Fever of unknown origin

Definition

Fever of unknown origin (FUO) refers to the presence of a documented elevation in body temperature for a specified time, for which a cause has not been found after basic medical evaluation. FUO is categorized as classic, hospital acquired FUO; FUO associated with low white blood cell counts (immunosuppression); and HIV-associated (AIDS-related) FUO.

Description

Fever, an elevation of normal body temperature, is a natural response of the body that helps fight off foreign substances, such as microorganisms (bacteria and viruses), parasites, fungi, and toxins. Body temperature is set by the thermoregulatory center, located in an area in the brain called the hypothalamus. Body temperature is not constant all day, but actually is lowest at 6 a.m. and highest around 4 to 6 p.m. Temperature also 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. Certain normal conditions can also effect body temperature, such as food ingestion, age, pregnancy, and certain hormonal changes.

Substances that cause fever are known as pyrogens, which can be either exogenous (originate outside the body, such as bacterial toxins) or endogenous (formed by the body's own cells in response to an outside stimulus, such as a bacterial toxin). Researchers have discovered that there are several endogenous pyrogens, each made up of small groups of amino acids, the building blocks of proteins. When these natural pyrogens, called 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.

In the complex process that produces fever, 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 process alone raises temperature by two to three degrees. Certain behavioral activities also occur, such as adding more clothes and seeking a warmer environment. If the hypothalamus requires more heat, shivering occurs.

In children, the definition of FUO is applied when fever has been present for 14 days with no apparent cause, even though physical examinations have been made and laboratory tests performed. Doctors pay special attention to the ears, nose, throat, sinuses, and chest as sites of infection, since most childhood infections are respiratory in nature. The majority of children with FUO are eventually found to have one of several infectious diseases or an autoimmune disease. In many cases the disease is common, and in some cases an allergic response is causing the fever. Fever increases the body's metabolic rate and oxygen consumption, which can have a devastating effect on individuals with poor circulation. In addition, fever can lead to seizures in the very young. Some possible infectious causes shown in studies of children with FUO are as follows:

• acute otitis media (middle ear infection)
• bacterial meningitis
• blastomycosis
• brucellosis
• cystic fibrosis
• ehrlichiosis
• endocarditis
• enteric infection
• herpes infection
• HIV infection
• infectious mononucleosis
• lower respiratory tract infection
• malaria
• osteomyelitis
• Rocky Mountain spotted fever
• strep infection (streptococcus infection)
• systemic viral syndrome
• tonsillophyaryngitis or tonsillitis
• tuberculosis
• tularemia
• urinary tract infection
• viral meningoencephalitis

Transmission

It is possible for a child with FUO to spread infection or illness to other individuals, particularly if an infectious organism is the underlying cause. If a child has FUO, it is best to reduce contact with other young children or immune compromised family members until the cause of the fever has been identified.

Demographics

Fever of unknown origin can occur in anyone, male or female, of any age at any time depending upon exposure to infectious organisms such as bacteria or viruses or to other causes of illness such as fungi, parasites, or toxins or to underlying autoimmune or allergic conditions. Because the underlying cause of the fever is usually recorded as the diagnosis, accurate statistics for those presenting with FUO are not available.

Causes and symptoms

There are many possible causes of FUO; generally though, a diagnosis can be found. The most frequent cause of FUO is still infection, though the percentage has decreased in the early 2000s. 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 that allow more precise identification of organisms and, therefore, more appropriate treatment. In addition, advances in diagnostic technologies have made it easier to identify non-infectious causes. For example, tumors and autoimmune diseases were as of 2004 easier to diagnose. An autoimmune disease is one that arises when the body's immune system attacks its own tissue as if it were foreign. This happens when the immune system does not recognize protein markers (antigens) on its own cells. In some cases, reactions to medications can also cause prolonged fever.

In about 10 percent of cases, no definite cause is found. In another 10 percent, "factitious fevers" (either self induced or no fever at all) are identified.

General constitutional symptoms tend to occur along with fever, including muscle aches and pains (myalgias), chills, and headache . Sometimes symptoms such as a rash suggest an allergic reaction.

