Fever is so hot right now…
‘Humanity has but three great enemies: fever, famine and war; of these by far the greatest, by far the most terrible, is fever’— William Osler1William Osler. The study of the Fevers of the South. JAMA 1896; 21: 999–1004
Fever is one of the cardinal signs of infection and — nearly 120 years after William Osler’s statement in his address to the 47th annual meeting of the American Medical Association on The Study of the Fevers of the South1 — infectious diseases remain a major cause of morbidity and mortality2. Despite this, it is unclear whether fever itself is truly the enemy or whether, in fact, the febrile response represents an important means to help the body fight infection. Furthermore, it is unclear whether the administration of antipyretic medications to patients with fever and infection is beneficial or harmful3,4.
The febrile response to infection is seen in a range of animal species including not only endotherms like mammals5-8 and birds9 but also ectotherms including reptiles10, amphibians11, and fish12. The febrile response in desert iguanas13 and bluegill sunfish14, like the response seen in humans, can be blocked by inhibition of cyclooxygenase (COX). As COX catalyses the generation of prostaglandins from arachidonic acid, this suggests that the pivotal role of PGE2 in the regulation of the thermostatic set point may be preserved in these species as well as in higher animals. A common biochemical mechanism regulating fever across such a diverse group of animals raises the possibility that the febrile response may have evolved in a common ancestor. If this is the case, then fever probably emerged as an evolutionary response more than 350 million years ago15.
As the febrile response comes at a significant metabolic cost16,17, its persistence across such a broad range of species provides strong circumstantial evidence that the response has some evolutionary advantage. Furthermore, given that the response appears ubiquitous it logically follows that the components of the immune system would have evolved to function optimally in the physiological febrile range.
There are a number of historical examples of dramatic responses to treatment with therapeutic hyperthermia in some infectious diseases. It has been known since the time of Hippocrates that episodes of ‘progressive paralysis’ due to neurosyphilis sometimes resolve after an illness associated with high fever. This observation led Julius Wagner-Jauregg to propose, in 1887, that inoculation of malaria might be a justifiable therapy for patients with ‘progressive paralysis’. His rationale was that one could substitute an untreatable condition for a treatable one – malaria being treatable with quinine. In 1917, he tested his hypothesis in nine patients with paralysis due to syphilis by injecting them with blood from patients suffering from malaria. Three of the patients had remission of their paralysis. This led to further experiments and clinical observations on more than a thousand patients where remission occurred in 30% of patients with neurosyphilis-related progressive paralysis ‘treated’ with fever induced by malaria compared to spontaneous remission rates of only 1%. This work on fever therapy led to Julius Wagner-Jauregg being awarded the Nobel Prize in Physiology or Medicine in 192718. Subsequently, fever therapy was shown to be effective in treating gonorrhoea. Inducing hyperthermia of 41.7°C for six hours with the Kettering hypertherm chamber led to cure in 81% of cases19.
The relevance of these historical examples to the modern era is unclear. Furthermore, arguments based on the evolutionary importance of the febrile response do not necessarily apply to critically ill patients who are, by definition, supported beyond the limits of normal physiological homeostasis. Humans are not adapted to critical illness. In the absence of modern medicine and Intensive Care, most critically ill patients with fever and infection would presumably die. Among critically ill patients, it seems likely that there is a balance to be struck between the potential benefits of reducing metabolic rate that come with fever control and the potential risks of a deleterious effect on host defence mechanisms. Where this balance lies is very uncertain as there are very few interventional studies of fever management in critically ill patients (see Table 1). Remarkably, although paracetamol is very widely used in ICU patients with fever and known or suspected infection, there are no randomised controlled trials of paracetamol in this patient population and the safety and efficacy of current clinical practice is uncertain. The efficacy and safety of administration of paracetamol to critically ill patients with fever and infection is currently being investigated in the HEAT trial (www.heat-trial.org.nz).
Table 1: Summary of randomised controlled trials investigating the management of fever in critically ill adults
|Bernard et al 1991 20||Double blind placebo-controlled trial of ibuprofen in patients with severe sepsis; n = 30|
|Bernard et al 1997 21||Double blind placebo-controlled trial of ibuprofen in patients with severe sepsis in seven centres in North America; n=455|
|Memis et al 2004 22||Double blind placebo-controlled trial of lornoxicam in patients with severe sepsis in one centre in Turkey; n=40|
|Morris et al 2011 23||Multicentre, randomised trial comparing the antipyretic efficacy of a single dose of placebo, 100mg, 200mg, or 400mg of IV ibuprofen in hospitalised patients of whom >90% had infections; n=120 (53 critically ill)|
|Haupt et al 1991 24||Multicentre, placebo-controlled randomised trial of ibuprofen in patients with severe sepsis; n=29|
|Schulman et al 2006 25||Single centre, unblinded, randomised trial of aggressive vs. permissive temperature management in febrile patients in a trauma ICU; n=82|
|Niven et al 2012 26||Multicentre, unblinded randomised trial of aggressive vs. permissive temperature management in febrile ICU patients; n=26|
|Schortgen et al 2012 27||Multicentre, randomised controlled trial of external cooling in patients with fever and septic shock receiving mechanical ventilation in seven centres in France; n=200|
Abbreviations: ARDS: Acute Respiratory Distress Syndrome; ICUs: Intensive Care Units.
Slides and Audio from ‘Fever: Friend or Foe?’ at SMACC 2013
References and Links
- William Osler. The study of the Fevers of the South. JAMA 1896; 21: 999–1004 (1896)
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- Jefferies S, Weatherall M, Young P, Eyers S, Perrin KG, Beasley CR, (2011) The effect of antipyretic medications on mortality in critically ill patients with infection: a systematic review and meta-analysis. Crit Care Resusc 13: 125-131. PMID: 21627583 [Free Full Text]
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- Parrott RF, Vellucci SV, Goode JA, (1999) Studies of endotoxin-dependent fever in pre-pubertal pigs following acute activation of the pituitary-adrenocortical axis: towards a new hypothesis of fever regulation. Res Vet Sci 66: 85-91 PMID: 10208885
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- MJ K, (1978) The evolution and adaptive value of fever. Am Scientist 66: 38-43 PMID: 623399
- Myhre K, Cabanac M, Myhre G, (1977) Fever and behavioural temperature regulation in the frog Rana esculenta. Acta Physiologica Scandinavica 101: 219-229 PMID: 303438
- Covert JB, Reynolds WW, (1977) Survival value of fever in fish. Nature 267: 43-45 PMID: 859637
- Bernheim HA, Kluger MJ, (1976) Fever: effect of drug-induced antipyresis on survival. Science 193: 237-239 PMID: 935867
- Reynolds WW, (1977) Fever and antipyresis in the bluegill sunfish, Lepomis macrochirus. Comp Biochem Physiol C. 57: 165-167 PMID: 20274
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- Owens C, (1936) The value of fever therapy for gonorrhea. JAMA 107: 1942-1946
- Bernard GR, Reines HD, Halushka PV, Higgins SB, Metz CA, Swindell BB, Wright PE, Watts FL, Vrbanac JJ, (1991) Prostacyclin and thromboxane A2 formation is increased in human sepsis syndrome. Effects of cyclooxygenase inhibition. Am Rev Respir Dis 144: 1095-1101 PMID: 1952438
- Bernard GR, Wheeler AP, Russell JA, Schein R, Summer WR, Steinberg KP, Fulkerson WJ, Wright PE, Christman BW, Dupont WD, Higgins SB, Swindell BB, (1997) The effects of ibuprofen on the physiology and survival of patients with sepsis. The Ibuprofen in Sepsis Study Group. NEJM 336: 912-918 PMID: 9070471 [Free Full Text]
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- Morris PE, Promes JT, Guntupalli KK, Wright PE, Arons MM, (2010) A multi-center, randomized, double-blind, parallel, placebo-controlled trial to evaluate the efficacy, safety, and pharmacokinetics of intravenous ibuprofen for the treatment of fever in critically ill and non-critically ill adults. Crit Care 14: R125 PMID: 20591173 PMCID: PMC2911773
- Haupt MT, Jastremski MS, Clemmer TP, Metz CA, Goris GB, (1991) Effect of ibuprofen in patients with severe sepsis: a randomized, double-blind, multicenter study. The Ibuprofen Study Group. Crit Care Med 19: 1339-1347 PMID: 1935150
- Schulman CI, Namias N, Doherty J, Manning RJ, Li P, Elhaddad A, Lasko D, Amortegui J, Dy CJ, Dlugasch L, Baracco G, Cohn SM, (2005) The effect of antipyretic therapy upon outcomes in critically ill patients: a randomized, prospective study. Surgical infections 6: 369-375 PMID: 16433601
- Niven DJ, Stelfox HT, Leger C, Kubes P, Laupland KB, (2012) Assessment of the safety and feasibility of administering antipyretic therapy in critically ill adults: A pilot randomized clinical trial. J Crit Care. 2013 Jun;28(3):296-302. doi: 10.1016/j.jcrc.2012.08.015. Epub 2012 Oct 24. PMID: 23102531
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