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Fever: Blessing or Curse? A Unifying Hypothesis
- From the Department of Veterans Affairs Medical Center and the University of Maryland School of Medicine, Baltimore, Maryland. Requests for Reprints: Philip A. Mackowiak, MD, Department of Veterans Affairs Medical Center, 10 North Greene Street, Room 5D145, Baltimore, MD 21201. Acknowledgments: The author thanks Theodore E. Woodward, MD, Sheldon E. Greisman, MD, and Ronald P. Rabinowitz, MD, for review of the manuscript and Celeste Marousek for manuscript preparation. Grant Support: By the Department of Veterans Affairs.
Abstract
Considerable data indicate that fever and its mediators have the capacity both to potentiate and to inhibit resistance to infection.It is difficult to reconcile these apparently contradictory observations if they are viewed solely from the standpoint of the individual. However, when viewed from the perspective of the species, both fever's salutary effects on mild to moderately severe infections and its pernicious influence on fulminating infections become teleologically plausible. If one accepts preservation of the species, rather than survival of the individual, as the essence of evolution, fever and its mediators might have evolved as mechanisms both for accelerating recovery of individuals from localized or mild to moderately severe systemic infections in the interest of continued propagation of the species and for hastening the elimination of fulminantly infected individuals who pose a threat of epidemic disease to the species.
Lear: But yet thou art my flesh, my blood, my daughter;
Or rather disease that's in my flesh,
Which I must needs call mine, thou art a boil,
A plague-sore, an embossed carbuncle,
In my corrupted blood.
Shakespeare
King Lear. 2.6
The teleologic significance of the febrile response has recently generated considerable controversy. Substantial data indicate both potentiating and inhibitory effects of the response on resistance to infection, and no unifying hypothesis has been offered to explain such apparently contradictory observations. As a result, confusion exists concerning appropriate clinical situations (if any) in which fever or its mediators should be suppressed.
Beneficial Effects
Data illustrating fever's beneficial effects come from several sources. Studies of the phylogeny of fever have shown that the response is widespread within the animal kingdom [1]. With few exceptions, reptiles, amphibians, and fish, as well as several invertebrate species, have been shown to manifest fever in response to challenge with microorganisms or other known pyrogens. This fact has been viewed by some as the strongest evidence that fever is an adaptive response, based on the argument that the metabolically expensive increase in body temperature that accompanies the febrile response would not have evolved and been so faithfully preserved within the animal kingdom unless fever had some net benefit to the host.
Further evidence of fever's beneficial nature can be found in many investigations showing that various animals have enhanced resistance to infection with increases in body temperature within the physiologic range [1]. Of these, several reported by Kluger and associates [1, 2] deserve particular attention because of the quality of the experimental fever model. The model involves infection of the reptile Dipsosaurus dorsalis with Aeromonas hydrophila, one of the animal's natural pathogens. In their initial work with the model, Kluger and associates established that D. dorsalis responds to infection by increasing its thermal set point in a fashion remarkably similar to that of the febrile response of mammals. Unlike mammals, however, D. dorsalis, a poikilotherm, raises its body temperature in response to infection by behavioral means and can do so only if placed in an environment having an appropriate thermal gradient. By manipulating the model's thermal gradient, Kluger and colleagues showed a direct correlation between body temperature and survival after infecting the lizards with A. hydrophila. They also showed that suppression of the febrile response of infected reptiles with sodium salicylate results in a substantial increase in mortality [3]. Covert and Reynolds [4] duplicated these findings in an experimental model involving goldfish.
In mammalian experimental models, increasing body temperature by artificial means has been reported to enhance resistance of mice to herpes simplex virus [5], poliovirus [6], Coxsackie B virus [7], rabies virus [8], and Cryptococcus neoformans[9] but to decrease resistance to Streptococcus pneumoniae[10]. Increased resistance of rabbits to S. pneumoniae[11] and C. neoformans[12], of dogs to herpes virus [13], of piglets to gastroenteritis virus [14], and of ferrets to influenza virus [15] has also been observed after induction of artificial fever. Unfortunately, because raising the body temperature by artificial means does not duplicate the physiologic alterations that occur during fever in homeotherms (and, indeed, entails several opposite physiologic responses [16]), data obtained using mammalian experimental models have been less convincing than those obtained using reptiles or fish.
