Fever

Anatomy or system affected: All

Definition: A symptom associated with a variety of diseases and disorders, characterized by body temperature above the normal 98.6 degrees Fahrenheit (37 degrees Celsius); considered very serious at 104 degrees Fahrenheit (40 degrees Celsius) and higher

Causes and Symptoms

Although the symptoms that often accompany a fever are well-known—shivering, sweating, thirst, hot skin, and a flushed face—what causes fever and its function during illness are not fully clear, even among medical specialists. Considerable literature exists on the differences between warm-blooded organisms (endotherms) and cold-blooded organisms (ectotherms) in what is called the normal state, when no symptoms of disease are present. Cold-blooded organisms depend on temperature conditions in their external environment to maintain various levels of temperature within their bodies. These fluctuations correspond to the various levels of activity that they need to sustain at given moments. Thus, reptiles, for example, may “recharge” themselves internally by moving into the warmth of the sun. Warm-blooded organisms, on the other hand, including all mammals, utilize energy released from the digestion of food to maintain a constant level of heat within their bodies. This level—a “normal” temperature—is approximately 98.6 degrees Fahrenheit (37 degrees Celsius) in humans. An internal body temperature that rises above this level is called a febrile temperature, or a fever.

If the temperature in the surrounding environment is low, warm-blooded animals must raise their metabolic rate (a measurement, in calories, of converted energy) accordingly to maintain a normal internal body temperature. In humans, this average rate of energy expenditure is between 1,800 and 2,300 calories per day, depending on age, sex, activity level, and more. If insufficient food is taken in to supply the necessary potential energy for this metabolic conversion into heat, the body will draw on its storage resource—fat—for energy. A potentially fatal condition called hypothermia, in which the body is too fatigued to maintain metabolic functions or has exhausted all its stores of calories, occurs when the internal temperature falls below normal. In humans, the temperature which qualifies as hypothermia is 95 degrees Fahrenheit (35 degrees Celsius) Although cold-blooded animals must also protect themselves against the danger that their body heat may fall too low to sustain life functions, they can support adjustments in their own internal temperature down to about 68 degrees Fahrenheit (20 degrees Celsius). At the same time, metabolic expenditures, as measured in calories, are very low in cold-blooded animals. For example, alligators must expend only 60 calories per day to create the same amount of heat as 1,800 calories per day in warm-blooded humans.

The question of internal temperature in warm-blooded animals is closely tied to management efficiency in the body. This function becomes critical when one considers abnormally high internal temperature, or fever. Generally, all essential biochemical functions in the human body can be carried out at optimal levels of efficiency at the set point of 98.6 degrees Fahrenheit (37 degrees Celsius). In the simplest of terms, any increase or decrease in temperature creates either more or less kinetic energy and has the potential to affect the chemistry of all body functions.

Endotherms can tolerate a certain range of involuntary change in their internal body temperature (brought about by disease or illness), but there is an upper limit of 113 degrees Fahrenheit (45 degrees Celsius), which constitutes a high fever. If the self-regulating higher set point associated with fever goes beyond this point, destructive biochemical phenomena will occur in the body—in particular, a breakdown of protein molecules. If these phenomena are not checked, they can bring about death.

Modern scientific approaches to the internal body processes that lead to fever, like a medical discussion of the effects that occur once fever is operating in the body, are much more complicated. They revolve around the concept of a change in the set point monitored in the brain. When this change in the brain’s normal 98.6 degrees Fahrenheit (37 degrees Celsius) thermostatic signal is called for, a process called phagocytosis begins, leading to a higher internal body heat level throughout the organism.

Phagocytosis, the ingestion of a solid substance (especially foreign material, such as invading bacteria), involves the appearance in the host’s system of large numbers of leukocyte cells. When these cells ingest the bacteria, small quantities of protein called leukocytic pyrogens are produced. According to most modern theories, these protein pyrogens trigger the biochemical reactions in the brain that alter the body’s temperature set point. After this point, changes that occur throughout the system and raise the body’s internal temperature depend on a component of the bacterial cell wall called endotoxin. By the end of the 1960s, researchers had drawn attention to at least twenty effects that activated endotoxins may have on the host organism. Key effects include enhancement of the production of new white blood cells (leukocytosis), enhancement of various forms of immunological resistance, reduction of serum iron levels, and lowering of blood pressure.

Most, if not all, of these effects brought about by endotoxins are accompanied by higher levels of heat throughout the body, the definition of fever. Closer biochemical examination of the source of the added heat yielded the suggestion, made by P. B. Beeson in 1948, that the host’s endotoxin-affected cells begin to produce a distinct form of protein, now called endogenous pyrogens. Pyrogens are thought to induce the first stage of fever by interacting with cells in tissues very close to the brain, specifically in the brain stem itself. Laboratory experiments in the first half of the twentieth century allowed researchers to produce almost immediate fever reactions when they injected pyrogen protein material into rabbits. Studies of the induced febrile state in laboratory animals, and therefore presumably also in humans, linked fever to immunological (virus-resistant and bacteria-resistant) reactions, not necessarily in the initially affected tissues around the brain but in various places throughout the organism. Scientific research into the effect of pyrogens on thermoregulation and into the febrile process, in general, remains ongoing.

Treatment and Therapy

The febrile response has been noted in five of the seven extant classes of vertebrates on earth (Agnatha, such as lampreys, and Chondrichthyes, such as sharks, are excluded). Scientists have determined that its function as a reaction to bacterial infection can be traced back as far as 400 million years in primitive bony fishes. The question of whether the natural phenomenon of fever actually aids in combating disease in the body, however, has not been fully resolved.

