Management of Fever and Hypersensitivity
Immediately discontinue any suspected drug culprit, as this is the cornerstone of management for drug-induced hypersensitivity syndrome, which commonly presents with fever, rash, and systemic involvement. 1
Initial Assessment and Drug Evaluation
The first critical step is identifying potential drug causes:
- Review all medications started within the past 3 weeks, as drug-induced fever has a mean lag time of 21 days after drug initiation (median 8 days). 2, 3
- Specific high-risk medications requiring immediate consideration include:
- Isoniazid (hypersensitivity with fever and rash) 4
- Rifampin/rifabutin (hypersensitivity with fever and rash) 4
- Cefoxitin (hypersensitivity with fever, rash, eosinophilia) 4
- Oxaliplatin (fever may be the sole initial manifestation before progression to severe reactions) 5
- Mesalazine (can cause severe hypersensitivity with fever, rash, hepatotoxicity, and atypical lymphocytosis) 6
Clinical Stability Assessment
Determine if the patient is clinically unstable, looking specifically for:
- Altered mental status, hypotension, tachycardia, or respiratory distress 2
- Signs of hepatic involvement (jaundice, elevated liver enzymes) 4, 1
- Hematologic abnormalities (eosinophilia, atypical lymphocytosis, leukopenia) 4, 1, 6
If the patient is unstable or deteriorating, start empiric intravenous ceftriaxone immediately without waiting for culture results. 2
Physical Examination for Hypersensitivity Features
Conduct a thorough examination for specific findings:
- Skin manifestations: rash, erythema, desquamation, or hives 4, 1, 6
- Systemic signs: lymphadenopathy, hepatosplenomegaly 2
- Mucosal changes: oral lesions, conjunctival injection 2
- Extremity findings: edema, arthralgias 4
Patients presenting with allergic or hypersensitivity features (rash, fever, lymphadenopathy, facial edema, arthralgias, eosinophilia, or atypical lymphocytosis) should not be rechallenged with the suspected drug, as these features are associated with poorer outcomes. 4
Laboratory Evaluation
Obtain the following tests to distinguish hypersensitivity from infection:
- Complete blood count with differential to identify eosinophilia, atypical lymphocytosis, leukopenia, or thrombocytopenia 4, 2, 1
- Comprehensive metabolic panel including liver enzymes (ALT, AST, alkaline phosphatase) to detect hepatotoxicity 4, 1, 6
- Multiple sets of blood cultures before administering antibiotics if infection is suspected 2
- Renal function tests if nephrotoxic drugs are involved 4
Management Algorithm
If Drug-Induced Hypersensitivity is Suspected:
- Discontinue the suspected drug immediately 1
- Initiate systemic corticosteroids as first-line therapy for drug-induced hypersensitivity syndrome/DRESS 1
- Monitor for visceral organ involvement with serial liver enzymes, renal function, and blood counts 4, 1
- Plan for longitudinal follow-up to evaluate for sequelae 1
If Infection Cannot be Excluded:
- Start empiric antibiotics if clinically unstable with intravenous ceftriaxone for 14 days 2
- Obtain cultures before antibiotic administration when possible 2
- Reassess diagnosis if no response within 24-48 hours to empiric therapy 2
Critical Pitfalls to Avoid
- Do not rechallenge patients who have experienced hypersensitivity reactions with fever, rash, or systemic symptoms, as this is associated with worse outcomes and potential progression to severe reactions. 4, 5
- Do not rely on antipyretics to guide management, as fever response to acetaminophen does not distinguish bacterial from viral infection or drug-induced fever. 2
- Do not overlook drug-drug interactions that enhance toxicity, such as clarithromycin with rifabutin (increases uveitis risk). 4
- Do not dismiss persistent symptoms after drug discontinuation, as drug-induced hypersensitivity syndrome can have prolonged sequelae requiring ongoing monitoring. 1
Monitoring During Treatment
For patients on multiple medications who develop fever: