What causes elevated lymphocytes?

Causes of Elevated Lymphocytes

Elevated lymphocytes result from either reactive processes (infections, stress, autoimmune conditions) or primary lymphoproliferative disorders, with viral infections—particularly EBV and CMV—being the most common benign causes, while chronic lymphocytic leukemia represents the most frequent malignant etiology in adults. 1, 2, 3

Infectious Causes

Viral Infections

• Epstein-Barr virus (EBV) and cytomegalovirus (CMV) are the most frequent viral triggers of lymphocytosis, characterized by marked increases in activated CD8+ T cells and NK cells 4, 5
• EBV-positive infectious mononucleosis specifically shows increased CD8+/CD57- cells and gammadelta T cells compared to other viral causes 5
• Other viral infections including respiratory syncytial virus, parainfluenza, adenovirus, and rotavirus can cause persistent lymphocytosis, particularly in immunocompromised patients 6
• HIV infection should be considered, especially when CD4+ lymphocyte counts are evaluated in the context of opportunistic infections 6

Bacterial and Fungal Infections

• Bacterial infections can trigger reactive lymphocytosis, though less commonly than viral causes 2, 3
• Invasive fungal infections, particularly in chemotherapy-induced immunosuppression, may cause lymphocytosis as part of secondary HLH 4

Malignant Causes

Chronic Lymphoproliferative Disorders

• Chronic lymphocytic leukemia (CLL) is the most common malignant cause in adults, often diagnosed incidentally with asymptomatic lymphocytosis 1, 3
• T-cell and NK-cell lymphomas/leukemias are strongly associated with hemophagocytic lymphohistiocytosis and marked lymphocytosis 4
• Diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma can present with elevated lymphocyte counts 4

Acute Leukemias

• Acute leukemias present with extremely elevated white blood cell counts and concurrent cytopenias, with patients typically appearing ill at presentation 3
• White blood cell counts above 100,000/mm³ represent a medical emergency due to risk of brain infarction and hemorrhage 3

Autoimmune and Inflammatory Conditions

Autoimmune Lymphoproliferative Syndrome (ALPS)

• ALPS requires chronic (≥6 months) nonmalignant, noninfectious lymphadenopathy or splenomegaly PLUS elevated double-negative T cells (DNT) ≥1.5% of total lymphocytes 6
• Caused by mutations in FAS, FASLG, or CASP10 genes affecting lymphocyte apoptosis 6
• May present with autoimmune cytopenias and polyclonal hypergammaglobulinemia 6

Rheumatoid Arthritis

• Can be associated with expanded populations of large granular lymphocytes, typically presenting with neutropenia and normal or elevated total leukocyte counts 7
• Usually occurs in older patients and may appear simultaneously with arthritis onset 7

Hemophagocytic Lymphohistiocytosis (HLH)

• HLH represents severe hyperactivation of lymphocytes and macrophages with high mortality if untreated, requiring at least 5 of 8 HLH-2004 criteria including fever, splenomegaly, cytopenias, and markedly elevated ferritin 8, 4, 9
• Can be triggered by infections (especially EBV, CMV), malignancies (particularly T-cell lymphomas), autoimmune conditions, or chemotherapy 8, 4
• Often presents with Omenn-like features including erythroderma, hepatosplenomegaly, lymphadenopathy, elevated IgE, and eosinophilia 6

Drug-Induced Causes

Medications

• Corticosteroids, lithium, and beta agonists are commonly associated with leukocytosis including lymphocytosis 3
• BTK inhibitors (ibrutinib) and PI3K inhibitors (idelalisib) cause redistribution lymphocytosis that does NOT indicate disease progression and should not prompt treatment discontinuation 1

Physiologic and Stress-Related Causes

Physical and Emotional Stress

• Physical stress from seizures, anesthesia, or overexertion can elevate lymphocyte counts 3
• Emotional stress represents a benign cause of transient lymphocytosis 3

Congenital Immunodeficiency Syndromes

Primary Immunodeficiencies

• Congenital athymia presents with CD3+ T lymphocytes <50 cells/µL but may show immune dysregulation with oligoclonal T-cell expansion (Omenn-like features) 6
• X-linked lymphoproliferative syndromes (XLP1, XLP2) are associated with EBV-triggered HLH and lymphoma development 4

Critical Diagnostic Pitfalls

• Do not assume all adult lymphocytosis is CLL—always consider reactive causes, particularly viral infections 1, 2
• Do not overlook HLH in patients with lymphocytosis plus fever and cytopenias, as delayed treatment dramatically increases mortality 1, 9
• Lymphocytosis from ibrutinib/idelalisib is expected pharmacologic effect, not treatment failure 1
• TCR-αβ double-negative T cells between 1.0-1.5% may be seen in healthy persons or systemic lupus erythematosus; levels ≥1.5% in the setting of normal/elevated lymphocyte counts are required for ALPS diagnosis 6