Episode 64: How to identify drug fever

In this episode, I’ll discuss how I identify drug fever.

Background

Drug fever is a common condition that coincides temporally with the administration of a drug and disappears after discontinuation of the medication. Unfortunately, it is usually an unclear diagnosis, often made by exclusion.

It is just as valuable to the healthcare team for the pharmacist to identify a drug that might be causing fever as it is to identify when medications are not involved in causing a fever.

An excellent review of drug fever was published by Ruchi Patel in Pharmacotherapy 2010.

A fever often leads clinicians to suspect and treat an infection. For this reason, drug fever can lead to over-utilization of antibiotics, putting a patient at risk of adverse effects and the development of antimicrobial resistance.

Drug fever that occurs during the course of treating an infection may mislead clinicians into believing that the patient is not responding to treatment for the infection.

Drug fever may precede or accompany more serious adverse drug reactions.

A key feature that differentiates drug fever from fever due to other causes is that it disappears once the offending drug is discontinued.

Many medications have been implicated in drug fever. I discussed in episode 27 how dexmedetomidine has been associated with drug fever. In episode 40 I discussed severe hyperthermia from serotonin syndrome, malignant hyperthermia, and neuroleptic malignant syndrome.

The most frequent drugs implicated are antimicrobials, anticonvulsants (carbamazepine and phenytoin), anti-arrhythmic agents (procainamide and quinidine), and other cardiac agents.  Here is a list of other medications that may cause drug fever.

Identification of drug fever

Identifying drug fever is complicated because fever can be a characteristic of many disease processes other than infection, including malignancy, thromboembolic disease, cerebrovascular accidents, collagen vascular diseases, acute gout, surgery, and trauma.

To identify drug fever, I review the patient’s clinical presentation, current medications, and lab values.

Interval between start of therapy and onset of fever

Drug fever may occur at any point during a course of drug therapy.
The median time between initiation of the offending agent and onset of fever is 7–10 days.

Here are the median & mean times of fever onset for the most common causes of drug fever:

Antineoplastics – median 0.5 days, mean 6 days
Antimicrobials – median 6 days, mean 7.8 days
CNS agents – median 16 days, mean 18.5 days
Cardiovascular agents – median 10 days, mean 44.7 days

Fever pattern

Various patterns of fever occur in patients:

Continuous fever – when body temperature is consistently elevated

Remittent fever – when elevated body temperature is interrupted by daily normal fevers

Hectic fever – a combination of continuous and remittent patterns

Most commonly, drug fever manifests with a hectic fever pattern.

Degree of temperature elevation

Elevated temperatures of 102–104°F (39-40°C) are most common, but can range from 99°F to 109°F (38-43°C).

Appearance

Patients with drug fever will usually appear “inappropriately well” for the degree of fever that they have.  They are also often unaware of their fevers.

Relative bradycardia

Relative bradycardia occurs when the heart rate does not increase to the extent that typically accompanies the temperature elevation.

To determine the presence of relative bradycardia, a temperature of at least 102°F is required, and sinoatrial disease or drugs that affect heart rate must not be present.

Take the last digit of the temperature in Fahrenheit, subtract 1, multiply by 10 then add 100. If the patient’s heart rate is less than this number, the patient has relative bradycardia.

For example, for a temperature of 102°F, the appropriate pulse response would be approximately 110 beats/minute. Any value less than this would be considered relative bradycardia.

If you know of a formula for relative bradycardia using Celsius, please let me know!

Skin manifestations

Approximately 1 in 4 patients with drug fever also have cutaneous manifestations. This rash may be maculopapular or urticarial.

Laboratory findings

I’ve never considered laboratory findings particularly helpful when trying to identify drug fever. Leukocytosis, eosinophilia, elevated erythrocyte sedimentation rate, elevated hepatic transaminase, and elevated lactic dehydrogenase levels may or may not be present in the setting of drug fever.

Treatment

If a drug is suspected as the cause of fever, it should be stopped and an alternative medication suggested for use if needed. The resolution of fever should occur within 72 hours.

Summary

To identify drug fever:

1. Examine the patient’s clinical condition, current medications, and laboratory findings.
2. Stop suspect medications and monitor for fever resolution.
3. Suggest alternative medications if needed for the drug that was discontinued.

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If you like this post, check out my book – A Pharmacist’s Guide to Inpatient Medical Emergencies: How to respond to code blue, rapid response calls, and other medical emergencies.

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