From prolonged febrile illness to fever of unknown origin: the challenge continues

Arch Intern Med. 2003 May 12;163(9):1033-41. doi: 10.1001/archinte.163.9.1033.


Background: Epidemiological changes and the ongoing expansion of the diagnostic armamentarium warrant a regular update of the spectrum of diseases that present as prolonged febrile illnesses.

Methods: We prospectively collected a series of 290 immunocompetent patients referred to our university hospital between 1990 and 1999 with a febrile illness (temperature >38.3 degrees C) of uncertain cause, lasting at least 3 weeks. Patients were categorized in 4 groups according to the timing of diagnosis: early diagnosis (within 3 in-hospital days or 3 outpatient visits), intermediate diagnosis (between days 4 and 7), late diagnosis (after day 7), and no diagnosis during index contact or follow-up.

Results: A final diagnosis was established early in 67 patients (23.1%), intermediate in 38 (13.1%), and late in 87 (30.0%). In the remaining 98 (33.8%), no diagnosis was made. The cause of the fever remained obscure in 50 (47.6%) of 105 patients with episodic fever vs 48 (25.9%) of 185 patients with continuous fever (P<.001). Among the 192 patients with a final diagnosis, noninfectious inflammatory diseases represented the most prevalent diagnostic category (35.4%), surpassing infections (29.7%), miscellaneous causes (19.8%), and malignancies (15.1%). Fourteen disorders accounted for over 59% of diagnoses, whether diagnosis was reached early, intermediate, or late. Hematological malignancies made up 11.5% of diagnoses, but were responsible for 14 (58.3%) of the 24 fatalities related to the febrile illness. Of the 80 patients discharged alive without diagnosis and for whom follow-up was available, 3 died, but the deaths were considered to be unrelated to the feverish illness.

Conclusions: Prolonged febrile illnesses remain a diagnostic challenge. Despite the technological progress of the late 20th century, the origin of the fever remains elusive in many patients, especially in those with episodic fevers. Noninfectious inflammatory diseases emerge as the most prevalent diagnostic category.

Publication types

  • Comparative Study

MeSH terms

  • Adult
  • Aged
  • Diagnosis, Differential*
  • Diagnosis-Related Groups / statistics & numerical data
  • Diagnostic Techniques and Procedures
  • Female
  • Fever of Unknown Origin / epidemiology
  • Fever of Unknown Origin / etiology*
  • Hospitalization / statistics & numerical data
  • Hospitals, University / statistics & numerical data
  • Humans
  • Inflammation / complications
  • Inflammation / diagnosis
  • Male
  • Middle Aged
  • Netherlands / epidemiology
  • Prospective Studies
  • Time Factors