Prior to any additional investigation, manipulation of the thermometer needs to be excluded. 3,5, 19–21 Lower incidences of specific infections, such as tuberculosis and brucellosis, and differences in availability of modern imaging techniques, such as CT, MRI and FDG-PET/CT, may among others cause these differences. 15–18 In several recent studies no cause could be found in a large proportion of patients (Table (Table1 1). In developing countries, infections are the major cause of FUO 7–14, whereas in developed countries NIID account for most cases. 3, 6 Overall, uncommon presentations of common diseases account for most cases. These causes can be subdivided in four categories: infections, malignancies, non-infectious inflammatory diseases (NIID, this group includes autoimmune and rheumatic diseases, vasculitis syndromes and granulomatous disorders) and miscellaneous causes.

Over 200 causes of FUO have been described in the literature. 3–5 The current definition of FUO is:ĭiagnosis uncertain despite thorough history-taking, physical examination and the following investigations: erythrocyte sedimentation rate or C-reactive protein, haemoglobin, platelet count, leukocyte count and differentiation, electrolytes, creatinine, total protein, protein electrophoresis, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, creatine kinase, antinuclear antibodies, rheumatoid factor, microscopic urinalysis, ferritin, three blood cultures, urine culture, chest X-ray, abdominal ultrasonography and tuberculin skin test. Instead of using arbitrary quantitative time criteria, a quantitative criterion of obligatory investigations was implemented in the definition. 2 However, as investigations in three outpatient visits and three inpatient days cannot be compared, different causes of FUO will be found in admitted patients. To reflect the increasing outpatient-based healthcare it was suggested to shorten the duration of investigation to three inpatient days or three outpatient visits. Immunocompromised patients are now excluded, 2 as these patients have other etiologies of FUO and need a different therapeutic approach. 1 In the following years this definition was modified.

Fever of unknown origin (FUO) was first defined by Petersdorf and Beeson in 1961, who defined FUO as body temperature above 38.3☌ (101☏) on three or more occasions and a duration of illness of at least three weeks, in which no diagnosis was made after one week of hospital admission.

Unknown origins