fever of unknown origin

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Fever of Unknown Origin

 

Definition

Fever of unknown origin (FUO) refers to the presence of a documented fever for a specified time, for which a cause has not been found after a basic medical evaluation. The classic criteria developed in 1961 included: temperature greater than 101 °F (38.3 °C), for at least three weeks, and inability to find a cause after one week of study. Within the past decade, a revision has been proposed that categorizes FUO into classic, hospital acquired FUO, FUO associated with low white blood counts, and HIV associated FUO (AIDS related).

Description

Fever is a natural response of the body that helps in fighting off foreign substances, such as microorganisms, toxins, etc. Body temperature is set by the thermoregulatory center, located in an area in the brain called hypothalamus. Body temperature is not constant all day, but actually is lowest at 6 A.M. and highest around 4-6 P.M. In addition, temperature varies in different regions of the body; for example, rectal and urine temperatures are about one degree Fahrenheit higher than oral temperature and rectal temperature is higher than urine. It is also important to realize that certain normal conditions can effect body temperature, such as pregnancy, food ingestion, age, and certain hormonal changes.
Substances that cause fever are known as "pyrogens." There are two types of pyrogens; exogenous and endogenous. Those that originate outside the body, such as bacterial toxins, are called "exogenous" pyrogens. Pyrogens formed by the body's own cells in response to an outside stimulus (such as a bacterial toxin) are called "endogenous" pyrogens.
Researchers have discovered that there are several "endogenous" pyrogens. These are made up of small groups of amino acids, the building blocks of proteins. These natural pyrogens have other functions in addition to inducing fever; they have been named "cytokines". When cytokines are injected into humans, fever and chills develop within an hour. Interferon, tumor necrosis factor, and various interleukins are the major fever producing cytokines.
The production of fever is a very complex process; somehow, these cytokines cause the thermoregulatory center in the hypothalamus to reset the normal temperature level. The body's initial response is to conserve heat by vasoconstriction, a process in which blood vessels narrow and prevent heat loss from the skin and elsewhere. This alone will raise temperature by two to three degrees. Certain behavioral activities also occur, such as adding more clothes, seeking a warmer environment, etc. If the hypothalamus requires more heat, then shivering occurs.
Fever is a body defense mechanism. It has been shown that one of the effects of temperature increase is to slow bacterial growth. However, fever also has some downsides; the body's metabolic rate is increased and with it, oxygen consumption. This can have a devastating effect on those with poor circulation. In addition, fever can lead to seizures in the very young.
When temperature elevation occurs for an extended period of time and no cause is found, the term FUO is then used. The far majority of these patients are eventually found to have one of several diseases.

Causes and symptoms

The most frequent cause of FUO is still infection, though the percentage has decreased in recent years. Tuberculosis remains an important cause, especially when it occurs outside the lungs. The decrease in infections as a cause of FUO is due in part to improved culture techniques. In addition, technological advances have made it easier to diagnose non-infectious causes. For example, tumors and autoimmune diseases in particular are now easier to diagnose. (An autoimmune disease is one that arises when the body tolerance for its own cell antigenic cell markers disappears.)
Allergies to medications can also cause prolonged fever; sometimes patients will have other symptoms suggesting an allergic reaction, such as a rash.
There are many possible causes of FUO; generally though, a diagnosis can be found. About 10% of patients will wind up without a definite cause, and about the same percentage have "factitious fevers" (either self induced or no fever at all).
Some general symptoms tend to occur along with fever; these are called constitutional symptoms and consist of myalgias (muscle aches), chills, and headache.

Diagnosis

Few symptoms in medicine present such a diagnostic challenge as fever. Nonetheless, if a careful, logical, and thorough evaluation is performed, a diagnosis will be found in most cases. The patient's past medical history as well as travel, social, and family history should be carefully searched for important clues.
Usually the first step is to search for an infectious cause. Skin and other screening tests for diseases such as tuberculosis, and examination of blood, urine, and stool, are generally indicated. Antibody levels to a number of infectious agents can be measured; if these are rising, they may point to an active infection.
Various x-ray studies are also of value. In addition to standard examinations, recently developed radiological techniques using ultrasound, computed tomography scan (CT scan) and magnetic resonance imaging (MRI) scans are now available. These enable physicians to examine areas that were once accessible only through surgery. Furthermore, new studies using radioactive materials (nuclear medicine), can detect areas of infection and inflammation previously almost impossible to find, even with surgery.
Biopsies of any suspicious areas found on an x-ray exam can be performed by either traditional or newer surgical techniques. Material obtained by biopsy is then examined by a pathologist to look for clues as to the cause of the fever. Evidence of infection, tumor or other diseases can be found in this way. Portions of the biopsy are also sent to the laboratory for culture in an attempt to grow and identify an infectious organism.
Patients with HIV are an especially difficult problem, as they often suffer from many unusual infections. HIV itself is a potential cause of fever.

