Evolution, Medicine, and Public Health Advance Access published April 20, 2014



Elspeth V. Best & Mark D. Schwartz





Downloaded from http://emph.oxfordjournals.org/ at Arizona State University West 2 on April 28, 2014

Department of Anaesthesia, Royal Infirmary Edinburgh Department of Population Health, NYU School of Medicine



Fever, an elevation above normal body temperature, is a frequent symptom of many infections[1]. It results from the release of endogenous pyrogens such as prostaglandins and cytokines,

which act on the anterior hypothalamus to increase the body’s temperature ‘set point’[1]. Antipyretics like paracetamol (acetaminophen) appear to work by antagonising prostaglandins, and are some of the most commonly used drugs in clinical


Fever is usually regarded as a ‘noxious’ state that should be reversed in order to reduce morbidity, including convulsions, and mortality[2]. This view is, surprisingly, not based on any experimental data[2] but rather a fear of any harmful effects(3). Although antipyretics may ease discomfort during illness, this is likely due to the analgesic effects

of most antipyretics rather than any reduction in temperature.

Few clinical trials provide evidence for the use of antipyretics. On the contrary, fever appears to be an evolved defence mechanism[2,5], the suppression of which appears to have negative consequences[1,4].

Evolutionary perspectives Fever is a highly regulated, primitive trait in most vertebrates

and some invertebrates, with

similar mechanisms suggesting it has been highly conserved[1]. Thus, fever likely has an important adaptive function in activating the immune system.

Increased body temperature leads to faster neutrophil migration, activation and proliferation of lymphocytes, production of cytokines including interferon, and increased movement of

lymphocytes[1]. There is also

evidence that fever inhibits the growth of bacteria and replication of viruses by reducing plasma iron [6].

Fevers are also usually tightly controlled by a negative feedback loop[1] that prevents derangement and damage to the individual.

Studies have demonstrated that antipyrexials can have detrimental effects: increasing mortality when used in critical care and in influenza infections{7], increasing viral shedding [8] and slowing the rate of parasite clearance in malaria[9] .

These findings suggest that fever is a highly effective defence mechanism that we should not routinely disrupt.

Future implications

Current research is insufficient to warrant changing clinical practice, but indicates the urgent need for further studies.

With a greater understanding of evolved defence mechanisms, clinicians will be able to better comprehend when these responses can be altered and when they should be preserved, and help demarcate the instances in which the febrile response is truly dangerous and should be

treated promptly(10).


  1. Cannon, J. G. (2011). Perspective on fever: The basic science and conventional medicine Review Literature And Arts Of The Americas, 2377-2393.

  2. Mackowiak, PA. Physiological rationale for suppression of fever. Clinical infectious Diseases: Infect Dis Soc America 2000;31: Suppl 5.

  3. Crocetti M, Moghbeli N, Serwint J. Fever Phobia Revisited: Have Parental Misconceptions About Fever Changed in 20 Years? Pediatrics 2001;107:1241–6.

  4. Kluger MJ. Is Fever Beneficial? Yale J Biol Med 1986;59:89-95.

  5. Mackowiak, PA. Diagnostic implications and clinical consequences of antipyretic therapy. Clinical Infectious Diseases: Infect Dis Soc America 2000;31: Suppl 5.

  6. Kluger M, Rothenburg B. Fever and reduced iron: Their interaction as a host defence response to bacterial infection. Science 1979; 203(4378):374-6.

  7. Eyers S, Weatherall M, et al. The effect on mortality of antipyretics in the treatment of influenza infection: Systematic review and meta-analysis. J Royal Society Med 2010;103(10):403-11.

  8. Graham NM, Burrell CJ, et al. Adverse effects of aspirin, acetaminophen, and ibuprofen on immune function, viral shedding, and clinical status in rhinovirus-infected volunteers. J Infect Dis 1990;162(6):1277-82.

  9. Brandts, C., & Graninger, W. Effect of paracetamol on parasite clearance time in Plasmodium falciparum malaria. Lancet 1997;350:704-709.

  10. Cuadrado F, Hyland Bruno J, Schwartz MD. Fever: Friend or Foe? Clinical Correlations, NYU Online J Med. Nov 20, 2013.

© The Author(s) 2014. Published by Oxford University Press on behalf of the Foundation for Evolution, Medicine, and Public Health.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse,

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