Fever of Unknown Origin

Aka: Fever of Unknown Origin, Fever of Undetermined Origin, Prolonged Febrile Illness, Prolonged Fever

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II. Types

  1. Classic Fever of Unknown Origin
    1. Daily or Intermittent Fever >= 38.3 C (101 F)
    2. Duration for 3 consecutive weeks
      1. Qualitative FUO definition does not set an absolute minimum duration
    3. No source by clinical evaluation
      1. Hospital evaluation for 3 days (previously 7) or
      2. Intensive outpatient evaluation for 7 days or
      3. Three outpatient visits
  2. Nosocomial Fever of Unknown Origin
    1. Daily or Intermittent Fever >= 38.3 C (101 F)
    2. Hospitalized >1 day without fever on admission
    3. Fever evaluation of 3 days of more
  3. Immune-Deficient Fever of Unknown Origin
    1. Daily or Intermittent Fever >= 38.3 C (101 F)
    2. Neutrophil Count <500 per mm3
    3. Fever evaluation of 3 days of more
  4. HIV-Associated Fever of Unknown Origin
    1. Daily or Intermittent Fever >= 38.3 C (101 F)
    2. Outpatient fever >4 weeks or
    3. Inpatient fever >3 days

III. Causes

  1. See Fever of Unknown Origin Causes
  2. See Fever of Unknown Origin Causes by Age
  3. See Fever in the Returning Traveler
  4. See Drug-Induced Fever

IV. History

  1. See Fever of Unknown Origin History
  2. See Fever Pattern

V. Exam

  1. See Fever of Unknown Origin Examination

VI. Labs

  1. First Line
    1. Complete Blood Count (CBC) with manual differential
    2. Basic metabolic panel (e.g. Chem8)
    3. Liver Function Tests
    4. Blood Cultures (3 sets)
    5. Urinalysis with Urine Culture
  2. Markers of inflammation or infection
    1. Erythrocyte Sedimentation Rate (ESR)
      1. Very high ESR (e.g. >100 mm/h) suggests significant cause such as abdominal abscess, Osteomyelitis, endocarditis
      2. Consider cancer, renal disease or inflammatory disease if ESR very high but no infectious cause identified
    2. C-Reactive Protein (C-RP)
    3. Procalcitonin
      1. Procalcitonin level > 0.5 mg/dl is associated with severe Bacterial Infections
    4. Lactate Dehydrogenase
      1. Increased in Malaria, Lymphoma and Leukemia among other FUO causes
    5. Serum Ferritin
      1. Serum Ferritin >561 ng/ml may be consistent with noninfectious cause of FUO
      2. Serum Ferritin >1000 ng/ml may be consistent with Adult Still's Disease
    6. Cryoglobulins (second-line test)
      1. Increased in endocarditis, Systemic Lupus Erythematosus, Leukemia, Lymphoma
  3. Common infection Screening Tests
    1. Monospot (consider EBV titer and CMV titer)
    2. Purified Protein Derivative (PPD) or TB Quantiferon (Interferon gamma release assay)
      1. Negative test does not exclude active pulmonary tuberculosiw
    3. HIV Test
    4. Viral Hepatitis A, B and E
  4. Autoimmune labs to consider
    1. Antinuclear Antibody (ANA)
    2. Rheumatoid Factor (RF)
    3. Antineutrophil Cytoplasmic Antibodies (ANCA)
    4. Creatine Kinase
  5. Other tests to consider
    1. Thyroid Stimulating Hormone (TSH)
    2. Peripheral Smear
    3. Serum Protein Electrophoresis (see indications below)
  6. Biopsies to consider
    1. Skin biopsy
      1. Consider when atypical skin lesions accompany fever
    2. Liver biopsy
      1. Consider for evaluation of malignancy or noninfectious inflammatory condition
    3. Lymph Node biopsy
      1. Consider in suspected Lymphoma, infectious disease, Granulomatous disease
    4. Temporal artery biopsy
      1. Consider in suspected Temporal Arteritis (accounts for 15% of FUO over age 55 years)
    5. Bone Marrow Biopsy
      1. Consider in cancer, Tuberculosis and other infection

