Consultant. No. 2

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Fever:

By ROBERT E. MORRISON, MD and JAMES B. LEWIS Jr, MD | February 1, 2004

University of Tennessee

Dr Morrison is professor of medicine at the University of Tennessee and chief of medicine at the Regional Medical Center, both in Memphis. Dr Lewis is associate professor of medicine and program director of the internal medicine residency training program at the University of Tennessee.

ABSTRACT: A methodical approach to diagnosis usually reveals the cause of fever. In patients with simple fever, a careful history taking and physical examination combined with basic laboratory and imaging studies (complete blood cell count with differential, urinalysis, and possibly a chest film and blood cultures) usually yield the diagnosis. In patients with prolonged fever whose cause remains undiagnosed after extensive examination (fever of unknown origin), repeat the history taking and physical examination; also order routine laboratory studies, an HIV test, a tuberculin skin test, 3 sets of blood cultures, and chest films. In addition, abdominal CT scanning is often useful. Further testing at this point may include [¹⁸F]fluorodeoxyglucose positron emission tomography, technetium-tagged white blood cell scanning, transesophageal echocardiography, liver biopsy, bone marrow examination, and/or temporal artery biopsy. Exploratory laparotomy is rarely indicated.

Fever is one of the most commonly encountered symptoms in the practice of medicine (Box). Often its cause is immediately apparent. However, when it is not, the dozens of different diseases and conditions associated with fever can make diagnosis challenging.

Here we present a systematic approach to the workup. We also discuss how to proceed when an initial comprehensive examination has failed to yield a diagnosis and a fever is classified as a "fever of unknown origin" (FUO).

WORKUP OF A PATIENT WITH FEVER

Initiate evaluation of fever in any patient with an oral temperature of 38.3°C (101°F) or higher. In immunosuppressed or obviously septic patients, consider an evaluation at lower temperatures. The cause of a fever is usually discerned based on symptoms, clues from the history, physical findings, and/or results of basic laboratory and imaging studies. Fevers in ambulatory patients are usually caused by respiratory tract infections, urinary tract infections, or chronic viral infections (ie, those caused by HIV, Epstein-Barr virus, herpesvirus, or hepatitis virus type B or C).

History. A detailed history-with a complete review of systems-is essential. Ask about:

Previous procedures.
Travel.
Animal exposures.
Tuberculosis exposure.

Be sure to assess:

Height and duration of the fever.
Fever pattern.
Relationship of fever to pulse.

A shaking chill, or rigor, suggests bacteremia, respiratory distress, pneumonia, or sepsis and hypotension. In febrile patients with an intravenous catheter-or any type of catheter- assume that a catheter-related infection is the cause of fever until proved otherwise.

Height and duration of fever. Evaluate patients with sustained temperature elevations below 38.8°C (102°F) for malignancy, cirrhosis, viral hepatitis, tuberculosis, legionnaire disease, or 1 of the zoonoses. Fever can be associated with almost any malignancy; it does not appear to be limited to liver or brain metastases. Malignancies do not usually cause high-grade fever, with the exception of renal cell carcinoma (the most common solid tumor cause of FUO) and lymphomas. In lymphomas, a Pel-Ebstein fever (which disappears and reappears over a period of several days to several weeks) may occur.

Temperatures higher than 38.8°C (102°F) with no obvious cause mandate evaluation for an abdominal, GI, or pelvic abscess. Pancreatitis in patients with a temperature of 38.8°C (102°F) or higher is usually the result of a pancreatic abscess or an infected pancreatic pseudocyst. Extreme hyperpyrexia (temperature higher than 41.1°C [106°F]) is usually associated with a noninfectious cause, such as heat stroke or CNS disease.

Fever patterns. Fever curves usually have no diagnostic significance except in uncommon conditions. Hectic, septic fever (fever that spikes several times a day)in hospitalized patients is usually associated with peritonitis; in-tra-abdominal, pelvic, or renal abscesses; or over-zealous use of antipyretics.

A single temperature spike below 38.8°C (102°F) very rarely has diagnostic significance-unless it occurs in an immunocompromised patient. Single temperature spikes above 38.8°C (102°F) usually result from manipulative or invasive procedures that induce transient bacteremias or from the infusion of blood products.

Double-quotidian fevers (fevers that spike twice in a 24-hour period) that are not related to antipyretic use are uncommon. However, such a fe-ver may be the only clue that points to adult-onset Still disease, juvenile rheumatoid arthritis, or culture-negative gonococcal endocarditis.

Fever-pulse relationship.Relative bradycardia (a pulse-temperature deficit) is associated with typhoid fever, legionnaire disease, chlamydial pneumonia, and possibly dengue fever and sandfly fever. Unfortunately, it is not possible to correlate fever and relative bradycardia with a specific diagnosis in any given patient.^1,2

Physical examination. Examine the skin for dermatologic manifestations of infection:

Petechiae, associated with meningococcemia (Figure) and Rocky Mountain spotted fever.
Pustules, seen in gonococcemia and staphylococcal disease.
Conjunctival petechiae, splinter hemorrhages, Osler nodes, and Janeway lesions-any of which may be seen in endocarditis.
Ecthyma gangrenosum, which is associated with Pseudomonas aeruginosa infections.
Extensive bullae over the extremities, which may occur in Vibrio vulnificus infections.

Percuss the paranasal sinuses for tenderness, which indicates sinusitis. Examine the optic fundi and posterior chambers of the eye for Roth spots, retinitis, and choroiditis. Any of these may be seen in endocarditis or in viral, mycobacterial, or fungal diseases. Inspect the tympanic membranes for evidence of otitis media.

