Drug fever: when a medicine causes a high temperature

A narrative review in Annals of Clinical Epidemiology defines drug fever as a febrile response that begins after a drug is started, resolves within 72 hours of stopping it without specific therapy, has no other cause identified, and does not relapse. It notes that there is no consensus definition and that other drug reactions, such as severe skin reactions or drug hypersensitivity syndrome, also include fever but are handled as separate conditions.

The main mechanism is thought to be an immune hypersensitivity response rather than a direct effect of the drug on the temperature centre. That is why drug fever overlaps with other allergic-type reactions and sometimes comes with a rash.

A systematic review of case reports in people after surgery says drug fever typically appears 7 to 10 days after the drug is given, though there are no definitive criteria and the interval can range from a few hours to several months. The pattern can be intermittent, remittent or continuous, so a particular fever curve does not prove or exclude it.

Timing can be shorter if the person has had the same class of drug before. In one cohort of piperacillin-related fever, the median time to onset was 22.5 days in people without earlier beta-lactam exposure and 13 days in those who had had one. This is one reason a second course of an antibiotic can trigger fever faster than the first.

No single finding is reliable, but several features raise suspicion. The narrative review reports that relative bradycardia, a pulse that is slower than expected for the temperature, has been described in many series of antibiotic-induced drug fever, and that its absence may help argue against the diagnosis. Some clinicians also describe a patient who looks surprisingly well despite the fever, although the evidence for this sign is limited.

Blood tests may show raised eosinophils, liver enzymes or inflammatory markers, but the review warns that the absence of eosinophilia does not exclude drug fever, and that results vary widely between studies. A rash, if present, is usually mild and widespread.

Antibiotics are the best-documented group, particularly beta-lactams such as penicillins and cephalosporins, alongside anticonvulsants and cancer medicines. In the post-surgical systematic review of 23 patients from case reports, the drugs reported most often were propofol, morphine and cephalosporins, and most people recovered after the drug was stopped, although two cases ended in death.

The review also notes that single-centre studies report drug fever in a minority of people given antibiotics or cancer treatment, and that it accounts for a small share of fevers in people admitted for investigation. Being a minority does not make it ignorable, because it can sit behind a fever that was assumed to be an unresolved infection.

A tentative diagnosis is made after a careful history, examination and tests to look for infection and other serious causes. The review advises that if drug fever is strongly suspected, the culprit drug is stopped; when several drugs could be responsible, stopping them one at a time every two to three days, beginning with the most likely, may be reasonable. Stopping is both the diagnostic test and the treatment, and no specific therapy is usually needed.

If fever continues beyond 72 hours after stopping, doctors reconsider: it may be another diagnosis, a different or more severe drug reaction, the wrong drug, or occasionally a prolonged drug fever. Re-challenge with the drug is controversial and is generally reserved for situations where the drug is essential, such as cancer treatment, because it carries risk.

The NHS advises that a high temperature in adults that is not improving or is getting worse needs an urgent GP appointment or NHS 111. If you develop a fever after starting a new medicine, tell the prescriber rather than assuming it is a simple infection.

Once a drug has been identified, it should be recorded as an adverse reaction so it is not restarted by accident. Describe the reaction (fever, with or without rash) and how long it took to settle. Suspected reactions can be reported through the MHRA Yellow Card scheme.