What causes neutropenia?

Causes of Neutropenia

Neutropenia is primarily caused by chemotherapy, infections, autoimmune disorders, bone marrow infiltration by malignancy, and drug reactions, with the risk of infection being inversely proportional to the neutrophil count and duration of neutropenia. 1, 2

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 1
• The risk of infection is greatest when neutrophil counts fall below 100/µL 2
• Duration of neutropenia is critical, with prolonged neutropenia (>10 days) significantly increasing infection risk 2

Primary Causes of Neutropenia

Decreased Production

• Chemotherapy-induced: Most common cause of neutropenia leading to febrile episodes 2
• Bone marrow infiltration: Malignancies can directly suppress neutrophil production 1
• Congenital disorders: Genetic mutations in genes such as ELANE, HAX1, and SBDS can cause severe congenital neutropenia 3
• Nutritional deficiencies: Vitamin B12, folate, or copper deficiencies can impair neutrophil production 3, 4

Increased Destruction

• Immune-mediated neutropenia: Autoimmune disorders can cause antibody-mediated destruction of neutrophils 5
• Drug-induced neutropenia: Can be immune-mediated or due to direct bone marrow suppression 6
• Infections: Bacterial, viral, and fungal infections can cause neutropenia through various mechanisms 1, 7

Abnormal Distribution

• Splenic sequestration: Excessive splenic pooling of neutrophils can lead to neutropenia 8

Infectious Causes in Neutropenic Patients

• Bacterial pathogens: Account for 60-70% of microbiologically documented infections in febrile neutropenia 7
  • Gram-negative bacteria (Escherichia coli, Klebsiella, Pseudomonas aeruginosa) 2, 6
  • Gram-positive bacteria (Staphylococcus, Streptococcus viridans, Enterococcus) 2, 7
• Fungal pathogens: Typically occur after prolonged neutropenia and broad-spectrum antibiotic use 7
  • Candida species (common with gastrointestinal mucositis) 7, 6
  • Aspergillus species (important in severe and prolonged neutropenia) 7, 6
• Viral pathogens: Herpes simplex virus, respiratory viruses, influenza, and varicella zoster virus 7

Clinical Implications and Complications

• Approximately 50-60% of patients who become febrile during neutropenia have an established or occult infection 2
• Primary sites of infection include the alimentary tract, sinuses, lungs, and skin 2
• Roughly 10-20% of patients with neutrophil counts less than 100/µL will develop bloodstream infections 2
• Ecthyma gangrenosum is a characteristic skin manifestation often associated with Pseudomonas aeruginosa infection 1, 9
• Neutropenic enterocolitis (typhlitis) is a common cause of acute abdominal pain in neutropenic cancer patients 1

Special Considerations

• Signs and symptoms of inflammation and infection are often diminished or absent in neutropenic patients 2
• Mortality rates vary by pathogen, with gram-negative bacteremia associated with higher mortality (18%) compared to gram-positive bacteremia (5%) 7
• Local epidemiology and resistance patterns should guide empiric antibiotic choices in febrile neutropenia 7
• Chemotherapy-related gastrointestinal mucositis predisposes patients to bloodstream infections 7

Management Principles

• Empirical broad-spectrum antibiotics should be administered urgently (within 2 hours) at the first clinical signs of infection 9
• Granulocyte colony-stimulating factor (G-CSF) may be beneficial in drug-induced neutropenia 6
• Treatment approach depends on the etiology and severity of neutropenia 3
• Antimicrobial prophylaxis may be indicated in high-risk patients with prolonged neutropenia 9