Excerpt from Fever of Unknown Origin

Synonyms, Key Words, and Related Terms: fever of unknown origin, FUO, febris, pyrexia, high temperature, feverish, bacteremia, bacterial disease, tuberculosis, urinary tract infection, UTI, endocarditis, hepatobiliary infection, osteomyelitis, Borrelia recurrentis, B recurrentis, Spirillum minor, S minor, Borrelia burgdorferi, B burgdorferi, Treponema pallidum, T pallidum, Rickettsia, Coxiella burnetii, C burnetii, chronic Q fever, Q fever endocarditis, rickettsial disease, Lyme disease, syphilis, rat-bite fever, ratbite fever, rat bite fever, herpes, herpes virus, acquired immunodeficiency syndrome, AIDS, human immunodeficiency virus, HIV, collagen vascular disease, autoimmune disease, granulomatous disease, drug fever, relapsing fever, hyperthyroidism, subacute thyroiditis, factitious fever

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Background

In 1961, Petersdorf and Beeson defined a fever of unknown origin (FUO) 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. This article provides a review of the etiologies of FUO and a rational approach to investigating a patient with this interesting condition.

Pathophysiology

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 between 5-15% of FUO cases defy diagnosis, despite exhaustive studies.

Variation in the disease, as found in the literature, reflects the populations and period studied. In children, infections are the most frequent cause of FUOs, whereas neoplasms and connective-tissue disorders are more frequent in the elderly. In patients with FUOs lasting more than 1 year, infections and neoplasms decline in frequency, and granulomatous diseases become the most frequent etiology.

Diagnostic advances continuously modify the spectrum of FUO-causing diseases; for example, serologic tests have reduced the importance of HIV and numerous rheumatic diseases (eg, systemic lupus erythematosus [SLE], juvenile rheumatoid arthritis [JRA], rheumatoid arthritis [RA]) as causes of FUO. Modern imaging techniques (eg, ultrasound, CT scan, MRI) enable early detection of abscesses and solid tumors that used to be extremely difficult to diagnose.

Patients with undiagnosed FUOs (5-15%) 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 an intensive and rational diagnostic evaluation usually results in the identification of the most serious diseases that initially manifest as FUOs.

Age

In patients older than 50 years, more than 30% of FUO cases are related to connective-tissue disorders and vasculitic disorders. Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are the 2 principal connective-tissue etiologies, and they account for 50% of the cases.

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