In a cancer patient with neutropenia and lymphocytosis, what are the likely causes and how should it be managed?

Neutropenia with Lymphocytosis in Cancer Patients

In a cancer patient presenting with low neutrophils and high lymphocytes, the most likely cause is an acute viral infection (EBV, CMV, HSV, VZV, or respiratory viruses), which requires immediate broad-spectrum antimicrobial prophylaxis if the absolute neutrophil count (ANC) is <0.5 × 10⁹/L, regardless of the lymphocytosis. 1

Immediate Risk Assessment

The priority is determining infection risk based on the severity and expected duration of neutropenia, not the lymphocytosis:

• Severe neutropenia is defined as ANC <0.5 × 10⁹/L or ANC <1.0 × 10⁹/L with predicted decline to <0.5 × 10⁹/L within 48 hours 2
• Febrile neutropenia (temperature >38.5°C for >1 hour with ANC <0.5 × 10⁹/L) constitutes a medical emergency requiring hospitalization within 2 hours 2, 3
• Patients with ANC <100 cells/μL for >7 days have the highest risk for invasive fungal infections 1

Differential Diagnosis by Clinical Pattern

Acute Presentation (Most Common)

• Viral infections cause transient lymphocytosis with relative or absolute neutropenia, presenting with fever and constitutional symptoms 1
• Common pathogens include EBV, CMV, HSV, VZV, and respiratory viruses 1
• This pattern is typically self-limited 1

Chronic/Persistent Pattern

• Chronic lymphocytic leukemia (CLL) frequently presents with lymphocytosis and concurrent neutropenia from bone marrow infiltration 1
• B-cell lymphoproliferative disorders can cause persistent lymphocytosis with neutropenia 1
• Common variable immunodeficiency (CVID) presents with recurrent infections, lymphoproliferation, and abnormal lymphocyte counts 1

Essential Diagnostic Workup

Obtain immediately:

• Complete blood count with differential to calculate ANC and absolute lymphocyte count 1
• At least two sets of blood cultures before starting antibiotics 3
• Serum immunoglobulins (IgG, IgA, IgM) and serum protein electrophoresis to detect monoclonal proteins or hypogammaglobulinemia 1
• Flow cytometry and peripheral blood smear if lymphocytosis is persistent, to screen for CLL 1
• Chest radiograph and additional imaging as indicated by clinical signs 3

Management Algorithm Based on Neutropenia Severity

High-Risk Patients (ANC <0.5 × 10⁹/L, anticipated neutropenia >10 days)

Immediate antimicrobial prophylaxis:

• Fluoroquinolone prophylaxis (levofloxacin preferred) during neutropenia 2
• Antiviral prophylaxis with acyclovir or valacyclovir against HSV and VZV 1
• Antifungal prophylaxis with fluconazole for prolonged neutropenia 1
• Consider G-CSF therapy at 5 mcg/kg/day subcutaneously if prolonged neutropenia is anticipated 2, 1, 4

Intermediate-Risk Patients (ANC <0.5 × 10⁹/L, anticipated neutropenia 7-10 days)

Consider antimicrobial prophylaxis:

• Fluoroquinolone prophylaxis during neutropenia 2
• Antifungal prophylaxis during neutropenia and for anticipated mucositis 2
• Antiviral prophylaxis during neutropenia and longer depending on risk 2

Low-Risk Patients (anticipated neutropenia <7 days)

No routine prophylaxis unless prior HSV episode 2

Management of Febrile Neutropenia

If fever develops (>38.5°C for >1 hour) with ANC <0.5 × 10⁹/L:

• Hospitalize immediately - this is a medical emergency 2, 3, 1
• Initiate empiric broad-spectrum antibiotics within 2 hours of presentation 3
• Vancomycin plus antipseudomonal agent (cefepime, carbapenem, or piperacillin-tazobactam) 3, 1
• Continue antibiotics until fever resolves and neutrophil count recovers 3
• Do not delay antibiotics while waiting for culture results 3

Special Considerations for Lymphocytosis

The lymphocytosis itself does not change neutropenia management but requires specific evaluation:

• Screen for hypogammaglobulinemia requiring immunoglobulin replacement 1
• Monthly IVIG treatment recommended until IgG levels ≥400 mg/dL if hypogammaglobulinemia is present 1
• Pneumococcal antibody levels before and 4-8 weeks after 23-valent pneumococcal vaccine to assess functional antibody response 1

Critical Pitfalls to Avoid

• Never underestimate skin lesions in neutropenic patients - even small or innocuous-appearing lesions require careful evaluation as signs of inflammation are often diminished or absent 3
• Do not withhold G-CSF in high-risk settings due to theoretical concerns about subsequent AML/MDS risk - the absolute risk is low (1.8% vs 0.7%) and benefits outweigh risks 2
• Avoid colony-stimulating factors in patients not at high risk for febrile neutropenia (risk <20%) or in patients with infections not related to neutropenia 2
• Do not assume viral infection without proper workup - persistent lymphocytosis may indicate CLL or lymphoproliferative disorder requiring flow cytometry 1

Prevention for Future Chemotherapy Cycles

For patients at high risk:

• Prophylactic fluoroquinolones for subsequent chemotherapy cycles 3
• Herpes virus prophylaxis with acyclovir or equivalent 3
• Pneumocystis jiroveci pneumonia prophylaxis with sulfamethoxazole-trimethoprim 3
• Continue anti-infective prophylaxis for minimum of 2 months and until CD4 count ≥200 cells/mm³ 3