Causes of Low White Blood Cell Count (Leukopenia)
Leukopenia results from either decreased bone marrow production or increased destruction/utilization of white blood cells, with the most common causes being medications (especially chemotherapy and immunosuppressants), infections, hematologic malignancies, autoimmune disorders, and bone marrow failure syndromes. 1
Medication-Induced Causes
Chemotherapy agents are the most frequent cause of drug-induced leukopenia through direct bone marrow suppression 1. This represents a predictable, dose-dependent toxicity in cancer treatment.
Immunosuppressive medications used for autoimmune conditions commonly cause leukopenia 1. Specific agents include:
- Azathioprine and 6-mercaptopurine (used in inflammatory bowel disease) cause bone marrow toxicity 1
- Immune checkpoint inhibitors induce hematologic immune-related adverse events 1
- Post-transplant immunosuppression regimens 1
Various prescription and non-prescription drugs, along with environmental toxins, can trigger leukopenia 1. When medication-induced leukopenia occurs, dose reduction or discontinuation of the offending agent should be considered 1.
Infection-Related Causes
Viral infections are important infectious causes, particularly:
- HIV infection increases risk of leukopenia and subsequent opportunistic infections 1
- Hepatitis C virus (HCV) 1
- Cytomegalovirus can lead to cytopenias including leukopenia 1
Bacterial infections can paradoxically cause leukopenia rather than leukocytosis. Community-acquired pneumonia with leukopenia (WBC <4,000 cells/mm³) is a minor criterion for severe CAP and consistently associates with excess mortality and increased complications like ARDS 1. This occurs in both pneumococcal and gram-negative infections 1.
Hematologic Malignancies
Bone marrow infiltration by malignant cells impairs normal white cell production:
- Chronic lymphocytic leukemia (CLL) causes cytopenias through bone marrow infiltration or immune-mediated mechanisms 1
- Acute leukemias 1
- Non-Hodgkin's lymphoma 1
- Myelodysplastic syndromes impair normal blood cell production 1
Autoimmune cytopenias in CLL deserve special mention—autoimmune hemolytic anemia and immune thrombocytopenia are more common than autoimmune granulocytopenia, but all can occur 1. Importantly, autoimmune cytopenias in CLL may have better prognosis than those from marrow infiltration 1.
Bone Marrow Failure Syndromes
Aplastic anemia causes pancytopenia including leukopenia through bone marrow failure 1. This represents a true production defect requiring specific evaluation.
Bone marrow diseases including fibrosis and other infiltrative processes 1.
Autoimmune and Immune-Mediated Causes
Systemic lupus erythematosus (SLE) frequently causes leukopenia—in one series, 30.9% of SLE patients had WBC <4.0 × 10⁹/L 2. Leukopenia with WBC <3.0 × 10⁹/L in SLE patients correlates with disease activity, showing lower complement levels and higher anti-dsDNA antibody positivity 2.
Immunoneutropenia represents antibody-mediated destruction 3.
Hypersplenism
Splenic sequestration causes peripheral leukopenia through increased destruction and pooling 3.
Nutritional Deficiencies
Megaloblastosis from vitamin B12 or folate deficiency can present with leukopenia alongside other cytopenias 3.
Primary/Hereditary Causes
Primary neutropenia is very rare and sometimes hereditary, particularly in children, potentially associated with other developmental defects 3.
Critical Clinical Context
Graft failure after allogeneic transplantation results in severe leukopenia with mortality up to 80% 1.
Infection risk increases dramatically when neutrophil counts fall below 500/mcL, with high risk (10-20%) at counts below 100/mcL 1. This risk is particularly elevated in cancer patients 1 and those with autoimmune disorders on immunosuppressive therapy 1.
Diagnostic Approach
Examine the peripheral blood smear to determine which white blood cell lines are affected and identify morphological abnormalities 1. This is essential before proceeding with further workup.
Check previous blood counts to assess the dynamic development of leukopenia 4. Acute versus chronic patterns provide diagnostic clues.
Evaluate all cell lines—bi- or pancytopenia usually implies insufficient bone marrow production 4, warranting bone marrow examination in unexplained persistent leukopenia, especially in older adults 1.
EDTA-dependent platelet agglutination can cause pseudo-thrombocytopenia and must be excluded when evaluating cytopenias 1.
Management Priorities
For febrile neutropenia, immediate empiric antimicrobial therapy with anti-pseudomonas β-lactam agent, carbapenem, or piperacillin-tazobactam is essential 1. Prompt antibiotic therapy is critical 1.
For autoimmune-mediated leukopenia, corticosteroids are first-line treatment 1. In CLL with autoimmune cytopenia and warm antibodies, corticosteroids are the initial treatment option 1.
Antimicrobial prophylaxis may be indicated in severe neutropenia, especially in cancer patients 1.
Monitoring frequency should be based on leukopenia severity and the underlying condition 1.
Critical Pitfall
In patients with leukopenia and fever, especially with agranulocytosis, admission is mandatory with immediate broad-spectrum antibiotics to reduce mortality 4. In alcohol abuse patients with leukopenia from CAP, adverse manifestations of septic shock and ARDS may be delayed or masked, benefiting from ICU monitoring 1.