Fever is an elevation of body temperature above the normal circadian range as the result of a change in the thermoregulatory center located in the anterior hypothalamus. Fever is not a disease itself, but a manifestation of a number of disease processes.

The first step to dealing with a fever is recognizing it. There are many different opinions as to what temperature constitutes a fever, but the classic "normal" temperature is 98.6^o F (37^o C) with a daily variation of 0.5-0.9^o F, and the classic definition of the lower limit of fever is 100.4^o F (38^o C). These values were established by Carl Reinhold August Wunderlich in the 1860’s after reviewing several million temperatures in over 25,000 patients over 18 years. However, he used a thermometer that may not have been very precise, used mainly axillary temperatures, and he did not present his raw data, so the accuracy of his claims has been challenged. Modern studies have typically found normal body temperature to be lower than the classic 98.6^o F. A recent study by Mackowiak, et al, found that the mean temperature for young, healthy adults was actually 98.2^o F +/- 0.7^o F (36.8^o C +/- 0.4^o C), and that the 99th percentile for maximum normal temperature in young, healthy adults was 98.9^o F (37.2^o C) at 0600 and 99.9^o F (37.8^o C) at 1600. Therefore, they concluded that any temperature in young adults over 99.0^o F (37.2^o C) in the morning or 99.9^o F (37.8^o C) at any time should be considered a fever. Older adults generally have lower normal body temperatures than young adults, and the range of normal has not been well established in children. There can be considerable variation in temperature depending on what site is measured, with rectal temperatures generally being higher than oral or tympanic membrane measurements.

Fever must be differentiated from hyperthermia. Fever occurs when the thermoregulatory set point is changed and the body maintains a temperature equivalent to that set point. In hyperthermia, body temperature increases above the thermoregulatory set point because the mechanisms of heat dissipation are impaired. A common example of this condition is heat stroke in association with exercise, but it can also occur with perspiration-inhibiting drugs or with a hot environment.

Body temperature is controlled by the hypothalamus through mechanisms of heat loss, and fever occurs when substances called pyrogens cause a change in the hypothalamic set point. Pyrogens can be considered exogenous; coming from outside the body, or endogenous; produced in the body. Many substances, such as toxins, drugs, or antigen-antibody complexes, may be exogenous pyrogens, but the most common exogenous pyrogens are the cell walls or products of microorganisms. In general, exogenous pyrogens act by inducing the formation of endogenous pyrogens from host cells, principally monocytes and macrophages. Endogenous pyrogens are cytokines such as IL-1 alpha and beta, tumor necrosis factor alpha and beta, IL-6, and alpha interferon. These endogenous pyrogens reach the preoptic/anterior hypothalamus through a permeable vascular network referred to as the organum vasculosum laminae terminalis, probably causing the releasing of prostaglandin E₂ which then presumably diffuses into the preoptic/anterior hypothalamus and affects the change in the hypothalamic set point by decreasing the firing rate of warm sensitive neurons. The increase in the hypothalamic set point results in physiologic changes designed to conserve and produce heat, such as vasoconstriction and shivering, and behavioral changes, such as putting on more clothes. As the endogenous and exogenous pyrogen stimulation is removed, the hypothalamic set point resets to normal temperature, resulting in physiologic changes designed to lose heat, such as sweating and vasodilatation, and behavioral changes, such as removing extra clothing.

As mentioned previously, fever is a manifestation of illness, but not an illness itself. By far, the most common cause of fever is infection. However, other causes of fever should always be kept in mind, such as malignancy (especially lymphoma and leukemia), connective tissue diseases, drugs, pulmonary embolism, and other less common causes.

Fever has historically been considered an ominous occurrence, but it is likely a beneficial response to a perceived health threat. With very few exceptions, reptiles, amphibians, fish, and mammals all produce febrile responses to pyrogens or bacteria. It is unlikely that so many diverse species would maintain a febrile reaction if it did not provide a survival benefit. Numerous animal models have shown that survival in the face of infection is enhanced by the production of fever (up to a certain temperature). In human in vitro and in vivo experiments, fever appears to have a beneficial effect on host defenses including enhancing neutrophil migration, increasing the production of antibacterial substances by neutrophils, and increasing T-cell proliferation.

While the diagnosis of a febrile illness can sometimes be straightforward, the evaluation of febrile illnesses often requires a careful evaluation of the history, physical, fever pattern, and laboratory values.

The history should begin with a detailed chronology of the events leading up to a fever, associated symptoms, any drugs used before or during the illness, and the duration of illness. The history should also include the following questions:

• recent sick contacts

• recent travel (especially overseas deployments or vacations in the preceding year)

• environmental exposures associated with jobs or hobbies (such as ticks, mosquitoes, raw sewage, swimming in ground water, etc.)

• animal exposure (including pets, birds, reptiles)

• unusual dietary habits (such as eating raw seafood, undercooked meat, or unpasteurized milk)

• high risk behavior (such as intravenous drug abuse (IVDA) or sexual behavior--always keep HIV seroconversion in mind)

• detailed history of past surgeries (including prosthetic material placed)

• hypersensitivities

• family illnesses (connective tissue diseases, malignancies, tuberculosis)

Understanding the Fever Pattern

The use of antipyretics and antibiotics can alter a fever pattern, and they are used so often that "classic" fever patterns are rarely seen. However, one should try to note the pattern of fever, as it can be a diagnostic aid.

• Continuous fevers are those that are constant with only slight remissions and can be seen in such diseases as lobar pneumonia and rickettsial diseases.

• An intermittent fever is one with wide fluctuations, usually normal in the morning and peaking in the afternoon or evening. This fever pattern can be seen in many viral illnesses as well as endocarditis or localized pyrogenic infections such as an abscess.

• A diurnal pattern, also known as typhus inversus, is a reversal of the normal circadian pattern in which the highest temperature is in the morning. It can be found in miliary TB, hepatic abscesses, and endocarditis.

• Tertian and quartan fevers, which occur on every third or fourth day respectively, are classic for malaria.

• Saddleback or biphasic fevers are those that are constant for several days, spontaneously reduce for 1 or 2 days, and then increase again. Saddleback fevers can be seen in such infections as Dengue, yellow fever, and influenza.

• A Pel-Ebstein fever is one that occurs daily for a period of about a week, resolves for about an equal time, and then recurs. Pel-Ebstein fevers are often seen in lymphomas.

• The Jarisch-Herxheimer reaction is a fever (and sometimes more systemic symptoms such as hypotension) that occurs several hours after treatment with antibiotics. It is a classic reaction for syphilis, but can also be seen in leptospirosis, relapsing fever, and brucellosis.