What are the causes of lymphocytosis?

Causes of Lymphocytosis

Lymphocytosis can be caused by infections (particularly viral), malignancies, autoimmune disorders, and drug reactions, with viral infections being the most common trigger. 1, 2, 3

Infectious Causes

• Viral infections:

  • Epstein-Barr virus (EBV) - most common viral cause 4, 1
  • Cytomegalovirus (CMV) 4, 1
  • Other herpesviruses
  • HIV
  • Hepatitis viruses

• Bacterial infections:

  • Tuberculosis
  • Pertussis (whooping cough)
  • Brucellosis

• Parasitic infections:

  • Toxoplasmosis
  • Babesiosis

Malignant Causes

• Lymphoproliferative disorders:
  • Chronic lymphocytic leukemia (CLL) - most common cause of persistent lymphocytosis in adults 2
  • T-cell and NK-cell lymphomas/leukemias 4
  • Diffuse large B-cell lymphoma (DLBCL) 4
  • Hodgkin lymphoma 4

Autoimmune/Inflammatory Causes

• Autoimmune disorders:

  • Rheumatoid arthritis 5
  • Psoriatic arthritis 5
  • Systemic lupus erythematosus
  • Autoimmune hemolytic anemia (AIHA) 4
  • Autoimmune thrombocytopenia (ITP) 4

• Inflammatory conditions:

  • Hemophagocytic lymphohistiocytosis (HLH) - characterized by excessive activation of macrophages and T lymphocytes 1, 6, 7
  • Sarcoidosis
  • Inflammatory bowel disease

Medication-Related Causes

• Drug reactions:
  • Anti-TNF-α agents (observed in 12% of rheumatoid and psoriatic arthritis patients) 5
  • Phenytoin
  • Certain antibiotics

Other Causes

• Stress-induced lymphocytosis:

  • Acute physical stress
  • Post-surgical states
  • Trauma

• Smoking

• Splenectomy (due to decreased lymphocyte removal)

Clinical Pearls

• In EBV-positive infectious mononucleosis, there is a characteristic increase in CD8+ T cells, NK cells, and γδ T cells compared to other causes of atypical lymphocytosis 3
• Lymphocytosis in CLL is typically incidental, found on routine blood tests 2
• Anti-TNF-α therapy can cause a mild, reversible CD4+ T-cell lymphocytosis that resolves after discontinuation of therapy 5
• Risk factors for developing lymphocytosis during anti-TNF-α therapy include higher baseline lymphocyte count, steroid use, and shorter disease duration before starting biological therapy 5

Diagnostic Approach

1. Evaluate persistence and degree of lymphocytosis
2. Review peripheral blood smear for atypical lymphocytes
3. Consider flow cytometry for persistent or significant lymphocytosis to determine lymphocyte subsets
4. Test for common viral causes (EBV, CMV) in acute presentations
5. Consider bone marrow examination if malignancy is suspected

Warning Signs Requiring Urgent Evaluation

• Persistent lymphocytosis >5,000 cells/μL
• Presence of other cytopenias
• Hepatosplenomegaly
• B symptoms (fever, night sweats, weight loss)
• Markedly elevated ferritin (>10,000 μg/L in children, though less specific in adults) 1

When evaluating lymphocytosis, it's crucial to distinguish between benign reactive processes and malignant conditions, as management and prognosis differ significantly.