In ancient and medieval times, it was believed that fever served to “cook” and separate out one of the four essential body “humors”—blood, phlegm, yellow bile, and black bile—that had become excessively dominant. Throughout the centuries, such beliefs even caused some physicians to try to induce higher internal body temperatures as a means of treating disease. Use of modern antipyretic drugs to reduce fever remained unthinkable until the nineteenth century.

It was the German physician Carl von Liebermeister who, by the end of the nineteenth century, set some of the guidelines that are still generally observed in deciding whether antipyretic drugs should or should not be used to reduce a naturally occurring fever during illness. Liebermeister insisted that the phenomenon of fever was not one of body temperature gone “out of control” but rather a sign that the organism was regulating its own temperature. He also demonstrated that part of the process leading to increased internal temperature could be seen in reactions that actually reduce heat loss at the body’s surface, notably decreases in skin blood flow and evaporative cooling through perspiration. Liebermeister determined that one of the positive effects of higher temperatures inside the body was to impede the growth of harmful microorganisms. At the same time, however, other side effects of fever during illness were deemed to be negative, such as loss of appetite, and, in some cases, actual degeneration of key internal organs. Liebermeister’s generation of physicians, therefore, tended to rely on antipyretic drugs only when high fevers persisted for long periods of time. Moderate fevers or even high fevers, if they did not continue too long, were deemed to contribute to the overall process of natural body resistance to disease.

In fact, a limited school of physicians followed the teaching of 1927 Nobel laureate Julius Wagner-Jauregg, who claimed that “fever therapy” methods should be adopted for the treatment of certain diseases. Wagner-Jauregg himself pioneered this theory by inoculating victims of neurosyphilis with fever-producing malaria. Part of his argument in favor of this experimental therapy was that malaria, with its accompanying fever, was a treatable disease (using quinine) and could be controlled at regular intervals during its “service” as a fighter against a disease that still had no known cure. Later use of fever therapy for treatment of other sexually transmitted diseases, specifically gonorrhea, proved to be moderately successful. When the typhoid vaccine was used to induce fevers in some patients, however, side effects, such as hypotension (low blood pressure) or cardiovascular shock, introduced what some considered to be dangerous risk factors. Nevertheless, certain fields of medicine, especially those involved with eye diseases and related eye ailments, have proved that fever-inducing agents (specifically those contained in typhoid and typhoid-paratyphoid vaccines) also induce beneficial secretion of the anti-inflammatory hormone cortisol.

By the second half of the twentieth century, the medical use of antipyretic drugs, containing such components as salicylates and indomethacin, had become widespread. This phenomenon was not caused by any compelling reversal of earlier general assumptions that moderate levels of fever, being a natural body reaction, were not necessarily harmful to patients suffering from a wide variety of diseases. Rather, physicians may have opted to use such drugs as much for their pain-relieving qualities as for their fever-reducing characteristics. Although patients receiving such drug treatment notice a diminishing of severe pains or general aching, the cause of the disease has not been combated merely by the removal of such symptoms as fever and pain.

Modern medical science has tended to support further study of particular circumstances in which induced fevers can actually produce disease-combating reactions. A newly emerging field by the late 1970s, for example, involved studying the benefits of higher temperatures in newborn infants fighting viral infections. Although specific circumstances and the nature of disease prevent a generalized conclusion in terms of the use of induced fevers as a form of treatment, researchers have shown that an elevated body temperature serves to increase the speed at which white blood cells, the body’s natural enemies against disease, move to infected areas.

Perspective and Prospects

Although doctors have been aware of the symptoms of fever since the beginnings of medical history, centuries passed before its importance as an indicator of disease was accepted. A certain degree of sophistication in the study of fevers became possible largely because of the development of the common thermometer, in a rudimentary form in the seventeenth century and then with greater technical accuracy in the eighteenth-century. Systematic use of the thermometer in the eighteenth-century enabled doctors to observe such phenomena as morning remission and evening peaking of fever intensity. Studies involving the recording of temperature in healthy individuals also yielded important discoveries. One such discovery was made in 1774, when use of the thermometer showed that, even in a room heated to the boiling point of water 212 degrees Fahrenheit (100 degrees Celsius), healthy subjects maintained an internal body heat that was very close to the normal 98.6 degrees Fahrenheit (37 degrees Celsius) level.

Medical reports as late as the end of the eighteenth century, however, indicate that even internationally recognized pioneers of science were still not close to understanding the causes of fever. The English doctor John Hunter, for example, declared himself opposed to the prevailing view that rising body heat came from the circulation of warmer blood throughout the body. Hunter suspected that the warmth was produced by an entirely different agent that was independent of the circulatory system. He never learned what that agent might be, however, and failed in defense of his theory that the source of added body heat was in the stomach. Even the famous French chemist Antoine-Laurent Lavoisier erred when he tried to explain fever in terms of some form of chemical “combustion” involving hydrogen and carbon. Lavoisier identified the lungs as the possible location for this spontaneous production of internal body heat.

Although these theories were identified as erroneous, the late eighteenth and early nineteenth century left one legacy that would develop into the twentieth century and is still practiced by physicians: systematic thermometry. In essence, thermometry involves the tracing of the upward or downward direction of fever during illness to judge the course of the disease and the effects brought about by different stages of treatment. In many diseases, for example, clinical records of the full course of previous cases can be studied by doctors responsible for treating an individual patient. With thermometry, the doctor can determine how far the body’s struggle against a certain disease has progressed. If thermometry shows a marked departure from what clinical records have charted as the normal course of disease under certain forms of treatment, then the physician may look for signs of another disease.

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