18. Fever of Unknown Origin (FUO)

Overview

A true fever of unknown origin is uncommon. FUO is defined as (1) temperature ≥ 38.3°C on several occasions (2) over at least three weeks of illness and (3) uncertain diagnosis after > 1 week of study in the hospital.

Differential Diagnosis

Traditionally divided into classic FUO, nosocomial, and immunodeficient (HIV-related, neutropenic, solid organ transplant).

  • Classic FUO
    • Infectious: accounts for about 1/3 of the diagnoses of FUO. Causes include: intra-abdominal or other abscesses (pelvic, dental), culture-negative endocarditis, TB, Lyme disease and other tick-borne illnesses, C. difficile, prostatitis, and mononucleosis syndromes (acute EBV, CMV, and HIV).
    • Autoimmune: accounts for about an additional 1/3 of diagnoses. Common culprits are Still’s disease, seronegative spondyloarthropathies, granulomatous hepatitis, SLE, cryoglobulinemia, polyarteritis nodosa and granulomatosis with polyangiitis. Giant cell arteritis and polymyalgia rheumatica rarely occur in those younger than 50 years old.
    • Malignancy: accounts for about 20% of FUO, especially Hodgkin’s or non-Hodgkins lymphoma, leukemia, sarcoma, metastatic disease, MDS, pancreatic, colon and renal cell carcinoma.
    • Other: includes diverse causes including drug reaction, DVT, alcoholic hepatitis, alcoholic withdrawal, toxic ingestion, and very rarely central fever or factitious fever.
    • Undiagnosed: up to 20% of patients with FUO will not have a confirmed diagnosis and will improve.
  • Nosocomial: for FUO developed in the hospital, also consider line infection, recurrent/untreated DVT/pulmonary embolus, transfusion-related viral infection +/- transfusion reactions, C. difficile, infected decubitus ulcer, sinusitis, and drug fever.
  • Immunodeficient: 
    • HIV-related: consider atypical/opportunistic infections (MAC, TB, PCP, cryptococcemia, disseminated histoplasmosis, and CMV), lymphoma/Kaposi’s, catheter infections, sinusitis, dental, groin and perianal abscesses. Patients with HIV are more prone to drug reactions and some HIV drugs can also cause fever: TMP-SMX, abacavir, nevirapine, and dapsone are common offenders.
    • Neutropenic: similar to HIV, although aspergillosis (and other molds), candidiasis, and herpes viruses are also frequently culpable.
    • Solid organ transplants: organ rejection, CMV disease, fungal infections, donor-derived infections, and postoperative wound infections.

Evaluation

Unfortunately, there is no perfect algorithm for the work-up of FUO. There is a “minimal evaluation” which is appropriate for most patients who meet the definition of a classic FUO.

  • Start with a detailed history (including travel history, food/water/animal exposures, blood product transfusions, medications [OTC and Rx], toxin exposures, localizing symptoms, and sick contacts) and careful physical examination (don’t forget to examine mouth, evaluate the genitals and peri-rectum, and percuss sinuses).
  • Appropriate minimal evaluation may include:
    • CBC with differential and smear, blood chemistries (including LDH, CK, ESR, CRP), urinalysis with micro, blood and urine cultures (ideally when off antibiotics), chest radiograph, HIV test.
    • Other blood tests: consider ANA, RF, ferritin; consider CMV and monospot testing.
    • Tuberculin skin testing vs IGRA.
    • Consider CT chest and CTAP.
  • In the setting of FUO, strongly pursue any abnormal clinical findings – i.e. “go where the money is” and have a lower threshold for TTE for murmurs, skin biopsy for rashes, etc.
  • Reconcile medications and discontinue those deemed high risk to cause fevers.
  • Consider CT scan of the abdomen and pelvis early to rule out occult intra-abdominal abscess or malignancy.
  • Bone marrow biopsy tends to be low-yield in FUO except in HIV patients, in whom mycobacterial and fungal infiltration of marrow is a more common cause of FUO. Can also consider in the setting of FUO with cytopenias.
  • TEE and serology for organisms causing culture-negative endocarditis should be considered in select patients with traditional risk factors (homelessness for Bartonella; farm animal exposure for Q fever or Brucella).
  • Radionuclide studies (e.g., tagged WBC scan) can be frustrating in a patient without localizing symptoms, yielding high rate of false-positive and false-negative results. PET-CT is now the nuclear imaging modality of choice as it appears to be more sensitive than tagged WBC scan for making a diagnosis in FUO (although specificity appears to be lower) and can be useful in diagnosing malignancy as well as infection. 

Management

  • Resist temptation to start antibiotics in stable patients unless there is clinical deterioration.
  • Low threshold to consult ID, rheumatology, and hematology/oncology if preliminary workup unrevealing.

Key Points

  • Most common infectious diagnoses in FUO are TB and abscesses. Remember that malignancy and connective tissue disease will constitute the majority of cases. 
  • Hold off on empiric therapy with antibiotics in clinically stable patients as this may only confound your management.
  • Most common rheumatologic diagnoses are Still’s disease, giant cell arteritis/PMR, and vasculitis.
  • Most common malignancies are lymphomas.
  • Don’t forget about drug fevers: many of the medications we give in the hospital can cause fever.
  • Up to 20% of cases may not receive a specific diagnosis, in which case there is generally a good prognosis.

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Armstrong WS, Katz JT, Kazanjian PH.  Human immunodeficiency virus-associated fever of unknown origin: a study of 70 patients in the United States and review.  Clin Infect Dis 1999;28:341-345.

Arnow PM, Flaherty JP.  Fever of unknown origin. Lancet 1997;350:575-580.

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Vanderschueren S, Knockaert D, Adriaenssens T, et al. From prolonged febrile illness to fever of unknown origin. Arch Intern Med 2003;163:1033-1041.

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(1):26‐38. doi:10.1097/MD.0b013e31802fe858

Keywords: Fever of unknown origin, HIV, neutropenia, nosocomial, connective tissue disease, malignancy, immunocompromised