What are the causes of lymphopenia?

Causes of Lymphopenia

Lymphopenia results from four primary mechanisms: insufficient lymphocyte production, increased lymphocyte destruction/catabolism, abnormal lymphocyte distribution, or multifactorial/idiopathic causes, with the specific etiology determined by clinical context, patient age, and associated findings. 1, 2

Definition and Diagnostic Thresholds

• Lymphopenia is defined as an absolute lymphocyte count <1,500/mm³ in adults and <4,500/mm³ in children younger than 8 months 1, 2
• CD4+ lymphopenia specifically warrants investigation when CD4+ T-cell counts are persistently <300 cells/mm³ in the absence of HIV infection 3, 4
• Severe lymphopenia (<500/mm³) represents a distinct subset with higher risk of opportunistic infections and may indicate primary immunodeficiency 5

Mechanism-Based Classification

1. Insufficient Lymphocyte Production (Decreased Thymic Output)

Primary Immunodeficiencies:

• Severe combined immunodeficiency (SCID) and combined immunodeficiency disorders present with profound T-cell lymphopenia, recurrent infections, and failure to thrive 3
• Immuno-osseous dysplasias (Schimke syndrome, cartilage-hair hypoplasia) combine skeletal abnormalities, growth retardation, and T-cell lymphopenia 3
• Dyskeratosis congenita causes lymphopenia affecting all subsets, presenting with the classic triad of lacy skin pigmentation, nail dystrophy, and oral leukoplakia 3
• Immunodeficiency with multiple intestinal atresia (TTC7A mutations) presents with SCID-like phenotype and high mortality from bloodstream infections 3

Secondary Production Defects:

• Malnutrition and zinc deficiency impair thymic function and lymphocyte production 1, 2
• Corticosteroid therapy reduces thymic output and lymphocyte production 1, 2

2. Increased Lymphocyte Catabolism/Destruction

Therapeutic Interventions:

• Radiation exposure causes predictable lymphocyte depletion, with a 50% decline in absolute lymphocyte count within 24 hours indicating potentially lethal exposure 3
• Chemotherapy and immunosuppressive medications (azathioprine, 6-mercaptopurine) cause bone marrow suppression 6
• Immune checkpoint inhibitors induce hematologic immune-related adverse events including lymphopenia 3, 6

Infectious Causes:

• HIV infection is the primary viral cause of persistent CD4+ lymphopenia 4, 2, 7
• Cytomegalovirus causes lymphopenia and presents with pneumonia, encephalitis, or gastrointestinal lesions 4, 6
• Dengue virus commonly causes lymphopenia with thrombocytopenia 4
• Herpes viruses (HSV, VZV) and ECHO viruses cause lymphopenia, with ECHO specifically causing CNS infections in agammaglobulinemia 4
• Hepatitis C virus (HCV) can cause leukopenia 6

Autoimmune Diseases:

• Systemic lupus erythematosus causes lymphopenia through lymphocytotoxic antibodies, excess apoptosis, complement-mediated cytolysis, and lymphopoiesis impairment 1, 2, 5
• SLE-associated lymphopenia <1 G/L is an independent risk factor for severe bacterial infections 5
• Autoimmune cytopenias in chronic lymphocytic leukemia occur through immune-mediated mechanisms, with corticosteroids as first-line treatment 6

3. Abnormal Lymphocyte Distribution/Trapping

Sequestration Mechanisms:

• Splenomegaly causes lymphocyte trapping and peripheral lymphopenia 1, 2
• Viral infections alter lymphocyte distribution patterns 1, 2
• Septic shock and extensive burns cause abnormal lymphocyte redistribution 1, 2
• Systemic granulomatosis (sarcoidosis, tuberculosis) sequesters lymphocytes in affected tissues 1, 2

4. Multifactorial and Idiopathic Causes

Malignancy-Related:

• Hematologic malignancies (chronic and acute leukemias, non-Hodgkin's lymphoma) cause lymphopenia through bone marrow infiltration 6
• Solid tumors can cause lymphopenia through unclear mechanisms 2
• Lymphoma itself causes lymphopenia, though distinguishing cause from effect requires follow-up 7

Other Causes:

• End-stage renal disease causes lymphopenia through multifactorial mechanisms 1, 2
• Ethnic variation (Ethiopians) demonstrates lower baseline lymphocyte counts 1
• Post-transplant graft failure results in severe leukopenia with mortality up to 80% 6

Idiopathic CD4+ Lymphocytopenia (ICL):

• Defined by persistent CD4+ counts ≤300 cells/mm³ or ≤20% of total lymphocytes without alternative diagnosis 3, 2, 7
• Most frequent presentations include cryptococcal infection, persistent HPV infection, and non-tuberculous mycobacterial infections 3
• Autoimmunity occurs in 23% of patients, most frequently systemic lupus erythematosus 3
• Heterozygous mutations in UNC119 and other genes have been identified in some cases 3

Clinical Significance and Risk Stratification

Infection Risk:

• CD4+ counts <300 cells/mm³ warrant suspicion for opportunistic infections in HIV-negative patients 3, 4
• CD4+ counts <200/mm³ require prophylaxis for Pneumocystis jirovecii and consideration for Mycobacterium avium complex prophylaxis 4
• Lymphopenia in all-cause hospitalizations has a pooled prevalence of 38% and is associated with increased risk of septic shock (RR 2.72) 8
• In-hospital mortality increases significantly with lymphopenia (RR 2.44), as does early mortality (RR 2.05) and late mortality (RR 1.59) 8

Common Pitfalls:

• Burns and trauma alone can cause lymphopenia independent of radiation exposure, complicating biodosimetry in combined injury scenarios 3
• EDTA-dependent platelet agglutination can cause pseudo-thrombocytopenia and should be excluded when evaluating cytopenias 6
• In SLE, lymphopenia <500/mm³ may represent a subset with primary immunodeficiency requiring specific management beyond standard SLE treatment 5
• Autoimmune cytopenias in CLL not responding to conventional therapy are indications for CLL-directed treatment, not just immunosuppression 6

Diagnostic Approach

Initial Evaluation:

• Examine peripheral blood smear to determine which white blood cell lines are affected and identify morphological abnormalities 6
• Measure lymphocyte subsets (CD4+, CD8+, B cells) to characterize the specific deficiency 3
• Consider bone marrow examination in unexplained persistent leukopenia, especially in older adults 6

Context-Specific Testing:

• For suspected primary immunodeficiency: immunoglobulin levels, mitogen proliferation, genetic testing 3
• For suspected ICL: exclude HIV, evaluate for opportunistic infections, screen for autoimmunity 3, 7
• For medication-related causes: review all prescription and non-prescription drugs, consider dose reduction or discontinuation 6