What are the common causes of neutropenia in neutropenic fever?

Common Causes of Neutropenia in Neutropenic Fever

The most common causes of neutropenia in neutropenic fever are myelosuppressive chemotherapy, bone marrow infiltration by malignancy, and prolonged antibiotic use, with bacterial infections being responsible for 60-70% of documented infections in these patients. 1, 2

Definition and Risk Factors

• 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 3
• Febrile neutropenia is defined as a rise in axillary temperature to above 38.5°C for more than 1 hour while having an ANC <0.5 × 10^9/L 3
• The risk of infection is inversely proportional to the neutrophil count, with greatest risk when counts are less than 100/µL 2
• Duration of neutropenia is a critical factor, with prolonged neutropenia (>10 days) significantly increasing infection risk 1, 2

Primary Causes of Neutropenia

1. Chemotherapy-Induced Neutropenia

• Myelosuppressive chemotherapy is the most common cause of neutropenia leading to febrile episodes 3
• Different chemotherapy regimens are associated with variable periods of myelosuppression 4
• The severity and duration of neutropenia depend on the specific chemotherapy agents, dosage, and patient factors 2

2. Hematologic Malignancies

• Bone marrow infiltration by malignant cells can directly cause neutropenia 5
• Patients with bone marrow metastases have a higher frequency of fever, infection, and death 5
• Acute leukemias commonly cause neutropenia due to bone marrow replacement 6

3. Stem Cell Transplantation

• High-dose chemotherapy followed by autologous or allogeneic stem cell transplantation causes prolonged periods of severe neutropenia 3, 4
• The period required for neutrophil recovery is usually longer after transplantation compared to standard chemotherapy regimens 4

4. Drug-Induced Neutropenia

• Certain antibiotics and other medications can cause neutropenia as an adverse effect 7
• Prolonged broad-spectrum antibiotic use can contribute to neutropenia in some patients 4

Infectious Causes in Neutropenic Patients

Bacterial Pathogens (60-70% of documented infections)

• Gram-negative bacteria are prominent causes of infection early in the course of fever and neutropenia 1, 2

  • Escherichia coli remains a common cause 2
  • Pseudomonas aeruginosa is particularly concerning due to high associated mortality 1, 2

• Gram-positive bacteria are increasingly common 3

  • Coagulase-negative staphylococci are among the most common gram-positive pathogens 2
  • Staphylococcus aureus, including MRSA 2
  • Viridans group streptococci, particularly in patients with chemotherapy-induced mucositis 1, 2
  • Enterococcus species, including vancomycin-resistant strains 1, 2

Fungal Pathogens (6-10% of documented infections)

• Fungal infections typically occur later in the course of neutropenia, particularly after prolonged neutropenia and broad-spectrum antibiotic use 1, 2
• Candida species are common, particularly with gastrointestinal mucositis 1, 2
• Aspergillus species and other filamentous fungi typically emerge after >2 weeks of neutropenia 1, 2
• Fungal infections are an important cause of morbidity and mortality in severely neutropenic patients 4

Viral Pathogens

• Viruses are occasional initial pathogens in febrile neutropenia 1
• Herpes simplex virus (HSV) is a common viral pathogen 1, 2
• Respiratory viruses including respiratory syncytial virus (RSV), parainfluenza virus, and influenza A and B can cause neutropenic fever 2

Clinical Considerations

• Approximately 50-60% of patients who become febrile during neutropenia have an established or occult infection 1, 2
• Primary sites of infection are the alimentary tract, sinuses, lungs, and skin 1, 2
• Roughly 10-20% of patients with neutrophil counts less than 100/µL will develop a bloodstream infection 1, 2
• Chemotherapy-related gastrointestinal mucositis predisposes patients to bloodstream infections 1
• Signs and symptoms of inflammation and infection are often diminished or absent in patients with neutropenia 3

Special Clinical Entities

Neutropenic Enterocolitis (Typhlitis)

• Most common cause of acute abdominal pain in neutropenic cancer patients 2
• Typically occurs 1-2 weeks after chemotherapy initiation 2
• Presents with neutropenia, fever, bowel wall thickening, diarrhea, and abdominal pain 2

Ecthyma Gangrenosum

• Cutaneous manifestation often associated with Pseudomonas aeruginosa infection 3
• Begins as painless, erythematous macules that rapidly become painful and necrotic 3
• Can occur with other bacterial and fungal pathogens as well 3