What causes lymphocytosis (increased lymphocytes)?

Causes of Lymphocytosis (Increased Lymphocytes)

Lymphocytosis is most commonly caused by infections (particularly viral), malignancies (especially lymphoproliferative disorders), and immune dysregulation conditions, with the specific etiology varying by age group and clinical context. 1

Infectious Causes

• Viral infections:
  • Epstein-Barr virus (EBV) - classic cause of infectious mononucleosis 2
  • Cytomegalovirus (CMV)
  • HIV
  • Hepatitis viruses
  • Common childhood viral illnesses 3
• Bacterial infections (less common than viral causes)
• Parasitic infections (can cause eosinophilia with lymphocytosis) 3

Malignant Causes

• Lymphoproliferative disorders:
  • Chronic lymphocytic leukemia (CLL) - most common cause of persistent lymphocytosis in adults 1, 4
  • T-cell and NK-cell lymphomas/leukemias (35% of adult cases) 5
  • B-cell lymphomas (32% of adult cases), especially diffuse large B-cell lymphoma (DLBCL) 5, 1
  • Hodgkin lymphoma (6% of adult cases) 5
  • Acute lymphoblastic leukemia
  • Large granular lymphocytic leukemia

Immune/Inflammatory Causes

• Hemophagocytic lymphohistiocytosis (HLH) - can be triggered by:
  • Malignancies (particularly lymphomas) 5, 1
  • Infections (viral, fungal, bacterial) 5
  • Immunosuppression/post-chemotherapy 5
• Autoimmune disorders:
  • Rheumatoid arthritis
  • Systemic lupus erythematosus
  • Other connective tissue diseases

Other Causes

• Physiologic stress responses:
  • Surgery
  • Trauma
  • Emotional stress
  • Exercise 3, 6
• Medications:
  • Corticosteroids
  • Lithium
  • Beta-agonists 6
• Other conditions:
  • Smoking
  • Obesity
  • Asplenia
  • Chronic inflammatory conditions 3

Age-Specific Considerations

• Children:
  • Viral infections are the most common cause 7
  • Primary (genetic) HLH is more common than in adults 1
  • Acute lymphoblastic leukemia is the most common malignant cause
• Adults:
  • CLL is a common cause of persistent lymphocytosis 4
  • Secondary (acquired) HLH is more common than in children 1
  • T-cell malignancies predominate in Asian countries, while DLBCL is more common in Western countries 5, 1

Diagnostic Approach

1. Evaluate persistence and degree of lymphocytosis

   • Transient lymphocytosis is typically benign
   • Persistent or severe lymphocytosis warrants further investigation

2. Assess for associated symptoms:

   • Fever, weight loss, night sweats (concerning for malignancy)
   • Hepatosplenomegaly, lymphadenopathy
   • Recurrent infections (immunodeficiency)
   • Skin rash, joint pain (autoimmune)

3. Laboratory evaluation:

   • Complete blood count with differential and peripheral blood smear
   • Immunophenotyping for suspected malignancy
   • Viral studies (EBV, CMV, HIV) for suspected infectious etiology
   • Additional testing based on clinical suspicion (bone marrow biopsy, lymph node biopsy)

Important Caveats

• Isolated atypical lymphocytosis without other clinical features (splenomegaly, pharyngitis, adenopathy) is often not due to infectious mononucleosis 7
• White blood cell counts above 100,000/mm³ represent a medical emergency due to risk of brain infarction and hemorrhage 6
• Persistent lymphocytosis should never be dismissed as benign without investigation, as early detection of underlying malignancies significantly impacts outcomes 1
• The presence of concurrent abnormalities in red blood cell or platelet counts increases suspicion for primary bone marrow disorders 6