What are the causes of atypical lymphocytosis?

Causes of Atypical Lymphocytosis

Atypical lymphocytosis represents a polyclonal immune response to antigenic stimulation and is most commonly caused by viral infections (particularly EBV, CMV, and HHV-6), but also occurs with other infections, malignancies, autoimmune disorders, drug reactions, and post-transplant states. 1

Infectious Causes

Viral Infections (Most Common)

• Epstein-Barr virus (EBV) is the classic cause, accounting for 40% of heterophile-negative cases with atypical lymphocytosis, and is characterized by increased CD57-negative CD8 T cells and gamma-delta T cells. 2, 3

• Cytomegalovirus (CMV) accounts for 39% of heterophile-negative cases with atypical lymphocytosis, with a trend toward association with Downey type I lymphocytes. 3

• Human herpesvirus 6 (HHV-6) causes 25% of cases and is significantly associated with Downey type III atypical lymphocytes. 3

• Other viral infections including HIV, dengue, and various bacterial and viral pathogens can trigger atypical lymphocytosis. 1, 4

Bacterial and Parasitic Infections

• Ehrlichia chaffeensis and other rickettsial infections are documented triggers for atypical lymphocytosis and can progress to secondary hemophagocytic lymphohistiocytosis (HLH). 4

• Toxoplasma infection accounts for approximately 3% of heterophile-negative cases with atypical lymphocytosis. 3

• Invasive fungi and bacterial infections, particularly in immunocompromised patients receiving chemotherapy, can trigger atypical lymphocytosis as part of HLH. 5

Malignancy-Associated Causes

• T-cell and NK-cell lymphomas or leukemias are the most frequent malignancy associations, accounting for 35% of adult HLH cases with atypical lymphocytosis. 5, 4

• Diffuse large B-cell lymphoma (DLBCL) is the predominant trigger in Western countries, representing 32% of B-cell lymphoma-associated cases. 5, 4

• Hodgkin lymphoma accounts for 6% of malignancy-associated HLH cases with atypical lymphocytosis. 5, 4

• Solid tumors can cause paraneoplastic atypical lymphocytosis, though this represents only 3% of malignancy-associated cases. 5

Autoimmune and Inflammatory Causes

• Autoimmune disorders including systemic lupus erythematosus, adult-onset Still's disease, and systemic juvenile idiopathic arthritis can trigger atypical lymphocytosis as part of macrophage activation syndrome (MAS). 6, 4

• Collagen diseases and other autoimmune disorders produce atypical lymphocytosis through immune dysregulation. 1

Iatrogenic and Drug-Related Causes

• Chemotherapy-induced immunosuppression creates vulnerability to infections that trigger atypical lymphocytosis and secondary HLH. 5, 4

• Post-transplant immunosuppression, particularly after kidney transplantation, is associated with infection-triggered atypical lymphocytosis and HLH. 5

• CAR T-cell therapy causes atypical lymphocytosis in 3.5% of patients as part of HLH/cytokine release syndrome. 6

• Drug reactions and allergens can stimulate atypical lymphocyte production through immune activation. 1, 7

Immunophenotypic Characteristics

All forms of atypical lymphocytosis share common features:

• Marked increase in activated CD8-positive T cells (CD3+/CD8+, CD8+/CD48-, CD8+/CD57-, CD8+/CD95+). 2

• Moderate increase in NK cells (CD3-/CD16/56+) and gamma-delta T cells (CD3+/gamma-delta+). 2

• No increase in CD4-positive T cells or B cells (CD19+), distinguishing reactive lymphocytosis from lymphoproliferative disorders. 2

• Increased size and active DNA synthesis, resembling lymphocytes transformed by mitogens or antigens in vitro. 1

Clinical Pitfalls

• Isolated atypical lymphocytosis without the classic triad (splenomegaly, pharyngitis, adenopathy) does not necessarily indicate infectious mononucleosis; only 1 of 45 children with ≥5% atypical lymphocytes had acute EBV infection. 8

• Multiple concurrent viral infections are common, with 70% of heterophile-negative patients showing positive serology for at least one pathogen, complicating definitive diagnosis. 3

• Peripheral blood lymphocyte count ≥2.375 × 10⁹/L has 68% sensitivity and 83% specificity for predicting atypical lymphocytes, while lymphocyte proportion >35.9% has 89% sensitivity and 76% specificity. 7

• Co-triggers frequently coexist, particularly viral infections acting as co-triggers in malignancy-associated cases, making it difficult to differentiate primary from secondary causes. 5, 4

• Do not overlook geographic or exposure history; tick-borne diseases can mimic other febrile illnesses and require pathogen-specific antimicrobial therapy. 4