Recognising severe cutaneous adverse drug reactions

Severe cutaneous adverse drug reactions (SCARs) are a major cause of morbidity and mortality in Australia and recognition is important. Key diagnostic features are present early in the presentation and common drug associations exist. Clinicians should become familiar with these reaction patterns to more effectively manage these dermatological emergencies.

Exanthemic eruptions represent the majority of drug reactions. Erythematous macules and papules begin on the trunk and may generalise, but patients are usually systemically well. Almost any drug can be responsible; common triggers include penicillins and anticonvulsants. Reactions typically appear after 7 to 14 days; a careful history usually uncovers the culprit medication, and cessation results in complete recovery. Like many drug eruptions, reactions are more common with concomitant viral infections, including human immunodeficiency virus.1

SCARs represent type IV delayed hypersensitivity. These T lymphocyte-mediated responses are driven by small molecule drugs acting as haptens presented by human leucocyte antigen class 1 proteins.1 Antiepileptics, antimicrobials and allopurinol are commonly responsible, and these reactions carry significant morbidity and mortality.

Making the correct diagnosis is vital; the causative agent can be identified and ceased immediately and early management initiated. Distinct clinical and morphological patterns of the eruption are clues (Box 1). Key clinical features to consider in suspected drug eruptions are shown in Box 2.

Stevens–Johnson syndrome and toxic epidermal necrolysis

Epidermal cell death and mucosal ulceration are common to Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), classified by the extent of body surface area involved: SJS if < 10%, TEN if 30%, and SJS/TEN overlap if 10–30%. Full thickness epidermal necrosis on biopsy is characteristic.

Drugs are responsible for the majority of cases. In a small number, no clear link is established.2 Mycoplasma pneumonia infection is associated in children.3

Patients are unwell, with flu-like symptoms, fever and eye irritation. Painful skin and early mucosal involvement are red flags and key diagnostic features (Box 3, A). Two or more sites are involved in 80% of cases, including ocular, oral, nasopharyngeal and anogenital mucosa.2 Severe lip crusting reflects oropharyngeal erosion and patients may be unable to swallow. Conjunctival erosions may lead to adhesions and blindness, and require aggressive treatment.

The rash appears dusky red and macular, with irregular targetoid lesions (Box 3, B). Epidermal necrosis evolves within these areas, becoming confluent (Box 3, C). In TEN, large areas of epidermis can sheet off exposing bright red erosions, behaving like an extensive superficial burn (Box 3, D).

Management requires intensive supportive care, ideally in a burns unit, with barrier nursing. Secondary infection is a major risk. Treatment is controversial and includes systemic corticosteroids, cyclosporin, intravenous immunoglobulin and anti-tumour necrosis factor agents.1,2

Drug reaction with eosinophilia and systemic symptoms

Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as drug-induced hypersensitivity syndrome, presents as a maculopapular drug reaction with fever, haematological changes and internal organ involvement. It may resemble a mononucleosis-like syndrome, including arthralgia, lymphadenopathy and pharyngitis.4

Facial and periorbital erythema and swelling are early red flags (Box 4, A). The rash spreads in a cephalocaudal pattern to become generalised (Box 4, B). Lack of skin or mucosal detachment distinguishes it from SJS/TEN.

Internal involvement predominates. Eosinophilia and atypical lymphocytosis are typical. The liver is most commonly affected (> 50%) and hepatitis may be fulminant.4 Renal, cardiac (myocarditis) and central nervous system inflammation may develop. Thyroiditis and other forms of delayed autoimmunity can manifest 2–3 months later, and the early tests for visceral and thyroid involvement must therefore be repeated.4

A protracted clinical course is typical, with cutaneous and visceral organ involvement lasting weeks or months after drug withdrawal. Flares commonly follow initial improvement.

The suspected medication is ceased immediately. Topical corticosteroids under wet dressings and antihistamines are useful. Prednisolone (1–2 mg/kg/day) is usually given with visceral involvement or severe symptoms, and typically needs to be continued for 50–60 days. Intravenous immunoglobulin and cyclosporin are options.1

There are fewer causative drugs and onset is later. The mortality rate of 2–10% reflects visceral involvement.4

Acute generalised exanthematous pustulosis

Acute generalised exanthematous pustulosis (AGEP) is characterised by early rapid onset, often within 48 hours following drug exposure, usually accompanied by fever.1

Widespread erythema and oedema is rapidly followed by the appearance of hundreds or thousands of small sterile pustules (Box 5, A). The superficial pustules are the diagnostic key (Box 5, B). These coalesce with superficial epidermal shedding. The rash favours body folds, and palms and soles are involved (Box 5, C).

The dramatic onset and appearance is often mistaken for SJS/TEN, but mucous membrane involvement occurs in a minority of cases, and is typically mild and non-erosive. Cutaneous changes dominate and internal involvement is rare. Facial involvement in AGEP differs from that in DRESS in being pustular rather than exanthematous.

Despite an acute and severe reaction, the prognosis is favourable. It is self-limited, and once the offending drug is withdrawn, the rash resolves with peeling and without scarring. Systemic corticosteroids are given only in severe cases.5

Most cases are drug induced, and re-exposure produces a dramatic recurrence. Viral and bacterial infections may trigger AGEP.5

Summary

In severe adverse drug reactions, clinical signs may evolve sequentially. Awareness of key diagnostic features is necessary for early diagnosis, intervention and referral that may be lifesaving.

Box 2 – Key features to consider in suspected drug-related eruptions

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AGEP = acute generalised exanthematous pustulosis. DRESS = drug reaction with eosinophilia and systemic symptoms. SJS = Stevens–Johnson syndrome. TEN = toxic epidermal necrolysis.

Box 3 – Stevens–Johnson syndrome and/or toxic epidermal necrolysis

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Early signs are lip and mucosal involvement (A). Painful dusky targetoid lesions (B) evolve into epidermal necrosis, blistering (C) and detachment (D).

Box 4 – Drug reaction with eosinophilia and systemic symptoms

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Facial and periorbital erythema and oedema are early signs (A), along with a generalised maculopapular rash (B), fever and internal involvement.

Box 5 – Acute generalised exanthematous pustulosis

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Hundreds of coalescing superficial pustules on an erythematous background appear rapidly (A, B). Palmar and plantar involvement is common (C).