It is pretty obvious that fever is useful. Work by Kluger and others has shown that increased temperatures decrease mortality during infection. Even for lizards! (When infected they crawl to warmer places.)
The mystery has been how fever works. Can higher body temperature alone inhibit pathogen growth? It seems unlikely that changing temperature by just a degree or so would have a major effect. Pathogens are too adaptable.
In a seminar discussion this week, Karl Sperling, from the Institute of Human Genetics, Charité – Universitätsmedizin Berlin, brought up the protective role of heat shock proteins, and how highly conserved they are. This quickly suggested that their original function might have been co-opted to cope with infection.
Sure enough, a quick search revealed a 2007 PNAS article by Varsha Singh, and Alejandro Aballay, showing
that that increased temperature results in the activation of a conserved pathway involving the heat-shock (HS) transcription factor (HSF)-1 that enhances immunity in the invertebrate Caenorhabditis elegans…HSF-1 is required for C. elegans immunity against Pseudomonas aeruginosa, Salmonella enterica, Yersinia pestis, and Enterococcus faecalis, indicating that HSF-1 is part of a multipathogen defense pathway.
So, it may be that fever itself may not be useful, but because HSPs have been co-opted to coordinate some aspects of the immune response, increased body temperature is the signal that turns on the response.
This has obvious major implications for treating infectious disease. Perhaps we can turn on these pathways without raising body temperature. Of course, we will need to be cautious. Natural selection has had a long time to adjust the system to various trade-offs. However, selection is constrained, and pathogens certainly also disrupt these systems, so finding out the details offers many possibilities.
All in all, this is a very nice example of the interesting ideas that pop up from interdisciplinary discussions among people with their evolution thinking caps on.
Now if we could just get NIH to invest in comprehensive studies on whether anti-inflammatory drugs speed or slow recovery from various kinds of infections, general physicians would have some fundamental knowledge they need, but lack.
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Fever: Heat Shock OR Apoptosis?
It’s clear that how fever can be beneficial, as part of the acute phase response remains unclear. See Hasday JD and Singh IS. Fever and the heat shock response: distinct, partially overlapping processes. Cell Stress Chaperones. 2000;5:471-80 for a good discussion. However, in a subsequent good discussion of the numerous effects of hyperthermic temperatures and the pros and cons of hyperthermia/fever, the same author barely mentions the heat shock response (Hasday JD, et al. Febrile-range hyperthermia augments pulmonary neutrophil recruitment and amplifies pulmonary oxygen toxicity. Am J Pathol. 2003;162:2005-17). (Sorry but this Comment section doesn’t seem to take hyperlinks.)
Based on my interest in the anorexia/cachexia component of the acute phase response, (LeGrand, EK. Why infection-induced anorexia? The case for enhanced apoptosis of infected cells. Med Hypotheses. 2000;54:597-602), I strongly suspect that the response to fever and to anorexia/cachexia is at least partially based on their being self-induced stressors which induce a dichotomous decision depending on whether the cell is infected (or neoplastic) or not. The discussion below would apply to intracellular infections and neoplasia, but would be less relevant for extracellular infections.
It is becoming apparent that cells can respond to stressors/damage/danger by either by undergoing a stress response if the cells are in reasonably good condition or by killing themselves (apoptosis) if already damaged. This involves either activating NF-KB (which stimulates an inflammatory response and inhibits apoptosis) or, if the cells are damaged, promoting apoptosis (and not activating NF-KB). This is likely the basis for NSAIDs’ reported inhibition of neoplasia in the intestine by promoting apoptosis (inflammation and apoptosis being two antithetical defenses). In regard to fever, Tran et al (Heat stress downregulates FLIP and sensitizes cells to Fas receptor-mediated apoptosis. Cell Death Differ. 2003 Oct;10:1137-47) pointed out that heat stress evokes the protective heat shock response in normal cells while inducing apoptosis in damaged cells. They made the suggestion that a benefit of fever is to induce heat stress in infected cells by predisposing them to Fas-mediated cell death from cytotoxic lymphocytes. I’m coming to believe that this decision point is an important general concept, and of course there is a clear military analogy. Defenders of a fort upon learning of an advancing army would have to make a decision: either gear up and defend the fort (inflammatory or heat shock response) or destroy the fort (apoptosis) so that the opposing army can’t make use of it. Worse than either choice would be to gear up to defend the fort and then lose it and its contents to the enemy (in this case, intracellular pathogens).
