How important is fever as a defense mechanism? The general assumption is that such a complex reaction must represent an integral and functional part of the inflammatory response and not simply an incidental or accidental biologic effect. However, answering the question of whether this response always is beneficial is more difficult. Defense mechanisms can go awry. Fluid retention in congestive heart failure is one example of a situation in which a defense mechanism in excess may do more harm than good.

The question often posed is: Is fever a friend or a foe? A more appropriate question would be: Under what conditions is fever beneficial and under what conditions is it harmful? Even granting that fever does have a role in defending the host against infection, in some circumstances fever still may do more harm than good. Also, fever may be a less important defense mechanism in higher animals, such as mammals with well-developed immunologic systems, than in fish and reptiles with more primitive immunologic systems. Many animal experiments that demonstrated a survival benefit due to fever involved cold-blooded animals (poikilotherms), such as fish and lizards, which do develop fever in response to infection but do so strictly by behavioral mechanisms, by moving to the warmest external environment available. Despite the differences between the immunologic systems of these animals and primates, poikilothermic animals often have been selected as laboratory models for the study of fever because of the convenience with which fever can be prevented without confounding the study by introducing drugs such as aspirin.

Studies in lizards and goldfish infected with Aeromonas hydrophila have demonstrated a higher mortality rate when the febrile response is prevented by denying the animals access to a warmer environment. A study in young adult volunteers with the common cold found prolonged viral shedding in those given aspirin compared to those given a placebo. In view of the current knowledge of the immunosuppressive effects of aspirin, studies that used this drug to evaluate the effect of fever reduction on morbidity or mortality, either in animals or humans, must be considered suspect because they do not distinguish between whether the effect was caused by the suppression of fever or by the antipyretic drug itself. One study found increased time to total scabbing of lesions in children given acetaminophen (which has no antiinflammatory effect) versus those given placebo.

The growth or survival of some pathogenic bacteria or viruses is impaired at temperatures in the range of 40°C (104°F). Many pathogenic bacteria require iron for their growth, and fever has been shown to be associated with a decrease in serum iron and a simultaneous increase in serum ferritin, resulting in reduced levels of free iron in the blood. Because these bacteria have an enhanced need for iron at high temperatures, some researchers have suggested that this response is a coordinated host defense mechanism designed to deprive bacteria of free iron when they need it most. In vitro studies have demonstrated the enhancement of several human immunologic functions at moderately elevated ambient temperatures. These functions include increased lymphocyte transformation response to mitogen, increased bactericidal activity of polymorphonuclear leukocytes, and increased production of interferon. However, as temperatures approached 40°C
(104°F) in these experiments, most of the functions decreased to below baseline levels.

In one study of rabbits infected with Pasteurella multocida, survival rates increased with moderate fever, but with fevers greater than 2.25°C above baseline, survival rates were lower than in the euthermic state. Another study demonstrated increased mortality rates associated with fever in rats infected with Salmonella enteritidis. Thus, fever, especially fever of moderate degree, appears to enhance several aspects of the immunologic response. At high body temperatures, however, these effects may be diminished or even reversed.