Palpate the thyroid gland. A tender gland in the setting of a sore throat and fever may represent subacute thyroiditis.

Carefully palpate the cervical, axillary, supraclavicular, inguinal, and epitrochlear lymph nodes. Nodes larger than 1 cm in diameter are often pathologic; consider lymph node aspiration in patients with HIV infection or a previous history of malignancy. Lymph node biopsy is useful in the diagnosis of lymphoma, tuberculosis, and a variety of other infections.

Examine the breasts, chest, and heart. Patients with heart disease may respond to fever with high-output angina or even heart failure. Crackles may indicate pneumonia, and dullness can be a sign of pleural effusion.

Perform a musculoskeletal examination that includes careful examination of the joints. Tenderness over the spine on percussion may be associated with infection or malignancy.

During the neurologic examination, be alert for meningismus and for changes in mentation. In older patients, fever may cause inability to concentrate, confusion, delirium, or stupor.

Laboratory and imaging studies. Basic laboratory tests for a patient with fever consist of a complete blood cell (CBC) count with differential and urinalysis. Also obtain a chest radiograph if signs or symptoms of respiratory disease are present. Order blood cultures in hospitalized patients with a temperature of 38.3°C (101°F) or higher and in any patient with fever in whom you suspect a serious bacterial infection, such as pneumonia, osteomyelitis, abscess, or meningitis. Two sets of blood cultures are indicated when the likelihood of bacteremia is low. Three sets of cultures are indicated when a continuous bacteremia is suspected, as in infective endocarditis.

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CLINICAL HIGHLIGHTS

Sustained temperature elevations below 38.8°C (102°F) can point to malignancy, cirrhosis, viral hepatitis, tuberculosis, legionnaire disease, or a zoonosis. Higher sustained temperatures with no obvious cause mandate evaluation for an abdominal, GI, or pelvic abscess.
Double-quotidian fevers (fevers that spike twice in a 24-hour period) that are not related to antipyretic use are uncommon. However, such a fever may point to adult-onset Still disease, juvenile rheumatoid arthritis, or culture-negative gonococcal endocarditis.
Relative bradycardia (a pulse-temperature deficit) is associated with typhoid fever, legionnaire disease, chlamydial pneumonia, and possibly dengue fever and sandfly fever. Unfortunately, it is not possible to correlate fever and relative bradycardia with a specific diagnosis in any given patient.
Malignancies do not usually cause high-grade fever, with the exception of renal cell carcinoma (the most common solid tumor cause of fever of unknown origin [FUO]) and lymphomas. In lymphomas, a Pel-Ebstein fever (which disappears and reappears over a period of several days to several weeks) may occur.
In 5% to 20% of patients with FUO, even a thorough evaluation proves nondiagnostic. However, if such patients remain stable, the prognosis is usually excellent-eventual defervescence and no subsequent emergence of serious disease.

A Pyrexia Primer

Fever has been recognized as a cardinal manifestation of disease since ancient times. It was discussed by Hippocrates, and references to fever are even found in Sumerian cuneiform dating back to 2000 BCE. Temperatures were first measured in the 17th century with a device constructed by an Italian physician, Santorio Santorio. In 1714, Gabriel Daniel Fahrenheit, a German instrument maker, developed the first effective thermometer.

In 1868, Reinhold August Wunderlich performed more than a million temperature readings in 25,000 persons; he concluded that 37°C (98.6°F) was the mean temperature in healthy adults. Wunderlich used a nonregistering mercury thermometer that had to be read in situ.¹⁵ In 1992, Philip Mackowiak reevaluated Wunderlich's findings using modern electronic thermometers positioned in the sublingual pocket. He recorded 700 temperatures in 148 persons.¹⁶ Mackowiak determined that normal body temperature ranges from 35.6°C (96°F) to 38.3°C (100.8°F), with a median of 36.8°C (98.2°F) and a mode of 36.7°C (98°F); he established that 37°C (98.6°F) has no particular significance. Mackowiak also discovered that temperatures in healthy persons go through a diurnal cycle, with the nadir at 6 AM and the zenith between 4 and 6 PM.

The brain and the hypothalamus maintain thermal homeostasis. The anterior hypothalamus is the region that is most involved in the development of fever.

Fever results whenbacterial toxins or other stimuli cause release of endogenous pyrogens-low molecular weight proteins cleaved from macrophages.These pyrogens travel to the brain and the anterior hypothalamus, where they stimulate a rise in the set point by causing release of prostaglandin E₂. Various cytokines have been implicated in the production of fever. Of those involved, interleukin-1β and interleukin-6 are felt to correlate best with the presence and severity of fever. Tumor necrosis factor α may actually lower febrile temperatures.

When the thermoregulatory set point is elevated, the heart rate increases (at an average of 4.4 beats per minute for each degree [C] of temperature rise) and shivering occurs to increase heat production. Another response to the elevated set point is peripheral vasoconstriction, which decreases heat loss. When a fever breaks, the thermoregulatory set point has begun to return to normal. Thus, a patient whose fever has recently broken is hyperthermic relative to his or her set point. During the period of defervescence, he feels warmer and sweats to produce heat loss.

Fever is usually an appropriate physiologic response to infection or other cause of thermoregulatory dysfunction. In fact, hypothermia in response to an infectious process is a bad prognostic sign. Various components of specific and nonspecific immunity are enhanced by febrile temperatures.

TOPIC INDEX

Developmental/Genetic

Nutritional/Metabolic

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