What are the causes of neutropenia?

Causes of Neutropenia

Neutropenia occurs due to insufficient circulating neutrophils, inadequate myeloid marrow reserve, or congenital/acquired defects in neutrophil function, with severity directly proportional to infection risk. 1

Definition and Classification

Neutropenia is defined as a reduction in absolute neutrophil count (ANC) below normal levels:

• Mild: ANC 1.0-1.5 × 10^9/L
• Moderate: ANC 0.5-1.0 × 10^9/L
• Severe: ANC < 0.5 × 10^9/L 2

Primary Causes of Neutropenia

Congenital/Genetic Causes

• Genetic mutations:

  • ELANE gene mutations (most common cause of severe congenital neutropenia) 3
  • Inheritance patterns: autosomal recessive, autosomal dominant, X-linked 2
  • Mitochondrial disease-associated neutropenia 2

• Congenital syndromes with neutropenia:

  • Shwachman-Diamond syndrome (with pancreatic insufficiency)
  • Glycogen storage disease type Ib
  • Kostmann syndrome
  • Cyclic neutropenia
  • WHIM syndrome (Warts, Hypogammaglobulinemia, Infections, Myelokathexis) 3, 4
  • Oculocutaneous albinism-associated neutropenia 4

Acquired Causes

1. Drug-induced neutropenia:

   • Antipsychotics (e.g., clozapine) 5
   • Antibiotics
   • Antithyroid medications
   • Chemotherapeutic agents

2. Infection-related:

   • Viral infections (most common cause of acquired neutropenia)
   • Bacterial infections (overwhelming sepsis)
   • Parasitic infections

3. Immune-mediated:

   • Autoimmune neutropenia
   • Alloimmune neutropenia (neonatal)

4. Bone marrow disorders:

   • Myelodysplastic syndromes
   • Leukemias (acute and chronic)
   • Aplastic anemia
   • Myelofibrosis

5. Nutritional deficiencies:

   • Vitamin B12 deficiency
   • Folate deficiency
   • Copper deficiency

6. Splenic sequestration:

   • Hypersplenism

7. Radiation exposure

Pathophysiologic Mechanisms

Neutropenia can result from:

1. Decreased production in bone marrow
2. Increased destruction in peripheral circulation
3. Abnormal margination or tissue sequestration
4. Functional defects in neutrophils 1, 6

Clinical Significance and Complications

The risk of infection is inversely proportional to the neutrophil count, with highest risk when ANC < 0.2 × 10^9/L 3. Patients with neutropenia are susceptible to:

• Bacterial infections: Primarily from indigenous colonizing flora 1
• Skin and soft-tissue infections: Occur in >20% of patients with chemotherapy-induced neutropenia 1
• Hematogenous dissemination from sinuses, lungs, and alimentary tract 1
• Oral manifestations: Acute gingivostomatitis and chronic periodontal disease 3
• Severe infections: Particularly in congenital forms, affecting respiratory system, digestive tract, and skin 2

Important Clinical Considerations

• Duration matters: Risk increases with prolonged neutropenia (>7 days) 1
• Depth matters: Severe neutropenia (ANC <500/μL) carries highest infection risk 1
• Timing matters: Initial infections (<7 days) typically bacterial; subsequent infections (>7 days) often involve resistant bacteria, fungi, or viruses 1
• Malignancy risk: Congenital neutropenia increases risk of developing acute myeloid leukemia or myelodysplastic syndromes 2
• Signs of infection: May be muted in neutropenic patients, but fever remains an important early sign 1

Diagnostic Approach

When neutropenia is detected, establish the etiology by:

• Confirming neutropenia with repeat CBC and differential
• Examining peripheral blood smear
• Reviewing medical and family history
• Bone marrow examination when appropriate
• Genetic testing for suspected congenital forms 6

Remember that neutropenia may be the first sign of a more complex disorder, and thorough evaluation is essential for proper management and prevention of life-threatening infections.