Type 4 Hypersensitivity Reaction (HSR)
Type 4 HSR is a delayed, T-cell mediated immune response that occurs hours to days after antigen exposure, characterized by lymphocyte activation rather than antibody production. 1, 2
Mechanism and Timing
- Type 4 reactions are T-cell dependent mechanisms that develop more than 1 hour after drug administration, but commonly manifest after many days of exposure 3
- Unlike immediate reactions (Type 1), these are not mediated by IgE antibodies but rather by activated T lymphocytes (both CD4+ and CD8+ cells) 1, 4
- The typical timeframe is 24-72 hours after antigen exposure, though reactions can occur at any time during treatment 5
Clinical Manifestations
Type 4 HSR presents with diverse cutaneous and systemic manifestations 1, 2:
- Maculopapular exanthema (drug rashes)
- Allergic contact dermatitis (e.g., nickel allergy, dental materials) 4, 5
- Severe cutaneous adverse reactions (SCARs) including:
- Stevens-Johnson syndrome (SJS)
- Toxic epidermal necrolysis (TEN)
- Drug reaction with eosinophilia and systemic symptoms (DRESS)
- Acute generalized exanthematous pustulosis (AGEP) 1
- Psoriasis 1
- Erythema multiforme 1
Subtypes of Type 4 HSR
Modern classification divides Type 4 reactions into four subtypes based on the dominant T-cell population and cytokine profile 6, 7:
- Type IVa: CD4+ Th1-mediated with interferon-gamma, causing contact dermatitis and granuloma formation 6, 7
- Type IVb: CD4+ Th2-mediated with IL-4, IL-5, IL-13, causing maculopapular exanthema with eosinophilia and chronic asthma 6, 7
- Type IVc: CD8+ cytotoxic T-cell mediated with perforin and granzyme B, causing bullous reactions like SJS/TEN 6, 7
- Type IVd: T-cell driven neutrophilic inflammation with IL-8 and GM-CSF, causing pustular reactions like AGEP 6, 7
Critical Management Distinctions
Type 4 reactions are typically NOT amenable to desensitization, unlike immediate Type 1 reactions 1:
- Severe T-cell mediated delayed reactions (SJS/TEN, DRESS) are associated with long-lasting memory T-cell responses and typically indicate the drug must be completely avoided 1
- Immediate discontinuation of the suspected culprit drug is essential 2, 3
- Treatment includes topical corticosteroids and oral antihistamines for mild-moderate reactions 2, 3
- Systemic corticosteroids and specialized care are required for severe reactions like SJS/TEN and DRESS 2, 3
Diagnostic Approach
- Delayed intradermal testing (dIDT) may be useful for certain cutaneous adverse reactions but should be avoided in SJS/TEN where sensitivity is low 1
- Patch testing is the primary diagnostic tool for contact allergic reactions, identifying allergens such as metals (gold, nickel, mercury, palladium), acrylates, and other haptens 5
- Complete blood count with differential, liver and kidney function tests, and HLA genotyping for specific drug-gene associations may aid diagnosis 2
Common Pitfalls
- Do not attempt desensitization for severe cutaneous adverse reactions (SCARs) - these require permanent drug avoidance 1
- Skin testing for chemotherapeutic agents may not be possible due to skin toxicity of the drugs themselves 1
- Clinical presentations often represent an overlap of cytokine pathways, with one reaction type dominating the final picture 6