Causes of Neutropenia
Neutropenia occurs due to three primary mechanisms: decreased bone marrow production, increased peripheral destruction, or excessive splenic sequestration of neutrophils. 1, 2
Definition and Classification
- Neutropenia is defined as an absolute neutrophil count (ANC) below 1500 cells/mm³
- Severity classification:
- Mild: ANC 1000-1500 cells/mm³
- Moderate: ANC 500-1000 cells/mm³
- Severe: ANC < 500 cells/mm³ 1
Major Causes of Neutropenia
1. Medication-Induced Neutropenia
- Chemotherapeutic agents: Most common cause in clinical practice 1
- Antibiotics: Particularly semisynthetic penicillins when used for >2 weeks 3
- Antirheumatic drugs: Medications used to treat rheumatoid arthritis 4
- Mechanism: Either hypersensitivity reaction or toxic dose-related suppression of white blood cell precursors 3
2. Infections
- Viral infections: Common cause of transient neutropenia
- Bacterial infections: Severe infections can cause neutropenia
- Parasitic infections: Including malaria, particularly in patients returning from endemic areas 1
3. Hematologic Disorders
- Acute leukemias: 35-48% of acute myelogenous leukemia (AML) cases at diagnosis 5
- Myelodysplastic syndromes
- Aplastic anemia
- Large granular lymphocytic leukemia: Often associated with Felty's syndrome 4
4. Immune-Mediated Neutropenia
- Autoimmune neutropenia: Including primary autoimmune neutropenia and secondary forms associated with other autoimmune disorders
- Rheumatoid arthritis-related: Autoimmune reaction against neutrophils 4
- Felty's syndrome: Combination of rheumatoid arthritis, splenomegaly, and neutropenia 4
5. Congenital/Genetic Causes
- Congenital neutropenia: Due to genetic abnormalities affecting neutrophil development 4, 6
- Constitutional neutropenia: Predominantly affects patients of African descent, usually moderate and well-tolerated 4
- Genetic defects: Affecting differentiation, adhesion, and apoptosis of neutrophil precursors 6
6. Nutritional Deficiencies
- Vitamin B12 deficiency
- Folate deficiency: Particularly important in patients taking methotrexate 4
- Copper deficiency
7. Other Causes
- Splenic sequestration: Hypersplenism from various causes
- Bone marrow infiltration: By malignancies or granulomatous diseases
- Radiation exposure: Affecting bone marrow production
- Myelosuppression: From peginterferon alpha treatment for hepatitis C 5
Clinical Implications
- Risk of infection increases with severity and duration of neutropenia
- Significant infection risk occurs when ANC < 500/μL, particularly high at < 100/μL 1
- Primary infection sites include alimentary tract, sinuses, lungs, and skin 1
- Fever may be the only sign of infection in neutropenic patients 1
Evaluation of Neutropenia
The diagnostic approach should include:
- Complete blood count with differential
- Examination of blood smear
- Medical and family history
- Physical examination focusing on signs of infection
- Bone marrow examination in cases of severe or persistent neutropenia 1
- Travel history to evaluate for parasitic causes 1
Management Considerations
- Discontinuation of potentially causative medications
- Granulocyte colony-stimulating factor (G-CSF) may be indicated in certain cases
- Prompt antibiotic therapy for febrile neutropenia
- Treatment of underlying causes (infections, nutritional deficiencies, etc.)
- G-CSF is contraindicated during radiotherapy to the chest due to increased complications 5
Understanding the various causes of neutropenia is essential for appropriate management and prevention of infectious complications, which are the primary concern with this condition.