Updated: 12/22/2021

Fever of Unknown Origin

Review Topic
  • Snapshot
    • A 54-year-old man presents to the emergency department due to myalgias and fever. His symptoms began approximately 3 weeks ago, and he underwent an extensive evaluation with his primary care physician. He denies any chest pain, shortness of breath, productive cough, dysuria, foul-smelling urine, or blood in his stools. He endorses feeling fatigued and having an unintentional 20-pound weight loss over the course of 8 months. He drinks alcohol occasionally and denies using illicit drugs. He is in a monogamous relationship with his wife and does not use condoms. Laboratory testing and CT scan of the chest and abdomen is unremarkable. He is admitted to the medicine unit for further evaluation of his fever.
  • Introduction
    • Definition
      • having a temperature of 101.0°F (38.3°C) for > 3 weeks of unclear etiology
  • Epidemiology
    • Incidence
      • as medicine advances, undiagnosed cases of fever of unknown origin will keep declining; however, 5-15% of cases remain undiagnosed
  • Etiology
    • Infectious (e.g., tuberculosis, Q fever, and brucellosis)
    • Malignancy (e.g., lymphoma, renal cell carcinoma, and leukemia)
    • Systemic rheumatic diseases (e.g., rheumatoid arthritis, microscopic polyangiitis, and systemic lupus erythematosus)
    • Miscellaneous (e.g., drug fever, thyroiditis, and Crohn disease)
  • Presentation
    • Symptoms/physical exam
      • fever
      • associated findings that suggest the cause of the fever
        • e.g., a malar rash can be suggestive of systemic lupus erythematosus the cause of fever
  • Studies
    • Making the diagnosis
      • based on an extensive history and physical exam along with diagnostic testing
    • Labs
      • recommended tests include
        • erythrocyte sedimentation rate (ESR)
        • C-reactive protein (CRP)
        • serum lactate dehydrogenase
        • tuberculin skin testing or interferon-gamma release assay
        • HIV immunoassay and viral load in high-risk patients
        • blood cultures
        • rheumatoid factor
        • creatine phosphokinase
        • antinuclear antibodies (ANA)
        • heterophile antibody testing (preferred in young adults and children)
  • Imaging
    • CT scan of the chest and abdomen
      • indication
        • the initial imaging modality in the workup of fever of unknown origin
          • CT scans can identify lymphadenopathy, which can be suggestive for malignancy and infection
  • Prognosis
    • In cases where a diagnosis is not established after an extensive workup, the course is typically benign
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