So as I’m coming to see it, fever, like anorexia/cachexia, is a self-induced generalized stressor. For intracellular infections it would make perfect sense to me that fever would force all cells in the body to make a choice: either gear up with the heat shock response and become more resistant to infection (or resistant to the collateral damage involved in fighting the infection) OR, if altered or damaged, undergo apoptosis. The cells already altered by virtue of being infected (e.g., several papers note that virally infected cells have substantially increased utilization of glucose, and microscopically a number of alterations can be seen) are presumably closer to the “apoptotic threshold” than normal cells. Infected cells are particularly dangerous by virtue of acting as a pathogen factory (or at least as a hiding place) and thus should have already undergone apoptosis. However, the fact that they haven’t killed themselves indicates there wasn’t enough apoptotic input to get them over the apoptotic threshold. In the case of nutrient deprivation afforded by the anorexia/cachexia response, the additional apoptotic input (to all cells in the body) likely provides some of the additional input that the infected cells require. I’m not sure to what extent the nutritional deprivation of anorexia/cachexia provides a protective heat shock-like response. Nevertheless, I’m coming to suspect that fever by acting as a systemic hyperthermic stressor induces a heat stress response in uninfected cells and helps promote an apoptotic response in already infected cells. The increased metabolic demands of generating a fever would tend to make the nutrient stress even greater, and fever and anorexia/cachexia likely work together in tandem as complementary co-stressors.
In reading the posted article by Singh and Aballay, it wasn’t clear exactly how the heat shock response, with chaperone induction, protects against infections. It may have direct antimicrobial effects (but could it help “cure” already infected cells?) or it may simply protect the host cells from the host’s own geared up defenses (e.g., free radical and enzymatic defenses). Also to be considered is that pathogens (bacteria and eukaryotes, but not viruses) respond to heat and other stresses by undergoing their own protective heat shock responses. I’m assuming that overexpression of heat shock proteins (which can prolong lifespan) comes at the expense of growth/reproduction. Indeed, looked at this way, hyperthermia could conceivably act to slow bacterial growth in infections while making the individual organisms more resistant. It’s all very complicated and very interesting!
As fascinating as fever is, anorexia/cachexia is even more so. Because so much clinical effort is directed at providing “good” nutrition for fighting infections and cancer, the role of anorexia/cachexia as a component of the acute phase response should be crying out for understanding.
Fever and Antipyretic/Anti-inflammatory Therapy
There have been a few studies on the role of anti-inflammatory/antipyretic treatment on the course of infection. Smith and co-workers showed that giving antipyretic drugs to ferrets (a common animal model for influenza) led to an increase in duration of influenza virus in nasal washings.
Work we did years ago with lizards (D. dorsalis) showed that treatment of infected lizards with sodium salicylate led to increased mortality ONLY when the animals were allowed to lower their body temperature. When they were prevented from selecting a cooler micro-climate (and thus remained at “febrile” temperatures) they survived their infection (Science 193:237-239, 1976).
But as Dr. Nesse points out, there really haven’t been any comprehensive study on the role of treatment of human subjects with NSAIDs, and that would make for a fascinating clinical study. The problem with this type of study is that it will be difficult to design, since one is not going to inject human volunteers with live virus or bacteria. So it seems to me that the best one could do would be to wait until flu season and randomly assign subjects (who perhaps have already signed their informed consent documents) to NSAID or placebo groups.
As a regular Sauna user ( we have a building in our yard), I know the value of a good fever. Normally, its a good time with a few friends and some food and drink. I have never exeriperinced
any side effects from this. But over the last year I have experienced one very unusual one: a protracted fever. Not once but twice about a year apart. The first time I went to see the Doc and my blood count was all over the place. He wanted to admit me to the hospital immediately. I balked, knowing what the outcome
would be: poverty. This latest time when it started I hunkered down for very long week in purgatory. The one night I did take a powder, it dropped my temperture and I completely soaked the sheets. I felt that whatever process was going on, ought not be tamperd with. So I decided against the powder. One morning, I phoned Lawrence Wilson, M.D. author of Sauna Therapy to hear what he had to say
He told me that my body was clearing out unresolved infections that had been treated with antibiotics. I am not sure I buy it, but so far, its the best I have to go on. Any readers of this blog have any ideas?
There may not be a controlled clinical trial of the benefit of fever in infection but the concept was introduced to me during my Family Practice residency 20 years ago. The guideline for children was that not treating fever in an acute infectious illness decreased the duration by about one day and that fever under 102 without other discomfort did not need to be treated. Treatment of fever over 102 seems to decrease toxicity and malaise. That has been my advice to patients over the last few decades.
Michael Mattin MD