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

Most Common Causes of Leukopenia (Low White Blood Cell Count)

Leukopenia is most commonly caused by medications, infections, cancer treatments, and bone marrow disorders, with neutropenia (low neutrophil count) being the predominant type of white blood cell deficiency responsible for most clinical consequences.

Primary Categories of Leukopenia Causes

1. Medication-Induced Leukopenia

• Chemotherapeutic agents - Most common medication cause due to bone marrow suppression 1
• Antibiotics - Particularly trimethoprim/sulfamethoxazole which can cause agranulocytosis, aplastic anemia, and leukopenia 2
• Other medications:
  • Antipsychotics (clozapine)
  • Antithyroid drugs
  • Immunosuppressants
  • Anticonvulsants
  • Certain NSAIDs

2. Infectious Causes

• Viral infections - Common cause of transient leukopenia:
  • Influenza
  • HIV
  • Hepatitis
  • Epstein-Barr virus
  • Cytomegalovirus
  • COVID-19
• Bacterial infections - Particularly overwhelming infections:
  • Typhoid fever
  • Tuberculosis
  • Brucellosis
  • Severe sepsis (can cause leukopenia through consumption)

3. Cancer and Cancer Treatments

• Direct bone marrow infiltration by malignant cells 1
• Chemotherapy and radiation therapy - Cause disruption of bone marrow function and mucosal barriers 1
• Hematologic malignancies - Leukemias, lymphomas, and myelodysplastic syndromes can cause leukopenia through bone marrow dysfunction 1

4. Autoimmune Disorders

• Systemic lupus erythematosus
• Rheumatoid arthritis
• Felty's syndrome
• Autoimmune neutropenia - Particularly in children

5. Congenital/Genetic Causes

• Primary immunodeficiency disorders 1:
  • Wiskott-Aldrich syndrome (WAS) - X-linked disorder with thrombocytopenia, small platelets, and variable immune defects 1
  • X-linked neutropenia - Rare variant of WAS 1
  • Severe congenital neutropenia
• 22q11.2 deletion syndrome - Associated with thrombocytopenia, anemia, and leukopenia 1

6. Nutritional Deficiencies

• Vitamin B12 deficiency - Can cause megaloblastic anemia with leukopenia
• Folate deficiency
• Severe malnutrition

7. Splenic Sequestration

• Hypersplenism - Due to portal hypertension, cirrhosis, or other causes of splenomegaly 3

Clinical Significance by Severity

Mild Leukopenia (WBC 3,000-4,000/μL)

• Often asymptomatic
• Minimal increased risk of infection
• May be normal variant in some populations

Moderate Leukopenia (WBC 2,000-3,000/μL)

• Increased risk of common infections
• Monitor closely, especially if neutropenic

Severe Leukopenia (WBC <2,000/μL with ANC <500/μL)

• High risk for life-threatening infections
• Requires urgent evaluation and often hospitalization
• Mortality risk increases significantly with ANC <100/μL 1

Diagnostic Approach

1. Complete blood count with differential - Essential to determine which cell lines are affected 1, 4
2. Peripheral blood smear - To evaluate cell morphology and identify abnormal cells 5
3. Review medication history - Identify potential medication causes
4. Evaluate for infections - Particularly viral etiologies
5. Assess for other cytopenias - Bicytopenia or pancytopenia suggests bone marrow disorder 5
6. Bone marrow examination - When cause remains unclear or malignancy suspected

Important Clinical Considerations

• The risk of infection is inversely proportional to the neutrophil count, with highest risk when neutrophil count is <100/μL 1
• Duration of neutropenia is a critical factor in determining infection risk 1
• Fever in a severely neutropenic patient represents a medical emergency requiring immediate broad-spectrum antibiotics 5
• In patients with unexplained leukopenia, hematology referral is warranted 1
• Patients with cancer often have multiple risk factors for leukopenia including the malignancy itself, chemotherapy, radiation, and malnutrition 1

Common Pitfalls

• Attributing leukopenia solely to a medication without considering other causes
• Failing to recognize ethnic variations in normal WBC counts (some populations normally have lower counts)
• Overlooking the possibility of bone marrow disorders in patients with isolated leukopenia
• Not recognizing the urgency of febrile neutropenia
• Inadequate follow-up of transient leukopenia that may represent early manifestation of serious disease

By systematically evaluating these common causes and following a structured diagnostic approach, the underlying etiology of leukopenia can be identified and appropriate management initiated promptly.