What is the appropriate diagnostic and treatment approach for a patient with fever of unknown origin, considering their potential demographic characteristics, medical history, and exposure history?

Fever of Unknown Origin: Diagnostic and Treatment Approach

Begin with chest radiography and at least two sets of blood cultures from different anatomical sites before initiating any antibiotics, then proceed with a structured diagnostic algorithm based on initial findings and patient risk factors. 1, 2

Definition and Initial Risk Stratification

Fever of unknown origin (FUO) is defined as temperature >38.3°C (100.9°F) persisting for at least 3 weeks without diagnosis despite appropriate evaluation. 1, 2 The condition is classified into four subcategories: classical, nosocomial, neutropenic, and HIV-related, with etiologies including infectious (20-40%), inflammatory/autoimmune, malignant, and miscellaneous causes. 1, 3

Critical principle: FUO is most often an atypical presentation of a common disease rather than a rare disease. 2, 4 Up to 75% of cases resolve spontaneously without reaching a definitive diagnosis. 1, 5

Age-Specific Considerations

For pediatric patients, immediate age stratification is essential:

• Infants <3 months: 8-13% rate of invasive bacterial infections, requiring hospitalization, lumbar puncture if high-risk features present, and empiric antibiotics immediately. 6
• Infants <28 days: Highest risk, warranting most aggressive approach. 6
• Children >3 months: Lower risk (~75% viral), can often be managed without immediate imaging if well-appearing. 6

Mandatory Initial Diagnostic Workup

Laboratory Testing (All Patients)

Obtain before any antibiotic administration: 1, 2

• At least two sets of blood cultures from different anatomical sites (ideally 60 mL total blood volume) 1
• Complete blood count with differential 1, 2
• C-reactive protein and erythrocyte sedimentation rate 1, 2
• Comprehensive metabolic panel (to identify hepatobiliary sources) 1, 2
• Urinalysis with culture 2, 4

Additional Initial Laboratory Tests

• Lactate dehydrogenase, creatine kinase 4
• Rheumatoid factor and antinuclear antibodies 4
• HIV testing with CD4+ T-cell counts and viral load (if positive) 2
• Region-specific serologic testing: tuberculosis, cytomegalovirus, Epstein-Barr virus 4

First-Line Imaging

Chest radiography is the only first-line imaging study recommended for all patients with FUO, particularly if pulmonary symptoms present or concern for atypical bacterial infection, HIV, tuberculosis, or malignancy. 2

Targeted History and Physical Examination

Focus on potentially diagnostic clues rather than generic comprehensive assessment: 1, 2

History must include:

• Recent travel and geographical exposures 2
• Animal exposures and occupational risks 2
• Complete medication history, especially recent antibiotics 2
• Immunosuppression history 2
• Symptoms suggesting specific organ involvement 2

Physical examination priorities:

• Cardiac auscultation for new murmurs (may indicate infective endocarditis) 2
• Skin examination for rashes 2
• Oral cavity and conjunctival examination 2
• Comprehensive lymph node examination 2

Advanced Imaging Algorithm

Post-Surgical Patients

For patients with recent thoracic, abdominal, or pelvic surgery and fever occurring several days postoperatively: 1, 2

• CT of the operative area with IV contrast (first priority)
• CT chest with IV contrast (identifies pulmonary sources in 72% of surgical ICU patients) 1
• CT abdomen/pelvis with IV contrast (81.82% positive predictive value for septic foci) 1

Patients with Abdominal Symptoms

Formal diagnostic ultrasound of the abdomen for patients with abdominal symptoms, abnormal liver tests, or recent abdominal surgery. 1, 2 Avoid routine abdominal ultrasound in patients without abdominal signs, symptoms, or liver function abnormalities. 1

FDG-PET/CT: The Highest-Yield Advanced Imaging

If initial evaluation is unrevealing, FDG-PET/CT whole body is the highest-yield diagnostic tool with 56% diagnostic yield and 84-86% sensitivity. 7, 1, 2, 6, 8

