Causes of Leukopenia
Leukopenia is primarily caused by decreased neutrophil production, increased destruction, or excessive sequestration, with the most common etiologies being infections, medications, malignancies, and autoimmune disorders. 1
Definition and Classification
Leukopenia is defined as a reduction in circulating white blood cells, particularly when the absolute neutrophil count (ANC) falls below 1,500 cells/mm³. It can be classified as:
- Mild: 1,000-1,500 cells/mm³
- Moderate: 500-1,000 cells/mm³
- Severe: <500 cells/mm³ 2
The severity and duration of leukopenia directly correlate with infection risk, with severe neutropenia (<500 cells/mm³) significantly increasing susceptibility to bacterial and fungal infections 3.
Major Causes of Leukopenia
1. Infections
- Viral infections: Most common cause of transient leukopenia, especially in children 4
- HIV, hepatitis, CMV, EBV
- Respiratory syncytial virus (RSV), parainfluenza, influenza A and B 5
- Bacterial infections:
- Typhoid fever, tuberculosis
- Gram-negative infections (E. coli, Klebsiella, Enterobacter, Pseudomonas) 5
- Overwhelming bacterial sepsis
2. Medications
- Chemotherapeutic agents: Major cause of predictable, dose-dependent leukopenia
- Immunosuppressants: Azathioprine, mycophenolate
- Antipsychotics: Clozapine
- Antibiotics: Trimethoprim-sulfamethoxazole, beta-lactams
- Anticonvulsants: Carbamazepine, valproic acid
3. Hematologic Malignancies
- Leukemias: Acute myeloid leukemia, hairy cell leukemia 5
- Myelodysplastic syndromes
- Lymphomas: With bone marrow infiltration
- Multiple myeloma
4. Autoimmune Disorders
- Systemic lupus erythematosus
- Rheumatoid arthritis
- Autoimmune neutropenia
- Felty's syndrome
5. Bone Marrow Failure Syndromes
- Aplastic anemia
- Congenital neutropenias
- Large granular lymphocytic leukemia
6. Splenic Sequestration
- Hypersplenism from portal hypertension, lymphoma, or myelofibrosis
- Cirrhosis with portal hypertension 5
7. Nutritional Deficiencies
- Vitamin B12 deficiency
- Folate deficiency
- Copper deficiency
- Severe malnutrition
8. Cancer-Related Causes
- Direct bone marrow infiltration by solid tumors
- Radiation therapy affecting bone marrow
- Post-chemotherapy myelosuppression 5
- Paraneoplastic immune-mediated destruction
9. Congenital Disorders
- Kostmann syndrome
- Cyclic neutropenia
- Shwachman-Diamond syndrome
- Fanconi anemia
Special Considerations in Cancer Patients
Cancer patients are particularly susceptible to leukopenia due to:
Myelosuppressive treatments: Chemotherapy and radiation therapy directly damage bone marrow stem cells 5
Disruption of mucosal barriers: Chemotherapy and radiation impair mucosal immunity, allowing invasion by local flora 5
Disease-related factors: Tumors may directly infiltrate bone marrow or cause paraneoplastic phenomena
Malnutrition: Common in advanced malignancy, further increasing infection risk 5
Clinical Significance and Risk Assessment
The clinical significance of leukopenia depends on:
- Severity: Risk increases dramatically with ANC <500 cells/mm³
- Duration: Prolonged neutropenia carries higher risk
- Rate of decline: Rapid falls indicate more severe underlying pathology
- Bone marrow reserve: Reflected in the rate of decline and recovery 5
Common Pitfalls in Evaluation
Failing to recognize neutropenic fever as a medical emergency requiring immediate broad-spectrum antibiotics 6
Attributing leukopenia solely to medications without excluding other serious causes including underlying hematological malignancies 6
Overlooking chronic lymphocytic leukemia (CLL) as a cause of recurrent infections due to hypogammaglobulinemia despite normal or elevated white cell counts 6
Ignoring other cytopenias, as many conditions affect multiple cell lines 6
Misinterpreting relative versus absolute leukopenia in patients with lymphocytosis
By understanding these diverse causes of leukopenia, clinicians can develop a systematic approach to diagnosis and management, focusing on the most likely etiologies based on clinical presentation, patient history, and associated findings.