What is the next step in evaluating a 79‑year‑old woman with fever of unknown origin, leukocytosis >26 000/µL, and sterile blood and urine cultures?

Immediate Next Steps for 79-Year-Old with Fever, WBC >26,000, and Sterile Cultures

Obtain a manual differential count immediately to calculate the absolute band count and assess for left shift, as this is the single most predictive laboratory marker for bacterial infection (likelihood ratio 14.5 for absolute band count ≥1,500 cells/mm³), and proceed with contrast-enhanced CT imaging of the chest, abdomen, and pelvis to identify occult infection sources or non-infectious causes such as malignancy or inflammatory conditions. 1, 2

Critical Laboratory Assessment

Manual Differential Analysis (Priority #1)

• Absolute band count ≥1,500 cells/mm³ has the highest likelihood ratio (14.5) for documented bacterial infection, even exceeding total WBC count as a predictor 1, 2, 3
• Band percentage ≥16% (left shift) carries a likelihood ratio of 4.7 for bacterial infection and can occur even with normal total WBC 1, 2, 3
• Neutrophil percentage >90% yields a likelihood ratio of 7.5 for bacterial infection 1, 2
• Automated analyzers are insufficient—manual 500-cell differential is mandatory for accurate band assessment 2, 3, 4

Additional Laboratory Studies

• C-reactive protein and ferritin levels to assess for inflammatory conditions and hemophagocytic syndrome 1, 5
• Lactate level—if >3 mmol/L indicates severe sepsis requiring immediate intervention 2
• Repeat complete metabolic panel to assess for metabolic derangements contributing to altered mental status if present 2

Targeted Imaging Strategy

Contrast-Enhanced CT Scan (Chest/Abdomen/Pelvis)

• This is the most reliable exam to diagnose intra-abdominal disease and occult infection sources in elderly patients, particularly when clinical examination is unrevealing 1
• CT has superior sensitivity compared to plain radiographs and ultrasound for identifying abscesses, pneumonia, malignancy, or inflammatory processes 1
• In immunocompromised or frail elderly patients, fever and leukocytosis may be mild or absent despite serious pathology, making liberal use of CT imaging appropriate 1

Clinical Assessment Priorities

Vital Signs and Systemic Infection Markers

• Temperature >38°C or <36°C (hypothermia), systolic BP <90 mmHg, heart rate >100 bpm, respiratory rate >20/min 2, 3
• Pulse oximetry—oxygen saturation <90% suggests pneumonia and predicts 30-day mortality 1
• Mental status changes or new confusion may be the sole manifestation of systemic bacterial infection in elderly patients 2, 3

Focused Physical Examination

• Respiratory: dyspnea, cough, chest pain suggesting pneumonia 2
• Urinary: dysuria, flank pain, frequency, new or worsening incontinence 2, 3
• Skin/soft tissue: erythema, warmth, purulent drainage, pressure ulcers 2, 3
• Abdominal: peritoneal signs, diarrhea (consider Clostridioides difficile testing) 1, 3
• Joints: arthralgias, myalgias (consider Adult-onset Still's disease with WBC >20,000) 6

Diagnostic Algorithm Based on Left Shift Results

If Left Shift Present (≥16% bands or ≥1,500 cells/mm³ absolute)

• Initiate empiric broad-spectrum antibiotics after obtaining blood cultures if bacteremia suspected clinically 2, 3
• Proceed with CT imaging immediately to identify infection source 1
• Consider sepsis protocol with aggressive fluid resuscitation if hypotension present 2
• Source control measures (drainage of abscesses, removal of infected devices) 2

If No Left Shift and Patient Hemodynamically Stable

• Complete CT imaging to evaluate for non-infectious causes 1, 7
• Consider malignancy workup (lymphoma, leukemia) given marked leukocytosis >26,000 7, 5
• Evaluate for inflammatory conditions: Adult-onset Still's disease (ferritin often >1,000 mcg/L), hemophagocytic syndrome (ferritin >1,900 U/L, elevated LDH, cytopenias) 5, 8, 6
• Consider 18F-FDG PET-CT if initial CT unrevealing and ESR/CRP elevated 7

Non-Infectious Differential Considerations

Hematologic Malignancy

• Leukemia, lymphoma, or myelodysplastic syndrome can present with fever and marked leukocytosis 7, 5
• Hemophagocytic syndrome may manifest with fever, cytopenias, elevated ferritin (>1,900 U/L), elevated LDH, and splenomegaly 5
• Bone marrow biopsy has relatively high diagnostic yield if non-invasive tests unrevealing 7

Inflammatory Conditions

• Adult-onset Still's disease: fever spikes, macular-papular rash, arthralgias, ferritin >1,000 mcg/L, neutrophilic leukocytosis >20,000 8, 6
• Temporal arteritis or other vasculitides in elderly patients 7
• Drug-induced fever (review all medications including NSAIDs, antibiotics) 8

Critical Pitfalls to Avoid

• Do not ignore left shift when total WBC is only mildly elevated—left shift can occur with normal WBC and still indicates serious bacterial infection 2, 3
• Do not rely on automated analyzer alone—manual differential is essential to assess band forms 2, 3, 4
• Do not attribute sterile cultures to absence of infection—elderly patients may have occult abscesses, pneumonia, or other deep-seated infections not detected by blood/urine cultures 1
• Do not delay CT imaging in elderly patients with unexplained fever and marked leukocytosis—clinical examination is often unrevealing and mortality increases with delayed diagnosis 1
• Do not start empiric antibiotics without cultures if patient is hemodynamically stable—complete diagnostic workup first to avoid masking non-infectious causes 2, 7
• Do not overlook non-infectious causes (malignancy, inflammatory disease) in elderly patients with fever of unknown origin—up to 75% may have uncommon presentations of common diseases or resolve spontaneously 7

Reassessment Timeline

• If CT imaging and manual differential are unrevealing and patient remains stable, consider PET-CT within 48-72 hours 7
• If diagnosis remains elusive after non-invasive testing, tissue biopsy (bone marrow, liver, lymph node, temporal artery) has highest diagnostic yield 7
• Empiric antimicrobial therapy should be avoided except in neutropenic, immunocompromised, or critically ill patients 7