Causes of Neutropenia
Neutropenia is caused by decreased neutrophil production, increased destruction, or abnormal sequestration, with common etiologies including medications, infections, autoimmune disorders, congenital conditions, and malignancies. 1
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 of neutropenia in clinical practice 2, 3
- Antibiotics: Particularly semisynthetic penicillins, typically after 2+ weeks of therapy 4
- Immunosuppressants: Used in rheumatologic conditions 5
- Mechanism: Either hypersensitivity reaction or direct toxic suppression of white blood cell precursors 4
2. Infectious Causes
- Viral infections: Common cause, especially HIV, hepatitis, influenza, EBV
- Bacterial infections: Overwhelming infections can cause neutrophil consumption
- Parasitic infections: Important to consider in patients with travel history to endemic areas 1
- Mechanism: Direct bone marrow suppression or increased peripheral destruction
3. Autoimmune Disorders
- Rheumatoid arthritis: Associated with Felty's syndrome or large granular lymphocyte (LGL) leukemia 5, 6
- Systemic lupus erythematosus (SLE): Through antineutrophil antibodies or increased neutrophil apoptosis 6
- Mechanism: Antineutrophil antibodies, immune complexes, or soluble Fas-ligand inducing neutrophil apoptosis 6
4. Congenital/Genetic Causes
- Ethnic neutropenia: Benign condition affecting individuals of African descent 5
- Congenital neutropenia syndromes: Kostmann syndrome, cyclic neutropenia, Shwachman-Diamond syndrome
- Mechanism: Genetic mutations affecting neutrophil production or maturation
5. Malignancy-Related
- Primary bone marrow disorders: Leukemia, myelodysplastic syndrome (MDS), myeloma
- Bone marrow infiltration: From metastatic solid tumors
- Mechanism: Displacement of normal bone marrow elements or paraneoplastic effect
6. Nutritional Deficiencies
- Vitamin B12 deficiency
- Folate deficiency: Particularly important in patients taking methotrexate 5
- Copper deficiency
- Mechanism: Impaired DNA synthesis affecting rapidly dividing myeloid precursors
7. Splenic Sequestration
- Hypersplenism: From portal hypertension, lymphoma, or other causes
- Mechanism: Abnormal pooling of neutrophils in enlarged spleen
Clinical Significance and Risk Assessment
- Infection risk increases with:
- Severity of neutropenia (significant risk at <500/μL, particularly high at <100/μL)
- Duration of neutropenia
- Rate of decline in neutrophil count 1
- Primary infection sites: alimentary tract, sinuses, lungs, and skin 1
- Common pathogens: gram-positive bacteria, gram-negative bacteria, antibiotic-resistant bacteria, fungi, and viruses 1
- Clinical presentation of infection may be muted, with fever often being the only sign 1
Evaluation Approach
- Complete blood count with differential
- Examination of peripheral blood smear
- Medical and medication history: Particularly important to identify drug-induced neutropenia
- Travel history: Essential for identifying potential parasitic causes
- Bone marrow examination: Indicated for severe or persistent neutropenia 1
Common Pitfalls to Avoid
- Failing to recognize drug-induced neutropenia
- Overlooking underlying causes in chronic neutropenia
- Delaying antibiotic therapy in febrile neutropenia
- Using G-CSF inappropriately (contraindicated during chest radiotherapy or immediately before/with chemotherapy) 1
- Missing nutritional deficiencies, particularly folate deficiency in patients on methotrexate 5
Neutropenia requires thorough evaluation to identify the underlying cause and determine appropriate management strategies to reduce the risk of serious infections and improve outcomes.