Treatment

Most patients who undergo evaluation for FUO do not receive treatment until a clear-cut cause is found. Antibiotics or medications designed to suppress a fever (such as NSAIDs) will only hide the true cause. Once physicians are satisfied that there is no infectious cause, they may use medications such as NSAIDs, or corticosteroids to decrease inflammation and diminish constitutional symptoms.

Key terms

AIDS — Acquired immune deficiency syndrome is often represented by these initials. The disease is associated with infection by the human immunodeficiency virus (HIV), and has the main feature of repeated infections, due to failure of certain parts of the immune system. Infection by HIV damages part of the body's natural immunity, and leads to recurrent illnesses.
Antibiotic — A medication that is designed to kill or weaken bacteria.
Computed tomography scan (CT Scan) — A specialized x-ray procedure in which cross-sections of the area in question can be examined in detail. This allows physicians to examine organs such as the pancreas, bile ducts, and others which are often the site of hidden infections.
Magnetic Resonance Imaging (MRI) — This is a new technique similar to CT Scan, but based on the magnetic properties of various areas of the body to compose images.
NSAID — Nonsteroidal anti-inflammatory drugs are medications such as aspirin and ibuprofen that decrease pain and inflammation. Many can now be obtained without a doctor's prescription.
Ultrasound — A non-invasive procedure based on changes in sound waves of a frequency that cannot be heard, but respond to changes in tissue composition. It is very useful for diagnosing diseases of the gallbladder, liver, and hidden infections, such as abscesses.
The development of FUO in certain settings, such as that acquired by patients in the hospital or in those with a low white blood count, often needs rapid treatment to avoid serious complications. Therefore, in these instances patients may be placed on antibiotics after a minimal number of diagnostic studies. Once test results are known, treatment can be adjusted as needed.

Prognosis

The outlook for patients with FUO depends on the cause of the fever. If the basic illness is easily treatable and can be found rather quickly, the potential for a cure is quite good. Some patients continue with temperature elevations for 6 months or more; if no serious disease is found, medications such as NSAIDs are used to decrease the effects of the fever. Careful follow-up and reevaluation is recommended in these cases.

Resources

Books

Gelfand, Jeffrey A., and Charles A. Dinarello. "Fever of Unknown Origin." In Harrison's Principles of Internal Medicine, edited by Anthony S. Fauci, et al. New York: McGraw-Hill, 1997.

fever

 [fe´ver]
1. an abnormally high body temperature; called also pyrexia. adj., adj fe´brile, fe´verish.
2. any disease characterized by marked increase of body temperature. For specific diseases, see the eponymic or descriptive name, such as rocky mountain spotted fever or typhoid fever. Other conditions involving elevated body temperature include heat exhaustion and heat stroke.

Normal body temperature when the body is at rest is 37°C (98.6°F). This is an average or mean body temperature that varies from person to person and from hour to hour in an individual. The route by which a body temperature is measured affects the reading. The normal oral temperature ranges from 36° to 37.5°C (96.8° to 99.5°F). If the temperature is measured rectally, the norm would be 0.5°C (1°F) higher. An axillary temperature would be 0.5°C (1°F) lower. Because of these differences, the number should always be followed by the route by which the temperature was taken when the reading is recorded.

Factors that can cause a temporary elevation in body temperature include age, physical activity, emotional stress, and ovulation. If a person has a consistently elevated temperature, fever is said to exist. A low-grade fever is marked by temperatures between 37.5° and 38.2°C (99.5° and 101°F) when taken orally. A high-grade fever is present when the oral temperature is above 38.2°C (101°F).

Types of fever include continued or continuous fever, one lasting more than 24 hours without significant variation or any return to normal body temperature; intermittent fever, in which at least once during a 24-hour period the fever spikes are separated by a return to normal body temperature; remittent fever, in which elevated body temperature shows fluctuations each day but never returns to normal; and recurrent (or relapsing) fever, in which periods of fever and normal body temperature alternate and last about 5 to 7 days each.

