fever of unknown origin

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/ (fe´ver)

1. pyrexia; elevation of body temperature above the normal (37°C).

2. any disease characterized by elevation of body temperature.

---

blackwater fever  a dangerous complication of falciparum malaria, with passage of dark red to black urine, severe toxicity, and high mortality.

boutonneuse fever  a tickborne disease endemic in the Mediterranean area, Crimea, Africa, and India, due to infection with Rickettsia conorii, with chills, fever, primary skin lesion (tache noire), and rash appearing on the second to fourth day.

cat-scratch fever  see under disease.

central fever  sustained fever resulting from damage to the thermoregulatory centers of the hypothalamus.

childbed fever  puerperal septicemia.

Colorado tick fever  a tickborne, nonexanthematous, febrile, viral disease caused by an arenavirus and seen in the Rocky Mountain area of the United States.

continued fever  one that varies only slightly in 24 hours.

Crimean-Congo hemorrhagic fever  a hemorrhagic fever caused by the Crimean-Congo hemorrhagic fever virus, transmitted by ticks and by contact with blood, secretions, or fluids from infected animals or humans; it occurs in the Crimea, Central Asia, and regions of Africa.

drug fever  febrile reaction to a therapeutic agent, such as a vaccine, antineoplastic, or antibiotic.

elephantoid fever  a recurrent acute febrile condition occurring with filariasis; it may be associated with elephantiasis or lymphangitis.

enteric fever  any of a group of febrile illnesses associated with enteric symptoms caused by salmonellae, especially typhoid fever and paratyphoid fever.

epidemic hemorrhagic fever  an acute infectious disease characterized by fever, purpura, peripheral vascular collapse, and acute renal failure, caused by viruses of the genus Hantavirus, thought to be transmitted to humans by contact with saliva and excreta of infected rodents.

familial Mediterranean fever  a hereditary disease usually seen in Armenians and Sephardic Jews, with short recurrent attacks of fever, pain in the abdomen, chest, or joints, and erythema like that of erysipelas; it may be complicated by amyloidosis.

Haverhill fever  the bacillary form of rat-bite fever, due to Streptobacillus moniliformis, and transmitted through contaminated raw milk and its products.

hay fever  a seasonal form of allergic rhinitis, with acute conjunctivitis, lacrimation, itching, swelling of the nasal mucosa, nasal catarrh, and attacks of sneezing, an anaphylactic or allergic reaction excited by a specific allergen (such as pollen).

hemorrhagic fevers  a group of diverse, severe viral infections seen around the world but mainly in the tropics, usually transmitted to humans by arthropod bites or contact with virus-infected rodents; they all have certain common features, including fever, hemorrhagic manifestations, thrombocytopenia, shock, and neurologic disturbances.

humidifier fever  malaise, fever, cough, and myalgia caused by inhalation of air that has been passed through humidifiers, dehumidifiers, or air conditioners contaminated by fungi, amebas, or thermophilic actinomycetes.

intermittent fever  an attack of malaria or other fever, with recurring fever episodes separated by times of normal temperature.

Katayama fever  fever associated with severe schistosomal infections, accompanied by hepatosplenomegaly and by eosinophilia.

Lassa fever  a highly fatal, acute, febrile disease seen in West Africa, caused by a virulent arenavirus and characterized by increasing prostration, sore throat, ulcerations of the mouth or throat, rash, and general aching.

metal fume fever  a disease of welders and others working with volatilized metals, marked by sudden thirst, metallic taste in the mouth, high fever with chills, sweating, and leukocytosis.

mud fever  a type of leptospirosis seen in workers in flooded fields and swamps in Germany and Russia.

nonseasonal hay fever , hay fever, perennial nonseasonal allergic rhinitis.