Like the animal data, clinical data include evidence of both beneficial effects of fever and adverse effects of antipyretics on the outcome of infections. In a retrospective analysis of 218 patients with gram-negative bacteremia, Bryant and colleagues [17] reported a positive correlation between maximum temperature on the day of bacteremia and survival. A similar relation has been observed in an analysis of 184 cases of polymicrobial sepsis using log linear models [18]. When Weinstein and colleagues [19] examined factors influencing the prognosis of spontaneous bacterial peritonitis, they identified an association between a temperature of greater than 38 °C and increased survival.
It has been reported that children with chickenpox who are treated with acetaminophen have a longer time to total crusting of lesions than controls who receive placebo [20]. Stanley and colleagues [21] have reported that adults infected with rhinovirus have more nasal viral shedding when they receive aspirin than when given placebo. Further, Graham and colleagues [22] have reported a trend toward longer duration of rhinovirus shedding in association with antipyretic therapy and have shown that use of aspirin or acetaminophen is associated with suppression of the serum-neutralizing antibody response and with increased nasal symptoms and signs. These data, like those reviewed above, can be interpreted in several ways and do not prove a causal relation between fever and improved prognosis during infection. Nevertheless, they are consistent with such a relation, and when considered in concert with the phylogeny of the febrile response and the animal data outlined above, the data leave little doubt that, at least in some situations, fever is an adaptive response.
Whereas the foregoing investigators examined the relation between the elevation of core temperature and the outcome of infection, others have considered the endogenous mediators of the febrile response. In such studies, all five of the major pyrogenic cytokines (that is, interleukin-1, tumor necrosis factor, interleukin-6, interferon, and interleukin-2) have been shown to have immune-potentiating capabilities that might theoretically enhance resistance to infection [23]. In vitro and in vivo investigations of these cytokines have provided evidence of a protective effect of interferon, tumor necrosis factor, or interleukin-1 against plasmodia species [24-26], Toxoplasma gondii[27], Leishmania major[28], Trypanosoma cruzi[29], and Cryptosporidium species [30]. In studies of Plasmodium berghei, Mellouk and colleagues [24] showed that interferon inhibits development of intrahepatic sporozoites by stimulating host cells to produce L-arginine-derived nitrogen oxides that are toxic to the intracellular parasite. Others have shown a similar phenomenon in macrophages stimulated by tumor necrosis factor in combination with interferon [28]. Several recent reports have also shown that pyrogenic cytokines enhance resistance to viral [31-33] and bacterial infections [34, 35].
Although the previous data make a convincing case for a beneficial effect of fever and its mediators on the outcome of infection, this benefit appears to be limited. Treatment of normal and granulocytopenic animals with interleukin-1 has been shown to prevent death in some gram-positive and gram-negative bacterial infections [35]. However, interleukin-1 is effective only if administered an appreciable time (for example, 24 hours) before initiation of infections having rapidly fatal courses. In less acute infections, interleukin-1 administration can be delayed until shortly after the infectious challenge. Such observations suggest that those physiologic alterations of fever that enhance resistance to infection might be clinically effective only against localized infections and the early stages of systemic infections when these infections are of only mild to moderate severity. It is of interest, in this regard, that the protection against A. hydrophila by fever in the lizard has been attributed to enhanced influx of inflammatory cells into the local site of inoculation of the gram-negative bacterium, thereby preventing its dissemination [36].
Adverse Effects
The febrile response's potential for harm is reflected in a recent flurry of reports suggesting that interleukin-1, tumor necrosis factor, interleukin-6, and interferon mediate the physiologic abnormalities of certain infections. Although proof of an adverse effect of fever on the clinical outcome of these infections has yet to be established, the implication is that if pyrogenic cytokines contribute to the pathophysiologic burden of infections, both the mediators themselves and the febrile response are potentially deleterious.
