What are the causes of chronic elevated lymphocytes?

Causes of Chronic Elevated Lymphocytes

Chronic lymphocytosis is most commonly caused by chronic lymphocytic leukemia (CLL), followed by other lymphoproliferative disorders, viral infections (particularly hepatitis B and C), and autoimmune conditions. 1, 2

Malignant Causes

Chronic Lymphocytic Leukemia (CLL)

• CLL is the most common leukemia in adults and the leading cause of sustained lymphocytosis, defined by ≥5 × 10⁹/L monoclonal B-cells in peripheral blood persisting for ≥3 months 1, 3, 4
• The malignant lymphocytes characteristically express CD5+, CD23+, CD20 dim+, surface immunoglobulin dim+, and are FMC7- on flow cytometry 1, 2
• Approximately 70-80% of patients are asymptomatic at diagnosis, with lymphocytosis discovered incidentally on routine blood work 3
• The disease results from specific genomic alterations (particularly del(17p) and TP53 mutations) that impair apoptosis of clonal B-cells 2, 5, 4

Other Lymphoproliferative Disorders

• Small lymphocytic lymphoma (SLL) presents similarly to CLL but with predominant lymph node involvement rather than blood lymphocytosis 6
• Mantle cell lymphoma can present with peripheral blood involvement and lymphocytosis 7
• Follicular lymphoma occasionally manifests with circulating lymphoma cells 6

Infectious Causes

Viral Infections

• Hepatitis C virus (HCV) is found in 58.53% of CLL patients with viral coinfections, suggesting a potential role in pathogenesis or disease progression 8
• Hepatitis B virus (HBV) is present in 34.41% of CLL patients with viral coinfections 8
• These hepatotropic viruses are potentially lymphotropic and may trigger more aggressive disease with elevated expression of poor prognosis markers (CD38, Bcl-2, cyclin D1) 8
• Epstein-Barr virus (EBV) can cause persistent lymphocytosis, particularly in immunocompromised patients or post-transplant lymphoproliferative disorder 7
• Cytomegalovirus (CMV) primarily causes lymphocytosis in transplant recipients 7

Chronic Infections

• Tuberculosis and other chronic bacterial infections can cause reactive lymphocytosis 1
• Factors contributing to lymphocytosis other than CLL (infections, steroid administration) must be excluded, particularly when lymphocyte doubling time is the only criterion suggesting malignancy 6

Autoimmune and Inflammatory Causes

Autoimmune Lymphoproliferative Syndrome (ALPS)

• ALPS should be considered in younger patients presenting with chronic lymphadenopathy, splenomegaly, and autoimmune cytopenias 1
• Characterized by elevated CD3⁺TCRαβ⁺CD4⁻CD8⁻ double-negative T cells 1

CLL-Associated Autoimmunity

• Autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP) occur in 5-7% of CLL patients, representing a dysregulated immune system rather than a separate cause of lymphocytosis 6
• More than 90% of autoimmune disorders in CLL are caused by nonmalignant B lymphocytes producing polyclonal high-affinity IgG via T-cell-mediated mechanisms 6

Immunodeficiency-Related Causes

Primary Immunodeficiencies

• Hypogammaglobulinemia in CLL patients increases susceptibility to encapsulated bacteria (particularly Streptococcus pneumoniae), leading to recurrent infections that may perpetuate lymphocytosis 6
• Multiple myeloma patients with functional hypogammaglobulinemia may develop secondary lymphocytosis 6

Secondary Immunodeficiency

• Heavily pretreated patients with fludarabine-refractory CLL (median 3 prior regimens) experience serious infectious complications in nearly 90% of cases, which can contribute to reactive lymphocytosis 6

Medication-Induced Causes

Corticosteroid Administration

• Corticosteroids are a common iatrogenic cause of lymphocytosis and must be excluded when evaluating persistent elevation 6
• Corticosteroid-induced lymphocytosis typically resolves after discontinuation 1

Critical Diagnostic Approach

Initial Evaluation

• Blood smear examination is the immediate first step to assess lymphocyte morphology—small, mature-appearing lymphocytes suggest CLL 1
• Flow cytometry immunophenotyping is the single most important test to distinguish neoplastic from reactive lymphocytosis 1
• Sustained lymphocytosis >5 × 10⁹/L for ≥3 months not explained by other disorders is indicative of CLL 1, 3

Common Pitfalls

• Do not rely solely on absolute lymphocyte count—patients with initial counts <30 × 10⁹/L may require longer observation to determine lymphocyte doubling time 6
• Exclude infections, steroid use, and other secondary causes before attributing lymphocytosis to primary lymphoproliferative disorders 6, 1
• Bone marrow biopsy is not required for initial CLL diagnosis when peripheral blood shows characteristic findings on flow cytometry 7, 1

When Malignancy is Suspected

• Excisional lymph node biopsy is the gold standard when lymphoma is suspected and blood film is non-diagnostic 7
• Additional workup should include LDH, β2-microglobulin, hepatitis B/C screening (if treatment is considered), and imaging (CT chest/abdomen/pelvis) to evaluate lymphadenopathy extent 7, 1