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

Causes of Low White Blood Cell Count (Leukopenia)

Leukopenia can be caused by a wide range of conditions including medications, infections, autoimmune disorders, bone marrow disorders, nutritional deficiencies, and genetic factors. Understanding the underlying cause is essential for appropriate management and preventing complications related to increased infection risk.

Common Causes of Leukopenia

Medication-Induced Leukopenia

• Chemotherapy agents - most common medication cause of leukopenia through bone marrow suppression
• Immunosuppressants - including azathioprine, which has been associated with leukopenia in 3.2% of patients 1
• Antibiotics - particularly sulfonamides, trimethoprim, and certain beta-lactams
• Antipsychotics - especially clozapine
• Antithyroid medications - propylthiouracil, methimazole
• Anti-seizure medications - carbamazepine, valproate
• Anti-inflammatory drugs - including some NSAIDs

Infections

• Viral infections - particularly HIV, hepatitis, influenza, Epstein-Barr virus
• Bacterial infections - overwhelming bacterial infections, typhoid fever, tuberculosis
• Rickettsial diseases - Rocky Mountain spotted fever
• Parasitic infections - malaria, leishmaniasis

Autoimmune Disorders

• Systemic lupus erythematosus (SLE) - leukopenia reported in 22-41.8% of cases 2
• Rheumatoid arthritis
• Adult-onset Still's disease - characterized by leukocytosis during disease flares but can present with leukopenia 1
• Felty's syndrome

Bone Marrow Disorders

• Acute leukemias - including acute promyelocytic leukemia 1
• Myelodysplastic syndromes
• Aplastic anemia
• Myelofibrosis
• Bone marrow infiltration - by cancer or granulomatous disease

Nutritional Deficiencies

• Vitamin B12 deficiency - can cause megaloblastic anemia with leukopenia 1
• Folate deficiency - similar to B12 deficiency 1
• Copper deficiency - can affect white blood cell production 3

Other Causes

• Hypersplenism - excessive sequestration and destruction of blood cells 4
• Congenital disorders - including severe combined immunodeficiency (SCID) 1
• Radiation exposure
• Alcoholism - direct toxic effect on bone marrow
• Idiopathic - no identifiable cause

Diagnostic Approach

Initial Assessment

1. Complete blood count (CBC) with differential - confirms leukopenia and identifies which white cell lines are affected 1
2. Peripheral blood smear - essential for identifying morphological abnormalities 5
3. Reticulocyte count - helps distinguish between production and destruction problems 1

Further Evaluation Based on Clinical Context

• Medication review - identify potential drug causes
• Bone marrow examination - when primary bone marrow disorder is suspected
• Autoimmune workup - ANA, RF, anti-dsDNA for suspected autoimmune causes
• Infectious disease testing - based on clinical presentation
• Nutritional assessment - vitamin B12, folate, copper levels

Special Considerations

Severity Assessment

• Mild leukopenia: WBC 3,000-4,000/mm³
• Moderate leukopenia: WBC 2,000-3,000/mm³
• Severe leukopenia: WBC <2,000/mm³
• Agranulocytosis: Absolute neutrophil count <500/mm³ - medical emergency 6

High-Risk Features

• Neutropenia - particularly concerning when absolute neutrophil count <500/mm³
• Fever with neutropenia - requires immediate antibiotic therapy 5
• Pancytopenia - suggests bone marrow failure or infiltration
• Rapid decline in WBC - may indicate drug reaction or acute leukemia

Management Principles

Management depends on the underlying cause, severity, and presence of complications:

1. Treat the underlying cause:

   • Discontinue offending medications when appropriate
   • Treat infections
   • Manage autoimmune conditions

2. Supportive care:

   • Infection prevention measures
   • Prompt treatment of infections
   • Nutritional support

3. Severe cases:

   • Granulocyte colony-stimulating factors may be considered in severe neutropenia
   • Hospitalization for febrile neutropenia
   • Antimicrobial prophylaxis in prolonged severe neutropenia

Common Pitfalls to Avoid

• Overlooking medication causes - Always review all medications, including over-the-counter drugs
• Focusing only on the white blood cell count - Evaluate all cell lines for pancytopenia
• Missing ethnic variations - Some populations have normally lower WBC counts (benign ethnic neutropenia)
• Delayed treatment of febrile neutropenia - This is a medical emergency requiring prompt antibiotics
• Attributing leukopenia to a known condition - Always consider new or alternative diagnoses, especially with significant changes in cell counts

Understanding the specific cause of leukopenia is crucial for appropriate management and prevention of complications, particularly infections in severely neutropenic patients.