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, often associated with mucosal or skin barrier disruption. 1

Definition and Classification

• Neutropenia is defined as an absolute neutrophil count (ANC) <500 cells/µL or <1000 cells/µL with a predicted decline to ≤500/µL over the next 48 hours 2
• Severity categories: mild (1.5-1g/L), moderate (1-0.5g/L), or severe (<0.5g/L) 3
• The risk of infection is inversely proportional to the neutrophil count, with greatest risk when counts are below 100/µL 2

Primary Causes

Medication-Related Causes

• Chemotherapy is the most common cause of neutropenia leading to febrile episodes 2, 4
• Many medications used to treat rheumatoid arthritis can induce neutropenia 3
• Drug-induced neutropenia can be immune-mediated or due to direct inhibition of bone marrow precursors 5

Infectious Causes

• Bacterial, viral, and fungal infections can cause neutropenia 4
• Approximately 50-60% of patients who become febrile during neutropenia have an established or occult infection 2, 4
• Common sites of infection include the alimentary tract, sinuses, lungs, and skin 2, 4

Hematologic/Oncologic Causes

• Bone marrow infiltration by malignancy 1
• Myelodysplastic syndromes 6
• Leukemias, particularly large granular lymphocytic leukemia 3
• Felty's syndrome (rheumatoid arthritis with splenomegaly and neutropenia) 3

Congenital/Genetic Causes

• Congenital neutropenia due to genetic abnormalities affecting differentiation, adhesion, and apoptosis of neutrophil precursors 6
• Constitutional neutropenia predominantly affecting patients of African descent 3
• Genetic defects affecting membrane structures, secretory vesicles, mitochondrial metabolism, ribosome biogenesis, transcriptional regulation, and cytoskeletal dynamics 6

Immune-Mediated Causes

• Autoimmune neutropenia related to rheumatoid arthritis 3
• Antibody-mediated destruction of neutrophils 7

Nutritional Causes

• Folic acid deficiency, particularly in patients taking methotrexate 3
• Nutritional deficiencies in transplant recipients 8

Other Causes

• Splenic sequestration 6
• Post-transplantation neutropenia (occurs in up to 25-30% of pediatric solid organ transplant recipients) 8
• Viral infections, particularly in transplant recipients 8
• Lymphoproliferative disorders 8

Clinical Implications

• Neutropenia predisposes to bacterial and fungal infections 5
• Common bacterial pathogens include gram-negative bacilli (E. coli, Klebsiella, Pseudomonas) and gram-positive organisms (Staphylococcus, Streptococcus viridans, Enterococcus) 5
• Common fungal pathogens include Candida and Aspergillus species 5
• Ecthyma gangrenosum is a characteristic skin manifestation, often associated with Pseudomonas aeruginosa infection 1
• Neutropenic enterocolitis (typhlitis) is a common cause of acute abdominal pain in neutropenic cancer patients 2

Management Considerations

• Treatment depends on the depth of neutropenia and findings from the etiological workup 3
• Neutrophil count below 0.5g/L with fever requires emergent treatment 3
• Discontinuation of potentially causative drugs is the first step in management 3
• Granulocyte colony-stimulating factor (G-CSF) may be beneficial in drug-induced neutropenia 5
• Pegfilgrastim (a pegylated, long-acting form of filgrastim) can be administered once per chemotherapy cycle 5