Delayed immune-mediated (T-cell) hypersensitivity reactions

Delayed immune-mediated hypersensitivity reactions are usually the result of T-cell (not IgE) mediated mechanisms, and produce a range of syndromes commonly characterised by maculopapular rash (exanthem). These reactions typically occur after more than one dose of a drug, with an onset days after starting treatment. However, delayed immune-mediated hypersensitivity can occur more rapidly on rechallenge (within 6 hours).

Delayed hypersensitivity reactions are far more common than immediate reactions. They often occur in patients with a viral infection and can be due to the infection or a drug–virus interaction; consequently, such reactions may not be reproducible upon a supervised challenge when the patient is well. In particular, a mild maculopapular rash caused by a penicillin, especially amoxicillin or ampicillin, is not strongly predictive of a future reaction and many patients tolerate the drug if it is administered at a later time.

Delayed severe reactions are uncommon but serious. They include:

• severe cutaneous adverse reactions (SCAR) – a group of T-cell mediated hypersensitivities with cutaneous plus internal organ or mucous membrane involvement
  • drug rash with eosinophilia and systemic symptoms (DRESS) – typically characterised by fever, eosinophilia, desquamative dermatitis and liver or kidney dysfunction
  • Stevens–Johnson syndrome / toxic epidermal necrolysis (SJS/TEN) – a rare, acute and potentially fatal skin reaction caused by acute keratinocyte death, resulting in fulminant epidermal skin and epithelial mucosal loss similar to burn injuries
  • acute generalised exanthematous pustulosis (AGEP) – characterised by dozens to hundreds of pin-sized pustules on a background of erythema, often with fever and leucocytosis, and rarely organ involvement; can have a quick onset following drug administration (eg 1 day)
• acute interstitial nephritis (AIN) – causes kidney dysfunction and can include eosinophilia, fever and exanthematous rash. Most commonly associated with penicillins
• serum sickness – characterised by vasculitic or urticarial rash, arthralgia/arthritis, fever, hypocomplementaemia and sometimes proteinuria; the onset is typically several days after starting treatment. More commonly associated with cefaclor than other cephalosporins, and also sulfonamides
• drug-induced liver injury (DILI) – see Clinical features of drug-induced liver injury.

A delayed severe hypersensitivity reaction is a contraindication to further drug exposure – including desensitisation – because this can be fatal.