What are the possible causes of a low white blood cell (WBC) count?

Causes of Low White Blood Cell Count

Low WBC count results from either decreased bone marrow production, increased destruction/utilization of white cells, or sequestration in tissues—with infections, medications, autoimmune conditions, nutritional deficiencies, bone marrow disorders, and hypersplenism accounting for the vast majority of cases. 1, 2

Primary Mechanisms

Decreased Bone Marrow Production

• Medications are among the most common causes, including chemotherapy agents, immunosuppressants, antithyroid drugs, and certain antibiotics that suppress marrow function 2
• Nutritional deficiencies, particularly vitamin B12 and folate deficiency, impair DNA synthesis and lead to ineffective white cell production with macrocytosis 3
• Bone marrow disorders including aplastic anemia, myelodysplastic syndromes, and infiltrative processes (leukemia, lymphoma, metastatic cancer) directly compromise production capacity 2
• Viral infections can temporarily suppress marrow function, with influenza A commonly causing leukopenia (WBC <4.0 in 8-27% of cases) and lymphopenia 3

Increased Destruction or Utilization

• Severe bacterial infections paradoxically cause leukopenia through overwhelming consumption of neutrophils, particularly in sepsis and pneumonia where leukopenia indicates poor prognosis and increased mortality 3, 1
• Autoimmune destruction occurs in conditions like systemic lupus erythematosus and rheumatoid arthritis, where antibodies target white cells 2
• Hypersplenism from any cause (cirrhosis, portal hypertension, storage diseases) leads to excessive sequestration and destruction of all blood cell lines 2

Redistribution

• Margination occurs when neutrophils adhere to vessel walls rather than circulating, creating falsely low counts without true deficiency 2

Clinical Context Matters

Infection-Related Leukopenia

• In influenza, leukopenia with lymphopenia is characteristic—Vietnamese children with H5N1 had mean WBC 2.44 with lymphocyte count 0.66, and 6 of 7 died, indicating severe disease 3
• Community-acquired pneumonia with leukopenia consistently predicts excess mortality and worse outcomes compared to normal or elevated counts 1
• The combination of fever plus leukopenia suggests severe bacterial infection with poor prognosis and requires immediate intervention 1

Chronic Inflammatory Conditions

• Adult-onset Still's disease typically presents with marked leukocytosis (50% have WBC >15,000,37% >20,000), but the absence of expected leukocytosis or frank leukopenia suggests bone marrow suppression from medications or disease complications 3
• Inflammatory bowel disease patients may develop leukopenia from thiopurine treatment (azathioprine, 6-mercaptopurine) or nutritional deficiencies 3

Medication-Induced

• Corticosteroids and lithium typically cause leukocytosis, so their presence makes drug-induced leukopenia less likely 4
• Chemotherapy agents predictably suppress all cell lines, with severity depending on dose and timing 3

Critical Assessment Framework

Immediate Evaluation Required

• Obtain manual differential count to calculate absolute neutrophil count (ANC)—this is more important than total WBC alone 1
• ANC ≥1.5 × 10³/μL with normal differentials in an otherwise healthy adult is clinically insignificant and requires only repeat testing in 4-6 weeks 1
• ANC <1.0 × 10³/μL indicates high infection risk and warrants hematology referral 1
• ANC <0.5 × 10³/μL represents severe neutropenia with substantial infection risk requiring urgent intervention 1

Complete Blood Count Analysis

• Assess all three cell lines (WBC, hemoglobin, platelets)—abnormalities in two or more suggest primary bone marrow pathology requiring hematology consultation 3
• Mean corpuscular volume (MCV) helps identify mechanism: low MCV suggests iron deficiency, high MCV suggests B12/folate deficiency or medication effect 3
• Reticulocyte count distinguishes production failure (low/normal reticulocytes) from increased destruction (elevated reticulocytes) 3

Red Flag Features Requiring Urgent Workup

• Progressive decline over serial measurements indicates evolving bone marrow disorder 1
• Recurrent infections despite adequate cell counts suggest functional immune deficiency 1
• Splenomegaly or lymphadenopathy raises concern for hematologic malignancy 1
• Constitutional symptoms including weight loss, night sweats, or bleeding/bruising mandate immediate hematology referral 4

Common Pitfalls

Do Not Assume Benign Causes Without Verification

• Mild leukopenia (WBC 3.0-4.0 × 10³/μL) requires repeat CBC in 4-6 weeks to assess trend, not immediate dismissal 1
• Normal ANC (≥1.5 × 10³/μL) indicates preserved infection-fighting capacity and argues against urgent intervention 1

Recognize Context-Dependent Significance

• In elderly patients with suspected infection, leukopenia carries worse prognosis than leukocytosis, and absence of leukocytosis does not exclude serious bacterial infection 1
• In acute leukemia, leukopenia at presentation paradoxically indicates better prognosis than leukocytosis 1

Avoid Over-Reliance on Total WBC Alone

• The differential count is essential—a patient with WBC 3.5 but ANC 2.0 has adequate neutrophil reserves, while WBC 4.0 with ANC 0.8 requires urgent action 1