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Fever and the thermal regulation of immunity: the immune system feels the heat

Evans et al., Nature Reviews Immunology, doi:10.1038/nri3843

May 2015

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Thermotherapy

45th treatment shown to reduce risk in December 2023

^*, now with p = 0.026 from 4 studies.

Lower risk for recovery.

No treatment is 100% effective. Protocols combine treatments. ^* >10% efficacy, ≥3 studies.

4,500+ studies for 81 treatments. c19early.org

Review of fever and the thermal regulation of immunity. Authors discuss how the evolutionary conservation of fever for over 600 million years argues for a protective role, with the survival benefit outweighing the metabolic cost. Febrile temperatures are proposed to boost innate and adaptive immunity through several mechanisms. These include improving neutrophil bactericidal activity, natural killer cell cytotoxicity, dendritic cell migration and antigen presentation, and lymphocyte trafficking into lymphoid tissues. Interleukin-6 is highlighted as a key mediator of both fever and lymphocyte homing through an endothelial trans-signalling mechanism involving soluble IL-6 receptor alpha. Thermal signals are also implicated in attenuating inflammation during recovery from infection. Additionally, new data reveals overlapping signaling pathways between fever-induced thermogenesis and immune cell function, suggesting tight interplay between temperature regulation and immunity.

Reviews covering thermotherapy for COVID-19 include1-6.

Important missing comments or errors? Let us know.

1. Kunutsor et al., Finnish sauna and COVID-19, Le Infezioni in Medicina, 1, www.infezmed.it/index.php/article?Anno=2021&numero=1&ArticoloDaVisualizzare=Vol_29_1_2021_160.infezmed.it.

2. Ramirez et al., Hydrothermotherapy in prevention and treatment of mild to moderate cases of COVID-19, Medical Hypotheses, doi:10.1016/j.mehy.2020.110363.sciencedirect.com, doi.org.

3. Mancilla-Galindo et al., Exploring the rationale for thermotherapy in COVID-19, International Journal of Hyperthermia, doi:10.1080/02656736.2021.1883127.tandfonline.com, doi.org.

4. Larenas-Linnemann et al., Enhancing innate immunity against virus in times of COVID-19: Trying to untangle facts from fictions, World Allergy Organization Journal, doi:10.1016/j.waojou.2020.100476.sciencedirect.com, doi.org.

5. Cohen, M., Turning up the heat on COVID-19: heat as a therapeutic intervention, F1000Research, doi:10.12688/f1000research.23299.2.f1000research.com, doi.org.

6. Evans et al., Fever and the thermal regulation of immunity: the immune system feels the heat, Nature Reviews Immunology, doi:10.1038/nri3843.nature.com, doi.org.

Evans et al., 15 May 2015, peer-reviewed, 3 authors.

This Paper Thermotherapy All

Fever and the thermal regulation of immunity: the immune system feels the heat

Sharon S Evans, Elizabeth A Repasky, Daniel T Fisher

Nature Reviews Immunology, doi:10.1038/nri3843

Fever is a cardinal response to infection that has been conserved in warm-blooded and cold-blooded vertebrates for more than 600 million years of evolution. The fever response is executed by integrated physiological and neuronal circuitry and confers a survival benefit during infection. In this Review, we discuss our current understanding of how the inflammatory cues delivered by the thermal element of fever stimulate innate and adaptive immune responses. We further highlight the unexpected multiplicity of roles of the pyrogenic cytokine interleukin-6 (IL-6), both during fever induction and during the mobilization of lymphocytes to the lymphoid organs that are the staging ground for immune defence. We also discuss the emerging evidence suggesting that the adrenergic signalling pathways associated with thermogenesis shape immune cell function.

Competing interests statement The authors declare no competing interests.

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