The most persuasive evidence in this regard originates from studies of gram-negative bacterial sepsis [37]. It has long been suspected that bacterial lipopolysaccharides play a pivotal role in the syndrome. Purified lipopolysaccharide induces a spectrum of physiologic abnormalities that are similar to those occurring in patients with gram-negative bacterial sepsis. In experimental animals, challenge with lipopolysaccharide causes tumor necrosis factor and interleukin-1 to be released into the bloodstream coincident with the appearance of signs of sepsis [38]. Interleukin-1, alone or in combination with other cytokines, induces many of the same physiologic abnormalities (for example, fever, hypoglycemia, shock, and death) seen after administration of purified lipopolysaccharide [39]. In a murine experimental model for septic shock, interferon administered before or as long as 4 hours after lipopolysaccharide challenge increases mortality, whereas pretreatment with anti-interferon antibody significantly reduces mortality [40]. In several recent investigations, the adverse effects of gram-negative bacterial sepsis or lipopolysaccharide injections or both have been attenuated by pretreating experimental animals with interleukin-1 antagonists [41, 42] and monoclonal antibodies directed against tumor necrosis factor [43, 44] and interleukin-6 [45]. Further, animals rendered tolerant to tumor necrosis factor by repeated injections of recombinant tumor necrosis factor are protected against the hypotension, hypothermia, and lethality of gram-negative bacterial sepsis [46]. This protection is believed to be related to the induction of manganous superoxide dismutase gene expression in hepatocytes [46].
Together, these observations have led to a growing conviction that pyrogenic cytokines are central mediators of the clinical and humoral manifestations of gram-negative bacterial sepsis and have generated intense interest in the clinical application of antagonists of these cytokines. Similar data suggest that pyrogenic cytokines might mediate at least some of the systemic and local manifestations of sepsis caused by gram-positive bacteria [37, 47, 48], the acquired immunodeficiency syndrome [49], spirochetal infections [50, 51], meningitis [52], the adult respiratory distress syndrome [39, 53], suppurative arthritis [54], and mycobacteriosis [55].
A Hypothesis
Is the febrile response a blessing or a curse? These data clearly indicate that it has the potential to be both. Thus, the teleologic significance of the febrile response is not a question of either/or, but of why. Why would nature have evolved a response that can be both beneficial and harmful? The explanation lies, I believe, with the particular vantage point from which the apparent paradox is examined.
If one considers the consequence of the febrile response and its mediators only from the point of view of the host, there can be no reconciliation between its reported capacity for benefit at certain times and harm at others. However, if one views the febrile response from the perspective of the species, its salutary effects on mild to moderately severe infections and its pernicious influence on fulminating infections become less paradoxic—that is, if one accepts preservation of the species rather than survival of the individual as the essence of evolution. An evolutionary process driven by such a principle might lead to sacrifice of the individual if it poses a threat to the species. In this context, the febrile response and its mediators might have evolved both as a mechanism for accelerating the recovery of infected individuals with localized or mild to moderately severe systemic infections and for hastening the demise of hopelessly infected individuals, who pose a threat of epidemic disease to the species. In the former instance, the physiologic response acts to preserve the life of a diseased but potentially redeemable individual so that it can continue to contribute to the proliferation of the species. In the latter instance, the same response accelerates the inevitable demise of a hopelessly infected and potentially highly contagious individual to limit spread of the infection within the species. Whether the response manifests the former or the latter effect could, in turn, be determined by the peak systemic concentrations of pyrogenic cytokines achieved during infection. At low systemic levels, benefit to the host might ensue, whereas at concentrations above some as-yet-undetermined critical level, the same cytokines might exert a harmful effect on the host.
Available data thus indicate that the febrile response has the capacity to be either blessing or curse, depending on the nature of the infection inducing the response. As a probable victim of fever's latter capacity, the septic patient, like Lear, may have to endure the consequences of a “product of the flesh” turned against itself. Whether modern measures directed against pyrogenic cytokines can reverse fever's occasional sinister effects remains to be determined.
- Copyright ©2004 by the American College of Physicians
