Fever of Unknown Origin 

Fever of unknown origin (FUO) was defined in 1961 by Petersdorf and Beeson as the following: (1) a temperature greater than 38.3°C (101°F) on several occasions, (2) more than 3 weeks' duration of illness, and (3) failure to reach a diagnosis despite 1 week of inpatient investigation.^{[1, 2]}

Diagnostic advances continuously modify the spectrum of FUO-causing diseases; for example, serologic tests have reduced the importance of the human immunodeficiency virus (HIV) and numerous rheumatic diseases (eg, systemic lupus erythematosus [SLE], juvenile rheumatoid arthritis [JRA], rheumatoid arthritis [RA]) as causes of FUO. (See Etiology and Serology.)

Modern imaging techniques (eg, ultrasonography, computed tomography [CT] scanning, magnetic resonance imaging [MRI]) enable early detection of abscesses and solid tumors that were once difficult to diagnose. (See Computed Tomography Scanning and Magnetic Resonance Imaging.)

Patients with undiagnosed FUO (5-15% of cases) generally have a benign long-term course, especially when the fever is not accompanied by substantial weight loss or other signs of a serious underlying disease. These findings suggest that the underlying cause is one of the more serious diseases that initially manifest as FUOs. Such underlying diseases are usually diagnosed after an intensive and rational diagnostic evaluation. (See Prognosis, History, and Diagnostic Considerations.)

FUOs are caused by infections (30-40%), neoplasms (20-30%), collagen vascular diseases (10-20%), and numerous miscellaneous diseases (15-20%). The literature also reveals that, as previously mentioned, between 5 and 15% of FUO cases defy diagnosis, despite exhaustive studies.

FUOs that persist for more than 1 year are less likely to be caused by an infection or neoplasm and are much more likely to be the result of a granulomatous disease (the most common cause in these cases).

The following conditions are sources of FUO:

• Abscesses
• Tuberculosis
• Urinary tract infections
• Endocarditis
• Hepatobiliary infections
• Osteomyelitis
• Rickettsia
• Chlamydia
• Systemic bacterial illnesses
• Spirochetal diseases
• HIV
• Acquired immunodeficiency syndrome (AIDS)
• Herpes viruses
• Fungal infections
• Parasitic infections
• Lymphomas
• Leukemias
• Solid tumors
• Malignant histiocytosis
• Collagen vascular and autoimmune diseases
• Sarcoidosis
• Regional enteritis
• Granulomatous hepatitis
• Drug fever
• Inherited diseases
• Endocrine disorders
• Peripheral pulmonary emboli and occult thrombophlebitis
• Kikuchi disease
• Factitious fever
• Giant cell arteritis (GCA)
• Polymyalgia rheumatica (PMR)
• Polyarteritis nodosa (PAN)

Abscesses

FUO should prompt consideration of abscesses, which are usually located intra-abdominally, even in the absence of localizing symptoms. The most common abscess locations include the subphrenic space, liver, right lower quadrant, retroperitoneal space, and the female pelvis.

Tuberculosis

Tuberculosis (TB) is usually considered in the FUO differential diagnoses. (See Differentials, below.)

Urinary tract infections

These rarely cause FUO, because urinalysis is an easily performed routine test that is used to detect most cases of urinary tract infection (UTI).

Endocarditis

Endocarditis is now a rare cause of FUO.

Systemic bacterial illnesses

Some systemic bacterial illnesses can manifest as FUOs. Brucellosis, still prevalent in Latin America and the Mediterranean, is very important. Researchers have also described systemic infections with Salmonella species, Neisseria meningitidis, and Neisseria gonorrhoeae as causes of FUO.

Spirochetal diseases

The most important spirochete is Borrelia recurrentis, which is transmitted by ticks and is responsible for sporadic cases of relapsing fever. Rat-bite fever (Spirillum minor), Lyme disease (Borrelia burgdorferi), and syphilis (Treponema pallidum) are other spirochetal diseases that can cause FUO.

Human immunodeficiency virus

Typical and atypical mycobacteria and cytomegalovirus (CMV) are opportunistic infections in persons with HIV infection that frequently cause prominent constitutional symptoms, including fever, with few localizing or specific signs. Other opportunistic infections (eg, salmonellosis, histoplasmosis, toxoplasmosis) can also present as FUO and elude rapid diagnosis in patients who are febrile with AIDS.

Parasitic infections

Consider toxoplasmosis in patients who are febrile with lymph node enlargement; Malaria can also be a cause of fever. Other parasites that cause FUO, albeit in rare cases, include Trypanosoma,Leishmania, and Amoeba species.

Leukemias

Acute leukemias are another important neoplastic group that can cause FUO.

Solid tumors

Among solid tumors, renal cell carcinoma is most commonly associated with FUO.

Other solid tumors, such as adenocarcinomas of the breast, liver, colon, or pancreas, as well as liver metastases from any primary site, may also manifest as fever.

Malignant histiocytosis

This rare, rapidly progressive malignant disease is an occasional cause of FUO.

Collagen-vascular and autoimmune diseases

SLE was once a relatively common cause of FUO. Systemic-onset JRA is another cause of FUO and is often difficult to diagnose.

PAN, RA, rheumatic fever, and mixed connective-tissue diseases (ie, other collagen vascular diseases), also cause FUO.

Regional enteritis

Crohn disease is the most common gastrointestinal cause of FUO.

Drug fever

Although a wide variety of drugs can cause drug fever, the most common are beta-lactam antibiotics, procainamide, isoniazid, alpha-methyldopa, quinidine, and diphenylhydantoin.

Inherited diseases

In patients of Mediterranean descent with FUO, familial Mediterranean fever is most often the cause.

Endocrine disorders

Hyperthyroidism and subacute thyroiditis are the 2 most common endocrinologic causes of FUO. Adrenal insufficiency is a rare, potentially fatal, very treatable endocrinologic source of FUO.

Kikuchi disease

Kikuchi disease is a self-limiting, necrotizing lymphadenitis. Its etiology is unknown.

Factitious fever

This is responsible for as many as 10% of FUO cases in some series and is most commonly encountered among young adults with health care experience or knowledge.

Polyarteritis nodosa

This condition ranks a distant third, behind GCA and PMR, as one of the vasculitides that causes FUO in patients older than age 50 years. PAN involves the medium- and small-sized muscular arteries. Incidence increases in patients with hepatitis B or C.

Uncommon causes of FUO include Wegener granulomatosis, Takayasu arteritis, and cryoglobulinemia.

More than 30% of FUO cases in persons older than 50 years are related to connective-tissue disorders and vasculitic diseases. GCA and PMR are the 2 principal connective-tissue etiologies, accounting for 50% of the cases.

In PAN, the male-to-female incidence ratio is 2:1.

Among patients with HIV infection, approximately 75% of cases of FUO are infectious in nature, about 20-25% of cases are due to lymphomas, and 0-5% of cases are due to the HIV itself.

Age predilection

Variations in FUO, as found in the literature, reflect the populations and periods studied. In children, infections are the most common cause of FUO, whereas neoplasms and connective-tissue disorders are more common in elderly persons.

The prognosis of FUO depends on the underlying cause and varies from patient to patient. Complications of FUO, if they occur, are case dependent.

However, careful review of the literature shows that patients with FUO usually have a benign long-term course, especially in the absence of substantial weight loss or other signs of a serious underlying disease.

For patient education information, see Fever in Adults and Fever in Children.