fever of unknown origin (FUO)

Introduction

• fever of > 38.3 C (101 F) measured on several occasions with a duration of > 2-3 weeks without a diagnosis
• also requires 2 outpatient visits or 3 days of hospitalization

Etiology

• 180 different diseases have been documented as a cause of FUO (also see causes of fever of unknown origin)
• most cases are unusual manifestations of common diseases
• infection, connective tissue disease & malignancies account for the majority of cases
• infection
  • intra-abdominal abscess, pelvic abscess
  • tuberculosis (especially extrapulmonary TB)
  • endocarditis
    • especially HACEK group, Bartonella, Legionella, Coxiella burnetii, Chlamydia psittaci & fungi
    • hold blood cultures for 2 weeks
  • ascending cholangitis
  • viral infection
    • HIV1 infection
    • infectious mononucleosis (EBV) most common viral cause in childeren
    • cytomegalovirus infection
  • endemic mysosis
  • C difficile colitis
  • chronic sinusitis
  • complicated urinary tract infection
• malignancy
  • lymphoma
  • leukemia
  • renal cell carcinoma
  • hepatocellular carcinoma
• connective tissue disease
  • polymyalgia rheumatica
  • giant cell arteritis
  • rheumatoid arthritis
    • adult onset Still's disease
  • systemic lupus erythematosus
  • vasculitis
    • polyarteritis nodosa
• granulomatous diseases
  • sarcoidosis
  • granulomatous hepatitis
  • inflammatory bowel disease
  • Wegener's granulomatosis
• endocrine disease
  • hyperthyroidism
  • subacute thyroiditis
• hereditary periodic fever syndrome
  • fever-free intervals of at least 14 days
  • hyperimmunoglobilin D syndrome
  • familial hibernian fever
  • Muckle-Wells syndrome
  • familial Mediterranean fever
• other
  • septic thrombophlebitis
  • deep vein thrombosis or pulmonary embolus
  • chronic sinusitis
  • drug fever
• factitious (patient may not have fever)
• observations
  • in 10% of cases, no source of fever is found
  • 30-50% of patients may not receive a specific diagnosis
  • the longer a fever persists without a diagnosis, the less likely an infectious or malignant origin

History

• documented fever
• travel history
• exposure
  • occupation
  • exposure to animals
  • drugs (days-weeks after initiation of new drug)
  • transfusions
  • surgery
  • tuberculosis
• sexual history
• genetic background

Clinical manifestations

• lymphadenopathy
• cardiac murmur
• skin lesions
  • skin rash
  • Janeway lesions, Osler's nodes, subconjunctival petechiae may portend serious underlying illnees
• hepatomegaly
• splenomegaly
• uveitis
• retinal lesions
• repeated examinations may reveal new &/or changing signs & symptoms

Laboratory

• complete blood count (CBC)
• repeated blood cultures (>= 3 sets)
• urinalysis & urine culture
• liver function tests
• serum TSH
• antinuclear antibody (ANA)
• rheumatoid factor (RF)
• erythrocyte sedimentation rate, serum CRP
• HIV testing
• serum protein electrophoresis
• Epstein-Barr serology
  • monospot for infectious mononucleosis
• cytomegalovirus serology
• serology for syphilis: RPR, VRDL
• tuberculin skin testing (PPD) vs Quantiferon TB testing
• consider ANCA is specific cases

Diagnostic procedures

• echocardiogram
• pulmonary function testing:
  • decreased DLCO suggests restrictive lung disease such as sarcoidosis
• colonoscopy
• biopsy
  • bone marrow biopsy & culture if hematologic abnormalities seen on laboratory testing
    • yields diagnosis in 24% of cases
  • percutaneous liver biopsy
  • biopsy of other tissues directed by clinical picture
    • skin
    • lymph nodes
    • blood vessels
      • temporal artery biopsy
    • kidney
• specialized tests directed by history & clinical findings

Radiology

• chest X-ray
• abdominal & thoracic or total body computed tomography (CT)
  • CT of abdomen & pelvis with & without contrast
  • 18F-FDG PET-CT may contribute to diagnosis in 75% of patients
• abdominal ultrasound
• upper GI series with small bowel follow-through
• barium enema
• gallium scintigraphy (Ga-labeled leukocyte imaging)
  • indium-labeled leukocyte imaging is relatively insensitive in working up FUO

Management

• discontinue non-essential medications
• direct therapy at underlying etiology
  • non-specific therapy should not be instituted until the source of the fever is identified
  • therapeutic trials may be misleading by producing temporary relief
• many patients will recover without therapy
  • patients with idiopathic FUO generally have good prognosis with resolution of fever within several months
  • 96% of patients < 35 years of age & 68% of patients > 65 will eventually become free of fever without therapy
  • after 3 weeks, careful evaluation, & 2 ambulatory visits, no further testing or treatment is indicated
• patients debilitated by symptoms
  • non-steroidal anti-inflammatory agent NSAID
  • steroids may be tried if:
    • patient fails NSAIDs
    • etiology unlikely to be infectious
• antibiotics
  • use of antibiotics is discouraged
  • if endocarditis is suspected & patient is deteriorating, antibiotic therapy may be reasonable, but should be be stopped is cultures are negative
• consider naproxen for paraneoplastic or prostaglandin-mediated fever

More general terms

• fever

Additional terms

• causes of fever of unknown origin