Approach to the adult with fever of unknown origin
- David H Bor, MD
David H Bor, MD
- Associate Professor of Medicine
- Harvard Medical School
Clinicians commonly refer to a febrile illness without an initially obvious etiology (sometimes called fever without localizing signs) as fever of unknown origin (FUO). This usage is not accurate. Most febrile illnesses either resolve before a diagnosis can be made or develop distinguishing characteristics that lead to a diagnosis. FUO refers to a prolonged febrile illness without an established etiology despite intensive evaluation and diagnostic testing.
Large case series of FUO applying this definition have been collected over a number of decades; these facilitate an approach to patients with FUO and an understanding of the changing patterns of FUO with time and newer diagnostic techniques.
The definitions and special populations with FUO as well as the diagnostic approach to the adult with this problem are reviewed here. A specific discussion of the common and uncommon entities causing FUO and the approach to children with FUO is presented separately. (See "Etiologies of fever of unknown origin in adults" and "Fever of unknown origin in children: Evaluation".)
The definition of FUO derived by Petersdorf and Beeson in 1961 from a prospective analysis of 100 cases has long been the clinical standard :
●Fever higher than 38.3ºC on several occasions
- PETERSDORF RG, BEESON PB. Fever of unexplained origin: report on 100 cases. Medicine (Baltimore) 1961; 40:1.
- Alt HL, Barker MH. Fever of unknown origin. JAMA 1930; 94:1457.
- Jacoby GA, Swartz MN. Fever of undetermined origin. N Engl J Med 1973; 289:1407.
- de Kleijn EM, Vandenbroucke JP, van der Meer JW. 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; 76:392.
- Knockaert DC, Vanneste LJ, Bobbaers HJ. Fever of unknown origin in elderly patients. J Am Geriatr Soc 1993; 41:1187.
- Miller RF, Hingorami AD, Foley NM. Pyrexia of undetermined origin in patients with human immunodeficiency virus infection and AIDS. Int J STD AIDS 1996; 7:170.
- Vanderschueren S, Knockaert D, Adriaenssens T, et al. From prolonged febrile illness to fever of unknown origin: the challenge continues. Arch Intern Med 2003; 163:1033.
- Zenone T. Fever of unknown origin in adults: evaluation of 144 cases in a non-university hospital. Scand J Infect Dis 2006; 38:632.
- Bleeker-Rovers CP, Vos FJ, de Kleijn EM, et al. A prospective multicenter study on fever of unknown origin: the yield of a structured diagnostic protocol. Medicine (Baltimore) 2007; 86:26.
- Cunha BA, Lortholary O, Cunha CB. Fever of unknown origin: a clinical approach. Am J Med 2015; 128:1138.e1.
- Petersdorf RG. Fever of unknown origin. An old friend revisited. Arch Intern Med 1992; 152:21.
- Durack DT, Street AC. Fever of unknown origin: Re-examined and redefined. In: Current Clinical Topics in Infectious Diseases, Remington JS, Swartz MN (Eds), Blackwell Science, Boston 1991. p.35.
- Konecny P, Davidson RN. Pyrexia of unknown origin in the 1990s: time to redefine. Br J Hosp Med 1996; 56:21.
- Mourad O, Palda V, Detsky AS. A comprehensive evidence-based approach to fever of unknown origin. Arch Intern Med 2003; 163:545.
- Horowitz HW. Fever of unknown origin or fever of too many origins? N Engl J Med 2013; 368:197.
- Naito T, Mizooka M, Mitsumoto F, et al. Diagnostic workup for fever of unknown origin: a multicenter collaborative retrospective study. BMJ Open 2013; 3:e003971.
- Sharma BK, Kumari S, Varma SC, et al. Prolonged undiagnosed fever in northern India. Trop Geogr Med 1992; 44:32.
- Ibidapo MO, Akinyanju OO. Acute sickle cell syndromes in Nigerian adults. Clin Lab Haematol 2000; 22:151.
- Wilson ME. Chapter 5. In: A World Guide to Infections: Diseases, Distribution, Diagnosis, Oxford University Press, New York 1991.
- Pizzo PA, Lovejoy FH Jr, Smith DH. Prolonged fever in children: review of 100 cases. Pediatrics 1975; 55:468.
- Sullivan M, Feinberg J, Bartlett JG. Fever in patients with HIV infection. Infect Dis Clin North Am 1996; 10:149.
- Bissuel F, Leport C, Perronne C, et al. Fever of unknown origin in HIV-infected patients: a critical analysis of a retrospective series of 57 cases. J Intern Med 1994; 236:529.
- Benito N, Núñez A, de Górgolas M, et al. Bone marrow biopsy in the diagnosis of fever of unknown origin in patients with acquired immunodeficiency syndrome. Arch Intern Med 1997; 157:1577.
- Hirschmann JV. Fever of unknown origin in adults. Clin Infect Dis 1997; 24:291.
- Zacharski LR, Kyle RA. Significance of extreme elevation of erythrocyte sedimentation rate. JAMA 1967; 202:264.
- Myklebust G, Gran JT. A prospective study of 287 patients with polymyalgia rheumatica and temporal arteritis: clinical and laboratory manifestations at onset of disease and at the time of diagnosis. Br J Rheumatol 1996; 35:1161.
- Knockaert DC, Mortelmans LA, De Roo MC, Bobbaers HJ. Clinical value of gallium-67 scintigraphy in evaluation of fever of unknown origin. Clin Infect Dis 1994; 18:601.
- Syrjälä MT, Valtonen V, Liewendahl K, Myllylä G. Diagnostic significance of indium-111 granulocyte scintigraphy in febrile patients. J Nucl Med 1987; 28:155.
- Bleeker-Rovers CP, Vos FJ, Mudde AH, et al. A prospective multi-centre study of the value of FDG-PET as part of a structured diagnostic protocol in patients with fever of unknown origin. Eur J Nucl Med Mol Imaging 2007; 34:694.
- Gafter-Gvili A, Raibman S, Grossman A, et al. [18F]FDG-PET/CT for the diagnosis of patients with fever of unknown origin. QJM 2015; 108:289.
- Hot A, Jaisson I, Girard C, et al. Yield of bone marrow examination in diagnosing the source of fever of unknown origin. Arch Intern Med 2009; 169:2018.
- Wang HY, Yang CF, Chiou TJ, et al. A "bone marrow score" for predicting hematological disease in immunocompetent patients with fevers of unknown origin. Medicine (Baltimore) 2014; 93:e243.
- Knockaert DC, Dujardin KS, Bobbaers HJ. Long-term follow-up of patients with undiagnosed fever of unknown origin. Arch Intern Med 1996; 156:618.
- Establishing that a patient has an FUO
- Changes over time
- - Age
- - AIDS
- - Neutropenia
- DIAGNOSTIC APPROACH
- History and physical examination
- Diagnostic testing
- - Test performance
- - Acute-phase reactants
- - CT scanning
- - Nuclear medicine testing
- - Other tests
- - Biopsy
- Therapeutic trials
- Emergent FUO therapy
- No diagnosis
- SUMMARY AND RECOMMENDATIONS