Episode 24: Why is fever beneficial?

This episode is our second related to the topic of fever. In episode 21 we discussed the connection between fever and rigors and whether either can predict bacteremia. For this episode, we discussed the role and benefits of fever in infectious diseases. To do so required us to go back a few hundred million years.

The emergence of fever

Amazingly, it appears that fever first appeared 600 million years ago. This is after the emergence of innate immunity but before adaptive immunity. All vertebrates, including ectotherms (i.e., organisms that are cold-blooded) experience fever. Given the downsides of fever – which we’ll touch on in a bit – it would be selected against if it didn’t come with strong benefits. At some point, you’d see an organism evolve away from fever. The fact this hasn’t occurred – that is it is “conserved” evolutionarily – suggests the benefits outweigh the risks.

As noted above, even ectotherms experience fever. Because ectotherms cannot regulate their own temperature they are subject to their environment. So, if their hypothalamus says “hey, I just increased our set-point” they have move to a warmer location to increase their temperature. Thinking about the drawbacks – and therefore the evolutionary pressure against fever – moving to a warmer environment typically places the animal in an area susceptible to predators. So it isn’t always good to be sunbathing.

There is remarkable experimental data supporting this.

The first is a famous series of studies by Matthew Kluger involving the ectothermic lizard Dipsosaurus dorsalis. In the first set of experiments, published in 1974, investigators infected the lizards with a known pathogen Aeromonas hydrophila and put them in a wooden box with one end at 30°C and the other at 50°C. The infected lizards moved in the box such that their temperature increased by 2°C. The following year Kluger published a study in which the same species of lizards were again infected with Aeuromas. This time temperature was controlled so the lizards were stuck at could not increase or decrease their own temperature. 75% of those placed in the warm box – set at 42°C (107.6°F) – survived. 25% survived at 38°C (100.4°F), and 0% survived at 34°C (93.2°F).

One explanation of these findings is that the colder temperatures themselves killed the lizards. A few things argue against this. First, ectotherms regulate their temperatures at a much wider range than do endotherms, about 8°C versus 1°C. But, the investigators also had a control where they injected lizards with saline. The survival rate at 34°C was 100%. Again, survival was 0% in the cold box when infected. So lizards do just fine in colder temperatures, as long as they’re not infected with Aeromonas.

Anything more than just lizards?

There are a multitude of fascinating studies showing the benefits of fever. A simple example: fish swim to warmer water when infected. And just as seen with lizards, if you infect fish with Aeuromas hydrophila survival increases as temperature increases.

Even more fascinating is fever in honey bees. Bees usually maintain a hive temperature higher than the ambient temperature. Honey bees exhibit a specialized behavioral response to the fungal parasite Ascosphaera apis, raising the temperature in the hive when the fungus is detected. This temperature is raised through a communal increase in wing muscle activity by the adult bees. This increases the temperature of the hive.

Finally, there is even evidence of febrile plants! The temperature of the leaves from the bean plant Phaseolus vulgaris increases by around 2°C following experimental fungal infection.

What about humans?

Studies directly linking fever to outcomes are harder in human as you can’t as easily control for just body temperature. Things like antipyretics have effects beyond just reduction in fever. That said, a 2017 meta-analysis showed that fever is associated with lower mortality in sepsis. If you had fever, mortality was 22%. If you had normal temperature, mortality was 31%, and those with hypothermia had a mortality of 47%.

Downsides of fever

The most obvious downside of fever is the metabolic cost. One study – published 100 years ago in 1921 – found that for every 1°C increase in temperature, the metabolic rate increases 13%. This requires additional caloric intake, something that hasn’t always been as easy to modulate.

What’s the benefit?

I had always assumed that fever-range temperatures directly affected pathogens. There is some data supporting this. For example, treponema pallidum – the spirochete that causes syphilis – is quite sensitive to fever range temperatures in vitro. This explains why fever therapy was used to treat syphilis, even after penicillin was discovered.

But, the immune-modulating effects of fever are probably more important. For example, there are myriad effects of fever on neutrophils: there is increased neutrophil release from the bone marrow, increased extravasation into tissues, and increased respiratory burst. Other innate immune cells are also affected. The same is seen with the adaptive immune system.

There is also overlap with iron. For example, the production of siderophores is temperature-dependent, with almost complete suppression at 40°C for Salmonella typhimurium. These siderophores are iron-chelating molecules that bacteria use to scavenge iron for their own use. At higher temperatures, these siderophores aren’t produced as well leading to decreased bacterial growth. 

Is blunting fever harmful?

There have been many studies of the treatment of fever in humans. Most show either no benefit or harm. Some examples include:

• Increased duration of viral shedding in RCT of aspirin in rhinovirus
• Decreased circulating neutralizing antibodies and an increase in symptoms in RCT of aspirin and acetaminophen in rhinovirus
• RCT in trauma ICU in which fever was treated for fevers greater >38.5 (101.3) or only if the temperature rose above 40 (140.0). There were more infections in the group that was given more aggressive antipyretics. The study was stopped early as there was also a different in the number of deaths – 7 versus 1 – during an interim analysis.
• Increased time to parasite clearance in RCT of paracetamol in malaria.

This video provides a wonderful summary of much of the risks of aggressively treating fever:

Take Home Points

1. Fever is preserved evolutionarily, suggesting benefit
2. There is a metabolic cost to fever which may partly explain why we’re not just evolving to be hotter
3. The benefit relates to its direct anti-pathogen effects and its ability to augment innate and adaptive immunity
4. Antipyretics are overused

CME/MOC

Click here to obtain AMA PRA Category 1 Credits™ (1.00 hours), Non-Physician Attendance (1.00 hours), or ABIM MOC Part 2 (1.00 hours).

Listen to the episode

https://oembed.libsyn.com/embed?item_id=18890630

Credits & Citation

◾️Episode and show notes written by Tony Breu
◾️Audio edited by Clair Morgan of nodderly.com

Breu AC, Cooper AZ, Abrams HR. Why is fever beneficial? The Curious Clinicians Podcast. April 28, 2021

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Image credit: Hasday, Jeffrey D., Christopher Thompson, and Ishwar S. Singh. “Fever, immunity, and molecular adaptations.” Comprehensive Physiology 4.1 (2011): 109-148.