What causes neutropenia?

Causes of Neutropenia

Neutropenia is primarily caused by insufficient circulating neutrophils, inadequate myeloid marrow reserve, or congenital/acquired defects in neutrophil function. 1, 2

Definition and Classification

Neutropenia is defined as an absolute neutrophil count (ANC) below 1500 cells/mm³, with:

• Mild: ANC 1000-1500 cells/mm³
• Moderate: ANC 500-1000 cells/mm³
• Severe: ANC <500 cells/mm³
• Very severe: ANC <100 cells/mm³ 2

Major Etiologic Categories

1. Decreased Production

• Bone Marrow Disorders

  • Hematologic malignancies (leukemia, myelodysplastic syndrome)
  • Aplastic anemia
  • Myelofibrosis
  • Congenital neutropenia syndromes 3, 4

• Nutritional Deficiencies

  • Vitamin B12 deficiency
  • Folate deficiency
  • Copper deficiency 4

• Drug-Induced Myelosuppression

  • Chemotherapy agents
  • Antipsychotics (clozapine)
  • Antibiotics (trimethoprim-sulfamethoxazole, beta-lactams)
  • Anticonvulsants (carbamazepine, phenytoin)
  • Anti-inflammatory drugs 5, 6

2. Increased Destruction or Utilization

• Immune-Mediated

  • Autoimmune neutropenia
  • Drug-induced immune neutropenia
  • Systemic autoimmune disorders (lupus, rheumatoid arthritis) 7, 6

• Infection-Related

  • Viral infections (HIV, hepatitis, CMV, EBV)
  • Bacterial sepsis
  • Overwhelming infections 1, 2

• Splenic Sequestration

  • Hypersplenism
  • Portal hypertension 4

3. Neutrophil Dysfunction or Defects

• Congenital Disorders

  • Severe congenital neutropenia (Kostmann syndrome)
  • Cyclic neutropenia
  • Shwachman-Diamond syndrome
  • Dyskeratosis congenita 4

• Acquired Dysfunction

  • Diabetes mellitus
  • Uremia
  • Alcoholism 7

Risk Factors for Neutropenia-Associated Complications

• Patient Factors

  • Age (elderly at higher risk)
  • Comorbidities
  • Poor nutritional status
  • Duration of neutropenia (>7 days increases risk)
  • Severity of neutropenia (ANC <100 cells/mm³)
  • Rapid decline in neutrophil count 2

• Treatment-Related Factors

  • Mucosal barrier disruption (mucositis)
  • Indwelling catheters
  • Prior antibiotic exposure 1

Clinical Significance

The risk of infection increases dramatically when ANC falls below 500/mm³, with primary infection sites including:

• Alimentary tract
• Sinuses
• Lungs
• Skin 2

Common pathogens in neutropenic patients include:

• Gram-positive bacteria (Staphylococcus, Streptococcus)
• Gram-negative bacteria (E. coli, Klebsiella, Pseudomonas)
• Fungi (Candida, Aspergillus)
• Viruses (HSV, RSV, influenza) 1, 2

Diagnostic Approach

1. Initial Assessment

   • Complete blood count with differential
   • Peripheral blood smear examination
   • Review of medication history
   • Evaluation for signs of infection 3

2. Further Investigations (based on clinical suspicion)

   • Bone marrow examination
   • Autoimmune markers
   • Vitamin B12 and folate levels
   • Genetic testing for congenital neutropenia 4

Management Considerations

For severe neutropenia (ANC <500/mm³):

• Prompt evaluation of fever (>38.5°C)
• Early initiation of empiric broad-spectrum antibiotics
• Consider granulocyte colony-stimulating factor (G-CSF) for treatment of established neutropenia or as prophylaxis in high-risk settings 2, 5

Key Pitfalls to Avoid

• Delaying antibiotic therapy in febrile neutropenia (should be initiated within 2 hours)
• Failing to recognize drug-induced neutropenia
• Overlooking underlying causes in chronic neutropenia
• Using G-CSF inappropriately (contraindicated during chest radiotherapy or with certain infections) 1, 2

Patients with neutropenia require careful monitoring and prompt intervention for fever or signs of infection, as the clinical presentation may be muted due to the lack of neutrophils to mount an inflammatory response 2.