What are the causes of mild persistent lymphocytosis?

Causes of Mild Persistent Lymphocytosis

Mild persistent lymphocytosis is most commonly caused by chronic lymphocytic leukemia (CLL), viral infections, large granular lymphocyte disorders, or reactive processes related to underlying conditions such as autoimmune disorders, malignancies, or immunosuppression. 1, 2

Common Causes of Persistent Lymphocytosis

Malignant Causes

• Chronic Lymphocytic Leukemia (CLL)

  • Most common cause in adults, often presenting incidentally with lymphocytosis on routine blood tests 2
  • Can present with mild lymphocytosis (<10 × 10^9/L) even without bone marrow infiltration 3
  • Immunophenotyping can detect monoclonal B-cell populations before bone marrow infiltration occurs

• Large Granular Lymphocyte (LGL) Leukemia

  • Characterized by CD3+/CD8+ T-cell or NK cell expansions 4
  • Often presents with mild lymphocytosis and associated autoimmune cytopenias
  • May be associated with rheumatoid arthritis and other autoimmune conditions

• Other Lymphoproliferative Disorders

  • T-cell or NK-cell lymphomas/leukemias
  • Hodgkin lymphoma
  • Diffuse large B-cell lymphoma (DLBCL) 5

Infectious Causes

• Viral Infections

  • Epstein-Barr virus (EBV) - characterized by increased CD8+/CD57- cells and γδ T cells 6
  • Cytomegalovirus (CMV)
  • HIV
  • Hepatitis viruses
  • Other viral infections causing atypical lymphocytosis

• Bacterial and Fungal Infections

  • More common in immunocompromised patients
  • Can trigger reactive lymphocytosis

Autoimmune/Inflammatory Causes

• Rheumatoid arthritis - often associated with LGL disorders 4, 7
• Other autoimmune disorders - can cause reactive lymphocytosis
• Hemophagocytic lymphohistiocytosis (HLH) - can present with lymphocytosis as part of immune dysregulation 5, 1

Drug-Induced and Other Causes

• Medication reactions
• Post-splenectomy - loss of normal lymphocyte sequestration
• Stress lymphocytosis - typically transient
• Smoking - can cause mild persistent lymphocytosis
• Immunosuppression - particularly following organ transplantation 5

Diagnostic Approach to Persistent Lymphocytosis

Key Diagnostic Tests

1. Complete blood count with differential - quantify lymphocytosis and assess other cell lines

2. Peripheral blood smear - evaluate lymphocyte morphology for atypical features

3. Immunophenotyping - essential for detecting clonality and differentiating between:

   • B-cell disorders (CLL): CD19+, CD20+, CD5+, CD23+
   • T-cell disorders (LGL): CD3+, CD8+, CD57+
   • NK-cell disorders: CD3-, CD16/56+

4. Molecular testing

   • Immunoglobulin heavy chain gene rearrangement for B-cell disorders
   • T-cell receptor gene rearrangement for T-cell disorders

Additional Workup Based on Clinical Suspicion

• Viral studies - EBV, CMV, HIV, hepatitis panels
• Autoimmune markers - ANA, RF, anti-CCP antibodies
• Bone marrow examination - if malignancy suspected
• CT imaging - to assess for lymphadenopathy or splenomegaly

Clinical Pearls and Pitfalls

• Mild lymphocytosis without bone marrow infiltration can still represent early CLL - immunophenotyping is crucial for early detection 3
• Monoclonal lymphocytosis frequently progresses to CLL - requires long-term monitoring 3
• Autoimmune phenomena are common in LGL disorders - check for associated cytopenias and autoantibodies 7
• EBV-positive and EBV-negative atypical lymphocytosis have distinct immunophenotypic profiles - helpful in differential diagnosis 6
• Consider HLH in patients with persistent lymphocytosis and systemic inflammatory symptoms - fever, cytopenias, hepatosplenomegaly, and elevated ferritin 5, 1

Persistent lymphocytosis should never be dismissed as benign without appropriate investigation, as early detection of underlying malignancies can significantly impact patient outcomes.