The regulation of body temperature is under the control of the hypothalamus. Thermolysis, or dissipation of body heat, is regulated by the anterior hypothalamus in conjunction with the parasympathetic nervous system. The overall effect of heat loss is accomplished by vasodilation of the peripheral blood vessels, increased sweating, and decreased metabolic and muscular activities. The production and conservation of body heat, or thermogenesis, is regulated by the posterior hypothalamus in conjunction with the sympathetic nervous system. The mechanisms by which body heat is produced and conserved are in opposition to those that increase heat loss; that is, by constriction of cutaneous blood vessels, decreased sweat gland activity, and increased metabolic and muscular activities.

Fever develops when there is some disturbance in the homeostatic mechanisms by which the hypothalamus maintains a balance between heat production and peripheral heat loss. Although dehydration, cerebral hemorrhage, heat stroke, thyroxine, and certain other drugs can cause an elevated body temperature or hyperthermia, fever, in the precise sense of the term, occurs as a result of inflammation or infection, or both. During the infectious and inflammatory processes certain substances called pyrogens are produced within the body. These endogenous pyrogens are the result of inflammatory reactions, such as those that occur in tissue damage, cell necrosis, rejection of transplanted tissues, malignancy, and antigen-antibody reactions. Exogenous pyrogens are introduced into the body when it is invaded by bacteria, viruses, fungi, and other kinds of infectious organisms.

Endogenous pyrogens act directly on the hypothalamus, affecting its thermostatic functions by “resetting” it to a higher temperature. When this happens, all of the physiologic activities concerned with heat production and conservation operate to maintain body temperature at a higher setpoint. The symptoms of chill and shivering are the result of increased muscular activity, which is an attempt by the body to raise its temperature to the higher setting. This increased muscular activity is accompanied by an elevation of the metabolic rate, which in turn increases the demand for nutrients and oxygen. Outward signs of these internal activities include a higher pulse rate, increased respirations, and thirst caused by the loss of extracellular water via the lungs. The pulse rate increases at the rate of about eight to ten beats per minute for each degree of temperature rise.

Once the body temperature reaches the setpoint of the hypothalamic thermostat, the mechanisms of heat production and heat loss keep it at a fairly constant level and the fever persists. This is sometimes called the second stage of fever. If it continues, fluid and electrolyte losses become more severe and there is evidence of cellular dehydration. During this stage delirium in older persons and convulsions in infants and children can occur. Febrile convulsions in children are believed to be closely related to cerebral damage that becomes evident as afebrile convulsions later in life.

Prolonged fever eventually brings about tissue destruction owing to the catabolism of body proteins. Because of this the patient experiences muscle aches and weakness, malaise, and the excretion of albumin in the urine. Anorexia also is present. If the body does not receive a sufficient supply of energy from dietary intake to meet its metabolic needs, it catabolizes its own fat and protein. The patient then rapidly loses weight and can develop ketosis and metabolic acidosis.

The period during which a fever abates is called the period of defervescence. It may occur rapidly and dramatically, as the temperature falls from peak to normal in a matter of hours. This is called the crisis, that is, the critical point at which the fever is broken. A more gradual resetting of the thermostat and slow decline of the fever is called resolution of the fever by lysis.
Treatment. It is not always necessary to reduce fever and in many cases it may be best not to treat it, at least until its cause is determined. The fever pattern can provide diagnostic information and is not necessarily harmful unless it is extremely high or the patient has cardiac or respiratory disease and cannot tolerate the additional tachycardia and dyspnea that may accompany fever. An elevated body temperature can inhibit bacterial replication and the action of viruses, spirochetes, and other pathogenic microorganisms.

If it is decided that treatment is necessary, there are two major goals: to identify the cause and to provide symptomatic relief. Antipyretic drugs such as aspirin and acetaminophen (Tylenol) are generally safe and effective. However, acetaminophen is preferred in children and when the patient has gastrointestinal sensitivity, allergy to aspirin, or a clotting disorder or is suspected of having Reye's syndrome.

