What is the management approach for fever of unknown origin (FUO)?

Management of Fever of Unknown Origin

The management of fever of unknown origin (FUO) requires a systematic diagnostic approach starting with thorough clinical evaluation followed by targeted investigations, with [18F]FDG PET/CT recommended as a valuable second-line imaging modality when initial workup fails to identify the cause. 1, 2

Definition and Classification

• FUO is defined as fever higher than 38.3°C (100.9°F) persisting for at least 3 weeks, with no diagnosis despite 3 outpatient visits or in-patient days 1, 2
• FUO is divided into four subcategories: classical, nosocomial, neutropenic, and HIV-related, with etiology varying according to subcategory and geographical location 1
• Inflammation of unknown origin (IUO), defined as unexplained and prolonged elevation of inflammatory markers without fever, shares similar etiologies 1

Initial Diagnostic Approach

• Begin with detailed history focusing on travel, animal exposures, occupational risks, and medication use 2, 3
• Perform thorough physical examination with special attention to skin, lymph nodes, heart, abdomen, and musculoskeletal system 2, 3
• First-line laboratory testing should include:
  • Complete blood count with differential 1
  • Comprehensive metabolic panel 4, 5
  • Inflammatory markers (C-reactive protein, erythrocyte sedimentation rate) 1, 2
  • Blood cultures (at least 2-3 sets) 6, 5
  • Urinalysis and urine culture 6
  • Chest radiography 1, 2

Advanced Diagnostic Approach

• If fever persists after initial evaluation (72-96 hours), proceed with:
  • Advanced imaging including thoracic CT scan 2
  • Abdominal and pelvic CT with contrast 1, 6
  • Consider ultrasound for evaluation of superficial or large fluid collections and collections within or adjacent to solid organs 1
• [18F]FDG PET/CT is highly recommended when initial workup is non-diagnostic:
  • High sensitivity (84-86%) with diagnostic yield of approximately 56% 1, 2
  • Should ideally be performed within 3 days of initiation of oral glucocorticoid therapy 1
  • Consider myocardial suppression preparation when there is potential cardiac etiology 1

Treatment Approach

• Empiric therapy may be necessary in critically ill patients while awaiting diagnostic results 1
• For suspected bacterial infections without identified source, broad-spectrum antibiotics may be initiated 1
• In cases of suspected tickborne rickettsial diseases, doxycycline should be considered 1
• For suspected autoimmune conditions like Adult-onset Still's disease, NSAIDs, corticosteroids, or immunosuppressive drugs may be indicated 1
• Avoid premature closure on a diagnosis before adequate evaluation 2
• Do not initiate empiric antimicrobial therapy before obtaining appropriate cultures, as this may mask the underlying cause 2

Special Considerations

• Neutropenic patients require prompt evaluation and empiric antimicrobial therapy 2
• In children with FUO, appropriate imaging tests include chest radiography, whole body MRI, and FDG-PET/CT 1, 2
• For febrile infants and young children without signs of respiratory infection, medical management without imaging is usually appropriate 1, 2
• Be aware that early use of glucocorticoids may suppress inflammatory activity and lead to false negative results on imaging studies 1, 2

Common Pitfalls to Avoid

• Premature initiation of empiric therapy before adequate diagnostic workup 2, 7
• Failure to consider non-infectious causes including malignancies, autoimmune conditions, and drug reactions 6, 7
• Overlooking the importance of repeated history and physical examinations, which may reveal new diagnostic clues 5, 3
• Excessive reliance on non-clue-based imaging and specific testing early in the FUO work-up 4
• Failure to recognize that up to 30% of FUO cases may never have a definitive diagnosis established 3