It is somewhat remarkable that in 2014 people are still arguing about the role of fever in illness.

To recap, Matthew Kluger back in the early 1970s showed that a behavioral fever was critical in keeping lizards alive after experimental infection with gram-negative bacteria. Kluger subsequently showed that fever improves bacterial killing by immune cells.

Edmund Legrand and I wrote in 2012 that fever and other components of the acute phase response, evolved because you can tolerate the costs of having a fever better than the parasite can. That difference in capacity to absorb costs usually leads to survival from infection, and the increase in survival conferred by fever led to its evolution and persistence in a wide variety of organisms, as shown here: Clin Infect Dis. 2000 Oct 31(Supplement 5) S185-9, Figure 1. Even some invertebrate organisms exhibit a behavioral fever, including honeybees!

So why are people still arguing about the use of tylenol in the emergency department, clinic, and hospital? In fact, during my last shift, the nurse asked/informed me about giving tylenol to our febrile patient in the ED. (It was busy and I did not object). However, animal studies suggest that antipyretic use (aspirin) increases mortality from Streptococcus pneumoniae infection and in humans no evidence exists to support the use of antipyretics for sick patients.

There is an ongoing study that I do hope will help clear up any uncertainty once and for all. This is the HEAT trial, a randomized controlled trial of antipyretic paracetamol (tylenol) in critically ill patients, and is currently underway.

So, evolutionary medics, how do you think that trial will work out?  I’ll give my prediction here. IV paracetamol will not reduce mortality in these patients. I will not be surprised if mortality is increased in the treatment group.

So if fever is adaptive during infection, what would you say about a study that experimentally reduced temperature below normal for a life-threatening infection? Would you predict that this would be good or bad?

With the evidence that fever improves survival from infection, and evidence that fever is part of an adapative suite of changes during the acute phase response that improve bacterial killing, it would be hard to imagine that hypothermia would be beneficial in bacterial meningitis. Yet, that proposition was recently tested.

A randomized but not blinded trial of critically ill patients with bacterial meningitis compared experimental hypothermia versus no intervention. Guess what happened?

Are we surprised that the induced hypothermia group had excess mortality, causing the study to be terminated early for futility? (Click on the link above for the details and the complete JAMA article). I am not alone in thinking that hypothermia for infection is wrongheaded and dangerous.

The JAMA results are important, and show the value in publishing negative results (read about publication bias here), from which we can learn as much as positive findings.

Like you , I hope, I will be very interested in the results of the HEAT trial when they are published. And maybe I will put up more of a fight next time I’m asked to prescribe antipyretics in the emergency department (more on that later).

Update: The HEAT trial failed to show increased survival in patients randomized to acetaminophen in the intensive care unit. There was no apparent harm, but as we predicted, no benefit from lowering temperature. Read the NEJM paper by Young and colleagues here.

Joe Alcock MD

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Joe Alcock

Emergency Physician, Educator, Researcher, interested in the microbiome, evolution, and medicine