What is the appropriate management for a patient with a high white blood cell count (leukocytosis) who has tested negative for infection?

Management of Leukocytosis with Negative Infection Tests

When a patient presents with an elevated white blood cell count (leukocytosis) but negative infection tests, a thorough diagnostic workup is essential to identify the underlying cause before determining appropriate management.

Diagnostic Approach

Initial Assessment

• Evaluate the degree of leukocytosis - a WBC count >14,000 cells/mm³ has a likelihood ratio of 3.7 for detecting bacterial infection, even with negative initial tests 1
• Assess for left shift (percentage of band neutrophils >16% or total band count >1,500/mm³), which has an even higher likelihood ratio (14.5) for bacterial infection 1
• Consider that the absence of fever does not exclude infection in this setting, particularly in older adults 2, 3

Further Diagnostic Testing

• Repeat the complete blood count with differential to evaluate trends and confirm findings 2, 3
• Obtain blood cultures if not already done, especially if the patient has systemic symptoms 1, 3
• Consider site-specific cultures based on clinical presentation (urine, respiratory, wound) 1
• Evaluate for non-infectious causes of leukocytosis, including medications (corticosteroids, lithium, beta-agonists), stress, and underlying inflammatory conditions 4, 5

Management Algorithm

If Infection is Still Suspected Despite Negative Tests

• Consider occult infection sites that may not be evident on initial testing 2, 6
• Evaluate for potential sources requiring specialized testing:
  • Intra-abdominal infections (consider CT imaging) 1
  • Endocarditis (echocardiography) 2
  • Bone/joint infections (appropriate imaging) 2
  • Discitis or vertebral osteomyelitis (MRI with contrast) 2

If Non-Infectious Causes Are More Likely

• Consider inflammatory conditions (autoimmune disorders, tissue damage) 5, 7
• Evaluate for hematologic disorders if extremely elevated WBC counts, concurrent abnormalities in red blood cell or platelet counts, or if there are concerning symptoms (weight loss, bruising, lymphadenopathy) 5, 8
• Urgent hematology consultation is warranted for WBC counts >100,000/mm³ due to risk of leukostasis 9

Management Based on Suspected Etiology

• For suspected occult bacterial infection:

  • Consider empiric antimicrobial therapy based on the most likely source and local resistance patterns 1
  • Limit antibiotic duration to 4-7 days if source control is adequate 1
  • Monitor response with serial WBC counts 2, 3

• For non-infectious inflammatory causes:

  • Treat the underlying condition 4, 7
  • Avoid unnecessary antibiotics, which can lead to resistant organisms and complications like C. difficile infection 7

• For medication-induced leukocytosis:

  • Consider modification of medication regimen if possible 4, 5

Special Considerations

Common Pitfalls to Avoid

• Treating asymptomatic patients with antibiotics based solely on mildly elevated WBC counts 6, 7
• Overlooking the significance of absolute neutrophil count elevation when total WBC count is only mildly elevated 6
• Failing to recognize that persistent leukocytosis without identified infection may represent the persistent inflammation-immunosuppression and catabolism syndrome (PICS), particularly in patients with extensive tissue damage 7

Monitoring

• Serial WBC counts to track response to therapy 2, 3
• Ongoing clinical assessment for development of new symptoms that might suggest a specific diagnosis 2, 3
• Consider hematology consultation if leukocytosis persists without clear etiology despite thorough workup 8, 9