Timing is critical: Perform FDG-PET/CT within 3 days of starting oral glucocorticoid therapy to avoid false-negative results. 1, 2

Pediatric data: In 110 pediatric patients, FDG-PET/CT identified the source in 48% of cases, with most common diagnoses being endocarditis (11%), systemic juvenile idiopathic arthritis (5%), and inflammatory bowel disease (5%). 7, 6 Treatment modifications were made in 53% of patients after FDG-PET/CT. 7, 6

Predictive markers for diagnostic FDG-PET/CT: Age >50 years, CRP >30 mg/L, and absence of intermittent fever increase likelihood of diagnostic yield. 8

Prognostic value: A negative FDG-PET/CT predicts favorable prognosis through spontaneous remission and potentially allows watchful waiting. 1

Special Population Management

Neutropenic Patients

Prompt broad-spectrum antibiotics with antipseudomonal activity are required before completing full workup. 1, 2 High-risk patients (neutropenia <100 cells/mm³ expected >7 days) should initiate monotherapy with β-lactam antibiotic such as piperacillin-tazobactam as first-line treatment. 1

Imaging for neutropenic patients: Chest radiography, CT paranasal sinuses (only if localizing symptoms), CT chest, CT abdomen/pelvis, and FDG-PET/CT. 2 Avoid routine sinus CT in prolonged febrile neutropenia without localizing symptoms, as abnormalities are common but non-discriminatory. 1

HIV-Positive Patients

Test CD4+ T-cell counts and HIV viral load to assess immune function. 2 Consider opportunistic infections: Mycobacterium tuberculosis, cytomegalovirus, and Pneumocystis jirovecii. 2

Patients with Central Venous Catheters

Obtain simultaneous central and peripheral blood cultures to calculate differential time to positivity. 1 Do not systematically remove central venous catheters in clinically stable patients unless there is microbiological evidence of catheter-related infection. 1

Treatment Principles

When to Treat Empirically

Avoid empiric antibiotics in non-neutropenic patients with FUO unless they are critically ill, as most cases (up to 75%) resolve spontaneously. 1, 2, 5 Empiric antimicrobial therapy has not been shown to be effective in treatment of FUO. 5

Exception: Severely neutropenic patients require prompt broad-spectrum antibiotics with antipseudomonal activity. 1

Targeted Treatment

Treatment should target the identified cause once diagnosis is established. 1 For patients with persistent fever under antibiotics, fever alone rarely constitutes an indication to modify the antibiotic regimen. 1 Empirical addition of vancomycin should not be done without microbiological documentation. 1

Antifungal Therapy

Consider antifungal therapy only in critically ill patients with persistent fever and new pulmonary infiltrates. 1

Critical Pitfalls to Avoid

Never use high-dose steroids without specific indication, as they increase risk of hospital-acquired infection, hyperglycemia, gastrointestinal bleeding, and delirium without improving mortality. 1, 2, 6 Steroids also mask inflammatory findings on subsequent imaging. 6

Avoid NSAIDs, as they impair renal and coagulation function and increase stress ulcer risk. 1, 2

Do not make non-directed antibiotic changes or switch from one empirical monotherapy to another without clinical or microbiological data justifying spectrum extension. 1

Do not diagnose FUO prematurely—it is a diagnosis of exclusion requiring thorough evaluation. 1, 6

Obtain blood cultures before initiating any antibiotics to avoid masking the underlying cause. 2

Surveillance and Re-evaluation

For neutropenic patients under antibiotics, perform daily surveillance including physical examination, review of systems for new symptoms, and cultures of suspect sites. 1 Re-evaluate after 2-4 days of empirical antibiotic treatment, during which most modifications of the initial regimen will be made. 1

Invasive Diagnostic Procedures

If noninvasive diagnostic tests are unrevealing, tissue biopsy has relatively high diagnostic yield and is the invasive test of choice. 5 Depending on clinical indications, consider liver, lymph node, temporal artery, skin, skin-muscle, or bone marrow biopsy. 5