What is the initial workup and treatment for a patient with fever of unknown origin (FUO)?

Initial Workup and Treatment for Fever of Unknown Origin (FUO)

The initial workup for fever of unknown origin should begin with a chest radiograph, blood cultures, and basic laboratory tests, followed by advanced imaging with 18F-FDG PET/CT if the diagnosis remains elusive after standard evaluation. 1, 2

Definition of FUO

FUO is defined as:

• Fever higher than 38.3°C (100.9°F)
• Persisting for at least 3 weeks
• No diagnosis despite 3 outpatient visits or in-patient days 1

FUO is categorized into four subcategories:

• Classical
• Nosocomial
• Neutropenic
• HIV-related 1

Initial Diagnostic Workup

First-line Tests

• Chest radiograph (best-practice statement) 1
• Complete blood count with manual differential
• Acute phase reactants (C-reactive protein, erythrocyte sedimentation rate)
• Liver function tests
• Blood cultures:
  • At least 2 sets (ideally 60 mL total)
  • For patients with central venous catheters: simultaneous central and peripheral cultures to allow calculation of differential time to positivity 1, 2
  • If central venous catheter cultures are indicated, sample at least two lumens 1

Physical Examination Focus Areas

• Adenopathy
• Hepatosplenomegaly
• Skin rashes
• Signs of infection 2

Advanced Diagnostic Testing

If initial evaluation is unrevealing:

Imaging Studies

1. For patients with abnormal chest radiograph:

   • Consider thoracic bedside ultrasound to identify pleural effusions and parenchymal pathology 1, 2

2. For patients with recent thoracic, abdominal, or pelvic surgery:

   • Perform CT in collaboration with surgical service 1

3. For patients with abdominal symptoms or abnormal liver function tests:

   • Perform formal bedside diagnostic ultrasound of abdomen 1, 2

4. For patients without an established etiology after standard workup:

   • Consider 18F-FDG PET/CT if transport risk is acceptable 1
   • High diagnostic yield in FUO cases (56%)
   • Sensitivity: 84-86%, specificity: 52-63% 1
   • Should be performed within 3 days of starting oral glucocorticoid therapy 1, 2

Important Considerations for 18F-FDG PET/CT

• A negative 18F-FDG PET/CT can predict favorable prognosis through spontaneous remission of fever 1
• Cost-effectiveness has been demonstrated, particularly when performed early in the diagnostic workup 1
• Can guide further investigations, biopsy, or specific treatment when the cause is established 1

Cautions and Contraindications

• Avoid routine use of antipyretic medications solely for the purpose of reducing temperature in critically ill patients with fever (weak recommendation, moderate quality evidence) 1
• Avoid routine abdominal imaging for patients without abdominal symptoms or liver function abnormalities 1, 2
• Avoid empiric antibiotics in patients with FUO unless they are neutropenic, immunocompromised, or critically ill 3, 4
• Avoid triggering multiple tests that may be costly and potentially harmful without clinical assessment first 2
• Insufficient evidence for evaluation of patients with FUO and normal inflammatory markers (CRP, ESR) 1

Common Etiologies to Consider

The etiology of FUO includes:

• Infectious causes
• Inflammatory/rheumatologic causes
• Malignant causes
• Miscellaneous causes 1, 3, 4

FUO is more often an atypical presentation of a common disease rather than an unusual disease 3, with up to 75% of cases resolving spontaneously without reaching a definitive diagnosis 4.

By following this systematic approach to the evaluation of FUO, clinicians can efficiently identify the underlying cause and initiate appropriate treatment, improving patient outcomes and reducing unnecessary testing.