Fever of Unknown Origin: Diagnosis and Treatment

A classic FUO is usually caused by one of the following conditions: Infections, Neoplastic, Collagen vascular diseases, Miscellaneous. The most common causes of nosocomial FUO include pneumonia, urinary tract infection, surgical site infection, catheter-

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The archetypical definition of a fever of unknown origin (FUO) includes: (1) temperature greater than 38.3°C (101°F) on multiple occasions, (2) duration of fever for at least 3 weeks, and (3) uncertain diagnosis after at least 1 week of investigation of pertinent clinical findings.

• The classic definition has undergone revision and is currently subdivided into four categories:

  1. Classic FUO: greater than 3 weeks duration, greater than 2 outpatient visits for evaluation or 3 days of hospitalization.
  2. Nosocomial FUO: hospital-acquired fever and uncertain diagnosis after 3 days of investigation.
  3. Immunodeficient FUO: greater than 3 days duration with an uncertain diagnosis after 48 hours of evaluation in an immunocompromised host.
  4. Human immunodeficiency virus (HIV) associated FUO: greater than 3 weeks duration (as an outpatient) or greater than 3 days duration as an inpatient in a confirmed HIV infected patient.

Classic Fever of Unknown Origin

A classic FUO is usually caused by one of the following conditions:

  • Infections (23%–36%): Tuberculosis, endocarditis, local suppurative process (eg, biliary tract, kidney), septic thrombophlebitis, cytomegalovirus, and Epstein-Barr virus
  • Neoplastic (7%–31%): Lymphoma, leukemia, renal cell carcinoma, and gastrointestinal tumors
  • Collagen vascular diseases (9%–20%): systemic lupus erythematosus, rheumatoid arthritis, mixed connective tissue disease, temporal arteritis
  • Miscellaneous (17%–24%): Drug fever, deep vein thrombosis, pulmonary emboli, sarcoidosis, factitious or fraudulent fever

Nosocomial Fever of Unknown Origin

The most common causes of nosocomial FUO include pneumonia, urinary tract infection, surgical site infection, catheter-related infections, Clostridium difficile colitis, and drugs.

Immunodeficiency- and Human Immunodeficiency Virus-Associated Fever of Unknown Origin

In addition to the causes of classic FUO, consider opportunistic infections caused by Mycobacterium tuberculosis, atypical mycobacteria, Pneumocystis jirovecii, and fungi (Histoplasma capsulatum, Cryptococcus neoformans, and Coccidioides immitis). Malignancies such as Kaposi sarcoma and primary brain lymphoma should also be entertained.

Signs and Symptoms

  • The initial evaluation should include a comprehensive history with emphasis on recent travel, exposure to pets and sick contacts, work environment, family history of fevers (familial Mediterranean fever), and a complete list of medication used by the patient.
  • On examination special attention should be directed toward identification of a rash or other skin lesion.  Fungal infections, HIV, measles, rubella, Epstein-Barr virus, hepatitis B virus, and ehrlichiosis usually present with a maculopapular rash. Herpes simplex virus and varicella-zoster virus present with a vesicular rash, whereas patients with Rickettsiae, yellow fever, viral hemorrhagic fever, and coxsackievirus may develop a petechial rash. A careful funduscopic, otoscopic, genital, and rectal examination should also be performed.
  • Lymphadenopathy may provide a vital clue to the underlying condition. Importantly, affected lymph nodes can be easily biopsied.
  • Nosocomial FUO requires special attention to all intravascular devices, previous surgical procedure sites, evidence of pneumonia, and medications.


• The diagnostic investigation should be guided by the history and physical examination.

• Complete blood count with manual differential, blood smear, erythrocyte sedimentation rate, blood cultures for bacteria, fungi, acid-fast bacilli (AFB), and fungal serologies may point toward the underlying diagnosis.

• Bone marrow aspiration and biopsy should be considered in patients with suspected hematologic or granulomatous diseases.

• Imaging studies such as computed tomography scan, magnetic resonance imaging, and ultrasound may prove useful when evaluating an affected organ system. Although highly sensitive, radiolabeled imaging is not very specific and its role in the evaluation of FUO is yet to be determined.


  • Empiric therapeutic trials pose significant risks and are usually met with limited success. As a general rule, treatment should be withheld whenever possible until the causes can be determined.
  • Hospitalized patients who are neutropenic or septic are an exception because of a high prevalence of serious bacterial infections. These patients should receive empiric broad spectrum antibiotics after obtaining appropriate cultures. B-lactam-aminoglycoside combinations, piperacillin with ciprofloxacin, or a single agent antipseudomonal cephalosporin or carbapenem are among several options available. Vancomycin should be considered for patients with indwelling vascular catheters or those at risk for resistant gram-positive pathogens.
  • With the exception of the fever that accompanies primary HIV infection, a fever that develops in a patient with known HIV is usually the result of an underlying infection.
  • Medications which have been associated with fever include, but is not limited to, atropine, amphotericin B, antihistamines angiotensin-converting enzyme inhibitors, barbiturates, cephalosporins, diuretics, heparin, nonsteroidal antiinflammatory drugs, macrolides, phenytoin, and penicillins.


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