Fever of unknown origin

Fever of unknown origin (FUO) is traditionally defined as fever higher than 38.3^oC 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, while others 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 investigating and managing adult patients who present with an acute febrile illness with no localising symptoms, which is a more common disease manifestation in the emergency department (ED).

Causes

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 workup.¹ 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 elderly.²

Epidemiological factors affect underlying causes. In the developed world, acute undifferentiated febrile illness is often due to self-limited viral conditions.⁴

Some common causes are listed below.

Infectious causes

• Abdominal or pelvic abscesses
• Cytomegalovirus infection
• Dental abscess
• Epstein-Barr virus infection
• HIV
• Infective endocarditis
• Malaria
• Osteomyelitis
• Pericarditis
• Prostatitis
• Sinusitis
• Typhoid or enteric fevers
• Wound infections

Non-infectious causes

• Neoplasm
• Connective tissue disorder
• Other

Assessment principles

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. See Flow chart on the assessment of FUO (PDF 216.1 KB).

History

Examination

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
• Testicular examination
• Palpate for lymphadenopathy
• Focal neurologic signs
• Musculoskeletal: bony tenderness, joint effusion.

Investigations

In the initial evaluation of patients with undifferentiated fever in the ED, the following investigations should be performed:

• Full blood count with differential
• Serum biochemistry (electrolytes, urea and creatinine, liver function tests)
• Erythrocyte sedimentation rate
• Urine and blood cultures
• Chest x-ray

Others to consider:

• HIV antibody
• Cytomegalovirus
• Immunoglobulin
• Q fever serology
• Hepatitis serology

Additional tests, including 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. In a Western Australian study on emergency department patients diagnosed with FUO, an organism was isolated in 12.6% of cases where blood cultures had been performed.⁴

Management

Disposition

The decision to admit or discharge a patient with acute FUO from ED can be difficult. Septic patients and those with significant risk factors (e.g. immunocompromised, elderly) warrant admission. Admission should be considered for intravenous drug users in most circumstances.

In a study of patients with FUO at an ED, characteristics and outcomes for admitted and discharged patients were compared. The study 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 illness.⁵

Antibiotic therapy

Empirical antibiotics are warranted only for individuals who are clinically unstable or neutropenic. In stable patients, empirical treatment is discouraged.

Prognosis

Many patients will remain undiagnosed (if discharged or admitted), but the majority will recover, even without specific diagnosis.

Resources

• Diagnosing HIV seroconversion factsheet for clinicians
  Source: NSW Health

References

1. Domino FJ. 5 Minute Clinical Consult Standard 2015, 23^rd ed. Philadelphia: Lippincott Williams & Wilkins; 2014.
2. Mourad O, Palda V, Detsky AS. A comprehensive evidence-based approach to fever of unknown origin. Arch Intern Med. 2003 Mar 10;163(5):545-51. DOI: 10.1001/archinte.163.5.545.
3. Thangarasu S, Natarajan P, Rajavelu P, et al. A protocol for the emergency department management of acute undifferentiated febrile illness in India. Int J Emerg Med. 2011 Sep 5;4:57. DOI: 10.1186/1865-1380-4-57.
4. Ingarfield SL, Celenza A, Jacobs IG, et al. Outcomes in patients with an emergency department diagnosis of fever of unknown origin. Emerg Med Australas. 2007 Apr;19(2):105-12. DOI: 10.1111/j.1742-6723.2007.00915.x
5. Gur H, Aviram R, Or J, et al. Unexplained fever in the ED: analysis of 139 patients. Am J Emerg Med. 2003;21(3):230-5. DOI: 10.1016/S0735-6757(03)00038-X