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ScientificWorldJournal. Author manuscript; available in PMC 2011 March 16.
Published in final edited form as: ScientificWorldJournal. ; 10: 490–503. doi:10.1100/tsw.2010.50.

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Fever
Tamas Bartfai and Bruno Conti Molecular and Integrative Neurosciences Department, The ScrippsResearch Institute, La Jolla, CA
Tamas Bartfai: tbartfai@scripps.edu; Bruno Conti: bconti@scripps.edu

Abstract
Measurement of body temperature remains one of the most common ways to assess health. An increase in temperature above what is considered to be a normal value is inevitably regarded as a sure sign of disease and referred to with one simple word: fever. In this review, we summarize howresearch on fever allowed the identification of the exogenous and endogenous molecules and pathways mediating the fever response. We also show how temperature elevation is common to different pathologies and how the molecular components of the fever-generation pathway represent drug targets for antipyretics, such as acetylsalicylic acid, the first “blockbuster drug”. We also show how fever researchprovided new insights into temperature and energy homeostasis, and into treatment of infection and inflammation.

Keywords fever; antipyretic; interleukin; temperature; hypothalamus

INTRODUCTION
Can a frog or a snake run a fever? Is the ramp fever (stage fright) a real fever like that in malaria? Did Moses see the burning bush in febrile hallucination since malaria was endemic along theNile? Is fever helping to fight infection? Should fever be treated or permitted? These are but a few of the questions we have received in the past 27 years from friendly, but incredulous, colleagues who have not understood why a well-trained scientist would “fiddle with fever”. Despite the fact that fever was used throughout history, and still continues to be used, as the most common noninvasivemeasure of disease, its study is considered by many to be useless. Among the arguments by skeptics towards the relevance of studying fever was the fact that, as pointed out by Carl Reinhold August Wunderlich, “Fever is not a disease, but rather the response of the body to a disease.” In addition, since fever can now be controlled effectively with a variety of inexpensive and safe antipyretics, the“battle against fever” from a therapeutic, pharmacological perspective can be considered won. As is the case when remarkable achievements are ultimately taken for granted, it is often forgotten that fever was a serious health concern until effective antipyretics, such as acetylsalicylic acid, paracetamol (acetaminophen), and ibuprofen, were found. The introduction of antipyretics had a large impact wellbeyond medicine and science. Acetylsalicylic acid (aspirin), the first synthetic antipyretic, was originally tested in a “one-patient clinical trial” and gained worldwide popularity during the Spanish flu pandemic before becoming an object of the peace terms of the First World War, forcing Bayer to give up its trademark.

Correspondence to: Tamas Bartfai, tbartfai@scripps.edu.

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Despite the general attention by the medical community to the benefits of reducing fever, Julius Wagner-Jauregg received the 1927 Nobel Prize in Physiology and Medicine for his malariabased fever therapy “of the general paralysis of the insane” caused by syphilis. Fever therapy has been replaced by antibiotics in the treatment of syphilis, and the mechanisms of fever are stillbeing elucidated and the question of whether fever is beneficial or detrimental to the organism remains unanswered. Fever can be described as an elevation of the central thermoregulatory set point, largely achieved by disinhibiting thermogenesis. This definition resulted from over 100 years of research during which the molecules mediating the fever response have been identified. Some were...