Oroya fever  see Carrión's disease.

paratyphoid fever  paratyphoid.

parenteric fever  a disease clinically resembling typhoid fever and paratyphoid, but not caused by Salmonella.

parrot fever  psittacosis.

pharyngoconjunctival fever  an epidemic disease due to an adenovirus, seen mainly in school children, with fever, pharyngitis, conjunctivitis, rhinitis, and enlarged cervical lymph nodes.

phlebotomus fever  a febrile viral disease of short duration, transmitted by the sandfly Phlebotomus papatasi, with dengue-like symptoms, seen in Mediterranean and Middle Eastern countries.

Pontiac fever  a self-limited disease marked by fever, cough, muscle aches, chills, headache, chest pain, confusion, and pleuritis, caused by a strain of Legionella pneumophila.

pretibial fever  an infection due to a serovar of Leptospira interrogans, marked by a rash on the pretibial region, with lumbar and postorbital pain, malaise, coryza, and fever.

puerperal fever  septicemia accompanied by fever, in which the focus of infection is a lesion of the mucous membrane of the parturient canal due to trauma during childbirth; usually due to a streptococcus.

Q fever  a febrile rickettsial infection, usually respiratory, first described in Australia, caused by Coxiella burnetii.

rat-bite fever  either of two clinically similar acute infectious diseases, usually transmitted through a rat bite, one form (bacillary) of which is caused by Streptobacillus moniliformis and the other form (spirillary) by Spirillum minor.

recurrent fever 

1. relapsing f.

2. recurrent paroxysmal fever occurring in various diseases, such as malaria.

relapsing fever  any of a group of infectious diseases due to various species of Borrelia, marked by alternating periods of fever and apyrexia, each lasting from five to seven days.

remittent fever  one that shows significant variations in 24 hours but without return to normal temperature.

rheumatic fever  a febrile disease occurring as a sequela to Group A hemolytic streptococcal infections, characterized by multiple focal inflammatory lesions of connective tissue structures, especially of the heart, blood vessels, and joints, and by Aschoff bodies in the myocardium and skin.

Rift Valley fever  a zoonotic febrile disease with dengue-like symptoms, due to an arbovirus, transmitted to humans by mosquitoes or by contact with diseased animals; first observed in the Rift Valley, Kenya.

Rocky Mountain spotted fever  infection with Rickettsia rickettsii, transmitted by ticks, marked by fever, muscle pain, and weakness followed by a macular petechial eruption that begins on the hands and feet and spreads to the trunk and face, with other symptoms in the central nervous system and elsewhere.

rose fever  a form of hay fever caused by grass pollens released while roses or other flowers are blooming.

scarlet fever  an acute disease caused by Group A β-hemolytic streptococci, marked by pharyngotonsillitis and a skin rash caused by an erythrogenic toxin produced by the organism; the rash is a diffuse, bright red erythema, and desquamation of the skin begins as fine scaling with eventual peeling of the palms and soles.

Sennetsu fever  a febrile disease seen in Japan and Malaysia and caused by Ehrlichia sennetsu, characterized by headache, nausea, lymphocytosis, and lymphadenopathy.

septic fever  fever due to septicemia.

South African tickbite fever  boutonneuse f.

trench fever  a louse-borne rickettsial disease due to Bartonella quintana, transmitted by the body louse, Pediculus humanus corporis, and characterized by intermittent fever, generalized aches and pains, particularly severe in the shins, chills, sweating, vertigo, malaise, typhus-like rash, and multiple relapses.

typhoid fever  infection by Salmonella typhi chiefly involving the lymphoid follicles of the ileum, with chills, fever, headache, cough, prostration, abdominal distention, splenomegaly, and a maculopapular rash; perforation of the bowel may occur in untreated cases.

fever of unknown origin  (FUO) a febrile illness of at least three weeks' duration (some authorities permit a shorter 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).

West Nile fever  see under encephalitis.

yellow fever  an acute, infectious, mosquito-borne viral disease, endemic primarily in tropical South America and Africa, marked by fever, jaundice due to necrosis of the liver, and albuminuria.

---

fever of unknown origin (FUO),

a febrile illness of at least 3 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 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