What is the initial step in evaluating a fever of unknown origin (FUO)?

Initial Evaluation of Fever of Unknown Origin (FUO)

The initial step in evaluating a fever of unknown origin should be a chest radiograph, as this is a best-practice recommendation from the Society of Critical Care Medicine due to pneumonia being the most common cause of fever in critically ill patients. 1

Definition and Initial Approach

FUO is defined as:

• Temperature greater than 38.3°C (100.9°F)
• Persisting for at least 3 weeks
• No diagnosis despite 3 outpatient visits or in-patient days 2

Diagnostic Algorithm

Step 1: Basic Laboratory Tests

• Complete blood count with manual differential
• Acute phase reactants (CRP, ESR)
• Liver function tests
• Blood cultures (at least 2 sets, ideally 60 mL total)
  • Collect from different anatomical sites without time interval between them 1
  • For patients with central venous catheters, collect simultaneous central and peripheral cultures 1

Step 2: Initial Imaging

• Chest radiograph (mandatory first imaging test) 1, 2
  • Rationale: Pneumonia is the most common cause of fever in ICU patients
  • Low-cost, noninvasive, and routinely available

Step 3: Focused Additional Testing Based on Clinical Findings

• If abnormal chest radiograph: Consider thoracic bedside ultrasound to identify pleural effusions and parenchymal pathology 1
• If recent abdominal/thoracic/pelvic surgery: Perform CT in collaboration with surgical service if etiology not identified by initial workup 1
• If abdominal symptoms or abnormal liver function tests: Perform formal bedside diagnostic ultrasound of abdomen 1
• If pyuria and suspected UTI: Replace urinary catheter and obtain cultures from newly placed catheter 1
• If suspected pneumonia or respiratory symptoms: Test for viral pathogens using nucleic acid amplification test panels 1

Special Considerations

For Patients with Persistent Undiagnosed Fever

If initial evaluation is unrevealing:

• Consider 18F-fluorodeoxyglucose positron emission tomography/CT (18F-FDG PET/CT) 1
  • High diagnostic yield in FUO cases (56%)
  • Sensitivity of 84-86%, specificity of 52-63% 1
  • Should be performed within 3 days of initiation of oral glucocorticoid therapy 1

Common Pitfalls to Avoid

1. Automatic order sets: Avoid triggering multiple tests that may be costly, disruptive, and potentially harmful without clinical assessment first 1
2. Routine abdominal imaging: For patients without abdominal symptoms or liver function abnormalities, routine abdominal ultrasound is not recommended 1
3. Empiric antimicrobial therapy: Should be avoided except in neutropenic, immunocompromised, or critically ill patients 3
4. Delayed diagnosis: Up to 75% of FUO cases may resolve spontaneously without reaching a definitive diagnosis 3

Differential Diagnosis Categories

• Infections (pneumonia, catheter-associated infections, tuberculosis, endocarditis)
• Malignancies (lymphomas, leukemias, solid tumors)
• Inflammatory diseases (adult-onset Still's disease, vasculitis, connective tissue diseases)
• Miscellaneous (venous thromboembolism, thyroiditis) 2, 3

The systematic approach outlined above allows for efficient evaluation of FUO while avoiding unnecessary testing, with the chest radiograph serving as the cornerstone of initial assessment due to the high prevalence of pneumonia as a cause of fever in critically ill patients.