When to call the doctor

An infant under three months should be seen as soon by a pediatrician as possible if a fever develops. If a toddler or older child has a fever for more than a day or two (48 to 72 hours), with or without other symptoms, the pediatrician should be consulted so that an early diagnosis can be made and treatment begun. It is especially important to watch for signs of dehydration , particularly if the child is not drinking liquids or seems too sick to drink. A crying child with fever may have pain associated with a specific condition and should be seen by the pediatrician as soon as possible.

Diagnosis

Few symptoms in medicine present such a diagnostic challenge as fever. Nonetheless, if a careful, logical, and thorough evaluation is performed, the underlying cause generally can be diagnosed. The child's medical history is first reviewed along with travel, social, and family history, which can reveal important clues.

The first step medically 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. Antibodies to a number of infectious agents can be measured; if antibody levels are rising, they may point to an active infection. In some cases, a febrile agglutination test can be performed to detect the presence in blood of certain infectious organisms that may stimulate the immune system to produce antibodies known as febrile agglutinins. The test helps diagnose or confirm certain febrile diseases that are known to be associated with febrile agglutinins. These may include:

• brucellosis, a type of infection caused by bacteria belonging to the genus Brucella and characterized by intermittent fever, sweating, chills, aches, and mental depression
• rickettsial infections, a group of diseases caused by the bacteria Rickettsia
• salmonellosis, caused by Salmonella bacteria and marked by nausea and severe diarrhea
• tularemia, also called rabbit fever, a bacterial infection characterized by a high fever and swollen lymph nodes

Various x-ray studies are of value and may be performed, particularly if organisms are identified that may indicate involvement of abdominal organs. Imaging techniques such as ultrasound, computed tomography (CT scan), and magnetic resonance imaging (MRI) may be performed. 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.

The removal and microscopic examination of tiny bits of tissue (biopsy) from 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 in order 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.

Fever in an individual with HIV, primary immune deficiency, recent transplant, on chemotherapy , or anyone else who is immunocompromised constitutes an especially difficult problem, as these patients often suffer from many unusual infections. HIV itself is a potential cause of fever.

Treatment

Most children 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 antipyretics (acetaminophen ) or non-steroidal anti-inflammatory drugs (NSAIDs) will only hide the true cause. Once physicians are satisfied that there is no infectious cause, they may recommend medications such as acetaminophen, NSAIDs, or corticosteroids to decrease inflammation and reduce constitutional symptoms. Parents are advised not to give children aspirin for fever because of a side effect called Reye syndrome, which may cause liver failure. Fluids are replenished by having the child consume clear liquids. A child too sick to drink may be hospitalized and given intravenous fluids.

The development of FUO in certain settings, such as when it is acquired by patients in the hospital or in immunosuppressed individuals with a low white blood count, often needs rapid treatment to avoid serious complications. Therefore, in these instances antibiotics may be given after a minimal number of diagnostic studies. Once test results are known and causative organisms identified, treatment can be adjusted appropriately.

Alternative treatment

Practitioners of complementary medicine recommend herbs to treat fever. A tea made with catnip, lobelia, and dandelion will reduce fever or catnip tea enemas administered daily. Rest is recommended and large quantities of clear liquids to flush out toxins and help prevent dehydration. Some practitioners recommend letting a fever run its course or cooling the body with cool sponge baths.

Supporting the immune system is one way to help avoid infection by exposure to bacteria, viruses, and toxins as a potential source of fever. Green drinks made with young barley are believed to cleanse the blood and supply chlorophyll and nutrients for maintaining healthy tissue. Because stress is known to produce biochemicals that reduce white blood cell functioning, it is important to get sufficient sleep and reduce stress to help keep the immune system functioning well. Therapeutic massage, yoga , and other types of stress reduction programs are available in most communities.

Prognosis

The outlook for children 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 children may continue to have an elevated temperature steadily or intermittently for six 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.

Prevention

Although FUO cannot actually be prevented because the sources are unknown, the immune system can be strengthened to help avoid infection from bacteria, viruses, and toxins. Several nutritional supplements are reported to help build the immune system. These include garlic (contains the essential trace element germanium), essential fatty acids (found in flax seed oil, evening primrose oil, and fish oils), sea vegetables such as kelp, acidophilus to supply natural bacteria in the digestive tract, and vitamins A and C, both powerful antioxidants that improve immune function and increase resistance to infection. Zinc is another nutrient essential to immune system functioning.

