What are the causes of neutropenia?

Causes of Neutropenia

Primary Etiologic Categories

Myelosuppressive chemotherapy is the leading cause of severe neutropenia, with 70-100% of cancer patients developing febrile episodes after intensive chemotherapy. 1

Acquired Causes

Chemotherapy-Induced Neutropenia

• Chemotherapy represents the most common cause of neutropenia leading to febrile episodes in clinical practice 1, 2
• The severity depends on chemotherapy dose intensity, duration of treatment, and baseline bone marrow reserve 1
• Both the rate of neutrophil decline and duration of neutropenia critically determine infection risk and clinical outcomes 1

Drug-Induced Neutropenia

• Idiosyncratic drug reactions can cause acute neutropenia 3, 4
• Corticosteroids and lymphocyte-depleting agents (such as fludarabine) can contribute to neutropenia while also masking infection signs 1

Infection-Related Neutropenia

• Bacterial, viral, and fungal infections can directly cause neutropenia 5, 4
• Acute neutropenia from infection is relatively frequent and often normalizes rapidly 6

Autoimmune Neutropenia

• Antibody-mediated destruction of neutrophils causes acute-onset neutropenia 3, 4
• Autoimmune disorders represent a significant category of acquired neutropenia 7

Nutritional Deficiencies

• Vitamin B12, folate, and copper deficiencies can cause neutropenia 7, 4

Bone Marrow Disorders

• Malignant infiltration by hematologic malignancies or metastatic solid tumors impairs neutrophil production 1, 5
• Myelodysplastic syndromes (MDS) cause ineffective hematopoiesis with qualitative and quantitative neutrophil defects 1

Congenital/Inherited Causes

Genetic Mutations

• ELANE gene mutations are the most common genetic cause of congenital neutropenia, presenting with autosomal dominant, recessive, or X-linked inheritance patterns 1, 7
• HAX1 and SBDS gene mutations also cause congenital neutropenia 7

Specific Genetic Syndromes

• Shwachman-Diamond syndrome (SDS) presents with pancreatic exocrine insufficiency, skeletal abnormalities, and neutropenia due to defective ribosome biogenesis 1
• SAMD9/SAMD9L mutations cause severe neutropenia with high MDS/AML risk, often with monosomy 7 or uniparental disomy 7q 1
• GATA2 deficiency causes MonoMAC syndrome with severe infections and high progression risk to MDS/AML 1
• Cyclic neutropenia represents another inherited form 4

Malignancy Risk in Congenital Neutropenia

• Congenital severe chronic neutropenia carries an 11% cumulative risk of progression to MDS/AML at a median age of 16.2 years, often preceded by CSF3R and RUNX1 somatic mutations 1
• Monosomy 7 in SAMD9/SAMD9L patients may spontaneously resolve in preschool children, making hematopoietic stem cell transplantation timing decisions challenging 1

Pathophysiologic Mechanisms

Three Primary Mechanisms

• Decreased neutrophil production by bone marrow (impaired proliferation and maturation of myeloid progenitor cells) 7, 3
• Immune-mediated destruction or increased peripheral destruction 7, 3
• Abnormal distribution or excessive splenic sequestration of neutrophils 7, 6

Critical Clinical Considerations

Infection Risk Stratification

• Risk of infection is inversely proportional to neutrophil count, with greatest danger when ANC <100 cells/µL 1, 2
• Duration of neutropenia >10 days significantly amplifies infection risk 1, 2
• Approximately 10-20% of patients with ANC <100 cells/µL develop bloodstream infections 1, 2
• 50-60% of febrile neutropenic patients have established or occult infections 1, 2

Diagnostic Imperative

• Congenital neutropenia requires genetic testing and long-term surveillance for MDS/AML transformation, particularly in patients requiring high-dose G-CSF 1
• Chronic neutropenia lasting ≥3 months warrants thorough investigation for underlying hematologic disorders 6