What causes a low white blood cell (WBC) count, or leukopenia?

Causes of Low White Blood Cell Count (Leukopenia)

Leukopenia (low white blood cell count) is most commonly caused by medications, infections, bone marrow disorders, autoimmune conditions, or nutritional deficiencies, with medication-induced leukopenia being the most frequent reversible cause in clinical practice.

Definition and Classification

Leukopenia is defined as a white blood cell (WBC) count below normal range, typically less than 3,000-4,000/mm³. Neutropenia, often used interchangeably with leukopenia, specifically refers to an absolute neutrophil count (ANC) less than 1,500/mm³ 1.

Major Causes of Leukopenia

1. Medication-Induced Leukopenia

• Chemotherapeutic agents: Most common cause of predictable leukopenia
• Immunosuppressants: Azathioprine, 6-mercaptopurine 2
• Antimicrobials: Anti-tuberculosis drugs (rifampicin, isoniazid) 3
• Antipsychotics: Clozapine and other psychotropic medications
• Anticonvulsants: Carbamazepine, valproate
• Anti-inflammatory drugs: Some NSAIDs

2. Infectious Causes

• Viral infections:

  • HIV/AIDS 2
  • Hepatitis viruses
  • Influenza
  • Epstein-Barr virus
  • Cytomegalovirus

• Bacterial infections:

  • Typhoid fever
  • Tuberculosis
  • Overwhelming sepsis (can cause initial leukocytosis followed by leukopenia)

• Parasitic infections:

  • Malaria
  • Leishmaniasis

3. Bone Marrow Disorders

• Hematologic malignancies:

  • Acute leukemias 2
  • Chronic leukemias 2
  • Myelodysplastic syndromes

• Bone marrow infiltration:

  • Metastatic cancer
  • Lymphomas
  • Multiple myeloma

4. Autoimmune Disorders

• Systemic lupus erythematosus
• Rheumatoid arthritis
• Adult-onset Still's disease (associated with leukopenia in some cases) 2
• Felty's syndrome
• Autoimmune neutropenia

5. Nutritional Deficiencies

• Vitamin B12 deficiency 2
• Folate deficiency 2
• Severe malnutrition

6. Splenic Sequestration

• Hypersplenism 1
• Portal hypertension
• Splenic diseases

7. Congenital Disorders

• Kostmann syndrome
• Cyclic neutropenia
• Shwachman-Diamond syndrome
• Fanconi anemia

8. Other Causes

• Radiation exposure
• Alcoholism
• Severe physical or emotional stress 4
• Aplastic anemia

Diagnostic Approach to Leukopenia

When evaluating leukopenia, the following diagnostic steps are recommended 2, 5:

1. Review previous blood counts to determine if the leukopenia is acute or chronic
2. Examine complete blood count with differential to identify which WBC types are affected
3. Check for associated cytopenias (anemia, thrombocytopenia) which may suggest bone marrow failure
4. Peripheral blood smear to assess cell morphology and identify dysplasia
5. Evaluate medication history for potential causative agents
6. Consider bone marrow examination if the cause remains unclear or primary bone marrow disorder is suspected

Clinical Significance and Management

The clinical significance of leukopenia depends on its severity, particularly the degree of neutropenia:

• Mild neutropenia (ANC 1,000-1,500/mm³): Generally low infection risk
• Moderate neutropenia (ANC 500-1,000/mm³): Increased infection risk
• Severe neutropenia (ANC <500/mm³): High risk of serious infections

Management Principles:

1. Identify and treat the underlying cause
2. For medication-induced leukopenia: Consider discontinuation or dose adjustment of the suspected agent
3. For severe neutropenia with fever: Prompt administration of broad-spectrum antibiotics 2
4. For chemotherapy-induced neutropenia: Consider granulocyte colony-stimulating factors (G-CSF) in high-risk patients 2
5. For chronic neutropenia: Regular monitoring and infection prevention strategies

Common Pitfalls

1. Failing to check a manual differential: Automated counts may be inaccurate in certain conditions
2. Overlooking drug-induced causes: Always review medication history thoroughly
3. Missing pseudo-leukopenia: Caused by in vitro agglutination or margination
4. Delaying treatment in febrile neutropenia: This is a medical emergency requiring immediate antibiotics
5. Attributing leukopenia to a common cause without excluding serious conditions: Always consider the possibility of underlying malignancy or bone marrow disorder

Understanding the various causes of leukopenia is essential for appropriate management and prevention of complications, particularly serious infections in severely neutropenic patients.