Fever of Unknown Origin
This clinical guideline is intended for use with adult patients. For information regarding assessment of fever in the paediatric patient populations, please click here.
Fever of unknown origin (FUO) is traditionally defined as fever higher than 38.3oC on several occasions for at least three weeks with uncertain diagnosis after one week of evaluation. In some definitions, this strictly applies to one week of in-hospital evaluation, whilst others have broadened to allow for outpatient evaluation. It is widely accepted that FUO is most commonly an atypical presentation of a common condition rather than an unusual disease.
Many studies have focused on FUO, but less is known about how to investigate and manage the adult patient who presents with an acute febrile illness with no localising symptoms, which is a much more common disease manifestation in the ED.
The three most common causes of FUO are infection, neoplasia, and connective tissue disease. Further, in up to 20% of cases, cause of fever will not be identified despite thorough workup1. The most common infectious causes documented in the literature are tuberculosis and intra-abdominal abscesses. The most common malignancies are Hodgkin disease and non-Hodgkin lymphoma. Temporal arteritis accounts for 16-17% of all causes of FUO in the elderly2.
Epidemiological factors affect underlying causes. In the developed world, acute undifferentiated febrile illness is often due to self-limited viral conditions3. Different causes have been found to be more common in certain age groups; in a Western Australian study of patients admitted or discharged from ED, most E.coli- positive blood cultures were in patients aged at least 55 years4.
Click here to view a table summarising the most common causes of fever of unknown origin.
Taking a thorough history and physical examination is key to identifying a possible diagnosis. Consider all symptoms as relevant. Continuous repeated assessment may elicit previously overlooked factors. For a flow chart on the assessment of FUO click here.
Past medical history
Known malignancy (recent chemotherapy, recent neutrophil count)
Previously treated diseases such as endocarditis, tuberculosis, rheumatic fever
Comorbid conditions (eg. diabetes)
Past surgical history
Type and date of surgery performed
Any indwelling foreign material
Full list of medications
Include over-the-counter and herbal remedies
Recent travel history
Sexual history including enquiring about sexual practices
Recreational drug use
Hobbies including exposure to pets/animals
Employment history including exposures
Unusual dietary habits eg. consumption of unpasteurised dairy products or rare meats
Full physical examination of all systems is important. Focus should be on areas of high diagnostic yield:
Skin and nail bed exam for clubbing, nodules, lesions, rashes
Temporal artery palpation
Gums and oral cavity
Auscultation for bruits and murmurs
Abdominal palpation for hepatosplenomegaly
Rectal examination for abscesses
Palpate for lymphadenopathy
Focal neurologic signs
Musculoskeletal: bony tenderness, joint effusion
In the initial evaluation of patients with undifferentiated fever in the ED, the following investigations should be performed:
FBC with differential
Serum biochemistry (EUC, LFTs)
Urine and blood cultures
Others to consider: HIV antibody, CMV IgM, Q fever serology, Hepatitis serology
Subsequent laboratory studies, including additional cultures obtained from affected areas, should be guided by any abnormal laboratory or clinical findings. If a rash or palpable lymph node is found, a directed biopsy should be done before beginning more advanced or costly investigations.
Although FUO is diagnosed infrequently in the ED, blood cultures remain useful in the evaluation of unexplained fever, particularly in adults as age increases. An organism was isolated from 12.6% presentations that had blood cultured in a Western Australian study of given an ED diagnosis of FUO4.
The decision to admit or discharge a patient with acute undifferentiated febrile illness from ED is a difficult one. Septic patients and those with significant risk factors (eg. immunocompromised, elderly) warrant admission. Intravenous drug users are a specific patient population for which admission should be considered in most circumstances.
In an observational study that examined patients with unexplained fever presenting to an ED, characteristics and outcomes for admitted and discharged patients were compared. It was found that admitted patients were older, had more comorbidities, higher leukocyte count, and anaemia, but not a higher degree of fever. It has been a consistent finding that height of fever is not associated with severity of illness5.
Empirical antibiotics are warranted only for individuals who are clinically unstable or neutropenic. In stable patients empirical treatment is discouraged.
Many patients will remain undiagnosed (if discharged or admitted), but the majority will recover, even without specific diagnosis.
Further References and Resources
1. Domino F.J. 5 Minute Clinical Consult Standard 2015, 23rd edition.
2. Mourad O., Palda V., Detsky A.S. A Comprehensive Evidence-Based Approach to Fever of Unknown Origin. Archives of Internal Medicine, 2003. 163: pp. 545-551.
3. Thangarasu S. et al. A protocol for the emergency department management of acute undifferentiated febrile illness in India. International Journal of Emergency Medicine, 2011. 4: 57.
4. Ingarfield S.L., Celenza A., Jacobs I.G., Riley T.V., Outcomes in patients with an emergency department diagnosis of fever of unknown origin. Emergency Medicine Australasia, 2007. 19 (2): pp.105-112.
5. Gur H., Aviram R., Or J., Sidi Y., Unexplained fever in the ED. American Journal of Emergency Medicine, 2003. 21(3): pp.230-235.
6. NSW Health - HIV Seroconversion Factsheet