7.1 Cutaneous Adverse Drug Reactions, SCARs & Dermatological Emergencies
Key Takeaways
- Stevens-Johnson syndrome involves epidermal detachment of less than 10% of body surface, overlap SJS/TEN 10% to 30%, and toxic epidermal necrolysis more than 30%.
- SCORTEN uses 7 criteria (age 40 or over, malignancy, heart rate 120 or more, detachment over 10%, urea over 10 mmol/L, bicarbonate under 20 mmol/L, glucose over 14 mmol/L) to predict TEN mortality.
- DRESS usually starts 2 to 8 weeks after starting the drug, with fever, facial oedema, rash, lymphadenopathy, eosinophilia, and organ involvement, most often of the liver.
- Acute generalised exanthematous pustulosis usually begins within about 48 hours of the drug, often an aminopenicillin, with many small non-follicular sterile pustules and neutrophilia.
- HLA-B*15:02 predicts carbamazepine-induced SJS/TEN in people of Southeast Asian ancestry, and HLA-B*58:01 predicts allopurinol-induced SCARs, especially in Han Chinese, Korean, and Thai people.
7.1 Cutaneous Adverse Drug Reactions, SCARs & Dermatological Emergencies
How Delayed Drug Reactions Work
Immediate (IgE-mediated) reactions are covered in the type I allergy section. Delayed T-cell reactions follow the Pichler subclassification of type IV hypersensitivity:
| Type | Main Effector | Typical Reactions |
|---|---|---|
| IVa | Th1 cells, macrophages (IFN-gamma) | Allergic contact dermatitis |
| IVb | Th2 cells, eosinophils (IL-4, IL-5) | Maculopapular exanthem, DRESS |
| IVc | Cytotoxic CD8+ T cells (perforin, granzyme B, granulysin) | SJS/TEN, fixed drug eruption |
| IVd | T cells recruiting neutrophils (CXCL8/IL-8) | AGEP |
Maculopapular Exanthem (MPE)
The most common drug eruption. Symmetric red macules and papules start on the trunk 4–14 days after starting a drug (antibiotics, anticonvulsants, allopurinol). It fades within 1–2 weeks of stopping. The classic amoxicillin rash in Epstein-Barr virus infection is usually not a true allergy. Red flags that suggest a SCAR are facial swelling, fever, mucosal lesions, blisters, skin pain, dusky or target lesions, pustules, and abnormal blood tests.
Fixed Drug Eruption (FDE)
- One or a few round, dusky red-violet plaques, sometimes blistering, that recur at the same site each time the drug is taken. Lips, genitals, hands, and feet are common.
- Culprits: NSAIDs, sulfonamides (co-trimoxazole), paracetamol, tetracyclines, barbiturates.
- Heals with slate-grey post-inflammatory pigmentation. Generalised bullous FDE can mimic SJS/TEN.
- Patch testing on the previously affected site can identify the drug.
Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (SJS/TEN)
| Category | Epidermal Detachment |
|---|---|
| SJS | Less than 10% of body surface |
| SJS/TEN overlap | 10–30% |
| TEN | More than 30% |
- Timing: usually 4–28 days after first exposure, after a fever-and-sore-throat prodrome.
- Clinical: painful dusky macules and atypical flat targets, which become blisters and sheets of detachment (positive Nikolsky sign), with erosions of at least two mucosal sites (eyes, mouth, genitals).
- High-risk drugs: allopurinol, carbamazepine, lamotrigine, phenytoin, phenobarbital, sulfonamides (co-trimoxazole), nevirapine, oxicam NSAIDs. Mycoplasma pneumoniae can cause a similar mucositis-predominant picture, especially in children.
- Pharmacogenetics: HLA-B*15:02 and carbamazepine (Southeast Asian ancestry; screen before prescribing in these groups); HLA-B*58:01 and allopurinol (Han Chinese, Korean, Thai); HLA-A*31:01 and carbamazepine DRESS and MPE in Europeans and Japanese.
- Histology: full-thickness epidermal necrosis with sparse dermal inflammation. A frozen section of the blister roof separates it quickly from staphylococcal scalded skin syndrome.
- Causality: the ALDEN algorithm scores drug timing, presence at onset, rechallenge, and notoriety.
SCORTEN (calculate within 24 hours of admission)
| Criterion (1 point each) |
|---|
| Age ≥ 40 years |
| Malignancy present |
| Heart rate ≥ 120 per minute |
| Epidermal detachment > 10% of body surface on day 1 |
| Serum urea > 10 mmol/L |
| Serum bicarbonate < 20 mmol/L |
| Serum glucose > 14 mmol/L |
Predicted mortality in the original validation: 0–1 points about 3%, 2 about 12%, 3 about 35%, 4 about 58%, 5 or more about 90%.
Management
- Stop the suspected drug immediately. Earlier withdrawal of drugs with a short half-life improves survival.
- Transfer to a burn unit or intensive care for extensive disease.
