What is the appropriate evaluation and management approach for a patient with a prolonged fever lasting more than 15 days, considering various potential causes including infections, autoimmune disorders, and malignancies?

Evaluation of Prolonged Fever (>15 Days)

For a patient with fever lasting more than 15 days, immediately assess clinical stability and initiate a systematic diagnostic workup focusing on the three major etiologic categories: infections (especially tuberculosis and enteric fever), malignancies (particularly lymphoma), and autoimmune conditions (notably adult-onset Still's disease), while simultaneously ruling out drug-induced fever. 1, 2, 3

Initial Risk Stratification and Clinical Assessment

Determine clinical stability first - this dictates the urgency and venue of evaluation:

• High-risk indicators requiring immediate hospitalization and empiric treatment: hypotension, altered mental status, respiratory distress, tachycardia, or signs of end-organ dysfunction 4, 1
• Assess for neutropenia: patients with absolute neutrophil count <500 cells/mm³ or anticipated prolonged neutropenia (>7 days) are at substantially increased risk for severe infection and require different management 4
• Document all medications started within the past 3 weeks: drug-induced fever has a mean lag time of 21 days after drug initiation and can persist 1-7 days after stopping the offending agent 4, 1

Focused History and Physical Examination

Travel history is critical - determine any travel to endemic areas within the past 3 weeks:

• South Asia, sub-Saharan Africa, or Mediterranean regions suggest enteric fever or rickettsial infections 1
• Safari/game park exposure raises concern for rickettsial disease 1

Examine for specific localizing signs:

• Rash patterns, lymphadenopathy (especially cervical), hepatosplenomegaly 1
• Conjunctival injection, oral mucosal changes, extremity edema 1
• Indwelling devices (urinary catheters, vascular access) - presence of catheter increases bacteremia risk 39-fold 4
• Chronic conditions: diabetes (predisposes to skin/UTI), COPD (pneumonia risk), poor swallowing (aspiration risk) 4

Essential Diagnostic Testing

Obtain before initiating antibiotics:

• Multiple sets of blood cultures (at least 2-3 sets): highest yield within first week for enteric fever (sensitivity 40-80%) 1
• Complete blood count with differential: identify neutropenia, thrombocytopenia, or atypical lymphocytes suggesting malignancy or viral infection 1
• Comprehensive metabolic panel: hyponatremia, hypoalbuminemia, and elevated liver enzymes are common in enteric fever 1
• Urinalysis and urine culture: use catheterized specimen to avoid contamination 1
• Chest radiography: essential for pneumonia, tuberculosis, or mediastinal lymphadenopathy 4, 1

Additional testing for prolonged fever (>3 weeks):

• Stool and urine cultures (become positive after first week when blood culture yield decreases for enteric fever) 1
• Do NOT use Widal test - lacks sensitivity and specificity 1
• Consider CT imaging of chest, abdomen, and sinuses if initial workup unrevealing 5, 3
• Serum procalcitonin (levels >0.5 ng/mL suggest bacterial infection; >10 ng/mL suggests septic shock) 4

Empiric Treatment Algorithm

For clinically unstable patients or those with deterioration:

• Start IV ceftriaxone immediately without waiting for culture results 1
• Continue for 14 days to reduce relapse risk (<8% relapse rate) 1
• Add vancomycin only if specific criteria met: catheter-related infection suspected, skin/soft tissue infection, hemodynamic instability, positive blood cultures for gram-positive organisms, or mucositis in centers with high viridans streptococci rates 4, 5

For neutropenic patients with persistent fever:

• If fever persists through days 4-7 without identified cause and neutropenia expected to last >7 days: initiate empiric antifungal therapy (amphotericin B, echinocandins, or voriconazole) 4, 5
• Perform fungal workup including CT chest/sinuses before starting antifungals when possible 5
• Continue antibiotics until neutrophil count >500 cells/mm³ with increasing trend 4

For clinically stable patients:

• If low-risk (anticipated brief neutropenia <7 days, no comorbidities): consider oral fluoroquinolone therapy 4
• Reassess after 3-5 days; if no improvement, broaden coverage or investigate for resistant organisms, abscess formation, or drug fever 5

Special Diagnostic Considerations

Enteric fever should be strongly suspected if:

• Fever duration >2 weeks (encephalopathy occurs in 10-15% with illness >2 weeks) 1
• Recent travel to endemic areas 1
• If rickettsial infection suspected, doxycycline should produce response within 24-48 hours; if no response, reconsider diagnosis 1

Tuberculosis and lymphoma are among the most common causes of classic fever of unknown origin and must be actively excluded 2, 3

Adult-onset Still's disease is a key autoimmune cause to consider 3

Critical Pitfalls to Avoid

• Do NOT rely on antipyretic response to guide management - fever response to acetaminophen does not distinguish bacterial from viral infection 1
• Do NOT add vancomycin empirically without specific indications - promotes resistance 1
• Do NOT dismiss travel-related infections even with prophylaxis - malaria can occur despite prophylaxis, and typhoid vaccination provides incomplete protection 1
• Do NOT stop evaluation prematurely - approximately 1-2% of cases remain undiagnosed despite thorough investigation 3

Duration of Therapy

For documented infections:

• Continue antibiotics for at least the duration of neutropenia (until ANC >500 cells/mm³) or longer if clinically necessary 4
• Enteric fever requires 14 days total to reduce relapse risk 1
• Adjust based on culture sensitivities; fluoroquinolones remain most effective if isolate is sensitive 1

For unexplained fever:

• Continue initial regimen until clear signs of marrow recovery (ANC >500 cells/mm³) 4
• In non-neutropenic patients with no identified source after 2 weeks of appropriate therapy, consider stopping antibiotics if patient can be observed carefully 4