“Fever of Unexplained Origin: Report on 100 Cases”
Medicine (Baltimore). 1961 Feb;40:1-30. [free full text]
In our modern usage, fever of unknown origin (FUO) refers to a persistent unexplained fever despite an adequate medical workup. The most commonly used criteria for this diagnosis stem from the 1961 series by Petersdorf and Beeson.
This study analyzed a prospective cohort of patients evaluated at Yale’s hospital for FUO between 1952 and 1957. Their FUO criteria: 1) illness of more than three week’s duration, 2) fever higher than 101º F on several occasions, 3) diagnosis uncertain after one week of study in hospital. After 126 cases had been noted, retrospective investigation was undertaken to determine the ultimate etiologies of the fevers. The authors winnowed this group to 100 cases based on availability of follow up data and the exclusion of cases that “represented combinations of such common entities as urinary tract infection and thrombophlebitis.”
126 cases were reviewed as noted above, and ultimately 100 were selected for analysis. In 93 cases “a reasonably certain diagnosis was eventually possible.” 6 of the 7 undiagnosed patients ultimately made a full recovery. Underlying etiology (see table 1 on page 3): infectious 36% (including TB in 11%), neoplastic diseases 19%, collagen disease (e.g. SLE) 13%, pulmonary embolism 3%, benign non-specific pericarditis 2%, sarcoidosis 2%, hypersensitivity reaction 4%, cranial arteritis 2%, periodic disease 5%, miscellaneous disease 4%, factitious fever 3%, no diagnosis made 7%.
Clearly, diagnostic modalities have improved markedly since this 1961 study. However, the core etiologies of infection, malignancy, and connective tissue disease / non-infectious inflammatory disease remain most prominent, while the percentage of patients with no ultimate diagnosis has been increasing (for example, see PMIDs 9413425, 12742800, and 17220753). Modifications to the 1961 criteria have been proposed (e.g. 1 week duration of hospital stay not required if certain diagnostic measures have been performed) and implemented in recent FUO trials. One modern definition of FUO: fever ≥ 38.3º C, lasting at least 2-3 weeks, with no identified cause after three days of hospital evaluation or three outpatient visits.
Per UpToDate, the following minimum diagnostic workup is recommended in suspected FUO: blood cultures, ESR or CRP, LDH, HIV, RF, heterophile antibody test, CK, ANA, TB testing, SPEP, CT of abdomen and chest.
1. “Fever of unknown origin (FUO). I A. prospective multicenter study of 167 patients with FUO, using fixed epidemiologic entry criteria. The Netherlands FUO Study Group.” Medicine (Baltimore). 1997 Nov;76(6):392-400.
2. “From prolonged febrile illness to fever of unknown origin: the challenge continues.” Arch Intern Med. 2003 May 12;163(9):1033-41.
3. “A prospective multicenter study on fever of unknown origin: the yield of a structured diagnostic protocol.” Medicine (Baltimore). 2007 Jan;86(1):26-38.
4. UpToDate, “Approach to the Adult with Fever of Unknown Origin”
5. “Robert Petersdorf, 80, Major Force in U.S. Medicine, Dies” The New York Times, 2006
Summary by Duncan F. Moore, MD