Fever in Hypersensitivity Reactions
Mechanism of Fever Generation
Fever in hypersensitivity reactions is primarily caused by immune-mediated cytokine release from activated T-cells, which act as endogenous pyrogens triggering the hypothalamic temperature set-point elevation. 1, 2
The pathophysiology involves several interconnected mechanisms:
T-cell activation and cytokine storm: Drug-specific CD4+ and CD8+ T-cells infiltrate tissues and secrete pro-inflammatory cytokines including TNF-α, IFN-γ, IL-5, and IL-8, which directly stimulate the hypothalamus to raise body temperature 1
Immune synapse formation: The drug (or its reactive metabolite) binds to HLA molecules and is presented to T-cell receptors, creating an immunological synapse that triggers massive T-cell proliferation and cytokine secretion 1
Tissue inflammation cascade: Activated T-cells recruit eosinophils, neutrophils, and other inflammatory cells through chemokine gradients, amplifying the inflammatory response and pyrogenic cytokine production 1
Temporal Pattern of Fever
The timing of fever onset provides critical diagnostic clues:
Delayed onset (1-6 weeks) after drug initiation is characteristic of true immune-mediated hypersensitivity, distinguishing it from immediate pharmacologic reactions 1, 3, 2
Most commonly occurs after 7-10 days of drug administration in classic drug-induced fever 3
Fever occurring >3 months after starting therapy is almost always due to another cause, not drug hypersensitivity 1
Rapid recurrence (within hours to days) if the drug is restarted after discontinuation, occurring much sooner than the initial reaction 1, 3
Clinical Characteristics
The fever in hypersensitivity syndrome is typically part of a triad: fever + rash + internal organ involvement. 2, 4
Key features include:
Persistent fever that continues as long as the offending drug is administered 3
Rapid defervescence (usually within 48-72 hours) after drug discontinuation 1, 3
Accompanied by systemic symptoms: Constitutional symptoms including malaise, lymphadenopathy, and atypical lymphocytosis frequently accompany the fever 1, 2, 5
Organ involvement markers: Fever associated with eosinophilia, elevated liver enzymes, or renal dysfunction suggests DRESS syndrome rather than isolated drug fever 1, 2, 4
Distinguishing Features by Drug Class
Different medications produce characteristic patterns:
Antiretrovirals (abacavir, nevirapine): Fever appears within 6 weeks, often with gastrointestinal symptoms and rash; CD8+ T-cell mediated with strong HLA associations 1
NSAIDs (ibuprofen): Can cause fever through hypersensitivity syndrome (1 day to 12 weeks onset) with T-cell and cytokine-mediated pathways 6, 2
Antibiotics (penicillins, cephalosporins, sulfonamides): Most common drug class causing hypersensitivity fever, typically 7-10 days after initiation 3, 5
Antiepileptics (phenytoin, carbamazepine, phenobarbital): Fever develops 1-8 weeks after exposure as part of hypersensitivity syndrome with cross-reactivity between aromatic anticonvulsants 7
Critical Pitfalls to Avoid
Do not assume fever >3 months after drug initiation is hypersensitivity - investigate alternative causes 1
Do not rechallenge with the suspected drug - this can precipitate severe or fatal reactions with fever recurring much more rapidly 1, 3
Do not overlook mild fever with rash - this may progress to severe DRESS syndrome with multi-organ involvement 2, 4
Do not continue the drug assuming "treating through" mild symptoms - while sometimes possible with isolated mild rash, fever indicates systemic involvement requiring immediate discontinuation 1, 6