2 weeks until ferritin is about 20 micrograms/L, or hydroxychloroquine 100 mg twice weekly; treat hepatitis C and HIV.
• Pemphigoid gestationis: potent topical corticosteroids, then prednisolone 0.5 mg/kg orally daily if severe; obstetric surveillance.

Contact and environmental. Paederus dermatitis: wash the skin with soap and water immediately without crushing the beetle, cold compresses, mometasone furoate 0.1% ointment once daily for 5 to 7 days. Eye contact (Nairobi eye): irrigate with saline and refer to ophthalmology. Treat secondary infection if present. Phytophotodermatitis and friction blisters need protection and wound care only.

Monitoring. Vital signs, fluid balance, percent body surface area involved, mucosal and eye assessment, electrolytes, renal function, infection signs.

Referral and escalation. Urgent dermatology for suspected immune bullous disease; same day dermatology and intensive care for Stevens-Johnson syndrome and toxic epidermal necrolysis; ophthalmology for eye involvement; surgery for necrotising infection; obstetrics for pregnancy related blistering.

Admission criteria. Mucosal involvement with detachment, over 10% body surface area, toxicity, necrotising infection, ophthalmic zoster, eczema herpeticum, extensive pemphigus, neonates, and immunocompromised patients.

Discharge and follow up. Review within 1 week for immune bullous disease started on treatment, then every 2 to 4 weeks. Safety net advice: return for new mouth or eye sores, spreading redness, severe pain, fever, or new blisters.