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

Initial Inpatient Workup for Fever of Unknown Origin (FUO)

The initial inpatient workup for fever of unknown origin should include chest radiography, comprehensive blood cultures, and laboratory testing, followed by advanced imaging such as [18F]FDG PET/CT if the initial evaluation is unrevealing. 1

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
• FUO is classified into four subcategories: classical, nosocomial, neutropenic, and HIV-related 1
• Etiology includes infectious, inflammatory, malignant, and miscellaneous causes, with distribution varying by subcategory and geographical location 1

Initial Diagnostic Approach

First-Line Investigations

• Perform a chest radiograph as the initial imaging study for all patients with FUO 1
• Collect at least two sets of blood cultures (ideally 60 mL of blood total) from different anatomical sites 1
• For patients with central venous catheters, obtain simultaneous central and peripheral blood cultures to calculate differential time to positivity 1
• Sample at least two lumens when collecting central venous catheter cultures 1
• Evaluate inflammatory markers including C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) 1, 2

Additional Testing Based on Clinical Presentation

• For patients with suspected urinary tract infection and pyuria, replace the urinary catheter and obtain urine cultures from the newly placed catheter 1
• For patients with suspected pneumonia or respiratory symptoms, test for viral pathogens using nucleic acid amplification test panels 1
• Test for SARS-CoV-2 by PCR based on community transmission levels 1
• Consider measuring procalcitonin (PCT) when the probability of bacterial infection is low to intermediate 1
• Avoid measuring PCT when the probability of bacterial infection is high 1

Advanced Diagnostic Workup

• If initial evaluation is unrevealing, [18F]FDG PET/CT has a high diagnostic yield (56%) with sensitivity of 84-86% 1, 3
• PET/CT should ideally be performed within 3 days of starting oral glucocorticoid therapy 1
• For patients who have recently undergone thoracic, abdominal, or pelvic surgery, perform CT imaging of the operative area if an etiology is not readily identified 1
• For patients with abdominal symptoms, abnormal physical examination, or liver function abnormalities, perform formal bedside diagnostic ultrasound of the abdomen 1
• For patients with abnormal chest radiograph, consider thoracic bedside ultrasound to identify pleural effusions and parenchymal or interstitial lung pathology 1
• If noninvasive tests are unrevealing, consider tissue biopsy (liver, lymph node, temporal artery, skin, skin-muscle, or bone marrow) based on clinical indications 2

Treatment Approach

• Treatment should target the identified cause once diagnosis is established 3
• Avoid empiric antimicrobial therapy except in patients who are neutropenic, immunocompromised, or critically ill 2
• In severely neutropenic patients, initiate broad-spectrum antibiotics with antipseudomonal activity promptly 3
• Consider antifungal therapy only in critically ill patients with persistent fever and new pulmonary infiltrates 1, 3
• Always assume and treat infection in patients in whom fever cannot be explained by other pathologies 1

Prognostic Considerations

• A negative [18F]FDG PET/CT can predict favorable prognosis through spontaneous remission of fever and potentially allows a watchful waiting approach 1
• Up to 75% of FUO cases may resolve spontaneously without reaching a definitive diagnosis 2
• Early use of [18F]FDG PET/CT in the diagnostic workup has been demonstrated to be cost-effective 1

Pitfalls to Avoid

• Do not diagnose "fever of unknown origin" prematurely - it is a diagnosis of exclusion requiring thorough evaluation 1
• Avoid empiric antimicrobial therapy without clear indication as it may mask the underlying cause 2
• Do not use high-dose steroids without specific indication as they increase risk of hospital-acquired infection, hyperglycemia, gastrointestinal bleeding, and delirium 1
• Avoid non-steroidal anti-inflammatory analgesics as they may impair renal and coagulation function and increase risk of stress ulcer formation 1
• Do not perform routine abdominal ultrasound in patients without abdominal signs/symptoms or liver function abnormalities 1