Fluids and electrolytes are replaced orally or intravenously as indicated by laboratory tests and signs of dehydration. Frequent, small feedings of high-calorie, high-protein foods are recommended to combat fatigue and debility caused by the increased metabolic rate. The selection of oral liquids and foods should be based on the patient's preferences. Vitamin supplements may be prescribed in prolonged, low-grade fevers.
Patient Care. The patient with acute hyperpyrexia or hyperthermia will require extreme measures to lower the body temperature as quickly and safely as possible in order to prevent brain damage. Victims of heat stroke should be cooled rapidly. In order to keep the temperature at a tolerable level until the thermostat is reset, a cooling blanket or hypothermia mattress may be used. Care must be taken to maintain the integrity of the skin and avoid sudden and extreme hypothermia when such a device is used. Other measures include sponging parts of the body with cool water to increase heat loss through evaporation of moisture. The part being sponged should be left exposed to the air until it is almost dry, and then should be lightly covered while another part is being sponged. A cold compress on the forehead helps to reduce the fever and relieve headache and delirium. An alternative to sponging and a cool bath is the application of ice packs to specific parts of the body, such as the abdomen, groin, axillae, and spine. Fanning can also be effective, especially if the patient's torso is covered with a sheet saturated with water.

Chills are uncomfortable and sometimes frightening to the patient. When the patient complains of feeling chilled or cold, some form of external warmth should be provided. An extra blanket is helpful as is a hot water bottle filled with warm, not hot, water. As the body temperature declines the difference between body temperature and environmental temperature will decrease and the patient will begin to feel warmer. During the second stage of fever the patient may complain of feeling hot; the skin feels warm to the touch and the face is flushed. These symptoms are the result of vasodilation of surface blood vessels, an attempt by the body to prevent further escalation of the body temperature.
fever of unknown origin (FUO) a febrile illness of at least three weeks' duration with a temperature of at least 38.3°C on at least three occasions and failure to establish a diagnosis in spite of intensive inpatient or outpatient evaluation (three outpatient visits or three days' hospitalization). The duration of febrile illness needed to establish a diagnosis of FUO varies among authorities and is sometimes given as shorter than three weeks.

Classic fever of unknown origin, as defined by the preceding criteria, is distinguished from neutropenic and nosocomial FUO, as well as that associated with human immunodeficiency virus infection. In the neutropenic form, fever is accompanied by a neutrophil level that is lower than 500/mm3 or is expected to fall below that level within one or two days. The nosocomial form is a fever that occurs on several occasions in a hospitalized patient in whom neither fever nor infection was present on admission. In HIV-associated FUO, fever occurs in a person with human immunodeficiency virus infection on several occasions over a period of four weeks of outpatient care or three days of hospitalization. In all three of these forms of FUO, the cause of the fever cannot be determined after three days of investigation, including two days of incubation of cultures.

fever of unknown origin

the presence of fever (temperature >101°F or 38.3°C) of unknown cause after intensive investigation. Exact criteria for use of term vary, especially regarding duration of fever and extent of clinical investigation; generally a duration of longer than 1 week (some authors require 2-3 weeks) and thorough inpatient investigation or at least three outpatient visits, including a careful history, physical examination, and laboratory tests such as cultures, serologic studies, and invasive procedures for biopsy and/or culture, as indicated by clinical clues or epidemiologic considerations.

fever of unknown origin (FUO)

a febrile illness of at least 3 weeks' duration with a temperature of at least 38.3° C (100.9° F) on at least three occasions and failure to establish a diagnosis in spite of intensive inpatient or outpatient evaluation (three outpatient visits or 3 days' hospitalization). The duration of febrile illness required to establish a diagnosis of FUO varies among authorities and is sometimes given as shorter than 3 weeks.

fever of unknown origin

Infectious disease A febrile state with temperature of ≥ 37ºC of 2 or more wks in duration, for which a cause cannot be identified despite thorough physical examination and aggressive and relevant lab work-up Etiology Infectious in 30-40%, collagen vascular in 15-20%; in adults, 20-30% of rest are due to CA, which comprises 10% of the rest in children; rare causes of FUO include sarcoidosis and colitis; hereditary FUOs are rare and appear in Fabry's disease, familial Mediterranian fever, type 1 hyperlipidemia, cyclic neutropenia

fe·ver of un·known or·i·gin

(FUO) (fē'vĕr ŭn'nōn ōr'i-jin)
A sustained elevation of temperature, lasting 2 weeks or longer, for which no explanation can be found despite vigorous diagnostic evaluation.
Synonym(s): pyrexia of unknown origin.

fe·ver of un·known or·i·gin

(fē'vĕr ŭn'nōn ōr'i-jin)
Presence of fever (temperature >101°F or 38.3°C) of unknown cause after intensive investigation. Exact criteria for use of term vary, especially regarding duration of fever and extent of clinical investigation; generally a duration of longer than 1 week (some authors require 2-3 weeks) and thorough inpatient investigation or at least three outpatient visits, including a careful history, physical examination, and laboratory tests.
Synonym(s): pyrexia of unknown origin