Causes of Neutropenia
Primary Etiologic Categories
Myelosuppressive chemotherapy is the leading cause of neutropenia in clinical practice, with 70-100% of patients developing febrile episodes after intensive chemotherapy. 1
Chemotherapy-Induced Neutropenia
- The severity and duration depend on chemotherapy dose intensity, treatment duration, and baseline bone marrow reserve 1
- Both the rate of neutrophil decline and duration of neutropenia are critical determinants of infection risk 1
- Chemotherapy-related neutropenia is the most common cause leading to febrile episodes requiring urgent intervention 2, 3
Congenital/Genetic Causes
- ELANE gene mutations are the most common genetic cause, presenting with autosomal dominant, recessive, or X-linked inheritance patterns 1, 4
- 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
- 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
- HAX1 and SBDS gene mutations also contribute to congenital forms 5
Bone Marrow Disorders
- Malignant infiltration by hematologic malignancies or metastatic solid tumors impairs neutrophil production 1, 3
- Myelodysplastic syndromes (MDS) cause ineffective hematopoiesis with qualitative and quantitative neutrophil defects 1
- Bone marrow failure syndromes represent a spectrum of disorders affecting neutrophil production 6
Infectious Causes
- Bacterial, viral, and fungal infections can directly cause neutropenia 3
- Approximately 50-60% of patients who become febrile during neutropenia have an established or occult infection 2, 3
- Common infection sites include the alimentary tract, sinuses, lungs, and skin 2, 3
Drug-Induced Neutropenia
- Trimethoprim-sulfamethoxazole can cause agranulocytosis, aplastic anemia, leukopenia, and neutropenia as hematologic adverse effects 7
- Multiple medications beyond chemotherapy can induce neutropenia through immune-mediated destruction or direct marrow suppression 5
Autoimmune and Immune-Mediated Causes
- Autoimmune disorders can cause immune-mediated neutrophil destruction 5
- Autoimmune phenomena are associated with congenital neutropenia syndromes 6
Nutritional Deficiencies
- Nutritional deficiencies, particularly affecting folate and vitamin B12, can impair neutrophil production 5
Abnormal Distribution and Sequestration
- Excessive splenic sequestration of neutrophils can result in peripheral neutropenia 8
- Abnormal distribution between marginated and circulating pools contributes to neutropenia 9
Critical Clinical Considerations
Risk Stratification
- Risk of infection is inversely proportional to neutrophil count, with greatest danger when ANC <100 cells/µL 1
- Duration of neutropenia >10 days significantly amplifies infection risk 1
- Approximately 10-20% of patients with ANC <100 cells/µL develop bloodstream infections 1
Common Pitfalls
- Congenital neutropenia requires genetic testing and long-term surveillance for MDS/AML transformation, particularly in patients requiring high-dose G-CSF 1
- Monosomy 7 in SAMD9/SAMD9L patients may spontaneously resolve in preschool children, making HSCT timing decisions challenging 1
- Corticosteroids and lymphocyte-depleting agents (fludarabine) blunt fever and mask infection signs, delaying diagnosis 1