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

Fever of Unknown Origin Workup

Initial Diagnostic Approach

Begin with chest radiography and at least two sets of blood cultures (ideally 60 mL total) from different anatomical sites before initiating any antibiotics. 1, 2

Mandatory First-Line Laboratory Tests

• Complete blood count with differential to identify leucocytosis, neutrophilia, or left shift suggesting bacterial infection 3, 4
• Inflammatory markers: C-reactive protein and erythrocyte sedimentation rate are essential baseline tests 2, 4
• Comprehensive metabolic panel including liver enzymes (transaminases, alkaline phosphatase, bilirubin) to identify hepatobiliary sources 1, 3
• Urinalysis and urine culture if urinary symptoms present or catheter in place 3
• Blood cultures: Obtain from different anatomical sites simultaneously; if central venous catheter present, draw both central and peripheral cultures to calculate differential time to positivity 2, 4

Additional Testing Based on Clinical Context

• Procalcitonin may be considered in patients with low-to-intermediate probability of bacterial infection without clear focus 3
• Lactate dehydrogenase, creatine kinase, rheumatoid factor, and antinuclear antibodies should be obtained in the initial workup 5
• HIV testing and region-specific serologies (cytomegalovirus, Epstein-Barr virus, tuberculosis) based on epidemiologic risk factors 5, 4

Advanced Imaging When Initial Workup Is Unrevealing

If the initial evaluation fails to identify an etiology, 18F-FDG PET/CT is the highest-yield advanced diagnostic tool with 84-86% sensitivity and 56% diagnostic yield. 2, 4

Timing and Considerations for PET/CT

• Perform PET/CT within 3 days of starting oral glucocorticoid therapy to avoid false-negative results 2, 4
• PET/CT is particularly useful for guiding tissue biopsy when diagnosis remains elusive 5, 6
• A negative PET/CT predicts favorable prognosis through spontaneous remission and may allow watchful waiting 2
• Early use of PET/CT has been demonstrated to be cost-effective 2

CT Imaging in Specific Clinical Scenarios

• For patients with recent thoracic, abdominal, or pelvic surgery: Perform CT of the operative area (in collaboration with surgical service) if fever occurs several days postoperatively and alternative cause not identified 1, 2
• For patients with abdominal symptoms, abnormal liver tests, or recent abdominal surgery: Perform formal diagnostic ultrasound of the abdomen 1, 3
• Avoid routine abdominal ultrasound or point-of-care ultrasound in patients without abdominal signs, symptoms, or liver function abnormalities 1, 3

CT Chest and Abdomen/Pelvis with IV Contrast

• CT chest with IV contrast identifies pulmonary sources in 72% of surgical ICU patients with suspected infection 1
• CT abdomen and pelvis with IV contrast has 81.82% positive predictive value for identifying septic foci, most commonly in abdomen (22%) and pelvis/genitourinary tract (20.5%) 1
• These studies resulted in management changes in 45% of patients, including antimicrobial changes, surgery, and drainage catheter placement 1

Treatment Principles

Avoid empiric antibiotics or steroids in stable patients with FUO, as they obscure diagnosis and may be harmful if malignancy or certain infections are present. 4, 2

Exceptions Requiring Empiric Therapy

• Severely neutropenic patients: Initiate broad-spectrum antibiotics with antipseudomonal activity promptly 2
• Suspected tickborne rickettsial diseases or critically ill patients may warrant empiric therapy 4
• Antifungal therapy should be considered only in critically ill patients with persistent fever and new pulmonary infiltrates 2

Treatment Once Diagnosis Established

• Target therapy to the identified cause once diagnosis is confirmed 2
• Treat confirmed diagnoses (malaria, adult-onset Still's disease, bacterial meningitis) according to established disease-specific guidelines 4

Critical Pitfalls to Avoid

• Do not diagnose "FUO" prematurely—it is a diagnosis of exclusion requiring thorough evaluation over at least 3 weeks 2, 4
• Avoid high-dose steroids without specific indication: They increase risk of hospital-acquired infection, hyperglycemia, gastrointestinal bleeding, and delirium without improving mortality 2, 4
• Avoid NSAIDs: They may impair renal and coagulation function and increase stress ulcer risk 2
• Do not perform sinus CT routinely in prolonged febrile neutropenia without localizing symptoms, as abnormalities are common but non-discriminatory 1
• Avoid empiric imaging without clinical clues: Most FUO cases are atypical presentations of common diseases, not rare conditions requiring extensive screening 7, 8

Invasive Diagnostic Procedures

If noninvasive tests are unrevealing, tissue biopsy has the highest diagnostic yield among invasive procedures. 6

• Lymph node biopsy: High yield (79%) in generalized lymphadenopathy; not helpful if confined to cervical or inguinal regions only 8
• Temporal artery biopsy: Consider in patients older than 55 years with elevated inflammatory markers 8
• Liver biopsy, bone marrow biopsy: Consider at later stages if directed by clinical clues 8

Prognosis

• Up to 75% of FUO cases resolve spontaneously without reaching definitive diagnosis 6
• Most cases represent uncommon presentations of common diseases rather than rare conditions 5, 7
• Patients with recurrent fever, normal ESR, and normal hemoglobin have significantly lower likelihood (<10%) of establishing diagnosis 8