What is the initial step in evaluating a patient with Pyrexia of Unknown Origin (PUO)?

Initial Evaluation of Pyrexia of Unknown Origin (PUO)

The initial step in evaluating a patient with Pyrexia of Unknown Origin (PUO) should be a thorough clinical history and detailed physical examination, followed by basic laboratory testing to guide further diagnostic workup. 1, 2

Definition and Classification of PUO

• PUO 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 3
• PUO is classified into four subcategories: classical, nosocomial, neutropenic, and HIV-related 4
• The etiology includes infectious, inflammatory, malignant, and miscellaneous causes 4, 5

Initial Diagnostic Approach

Step 1: Clinical Assessment

• Focus on travel history, animal exposure, medication use, and occupational risks 2, 5
• Pay special attention to subtle physical findings that may suggest specific diagnoses (rashes, lymphadenopathy, heart murmurs) 2
• Document fever pattern and associated symptoms (night sweats, weight loss, joint pain) 5, 6

Step 2: First-Line Laboratory Testing

• Complete blood count with differential 2
• Comprehensive metabolic panel 2
• Inflammatory markers (C-reactive protein, erythrocyte sedimentation rate) 3, 1
• Blood cultures (multiple sets) 2, 5
• Urinalysis and urine culture 2

Step 3: Basic Imaging

• Chest radiography should be performed if pulmonary symptoms are present or if there is concern for atypical bacterial infection, tuberculosis, or oncologic processes 3
• No imaging tests are considered "usually appropriate" for initial evaluation of PUO in children 3

Second-Line Diagnostic Approach

Advanced Imaging

• If fever persists after initial evaluation (72-96 hours), consider:
  • Thoracic CT scan (should be available within 24 hours of clinical indication) 3
  • CT scan of paranasal sinuses if symptoms of sinusitis are present 3

Advanced Diagnostic Procedures

• If lung infiltrates are detected on CT scan, bronchoalveolar lavage (BAL) should be performed within 24 hours 3
• BAL samples should be processed within 4 hours of collection 3

Role of PET/CT in PUO Evaluation

• FDG-PET/CT is recommended as a valuable second-line imaging modality when initial workup fails to identify the cause 1
• FDG-PET/CT has high sensitivity (84-86%) in identifying the source of fever 3, 1
• The diagnostic yield of FDG-PET/CT is approximately 56% in patients with PUO 3, 1
• FDG-PET/CT should ideally be performed within 3 days of initiation of oral glucocorticoid therapy to prevent suppression of inflammatory activity 3, 1
• A negative FDG-PET/CT can predict favorable prognosis and potentially allow a watchful waiting approach 3

Special Considerations

Neutropenic Patients

• Neutropenic patients require prompt evaluation and empiric antimicrobial therapy 3
• Consider imaging tests to identify sources of infection, including chest radiography, CT of paranasal sinuses, chest CT, and CT of abdomen and pelvis with IV contrast 3

Pediatric Patients

• In children with PUO, imaging tests that may be appropriate include chest radiography, whole body MRI, and FDG-PET/CT 3
• For febrile infants and young children without signs of respiratory infection, medical management without imaging is usually appropriate 3

Common Pitfalls and Caveats

• Avoid premature closure on a diagnosis before adequate evaluation 2, 5
• Do not initiate empiric antimicrobial therapy before obtaining appropriate cultures, as this may mask the underlying cause 3, 2
• Recognize that up to 50% of patients with PUO may have no cause found despite adequate investigations 4
• Avoid excessive or unfocused diagnostic testing; investigations should be guided by clinical findings 2, 5
• Be aware that early use of glucocorticoids may suppress inflammatory activity and lead to false negative results on imaging studies 3, 1