What are the causes of leukopenia (low white blood cell count)?

Causes of Leukopenia

Leukopenia results from either decreased production of white blood cells in the bone marrow, increased destruction/utilization, or both, with the most common causes being medications (especially chemotherapy and immunosuppressants), infections, hematologic malignancies, autoimmune disorders, and bone marrow failure syndromes. 1, 2

Medication-Induced Causes

Chemotherapy and Immunosuppressive Agents

• Chemotherapy agents are the most common cause of leukopenia through direct bone marrow suppression, affecting production of all white blood cell lines 1, 2
• Immunosuppressive medications including azathioprine and 6-mercaptopurine cause bone marrow toxicity leading to leukopenia, particularly in inflammatory bowel disease treatment 1, 2
• Thiopurines (azathioprine, 6-mercaptopurine) cause severe bone marrow toxicity especially in patients with thiopurine methyltransferase (TPMT) deficiency, requiring TPMT testing before treatment initiation 2
• Sulfonamides (including trimethoprim-sulfamethoxazole) can cause agranulocytosis, aplastic anemia, leukopenia, and neutropenia as hematologic adverse effects 3
• Chronic use of sulfamethoxazole-trimethoprim at high doses or extended periods causes bone marrow depression manifested as leukopenia 3

Other Medications

• Immune checkpoint inhibitors induce hematologic immune-related adverse events including leukopenia 1
• Various prescription and non-prescription drugs, including environmental toxins, can cause leukopenia 1

Hematologic Malignancies

Direct Bone Marrow Involvement

• Acute and chronic leukemias cause leukopenia through bone marrow infiltration, replacing normal hematopoietic cells 1, 2
• Chronic lymphocytic leukemia (CLL) causes cytopenias through both bone marrow infiltration and immune-mediated mechanisms 1
• Non-Hodgkin's lymphoma can infiltrate bone marrow leading to leukopenia 1
• Myelodysplastic syndromes impair normal blood cell production in the bone marrow 1

Autoimmune Mechanisms in Malignancy

• In CLL, autoimmune mechanisms cause cytopenias with autoimmune granulocytopenia being less common than autoimmune hemolytic anemia or immune thrombocytopenia 1
• Corticosteroids are the first-line treatment for autoimmune cytopenias with warm antibodies in CLL 1
• Autoimmune cytopenias not responding to conventional therapy are indications for CLL-directed treatment 1

Bone Marrow Failure Syndromes

• Aplastic anemia causes pancytopenia including leukopenia through failure of all bone marrow cell lines 1
• Bone marrow fibrosis impairs normal hematopoiesis leading to leukopenia 1

Infection-Related Causes

• Viral infections, particularly HIV and hepatitis C virus (HCV), cause leukopenia 1
• Cytomegalovirus infection leads to cytopenias including leukopenia 1
• Bacterial infections can cause leukopenia, especially in severe sepsis 2

Autoimmune and Immune-Mediated Causes

• Autoimmune disorders cause leukopenia through immune-mediated destruction of white blood cells 1
• Systemic lupus erythematosus causes leukopenia, lymphopenia, and neutropenia with prevalence of leukopenia reported in 22-41.8% of cases 4
• Corticosteroids are often first-line treatment for autoimmune-mediated leukopenia 1, 2

Post-Transplant and Immunosuppression

• Post-transplant immunosuppression causes leukopenia 1
• Graft failure after allogeneic transplantation results in severe leukopenia with mortality up to 80% 5

Clinical Context: Severe Community-Acquired Pneumonia

• Leukopenia (WBC count <4,000 cells/mm³) resulting from community-acquired pneumonia is a minor criterion for severe CAP, consistently associated with excess mortality and increased risk of complications such as acute respiratory distress syndrome 5
• Leukopenia occurs in both bacteremic pneumococcal disease and gram-negative CAP 5
• In patients with alcohol abuse history, adverse manifestations of septic shock and ARDS may be delayed or masked when leukopenia is present, benefiting from ICU monitoring 5

Important Clinical Pitfalls

Diagnostic Considerations

• Always examine peripheral blood smear to determine which white blood cell lines are affected and look for morphological abnormalities 1
• Check previous blood counts to assess dynamic development of leukopenia 6
• Evaluate for bi- or pancytopenia, which usually implies insufficient bone marrow production 6
• Consider bone marrow examination in patients with unexplained persistent leukopenia, especially older adults 1
• Exclude EDTA-dependent platelet agglutination causing pseudo-thrombocytopenia when evaluating cytopenias 1

Risk Assessment

• The risk of infection increases significantly when neutrophil counts fall below 500/mcL, with highest risk (10-20%) at counts below 100/mcL 1, 2
• Approximately 50-60% of patients who become febrile during neutropenia have an established or occult infection 2
• Patients with cancer and leukopenia are at particularly high risk for infectious complications 1

Management Priorities

• For febrile neutropenia, immediate empiric antimicrobial therapy with an anti-pseudomonas β-lactam agent (carbapenem or piperacillin-tazobactam) is essential 1, 2
• Antimicrobial prophylaxis may be indicated in severe neutropenia, especially in cancer patients 1, 2
• For medication-induced leukopenia, consider dose reduction or discontinuation of the offending agent 1
• Most cases of drug-induced leukopenia recover spontaneously or remain stable during continued therapy, but progressive decreases require drug cessation 7