Internal Diseases and Therapy · MU Sofia

136. Drug allergy: type IV a,b,c,d

Explains delayed T-cell-mediated drug allergy (type IV) and its Pichler subtypes IVa to IVd, set out in a table giving effector cells, cytokines, mechanisms and typical drug reactions. Covers common non-severe reactions, severe cutaneous reactions such as SJS/TEN, DRESS and AGEP with their culprit drugs, HLA associations, diagnostic tests including patch and lymphocyte transformation tests, and management steps.

Inside: 1 section · 1 table · 1 min

Topic 137 of 139 in the MU Sofia syllabus for Internal Diseases and Therapy (Medicine, Years 4 and 5). The free AceMed note covers it in 1 section, about 668 words (1 min of reading).

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  1. Drug allergy: type IV a,b,c,d

Drug allergy: type IV a,b,c,d

Type IV hypersensitivity is the delayed, T-cell-mediated type of drug allergy. No antibodies are involved: drug-specific T cells recognise the drug presented on HLA molecules (as a hapten bound to proteins, or by binding directly to the T-cell receptor or HLA – the p-i concept), then release cytokines or kill target cells. The skin is the main target; liver, kidneys and lungs can be involved.

The reaction typically appears more than 48–72 hours after exposure; on a first course, after days to weeks (SJS/TEN usually 4–28 days, DRESS 2–8 weeks). On re-exposure it appears much faster.

Pichler subclassification (types IVa–IVd)

Subtypes often combine (e.g. a maculopapular exanthem involves IVb and IVc).

Common non-severe reactions

  • Maculopapular exanthem – the most common drug allergy; itchy red macules and papules on trunk and limbs 4–14 days after starting the drug (aminopenicillins, especially during EBV infection; sulfonamides; anticonvulsants)
  • Fixed drug eruption – one or a few round dusky-violet plaques that recur at the same site on each exposure and leave pigmentation (co-trimoxazole, NSAIDs, tetracyclines)

Severe cutaneous adverse reactions (SCARs)

  • SJS/TEN (type IVc)
  • Fever and sore throat, then painful dusky macules, blisters, positive Nikolsky sign and sheet-like epidermal detachment; mucosal erosions (mouth, eyes, genitals) in more than 90%
  • Detachment: SJS less than 10% of body surface, overlap 10–30%, TEN more than 30%; TEN mortality up to about 30% (SCORTEN)
  • Culprits: allopurinol, carbamazepine, phenytoin, lamotrigine, sulfonamides, oxicam NSAIDs, nevirapine
  • DRESS (type IVb) – drug reaction with eosinophilia and systemic symptoms
  • Onset 2–8 weeks after starting the drug; fever, widespread rash, facial oedema, lymphadenopathy
  • Eosinophilia, atypical lymphocytes and organ involvement – liver most often, also kidney, lungs, heart; HHV-6 reactivation; mortality up to about 10%
  • Culprits: aromatic anticonvulsants, allopurinol, sulfonamides (incl. dapsone), minocycline, vancomycin
  • AGEP (type IVd)
  • Onset within 1–2 days; fever and many small sterile non-follicular pustules on red, oedematous skin, starting in skin folds; neutrophilia
  • Resolves within about 2 weeks of stopping the drug; good prognosis
  • Culprits: β-lactams (aminopenicillins), macrolides, hydroxychloroquine, terbinafine, diltiazem

Red flags – stop the drug and admit:

  • Mucosal erosions, skin pain, blisters or skin detachment → SJS/TEN
  • Fever, facial oedema, lymphadenopathy, eosinophilia, raised liver enzymes → DRESS

HLA associations

  • HLA-B*57:01 – abacavir hypersensitivity: screen before abacavir; carriers must not receive it
  • HLA-B*15:02 – carbamazepine SJS/TEN in Han Chinese and South-East Asian patients (screen before use)
  • HLA-B*58:01 – allopurinol SJS/TEN and DRESS (especially Han Chinese, Thai, Korean)

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