- Supportive care: warm room, fluids, nutrition, analgesia, non-adherent dressings (leave detached epidermis in place as a biological dressing), infection surveillance without routine prophylactic antibiotics, and thromboprophylaxis.
- Daily ophthalmology review, plus oral, genital, and urological care to prevent scarring.
- Immunomodulation is debated. Ciclosporin, IVIG, systemic corticosteroids, and TNF-alpha inhibitors (etanercept) are used in different centres, and no option is universally proven.
- Afterwards, give a written allergy record and avoid the drug and closely related drugs for life. Long-term complications include dry eye, visual loss, nail loss, and genital strictures.
DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms)
- Timing: 2–8 weeks after starting the drug, which is later than other drug reactions.
- Features: fever, widespread rash, facial oedema, lymphadenopathy, eosinophilia, atypical lymphocytes, and organ involvement: liver (most common), kidney, lung, heart, pancreas, and thyroid.
- Drugs: aromatic anticonvulsants (carbamazepine, phenytoin, lamotrigine), allopurinol, sulfonamides, dapsone, minocycline, vancomycin, and others.
- Viral reactivation: HHV-6, and also EBV, CMV, and HHV-7, often in sequence.
- RegiSCAR score: fever, lymphadenopathy, eosinophilia, atypical lymphocytes, skin involvement, organ involvement, time to resolution, and exclusion of other causes. < 2 no case, 2–3 possible, 4–5 probable, > 5 definite.
- Treatment: stop the drug. Use potent topical steroids for mild disease without significant organ involvement, and systemic corticosteroids (for example prednisolone 0.5–1 mg/kg/day) tapered slowly over weeks to months when organs are involved. Ciclosporin is an option. Relapse is common if the taper is fast.
- Late sequelae: autoimmune thyroiditis, type 1 diabetes, and other autoimmune disease months later.
Acute Generalised Exanthematous Pustulosis (AGEP)
- Timing: rapid, usually within 48 hours (often within a day for antibiotics).
- Clinical: fever, and many small non-follicular sterile pustules on red, oedematous skin, starting in the face and flexures. There is neutrophilia, and mild organ involvement is possible.
- Drugs: aminopenicillins, pristinamycin, hydroxychloroquine (longer latency), diltiazem, terbinafine, and others.
- Histology: subcorneal or intraepidermal spongiform pustules, papillary oedema, and sometimes eosinophils.
- Course: resolves within about 2 weeks with superficial desquamation. Treat by stopping the drug and applying topical steroids.
- Differential: generalised pustular psoriasis (longer course, psoriasis history).
Testing After Recovery
For delayed reactions, patch tests (useful in DRESS, AGEP, FDE on the affected site, and MPE), delayed-reading intradermal tests, and the lymphocyte transformation test can help identify the culprit. Drug provocation is contraindicated after SJS/TEN or DRESS.
Other Dermatological Emergencies
| Emergency | Key Features | Immediate Action |
|---|---|---|
| Erythroderma | Over 90% of body surface red and scaling; causes: eczema, psoriasis, drugs, cutaneous T-cell lymphoma (Sézary syndrome), PRP, idiopathic | Admit if unwell; fluids, warmth, emollients; biopsies, blood film and Sézary cell count; stop likely drugs; treat the cause |
| Eczema herpeticum | Monomorphic punched-out erosions in atopic skin, fever | Aciclovir (IV if unwell or periocular); eye review |
| Staphylococcal scalded skin syndrome (SSSS) | Mainly young children; tender erythema, superficial (subcorneal) peeling, crusting around the mouth, no mucosal involvement; exfoliative toxins A and B cleave desmoglein 1 | IV anti-staphylococcal antibiotic (flucloxacillin), fluids, pain relief |
| Purpura fulminans | Rapidly spreading purpura and skin necrosis with DIC, often meningococcal sepsis or protein C deficiency | Emergency sepsis care, antibiotics, protein C replacement where indicated |
| Necrotising fasciitis, anaphylaxis, GPP, pemphigus flares | See their own sections | — |
A 55-year-old man with metastatic lung cancer develops TEN 3 weeks after starting a new anticonvulsant. On admission, his heart rate is 128 per minute, detachment covers 35% of body surface, serum urea is 8 mmol/L, bicarbonate 22 mmol/L, and glucose 9 mmol/L. What is his SCORTEN?
Five weeks after starting carbamazepine, a patient develops fever, a widespread itchy rash, marked facial swelling, cervical lymphadenopathy, eosinophilia of 2.5 × 10⁹/L, and raised liver enzymes. What is the most likely diagnosis?
A 3-year-old child has fever, tender generalised redness, and superficial peeling of the skin with crusting around the mouth and nose. The mouth, eyes, and genitals are not affected. What is the most likely diagnosis and mechanism?
A patient of Han Chinese ancestry is about to start allopurinol for recurrent gout. Which HLA allele is most strongly associated with allopurinol-induced SJS/TEN and DRESS?