Fever

Department of the Navy
Bureau of Medicine and Surgery
Peer Review Status: Internally Peer Reviewed

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.

A thorough physical exam is very important in the diagnosis of febrile illnesses and should be repeated during the course of illness to evaluate for changes. While the exam is often directed by symptoms, special attention should be paid to the skin, lymph nodes, eyes, nail beds, cardiovascular system, chest, abdomen, joints, and neurologic system. A genital/pelvic exam and rectal exam should be considered part of a complete evaluation.

Symptoms and physical findings should guide the laboratory evaluation. Often, no lab studies are required to make the diagnosis of a simple viral illness. When the diagnosis is not as clear:

• A complete blood count should almost always be ordered, with special attention paid to the differential. The presence of increased neutrophils and band forms (as well as toxic granulations and Dohle bodies) may indicate a bacterial infection, while neutropenia might be seen in viral infections or infiltrative processes of the bone marrow such as malignancy, TB, or histoplasmosis. Lymphocytosis may be seen in viral infections, typhoid fever, brucellosis, or TB, and atypical lymphocytes are frequently seen with infections with Epstein-Barr virus, cytomegalovirus, or HIV. Monocytosis may be seen with typhoid fever, TB, or lymphoma. Eosinophilia can be seen with certain parasitic infections, a hypersensitivity drug reaction, or lymphoma.

• Urinalysis with examination of the urinary sediment is indicated when symptoms suggest involvement of the genitourinary system or when another exclusive diagnosis is not readily apparent.

• Electrolytes, glucose, BUN, and creatinine should be checked as a general measure of the patient’s condition. Liver function tests are also generally indicated if other signs and symptoms do not specifically point away from hepatic involvement.

• Smears and cultures of specimens from the throat, urethra, anus, cervix, or vagina should be obtained when symptoms or signs indicate involvement of those systems. Cultures of blood and urine are indicated whenever the illness is thought to be more than a simple viral infection, especially if the diagnosis is unclear and empiric antibiotics are being considered.

• Cerebrospinal fluid should be examined and cultured if there is an associated severe headache, meningismus, a change in mental status. If signs of increased intracranial pressure, such as a focal neurologic deficit or papilledema, are present, a CT of the head should be performed to rule out a mass lesion before performing a lumbar puncture.

• Any abnormal fluid collection (pleural, peritoneal, or joint) found in the presence of fever should be examined and cultured.

• If a fever is severe or prolonged, it is appropriate to order an erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) as a baseline. These tests are too non-specific to use for diagnostic purposes, but can be used to follow the patient’s progress.

• A chest x-ray should be considered standard in any patient with an unclear diagnosis or if signs and symptoms point to the chest. X-rays of other areas, such as the abdomen or an extremity, may be indicated by the patient’s symptoms.

Whether or not to treat an elevated temperature is a common question. To determine an answer, one must first identify the cause of the elevated temperature, the degree of elevation, and then establish the goals of therapy.

If the patient is diagnosed with hyperthermia due to heat stroke or a drug reaction, specific therapy should include lowering the patient’s temperature to prevent the widespread organ dysfunction that occurs between 41-42^o C. If the patient has hyperthermia to >40^o C due to a fever, animal models and human data would suggest that the potential organ dysfunction found at this temperature outweighs the potential immunologic benefit from fever, and the patient should be treated with antipyretics or cooling blankets as indicated.

In patients with fever of <40^o C, the benefit of antipyretic therapy is less clear. Studies have shown that children with chicken pox treated with acetaminophen took longer to crust than controls, adults with rhinovirus treated with aspirin had more viral shedding and a longer duration of symptoms than controls, and children with a non-specific febrile illness considered to be viral had no significant improvement in symptoms when treated with acetaminophen. Furthermore, the use of antipyretics is likely to alter the fever pattern, which might be potentially useful for making the diagnosis. However, although aspirin should be avoided in children with viral illnesses to reduce the risk of Reye’s syndrome, there is little actual risk involved in treating patients with either acetaminophen or ibuprofen in recommended doses. The accompanying symptoms of febrile illnesses, such as myalgias and malaise, are widely believed to be eased by these medicines.

In the immunocompetent patient, empiric antibiotics for undifferentiated febrile illnesses should be avoided. An effort should always be made to make a specific diagnosis, including isolating a specific organism when possible, before starting antibiotics. Immunocompromised patients, such as neutropenic patients or HIV patients, sometimes require broad, empiric antibiotic coverage for febrile illnesses, but these patients should be referred to a specialist to help direct therapy.

References

1. Fever: Basic Mechanisms and Management, Second Edition. Edited by Philip A Mackowiak. Lippincott-Raven Publishers, Philadelphia, 1997.

2. Gelfand JA and Dinarello CA. Fever and Hyperthermia. Harrison’s Principles of Internal Medicine, 14th edition. Edited by Anthony Fauci, et al. McGraw-Hill Companies, Inc. USA, 1998: 84-89.

3. Mackowiak PA, et al. Concepts of fever: recent advances and lingering dogma. Clinical Infectious Diseases 1997; 25:119-138.