VII. Imaging

  1. First-line
    1. Chest XRay
    2. Abdominal and pelvic Ultrasound (consider)
      1. Initial screening at low cost and without radiation exposure
  2. Second-line
    1. CT Chest, Abdomen and Pelvis with contrast
      1. Source found in 19% of patients
    2. Nuclear imaging
      1. Full body scan identifies inflammatory or malignant foci
      2. Techetium-Based Scan
      3. 18F Fluorodeoxyglucose PET Scan
      4. Gallium Ga 67 Scan (older)
  3. Other imaging with specific indications
    1. Echocardiogram
      1. Endocarditis
    2. Venous extremity Doppler Ultrasound
      1. Deep Vein Thrombosis
    3. MRI Aortic arch and Great Vessels
      1. Vasculitis evaluation

VIII. Evaluation: Subsequent to consider

  1. Infectious cause suspected
    1. Second line tests
      1. AFB Sputum Cultures
      2. Rapid Plasmin Reagin (RPR)
      3. HIV Test
      4. ASO Titer
    2. Third line tests
      1. Transesophageal Echocardiogram (may start with Transthoracic Echocardiogram)
        1. Evaluate for endocarditis
      2. Lumbar Puncture
      3. Sinus CT
      4. Gallium Ga 67 Scan or 18F Fluorodeoxyglucose PET Scan
  2. Non-Hematologic Malignancy suspected
    1. Second line tests
      1. Mammogram
      2. Chest CT
      3. Upper endoscopy
      4. Lower endocscopy
      5. Gallium Ga 67 Scan or 18F Fluorodeoxyglucose PET Scan
    2. Third line tests
      1. Brain MRI
      2. Enlarged Lymph Node biopsy
      3. Skin lesion biopsy
      4. Liver biopsy
      5. Exploratory laparoscopy
  3. Hematologic Malignancy suspected
    1. Peripheral Smear
    2. Serum Protein Electrophoresis
    3. Consider Bone Marrow Biopsy
  4. Autoimmune Condition suspected
    1. Rheumatoid Factor
    2. Antinuclear Antibody
    3. Antineutrophil Cytoplasmic Antibodies (ANCA)
    4. Creatine Kinase
    5. Consider temporal artery biopsy
    6. Consider Lymph Node biopsy

IX. Differential Diagnosis: Occult Bacteremia

  1. Consider hospitalization if fever >2 weeks
  2. Risk factors
    1. Age over 50 years
    2. Diabetes Mellitus
    3. Complete Blood Count: Leukocytosis and Left Shift
    4. Erythrocyte Sedimentation Rate >30
    5. Toxic appearance
    6. Immunocompromised patients
    7. Valvular heart disease
    8. Intravenous Drug Abuse
  3. References
    1. Mellors (1987) Arch Intern Med 147:666 [PubMed]

X. Management

  1. Consider hospitalization (especially for signs of Critical Illness)
  2. Follow specific protocols that apply (e.g. Neutropenic Fever)

XI. Prognosis

  1. The majority of patients recover from FUO or follow a benign course
    1. Spontaneous resolution in 70%
  2. However, 12-35% of patients die from the cause of FUO

XII. References

  1. Claudius in Majoewsky (2012) EM: Rap 12(11): 9
  2. Libman in Noble (2001) Primary Care Medicine, p. 194
  3. Mackowiak in Mandell (2000) Infectious Disease, p. 622
  4. Cunya (1996) Infect Dis Clin North Am 10:111-27 [PubMed]
  5. David (2022) Am Fam Physician 105(2): 137-43 [PubMed]
  6. Hersch (2014) Am Fam Physician 90(2): 91-6 [PubMed]
  7. Mourad (2003) Arch Intern Med 163:545-51 [PubMed]
  8. Roth (2003) Am Fam Physician 68:2223-8 [PubMed]

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