Fever of unknown origin

Fever of unknown origin (FUO), pyrexia of unknown origin (PUO) or febris e causa ignota (febris E.C.I.) refers to a condition in which the patient has an elevated temperature but despite investigations by a physician no explanation has been found.

If the cause is found it is usually a diagnosis of exclusion, that is, by eliminating all possibilities until only one explanation remains, and taking this as the correct one.

Definition

In 1961 Petersdorf and Beeson suggested the following criteria:

• Fever higher than 38.3°C (101°F) on several occasions
• Persisting without diagnosis for at least 3 weeks
• At least 1 week's investigation in hospital

A new definition which includes the outpatient setting (which reflects current medical practice) is broader, stipulating:

• 3 outpatient visits or
• 3 days in the hospital without elucidation of a cause or
• 1 week of "intelligent and invasive" ambulatory investigation.

Presently FUO cases are codified in four subclasses.

Classic FUO

This refers to the original classification by Petersdorf and Beeson. Studies show there are five categories of conditions:

• infections (e.g. abscesses, endocarditis, tuberculosis, and complicated urinary tract infections),
• neoplasms (e.g. lymphomas, leukaemias),
• connective tissue diseases (e.g. temporal arteritis and polymyalgia rheumatica, Still's disease, systemic lupus erythematosus, and rheumatoid arthritis),
• miscellaneous disorders (e.g. alcoholic hepatitis, granulomatous conditions), and
• undiagnosed conditions.

Nosocomial

Nosocomial FUO refers to pyrexia in patients that have been admitted to hospital for at least 24 hours. This is commonly related to hospital associated factors such as, surgery, use of urinary catheter, intravascular devices (i.e. "drip", pulmonary artery catheter), drugs (antibiotics induced Clostridium difficile colitis, and drug fever), immobilization (decubitus ulcers). Sinusitis in the intensive care unit is associated with nasogastric and orotracheal tubes. Other conditions that should be considered are deep-vein thrombophlebitis, and pulmonary embolism, transfusion reactions, acalculous cholecystitis, thyroiditis, alcohol/drug withdrawal, adrenal insufficiency, pancreatitis.

Immune-deficient

Immunodeficiency can be seen in patients receiving chemotherapy or in hematologic malignancies. Fever is concomitant with neutropenia (neutrophil <500/uL) or impaired cell-mediated immunity. The lack of immune response masks a potentially dangerous course. Infection is the most common cause.

Human immunodeficiency virus (HIV)-associated

HIV-infected patients are a subgroup of the immunodeficient FUO, and frequently have fever. The primary phase shows fever since it has a mononucleosis-like illness. In advanced stages of infection fever mostly is the result of a superimposed infections.

African hantavirus (Sangassou virus)

In 2010, the first indigenous African hantavirus, Sangassou virus (SANGV) was isolated from an African wood mouse in a forest in Guinea, West Africa. A retrospective seroepidemiological analysis revealed the presence of Sangassou virus-specific neutralizing antibodies in the sera of patients suffering from fever of unknown origin.

Some important causes

Extrapulmonary tuberculosis is the most frequent cause of FUO. Drug-induced hyperthermia, as sole symptom of an adverse reaction to medication, should always be considered. Disseminated granulomatoses such as Tuberculosis, Histoplasmosis, Coccidioidomycosis, Blastomycosis and Sarcoidosis are associated with FUO. Lymphomas are the most common cause of FUO in adults. Thromboembolic disease (i.e. pulmonary embolism, deep venous thrombosis) occasionally shows fever. Although infrequent, its potentially lethal consequences warrant evaluation of this cause. Endocarditis, although uncommon, is another important etiology to consider. An underestimated reason is factitious fever. Patients frequently are women that work, or have worked, in the medical field and have complex medical histories. Bartonella infections are also known to cause fever of unknown origin.

Diagnosis

A comprehensive and meticulous history (i.e. illness of family members, recent visit to the tropics, medication), repeated physical examination (i.e. skin rash, eschar, lymphadenopathy, heart murmur) and myriad laboratory tests (serological, blood culture, immunological) are the cornerstone of finding the cause.

Other investigations may be needed. Ultrasound may show cholelithiasis, echocardiography may be needed in suspected endocarditis and a CT-scan may show infection or malignancy of internal organs. Another technique is Gallium-67 scanning which seems to visualize chronic infections more effectively. Invasive techniques (biopsy and laparotomy for pathological and bacteriological examination) may be required before a definite diagnosis is possible.

Positron emission tomography using radioactively labelled fluorodeoxyglucose (FDG) has been reported to have a sensitivity of 84% and a specificity of 86% for localizing the source of fever of unknown origin.

Despite all this, diagnosis may only be suggested by the therapy chosen. When a patient recovers after discontinuing medication it likely was drug fever, when antibiotics or antimycotics work it probably was infection. Empirical therapeutic trials should be used in those patients in which other techniques have failed.

Therapy

Unless the patient is acutely ill, no therapy should be started before the cause has been found. This is because non-specific therapy is rarely effective and mostly delays diagnosis. An exception is made for neutropenic patients in which delay could lead to serious complications. After blood cultures are taken this condition is aggressively treated with broad-spectrum antibiotics. Antibiotics are adjusted according to the results of the cultures taken.

HIV-infected persons with pyrexia and hypoxia will be started on medication for possible Pneumocystis jirovecii infection. Therapy is adjusted after a diagnosis is made.

Prognosis

Since there is a wide range of conditions associated with FUO, prognosis depends on the particular cause. If after 6 to 12 months no diagnosis is found, the chances diminish of ever finding a specific cause. However, under those circumstances prognosis is good.

References