What is lymphocytosis?

Lymphocytosis: Definition and Clinical Significance

Lymphocytosis is defined as an elevated absolute lymphocyte count in peripheral blood above the normal reference range, typically greater than 4 × 10^9/L (4000/μL) in adults. 1

Causes of Lymphocytosis

Lymphocytosis can be categorized as either reactive (benign) or malignant:

Reactive Lymphocytosis

• Infections:
  • Viral: Epstein-Barr virus (EBV), cytomegalovirus (CMV), HIV, hepatitis viruses
  • Bacterial: Pertussis, tuberculosis
• Autoimmune disorders: Rheumatoid arthritis, systemic lupus erythematosus
• Drug reactions: Anti-TNF-α agents can cause mild T CD4+ lymphocytosis in approximately 12% of rheumatoid arthritis and psoriatic arthritis patients 2
• Stress responses: Physical or emotional stress
• Post-transplantation: Large granular lymphocytosis can occur after allogeneic blood or marrow transplantation 3

Malignant Lymphocytosis

• Chronic lymphocytic leukemia (CLL): Most common cause of persistent lymphocytosis in adults 4
• Other lymphoproliferative disorders:
  • T-cell and NK-cell lymphomas/leukemias
  • Diffuse large B-cell lymphoma (DLBCL)
  • Hodgkin lymphoma 1

Diagnostic Approach to Lymphocytosis

When lymphocytosis is detected, evaluation should include:

1. Assessment of persistence and degree: Transient lymphocytosis is often reactive, while persistent lymphocytosis warrants further investigation
2. Peripheral blood smear examination: To identify atypical lymphocytes
3. Flow cytometry: Recommended for persistent or significant lymphocytosis to determine lymphocyte subsets and clonality
4. Viral testing: For EBV, CMV, and other common viral causes in acute presentations 1

Clinical Significance and Management

Chronic Lymphocytic Leukemia (CLL)

CLL is a common cause of persistent lymphocytosis in adults. According to guidelines:

• Asymptomatic early-stage CLL (Rai 0, Binet A) should be monitored without therapy unless there is evidence of disease progression 5
• Treatment should only be initiated when there is clear evidence of "active disease" 5
• Progressive lymphocytosis with an increase of more than 50% over a 2-month period or lymphocyte doubling time of less than 6 months may indicate need for treatment 5
• The absolute lymphocyte count alone should not be used as the sole indicator for treatment 5

Hemophagocytic Lymphohistiocytosis (HLH)

HLH is a severe hyperinflammatory syndrome that can present with lymphocytosis:

• Characterized by excessive activation of macrophages and cytotoxic T cells 5
• Can rapidly progress to multi-organ failure if left untreated 1
• Diagnosis requires meeting specific HLH-2004 criteria, including fever, splenomegaly, cytopenias, and elevated ferritin levels 5, 1

Important Clinical Considerations

1. Distinguishing benign from malignant causes: Most cases of lymphocytosis are benign and self-limited, but persistent lymphocytosis requires thorough evaluation 4

2. Risk factors for malignant lymphocytosis:

   • Age >50 years
   • Persistent lymphocytosis
   • Presence of other cytopenias
   • Lymphadenopathy or organomegaly
   • B symptoms (fever, night sweats, weight loss)

3. When to refer to hematology:

   • Persistent unexplained lymphocytosis
   • Lymphocyte count >10 × 10^9/L
   • Presence of abnormal lymphocyte morphology
   • Associated cytopenias or organomegaly

Pitfalls to Avoid

1. Overlooking transient causes: Many cases of lymphocytosis are transient and reactive, especially in the setting of acute infections

2. Premature treatment: Early treatment with chemotherapeutic agents does not translate into a survival advantage in patients with early-stage CLL 5

3. Failure to recognize HLH: HLH can present with a phenotype indistinguishable from sepsis or multiple organ dysfunction syndrome, and delayed diagnosis can lead to poor outcomes 6, 7

4. Overreliance on absolute lymphocyte count: The absolute lymphocyte count should not be used as the sole indicator for treatment in CLL 5