Causes of Lymphocytosis (High Lymphocytes)
Lymphocytosis is most commonly caused by infections (particularly viral), but can also result from malignancies, autoimmune disorders, medications, and stress responses. The underlying causes can be broadly categorized into reactive (benign) and malignant etiologies.
Reactive (Benign) Causes
Viral Infections
- Epstein-Barr virus (infectious mononucleosis)
- Cytomegalovirus (CMV)
- HIV
- Hepatitis viruses
- Other viral infections
Bacterial Infections
- Certain bacterial infections can trigger lymphocytosis
- Particularly those causing prolonged immune stimulation
Autoimmune Disorders
- Rheumatoid arthritis
- Systemic lupus erythematosus
- Other autoimmune conditions 1
Medications
- Corticosteroids
- Lithium
- Beta agonists 2
Stress Responses
- Physical stress (seizures, anesthesia, overexertion)
- Emotional stress 2
Other Reactive Causes
- Post-splenectomy state
- Smoking
- Hypersensitivity reactions
Malignant Causes
Lymphoproliferative Disorders
- Chronic lymphocytic leukemia (CLL) - most common cause of persistent lymphocytosis in adults 3
- Lymphomas (particularly T-cell and NK-cell lymphomas)
- Acute lymphoblastic leukemia
Myeloproliferative Disorders
- Can occasionally present with lymphocytosis 2
Hemophagocytic Lymphohistiocytosis (HLH)
- Can be associated with:
- T-cell and NK-cell lymphomas/leukemias
- Diffuse large B-cell lymphoma (DLBCL)
- Hodgkin lymphoma 4
- Often triggered by viral infections, particularly EBV-associated lymphomas 4
Diagnostic Approach
Initial Assessment
- Complete blood count with differential
- Peripheral blood smear examination
- Presence of abnormal cells (blasts, lymphoma cells) suggests malignancy
- Reactive lymphocytes (larger, more cytoplasm, irregular nuclei) suggest viral infection 5
Risk Factors for Malignancy
- Age (risk increases with age) 4
- Persistent lymphocytosis without explanation
- Concurrent abnormalities in red blood cell or platelet counts
- Weight loss, bleeding/bruising
- Hepatosplenomegaly or lymphadenopathy 2
Warning Signs
- White blood cell counts above 100,000/mm³ represent a medical emergency due to risk of brain infarction and hemorrhage 2
- Monomorphic appearance of lymphocytes suggests malignancy
- Pleomorphic lymphocytes suggest reactive causes 5
Special Considerations
Chronic Lymphocytic Leukemia
- Most patients present incidentally due to lymphocytosis found on routine blood tests
- Outcomes vary based on genetic predisposition and prognostic markers (age, staging, B2-microglobulin) 3
- Patients with CLL have increased risk of major infections, secondary cancers, and autoimmune diseases 6
Distinguishing Features
- Malignant lymphocytosis: monoclonal population, abnormal morphology, persistent elevation
- Reactive lymphocytosis: polyclonal, normal or atypical morphology, usually transient
Common Pitfalls
- Assuming all lymphocytosis is benign in the absence of symptoms
- Failing to follow up on persistent lymphocytosis
- Not considering medication effects when evaluating lymphocytosis
- Missing the diagnosis of CLL, which often presents asymptomatically with isolated lymphocytosis
When evaluating lymphocytosis, the clinical context, duration, degree of elevation, and morphologic features of the lymphocytes are crucial in determining whether the cause is benign or malignant.