Initial Management of Fever of Unknown Origin
Begin with a structured diagnostic evaluation including at least two sets of blood cultures from different anatomical sites, chest radiography, comprehensive metabolic panel, inflammatory markers (ESR and CRP), and urinalysis—all obtained before initiating any antibiotics—while avoiding empiric antimicrobial therapy in non-neutropenic patients unless they are critically ill. 1, 2
Definition and Patient Stratification
FUO is defined as fever >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 The critical first step is determining whether the patient falls into one of four subcategories: classical, nosocomial, neutropenic, or HIV-related, as management differs substantially. 1
Neutropenic patients require immediate broad-spectrum antibiotics with antipseudomonal activity (such as piperacillin-tazobactam, cefepime, or a carbapenem) before completing the diagnostic workup, as delayed treatment significantly increases mortality. 3, 1, 2
Initial Diagnostic Workup
Mandatory First-Line Testing
Blood cultures: Obtain at least two sets (ideally 60 mL total) from different anatomical sites simultaneously before any antibiotics. 2 If a central venous catheter is present, draw simultaneous central and peripheral cultures to calculate differential time to positivity. 2
Chest radiography: Essential initial imaging to identify pulmonary sources. 2
Laboratory panel: Complete blood count, comprehensive metabolic panel (to identify hepatobiliary sources), urinalysis with culture, ESR, and CRP. 2, 4
Additional serologies: Consider HIV testing, region-specific serologies (tuberculosis, cytomegalovirus, Epstein-Barr virus), rheumatoid factor, and antinuclear antibodies based on epidemiologic risk. 5
Targeted Imaging Based on Clinical Clues
Abdominal ultrasound or CT: Perform formal diagnostic ultrasound for patients with abdominal symptoms, abnormal liver tests, or recent abdominal surgery. 2 Avoid routine abdominal imaging in patients without localizing signs. 2
CT chest with IV contrast: Identifies pulmonary sources in 72% of cases when clinically indicated. 2
CT abdomen/pelvis with IV contrast: Has 81.82% positive predictive value for identifying septic foci, most commonly in abdomen and pelvis. 2 For postoperative patients with fever several days after thoracic, abdominal, or pelvic surgery, CT of the operative area should be performed if no alternative cause is identified. 2
Advanced Imaging When Initial Workup is Unrevealing
If the initial evaluation is non-contributory and ESR or CRP are elevated, proceed to [18F]FDG PET/CT, which has a diagnostic yield of 56% and sensitivity of 84-86% for identifying the cause of FUO. 1, 2 This should ideally be performed within 3 days of initiating oral glucocorticoid therapy if steroids are being considered. 1
A negative PET/CT predicts favorable prognosis through spontaneous remission and may allow a watchful waiting approach. 2 Early use of PET/CT has been demonstrated to be cost-effective. 2
Invasive Diagnostic Procedures
If noninvasive testing remains unrevealing, tissue biopsy has the highest diagnostic yield and is the invasive test of choice. 4 Consider liver, lymph node, temporal artery, skin, skin-muscle, or bone marrow biopsy based on clinical indications and PET/CT findings. 4
For patients with lung infiltrates, bronchoalveolar lavage should be performed at a segmental bronchus supplying an area of radiographic abnormalities. 1
Treatment Principles
Non-Neutropenic Patients
Avoid empirical antibiotic therapy in non-neutropenic patients with FUO unless they are critically ill, as up to 75% of cases resolve spontaneously without a definitive diagnosis. 2, 4 Empiric antimicrobials have not been shown to be effective and may obscure the diagnosis. 4, 5
For persistent fever under antibiotics, fever alone rarely constitutes an indication to modify the antibiotic regimen. 2 Avoid non-directed antibiotic changes or switching from one empirical monotherapy to another without clinical or microbiological justification. 2
Neutropenic Patients
For high-risk neutropenic patients (neutrophil count <100 cells/mm³ expected >7 days), initiate monotherapy with an antipseudomonal β-lactam such as piperacillin-tazobactam, cefepime, or a carbapenem (imipenem-cilastatin, meropenem, or doripenem). 3, 2
Add vancomycin or other gram-positive coverage (linezolid, daptomycin, or ceftaroline) only if there is microbiological documentation or clinical evidence of gram-positive infection, not empirically. 3, 2
If fever persists despite 4-7 days of broad-spectrum antibiotics in neutropenic patients, add empiric antifungal therapy with voriconazole or liposomal amphotericin B, particularly if new pulmonary infiltrates develop. 3, 1 However, empiric antifungal treatment should only be considered in critically ill patients with fever of unknown origin and new pulmonary infiltrates. 1
Persisting fever is less concerning if the granulocyte count is increasing. 1
Surveillance and Re-evaluation
Perform daily surveillance of all neutropenic patients under antibiotics, including daily physical examination, review of systems for new symptoms, and cultures of suspect sites. 2 Re-evaluate after 2-4 days of empirical antibiotic treatment, during which most modifications of the initial regimen will be made. 2
Critical Pitfalls to Avoid
Do not remove central venous catheters systematically in clinically stable patients with FUO unless there is microbiological evidence of catheter-related infection. 2
Avoid high-dose steroids without specific indication, as they increase risk of hospital-acquired infection, hyperglycemia, gastrointestinal bleeding, and delirium. 2
Do not use NSAIDs, as they may impair renal and coagulation function and increase risk of stress ulcer formation. 2
Do not delay antibiotic administration in neutropenic or critically ill patients while waiting for culture results, as mortality in untreated neutropenic sepsis is unacceptably high. 6
Geographic and Epidemiologic Considerations
In developing countries and endemic areas, tuberculosis remains a leading cause of FUO, particularly extrapulmonary tuberculosis in older patients. 7 Hematological malignancies are significant diagnoses in younger patients. 7 Always consider local infection profiles and geographic variations when investigating FUO. 7