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Fever and the Acute Phase Response – Updated!

This is part two of a post on the evolution and adaptive value of fever and whether physicians should be treating it . Read Part 1 here first.

Sir William Osler wrote:

‘Humanity has but three great enemies:
fever, famine and war; of these by far the greatest,
by far the most terrible, is fever’


Over a century ago, when Osler spoke those words at an address to the American Medical Association, fever was deemed a grave threat to survival. Of course, Osler used fever as a shorthand for infection, and this was in the pre-antibiotic era. However,  fever continues to be a contentious area in critical care medicine.

Young and Saxena have a must-read recently published review in the journal Critical Care on fever and its treatment.

They write:

“Remarkably, at present we do not know what effect treating fever in critically ill patients with infections has on patient-centered outcomes.”


“arguments based on the evolutionary importance of the febrile response do not necessarily apply to critically ill patients who are, by definition, supported beyond the limits of normal physiological homeostasis. Humans are not adapted to critical illness.”

While it is true that humans are not adapted to current treatments of critical illness – being on a ventilator, receiving medications by central venous line, getting dialysis – humans certainly have been getting seriously ill from infections throughout human and pre-hominin evolution. It would follow that fever benefited many of our ancestors. So why is it so hard to figure out whether fever is a good or bad thing for our sickest patients in the hospital?

Along these lines an excellent point counter-point series was published in the journal Chest last year.

In the first, Drewry and Hotchkiss  argue for giving antipyretic (anti-fever) treatment for patients with sepsis (blood infection).

In a rebuttal, Moer and Doerschug write that we should not ignore the evidence that cooling febrile patients with sepsis can save lives; they also concede the following:

“Fever is an adaptive response and affords some host protection” and “Fever control in life threatening infection merits further high-quality study.”

I agree with those conclusions, if not the contention that we should be routinely cooling our patients. If fever is adaptive, which all these authors agree is true, then its benefits should be manifested most when there is a high risk of death. After all, mortality is the main driver of selection for host responses, like fever and the acute phase response generally.

So what is the evidence:

This forest plot, from Moer and Doerschug illustrates the benefit/harm from cooling therapies. No single study reaches significance either way, and the group analysis leaves room to question still whether these therapies help or hurt patients:

Forest Plot Antipyretic Treatment

One of the studies above was this randomized controlled trial by Schortgen and colleagues, suggesting a benefit from external cooling blankets in critically ill patients. They reported improved 14 day mortality, although no difference was seen in mortality at time of hospital discharge.

Obviously this in an ongoing area of controversy and study. We will keep our eyes out for what should be a definitive trial of antipyretic therapy – the HEAT trial – a large randomized controlled trial of antipyretics currently being conducted by Young and colleagues.

Updated: Podcast link!

Update: Listen to Paul Young give an evolution-minded lecture on the function of fever and the HEAT trial

 (Skip to minute 3:48 for the beginning of the talk)

Categories: Uncategorized

Joe Alcock

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

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