What is drug-induced fever?

Drug-Induced Fever: Characteristics, Mechanisms, and Management

Drug-induced fever is a febrile response that coincides temporally with medication administration and resolves after discontinuation of the offending agent, typically occurring after a mean of 21 days (median 8 days) of drug exposure and resolving within 1-3 days after drug withdrawal. 1

Clinical Characteristics

• Fever typically develops after 7-10 days of drug administration but can be highly variable depending on the medication 1, 2
• Fever persists as long as the drug is continued and typically resolves within 1-3 days after discontinuation, though it may take up to 7 days to fully normalize 1
• Rash and eosinophilia are uncommon accompaniments to drug-induced fever 1
• Patients often appear inappropriately well for the degree of fever they have 3
• Drug-induced fever is usually diagnosed when no other cause for the fever can be identified 2

Mechanisms of Drug-Induced Fever

Drug-induced fever can occur through several mechanisms:

• Hypersensitivity reactions: Most common mechanism, involving immune-mediated responses to the drug 4
• Drug metabolism: Some drugs become immunogenic through metabolism to reactive intermediates that bind to proteins 1
• Direct pharmacological interaction: Some medications may interact directly with T-cells through MHC-restricted pathways 1
• Drug withdrawal: Discontinuation of certain drugs (alcohol, opiates, barbiturates, benzodiazepines) can cause fever with associated tachycardia, diaphoresis, and hyperreflexia 1

Medications Commonly Associated with Drug Fever

• Antimicrobials: Beta-lactams (penicillins, cephalosporins) are among the most common causes 4, 5
• Antipsychotics: Can cause fever through neuroleptic malignant syndrome 1, 4
• Anticonvulsants: Phenytoin can cause fever as part of Anticonvulsant Hypersensitivity Syndrome 6
• Antihypertensives: Clonidine has been reported to cause drug fever 7
• Sedatives: Propofol has been implicated in cases of drug fever in intensive care settings 3

Specific Drug-Induced Fever Syndromes

Neuroleptic Malignant Syndrome

• Associated with antipsychotic medications (phenothiazines, thioxanthenes, butyrophenones) 1
• Characterized by muscle rigidity, hyperthermia, elevated creatinine phosphokinase, and central initiation of muscle contraction 1
• Requires immediate discontinuation of the antipsychotic and intensive supportive care 8

Anticonvulsant Hypersensitivity Syndrome

• Rare but potentially fatal multiorgan syndrome 6
• Characterized by fever, rash, lymphadenopathy, and often hepatic involvement 6
• Typically occurs 2-4 weeks after drug exposure 6
• Higher risk in Black patients and those with family history of the syndrome 6

Diagnosis

Drug-induced fever is primarily a diagnosis of exclusion:

• Establish temporal relationship between drug administration and fever onset 8
• Rule out infectious causes through appropriate cultures and clinical evaluation 8, 9
• Consider drug fever when fever persists despite appropriate antibiotic therapy 4
• Discontinuation of the suspected drug with subsequent resolution of fever confirms the diagnosis 1, 2

Management

• Primary approach: Discontinue the suspected medication after assessing risk/benefit ratio 1, 8, 9
• Supportive care: Provide antipyretics and hydration while waiting for resolution 4, 8
• Monitoring: Observe for at least 24-48 hours after discontinuation to ensure symptom resolution 8
• Rechallenge: Generally not recommended as it may cause recurrence of fever within hours and potentially more severe reactions 2
• Special considerations: Never rechallenge patients who experienced anaphylaxis or toxic epidermal necrolysis 1

Important Considerations

• Drug-induced fever is often misdiagnosed, leading to unnecessary diagnostic procedures and treatments 2, 9
• Early diagnosis can reduce inappropriate antimicrobial therapy and expensive interventions 2
• For severe syndromes like neuroleptic malignant syndrome, immediate intervention is critical 8
• In pregnant women, acetaminophen is preferred for fever management 4
• In patients with unexplained persistent fever, always review the medication list for potential culprits 9, 7