Things We Do For No Reason™: Treatment of Infection-Related Fever in Hospitalized Patients

Physicians, nurses, and caregivers also commonly believe that fever is inherently noxious and that treatment of infection-­related fever contributes to fighting the infection itself.^2,3,6 The pediatric literature describes parents, caretakers, and clinicians who suffer from “fever phobia,” the worry that fevers contribute to long-term neurologic complications, recurrent febrile seizures, and death.^6,7

Finally, healthcare providers administer antipyretic medication to mitigate the demand fever places on the cardiovascular and pulmonary systems.³ An elevated temperature increases the body’s metabolic rate, oxygen consumption, and cardiac output that critically ill patients who have acute and/or chronic compromise to those systems may not tolerate. For example, patients requiring pressor support for hemodynamic shock or mechanical ventilation for respiratory failure may not tolerate an elevated temperature.⁸

Fever serves as an adaptive host response to infection, boosting innate and adaptive immunity in a multitude of ways.⁸ In animal models, fever slows the replication of pathogenic bacteria and enhances the activity of antibiotic agents.⁸ In vitro studies demonstrate that fever increases mobility of leukocytes, phagocytic activity, and proliferation of T cells.⁸ Retrospective case-control studies of patients hospitalized with severe bacterial illnesses, including gram-negative bacteremia, spontaneous bacterial peritonitis, and community-­acquired pneumonia, found that patients with a documented febrile response had increased survival compared with those who remained afebrile during the infection.⁹ In addition, a large retrospective cohort study of septic ICU patients found a progressive decline in mortality in association with increasing peak temperature on the day of ICU admission.¹⁰

In addition to the above studies supporting the important role of fever in fighting infection, recent evidence definitively demonstrates no mortality or morbidity benefit of using antipyretic medications in infected patients. A 2017 meta-analysis that included eight observational and eight randomized studies, totaling 18,939 adult septic ICU patients, demonstrated no difference in hospital and 28-day mortality in patients treated with antipyretics vs those who were not.¹¹ The authors again found no mortality benefit with antipyretic use when separately analyzing data from only the randomized controlled trials (1,507 patients) or when stratifying patients based on the type of antipyretic received (acetaminophen, NSAIDs, or physical cooling).¹¹ They reported no differences in predefined secondary outcomes of shock reversal or nosocomial infections. The authors commented that these robust results likely would not change even with more data from additional trials. In children, a recent meta-analysis of three randomized controlled trials (540 patients) did not find the use of acetaminophen, ibuprofen, or diclofenac effective in preventing febrile seizures.¹²Pediatric practice guidelines consistently recommend using antipyretic medication to alleviate discomfort caused by fever and not solely to reduce temperature.^13,14

Antipyretic agents interfere with the effectiveness of the body’s immune response, as demonstrated in a number of infectious diseases.^2,15-18 Two randomized controlled studies conducted in healthy adult volunteers challenged with rhinovirus reported increased viral shedding and decreased antibody response in those subjects who received aspirin or acetaminophen, compared with those given placebo.^15,16 In another randomized controlled trial conducted in African children with malaria, paracetamol use delayed parasite clearance by 16 hours.¹⁷ A large case-control study correlated the use of NSAIDs with an increased risk of severe skin and soft-tissue complications in children with varicella and in adults with varicella zoster. ¹⁸ The international scientific community has raised concerns about worse outcomes with NSAID use in patients with COVID-19, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); NSAIDs should be avoided in stable patients with COVID-19 until more data are available. ¹⁹

Additional risks and potential harms accompany antipyretic fever therapy. First, NSAIDs or acetaminophen may adversely affect patients with renal or hepatic insufficiency.^2,3 Second, masking fevers may impair the clinician’s ability to diagnose or evaluate response to treatment. Third, unnecessarily waking a sleeping patient to check temperature or administer unneeded antipyretics can contribute to hospital-associated problems, including delirium, insomnia, and falls. Treating these iatrogenic problems in turn may require additional medications or interventions. These unintended consequences may potentially prolong hospital stays, increase medication errors and polypharmacy, and detract from a patient’s overall healing and recovery.

While the use of antipyretic medications improves fever-­related symptoms, it comes at the cost of blunting a protective host response and exposes patients to medication risks without providing a clinical benefit. In sleeping, asymptomatic, or minimally symptomatic hospitalized patients, the risks of administering antipyretic medications clearly outweigh the benefits.