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Chapter 20: Fever of Unknown Origin

Authors: Chantal P. Bleeker-Rovers; Catharina M. Mulders-Manders; Jos W. M. van der Meer

Introduction

  • Fever of Unknown Origin (FUO):
  • Definition:
    1. Fever ≥38.3°C (≥101°F) on at least two occasions.
    2. Illness duration of ≥3 weeks.
    3. No known immunocompromised state.
    4. Diagnosis remains uncertain after:
    5. Thorough history and physical examination.
    6. Obligatory investigations:
      • ESR, CRP levels.
      • Complete blood count with differential.
      • Basic metabolic panel.
      • Liver enzymes.
      • Ferritin, antinuclear antibodies, rheumatoid factor.
      • Protein electrophoresis.
      • Urinalysis and cultures.
      • Chest X-ray.
      • Abdominal ultrasonography.
      • Tuberculin skin test (TST) or interferon-γ release assay (IGRA).
  • Inflammation of Unknown Origin (IUO):
    • Similar to FUO but without elevated body temperature.
    • Presence of elevated inflammatory markers for at least 3 weeks.

Etiology and Epidemiology

  • Causes of FUO have evolved due to:
  • Changes in disease spectrum.
  • Widespread antibiotic use.
  • Advanced diagnostic techniques.
  • Common causes in Western countries:
  • Noninfectious Inflammatory Diseases (NIIDs):
    • Autoimmune, autoinflammatory, granulomatous diseases, vasculitides.
  • Infections:
    • Less common than in the past due to early detection.
  • Common causes in non-Western countries:
  • Infections:
    • Up to 50% caused by Mycobacterium tuberculosis.
  • Neoplasms:
  • Malignancies, especially lymphomas, can cause FUO.
  • Undiagnosed cases:
  • More than one-third remain undiagnosed.
  • Many patients without a diagnosis have a favorable prognosis.

Differential Diagnosis

  • Infections:
  • Atypical presentations of common infections (e.g., endocarditis, tuberculosis).
  • Rare infections like Q fever (Coxiella burnetii), Whipple's disease (Tropheryma whipplei).
  • Travel-related diseases: malaria, leishmaniasis, histoplasmosis, coccidioidomycosis.
  • Noninfectious Inflammatory Diseases (NIIDs):
  • Adult-onset Still's disease.
  • Large-vessel vasculitis (e.g., giant cell arteritis).
  • Polymyalgia rheumatica.
  • Systemic lupus erythematosus (SLE).
  • Sarcoidosis.
  • Autoinflammatory syndromes (e.g., familial Mediterranean fever).
  • Neoplasms:
  • Malignant lymphoma is the most common neoplasm causing FUO.
  • Miscellaneous Causes:
  • Drug-induced fever:
    • Common culprits: antibiotics (sulfonamides, beta-lactams), anticonvulsants, allopurinol.
    • Often accompanied by eosinophilia and lymphadenopathy.
  • Factitious fever:
    • Self-induced fever, more common in health-care workers.
    • Clues: Discrepancies in temperature measurements, lack of expected physiological responses.
  • Exercise-induced hyperthermia:
    • Associated with strenuous exercise, lacks elevated inflammatory markers.

Approach to the Patient with FUO

First-Stage Diagnostic Tests

  • Goal: Identify Potentially Diagnostic Clues (PDCs).
  • History and Physical Examination:
  • Detailed medical history, including travel, exposures, medications.
  • Thorough physical examination, repeated as necessary.
  • Obligatory Investigations:
  • Laboratory tests: ESR, CRP, CBC with differential, liver and kidney function tests.
  • Cultures: Blood (three sets), urine.
  • Imaging: Chest X-ray, abdominal ultrasound.
  • TST or IGRA for tuberculosis.
  • Important Considerations:
  • Discontinue antibiotics and glucocorticoids to avoid masking symptoms.
  • Avoid unnecessary broad testing without PDCs.
  • Reassess and repeat examinations to identify new PDCs.

Imaging Studies

  • 18F-FDG PET/CT Scan:
  • Useful in detecting inflammatory, infectious, and neoplastic processes.
  • Helps localize areas for targeted biopsy.
  • Limitations:
    • Non-specific uptake in areas like the brain, heart, kidneys.
    • False positives due to physiological uptake.
  • Conventional Scintigraphy:
  • Alternatives when PET/CT is not available.
  • Lower sensitivity and specificity.

Later-Stage Diagnostic Tests

  • Targeted Biopsies:
  • Based on abnormalities found in imaging studies.
  • Lymph node biopsy for unexplained lymphadenopathy.
  • Temporal artery biopsy in suspected giant cell arteritis.
  • Additional Imaging:
  • Chest and abdominal CT scans.
  • Bone marrow biopsy (limited utility without PDCs).
  • Re-evaluation:
  • Repeat history-taking and physical examination.
  • Consider second opinion in expert centers.

Recurrent Fever

  • Approach:
  • Similar initial workup as FUO.
  • Focus on known recurrent fever syndromes.
  • Perform diagnostic tests during febrile episodes.

Treatment of FUO

  • Avoid Empirical Therapy:
  • Empirical antibiotics or antituberculous therapy can hinder diagnosis.
  • Exceptions:
    • Hemodynamic instability.
    • Neutropenia.
  • Symptomatic Treatment:
  • NSAIDs: May be helpful in conditions like adult-onset Still's disease.
  • Glucocorticoids:
    • Effective in giant cell arteritis and polymyalgia rheumatica.
    • Use cautiously to avoid masking other diagnoses.
  • Interleukin-1 Inhibitors:
  • Anakinra:
    • Used in autoinflammatory syndromes.
    • Can be considered in undiagnosed cases after extensive evaluation.

Prognosis

  • Undiagnosed FUO:
  • Generally favorable prognosis.
  • Low mortality rates reported in studies.
  • Outcome Depends on Underlying Cause:
  • Early diagnosis and treatment improve outcomes in treatable conditions.

Note: This guide is structured to facilitate quick revision, highlighting key points and terminology related to Fever of Unknown Origin as discussed in the chapter.