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Fever and sepsis – host defenses and new normals

When to treat and when to leave alone…

In this week’s class, we will explore the idea of normal in medicine. What is normal? Can the concept of adaptation help guide what to do with an “abnormal finding”? We confront these questions all the time in the hospital. Now it is your turn to weigh in.

Lets start with a patient case: He is 48 years old, with a history of alcohol abuse, and a fever for 2 days. He has been coughing with grey sputum and bloody streaks for the last 24 hours. Increasingly short of breath, he calls 911 and is brought to the emergency department.

His chest x-ray looks like this:

Left lower lobe pneumonia

His temperature is 40°C.  Anything above 38°C (100.4 °F) is considered a fever.

Blood cultures are drawn and antibiotics given. He is transferred to the ICU because his oxygen levels and blood pressure continue to drop. In the ICU, his doctor diagnoses him with septic shock. She also orders a dose of acetaminophen (also known as tylenol or paracetamol) to reduce the fever. Medications like tylenol that reduce fever are known as antipyretics, and are commonly prescribed for febrile patients in and out of the hospital.

Is it a good idea to reduce the fever?

Evidence from animal studies support the view that fever is beneficial (read the abstracts in the links in this section). 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.

One relevant fact, arguing for the evolution  of fever, is the fact that it exists in a wide variety of organisms, as reviewed here. Even some invertebrate organisms exhibit a behavioral fever, including grasshoppers, honeybees and snails.  Animal studies suggest that antipyretic use (aspirin) increases mortality from Streptococcus pneumoniae infection With these lines of evidence, you would think that we should certainly not treat fever with tylenol. But we still do, all the time. The human data is not as clear as the animal studies.

Young and Saxena wrote in the journal Critical Care on fever and its treatment:

“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.

This logic was expressed by Foddy (2012) who wrote: “The argument from evolution assumes some degree of continuity in environmental circumstances, but at present there are strong discontinuities in the structure of our world. Given these changes, it would be foolish to place too much trust in the adaptive quality of traits that evolved across aeons of nomadic hunting and gathering.”

On the other hand, consider the argument from Fukuyama (2002) who wrote:

“There are good prudential reasons to defer to the natural order of things and not to think that human beings can easily improve on it through causal intervention. This has proven true with regard to the environment: ecosystems are interconnected wholes whose complexity we frequently don’t understand, building a dam or introducing a plant monoculture into an area disrupts unseen relationships and destroys the system’s balance in totally unanticipated ways. So too with human nature … doing nature one better isn’t always that easy, evolution may be a blind process, but it follows a ruthless adaptive logic that makes organisms fit for their environments.”

Depending on your point of view, fever might or might not be adaptive for our sickest patients.   We will discuss whether evolution and adaptation is irrelevant for ICU patients who are closest to death.

Listen to this excellent talk by an expert on fever:

Paul Young’s evolution-minded lecture on the function of fever and the HEAT trial, a large randomized controlled trial of antipyretics.

Fast forward to minute 3:48 for the good stuff.

Reading 1 Matthew Kluger’s review on fever: The Adaptive Value of Fever

Reading 2 (read the abstract and conclusions)  Young The Heat Trial NEJM

Reading 3 Smoke Detector Principle -Nesse

Listen also to the EvolutionMedicine podcast #2 (July 4, 2016)

Writing assignment:

A start-up biotechnology company has come out with a novel long-acting fever reducing drug. Instead of lasting 4 hours like acetaminophen (Tylenol) and ibuprofen (Motrin), the new drug Qoolaid lasts much longer. A single dose of Qoolaid reduces body temperature and prevents fever for 2 weeks. The company executives are excited to report that because Qoolaid also has a rapid onset of action, reducing body temperature after only 90 seconds, it will provide comfort to patients with a wide range of infections. Wall Street is anticipating that the public stock offering of this “blockbuster” drug will bring in millions of dollars. Should you invest in Qoolaid? Why or why not?


Categories: Uncategorized

Joe Alcock

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

5 replies

  1. Dear Joe
    As a current Evol Med devotee and faculty student of Steve Stearns and still working Yale, I wish you would give the full credit for the lizard fever work of the 1970s. It is an epoch paper absorbed into general knowledge. We had more in the 70s too It is: Br J Exp Pathol. 1978 Feb;59(1):76-84.Effects of fever on host defense mechanisms after infection in the lizard Dipsosaurus dorsals. Bernheim HA, Bodel PT, Askenase PW, Atkins E.

    1. We discussed your lizard fever research in class. Thanks for your contribution to the field! Very interesting stuff. Best, Joe

  2. We have the same problem of whether to medicate or not to medicate groups of farm animals with fever. This is a common problem in baby pigs that have been recently weaned from their mothers. One side says that if you use antipyretic agents the animals-in my case, pigs-will continue to grow while another group says if you use the antipyretic agents the mortality will increase and offset the benefits of increased growth with antipyretic therapy. It is an argument sourounding revenue lost from feed/gain or from mortality. However, it is evident that medication usually increases morbidity/mortality compared to allowing the animals to express a normal fever response.


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