What causes neutropenia?

Causes of Neutropenia

Neutropenia is most commonly caused by chemotherapeutic agents, but can also result from acute leukemias, drug reactions, infections, bone marrow production abnormalities, and peripheral destruction of neutrophils. 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

Medication-Related Causes

• Chemotherapeutic agents: Most common cause in clinical practice 1
• Antibiotics: Particularly semisynthetic penicillins, chloramphenicol, and other antibiotics can cause neutropenia through hypersensitivity reactions or direct toxic effects on bone marrow 2, 3
• Other medications: Anticonvulsants, antipsychotics, antithyroid drugs, and immunosuppressants

Hematologic Malignancies

• Acute leukemias: Particularly acute myelogenous leukemia (AML), associated with neutropenia in 35-48% of cases at diagnosis 1
• Myelodysplastic syndromes: Associated with high risk of neutropenia 4
• Risk increases with severity of neutropenia - moderate to severe neutropenia (ANC < 1.0 G/L) has a 46-fold increased risk of hematologic malignancy 4

Infectious Causes

• Viral infections: Significantly associated with neutropenia, with odds ratios of 2.32-4.77 depending on neutropenia severity 4
• HIV infection: Particularly strong association with neutropenia 4
• Parasitic infections: Such as malaria, particularly in patients returning from endemic areas 1

Bone Marrow Production Abnormalities

• Congenital neutropenias: Genetic defects affecting differentiation, adhesion, and apoptosis of neutrophil precursors 5
• Acquired disorders: Affecting myeloid progenitor cells 5
• Decreased proliferation of neutrophil precursors in the bone marrow 6

Peripheral Destruction/Utilization

• Antibody-mediated destruction: Immune neutropenia 6
• Increased peripheral utilization: When neutrophil use outpaces production 6
• Splenic sequestration: Excessive trapping of neutrophils in the spleen 5

Clinical Significance and Risk Assessment

• Risk of infection increases significantly with:

  • ANC < 500/μL (severe neutropenia)
  • Particularly high risk at ANC < 100/μL
  • Longer duration of neutropenia
  • Rapid decline in neutrophil count 1

• The lower the ANC, the greater the likelihood of serious underlying conditions:

  • Moderate-severe neutropenia (ANC < 1.0 G/L) carries a 40% absolute risk of hematologic malignancy
  • Severe neutropenia is associated with >50% mortality from any cause within 4 years 4

Diagnostic Approach

When neutropenia is discovered, evaluation should include:

1. Complete blood count with differential
2. Examination of blood smear
3. Thorough medical and medication history
4. Travel history (crucial for identifying potential infectious causes)
5. Bone marrow examination in cases of severe or persistent neutropenia 1

Common Pitfalls in Neutropenia Management

• Failing to recognize drug-induced neutropenia
• Overlooking underlying causes in chronic neutropenia
• Delaying appropriate evaluation of severe neutropenia
• Missing the connection between neutropenia and viral infections 1

Neutropenia is an ominous sign that requires careful follow-up, with particular attention to potential viral diseases and hematologic malignancies, especially when the neutropenia is moderate to severe 4.