Nutritional concerns

Immune system function requires ingesting certain essential nutrients and avoiding others that depress immunity. A diet that improves immune system functioning includes fresh fruits and vegetables, as many eaten raw as possible to provide necessary enzymes; whole grain cereals, brown rice, and whole grain pasta for essential vitamins, minerals , and fiber; and non-meat sources of protein such as nuts, seeds, tofu, legumes (beans), and eggs. Fish, fowl, and lean meats can be consumed in small amounts. Sweets, especially if sweetened with refined sugars, should be reduced or avoided altogether. A diet high in fats and processed foods made with refined flours and sugars can actually suppress the immune system. Alcohol and caffeine should be avoided.

Parental concerns

When FUO is present, parents may be concerned that effective treatment will be delayed by waiting for a diagnosis, which may depend on waiting for the results of diagnostic tests. Depending on the extent of the fever, keeping the child quiet and in bed is probably recommended until all results are available and a definitive diagnosis is made. The doctor will undoubtedly recommend giving clear liquids as often as possible to avoid dehydration from the high body temperature. After the tests have been performed, the physician may recommend fever-reducing medications such as acetaminophen or ibuprofen. If the fever is high enough for concern, physicians may prescribe a broad spectrum antibiotic as initial treatment rather than waiting for the results of all diagnostic tests. When results are available, the physician will likely prescribe a new medication most appropriate for the diagnosis.

KEY TERMS

Acquired immune deficiency syndrome (AIDS) —A disease associated with infection by the human immunodeficiency virus (HIV) that attacks the immune system.

Antibiotics —Drugs that are designed to kill or inhibit the growth of the bacteria that cause infections.

Antibody —A special protein made by the body's immune system as a defense against foreign material (bacteria, viruses, etc.) that enters the body. It is uniquely designed to attack and neutralize the specific antigen that triggered the immune response.

Antigen —A substance (usually a protein) identified as foreign by the body's immune system, triggering the release of antibodies as part of the body's immune response.

Computed tomography (CT) —An imaging technique in which cross-sectional x rays of the body are compiled to create a three-dimensional image of the body's internal structures; also called computed axial tomography.

Culture —A test in which a sample of body fluid is placed on materials specially formulated to grow microorganisms. A culture is used to learn what type of bacterium is causing infection.

Immunosuppression —Techniques used to prevent transplant graft rejection by the recipient's immune system.

Magnetic resonance imaging (MRI) —An imaging technique that uses a large circular magnet and radio waves to generate signals from atoms in the body. These signals are used to construct detailed images of internal body structures and organs, including the brain.

Nonsteroidal anti-inflammatory drugs (NSAIDs) —A group of drugs, including aspirin, ibuprofen, and naproxen, that are taken to reduce fever and inflammation and to relieve pain. They work primarily by interfering with the formation of prostaglandins, enzymes implicated in pain and inflammation.

Toxin —A poisonous substance usually produced by a microorganism or plant.

Ultrasonography —A medical test in which sound waves are directed against internal structures in the body. As sound waves bounce off the internal structure, they create an image on a video screen. Ultrasonography is often used to diagnose fetal abnormalities, gallstones, heart defects, and tumors. Also called ultrasound imaging.

See also HIV infection and AIDS; Rheumatic fever.

Resources

BOOKS

Hay, William. Current Pediatric Diagnosis & Treatment. New York: McGraw Hill, 2002.

Matten, Grace. Fever of Unknown Origin. Durham, NC: Oyster River Press, 2001.

ORGANIZATIONS

American Medical Association. 515 N. State St., Chicago, IL 60612. Web site: <www.ama-assn.org>.

Centers for Disease Control and Prevention. 1600 Clifton Rd., NE, Atlanta, GA 30333. Web site: <www.cdc.gov>.

WEB SITES

Chan-Tack, Kirk M., and John Bartlett. "Fever of Unknown Origin." emedicine, November 17, 2004. Available online at <www.emedicine.com/med/topic785.htm> (accessed November 18, 2004).

L. Lee Culvert David Kaminstein, MD

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.