What are the causes of neutropenic fever?

Causes of Neutropenic Fever

Bacterial pathogens are the predominant cause of neutropenic fever, accounting for 60-70% of microbiologically documented infections, while fungi (6-10%) and viruses are less common initial pathogens. 1

Bacterial Pathogens

Gram-Positive Bacteria

• Coagulase-negative staphylococci are among the most common gram-positive pathogens in neutropenic patients 2
• Staphylococcus aureus, including methicillin-resistant strains (MRSA) 2
• Viridans group streptococci, which can cause severe infections, particularly in patients with chemotherapy-induced mucositis 2, 1
• Streptococcus pneumoniae and Streptococcus pyogenes 2
• Enterococcus species, including vancomycin-resistant strains (VRE), which account for >50% of resistant isolates in some centers 2, 1

Gram-Negative Bacteria

• Escherichia coli remains a prominent cause of infection in febrile neutropenia 2, 1
• Klebsiella species, including carbapenemase-producing isolates 2
• Pseudomonas aeruginosa, which is particularly concerning due to high associated mortality 2, 1
• Enterobacter species 2
• Citrobacter species 2
• Acinetobacter species 2
• Stenotrophomonas maltophilia 2

Fungal Pathogens

• Fungi are rarely identified as the cause of first fever early in neutropenia but become more common after the first week of prolonged neutropenia and empirical antibiotic therapy 2
• Candida species typically cause superficial infections of mucosal surfaces (thrush) but can enter the bloodstream through chemotherapy-induced mucositis 2, 1
• Aspergillus species and other filamentous fungi typically emerge after >2 weeks of neutropenia, causing life-threatening infections of the sinuses and lungs 2, 1
• Increasing infections with fluconazole-resistant Candida strains are being reported 1

Viral Pathogens

• Herpes simplex virus (HSV) is a common viral pathogen in febrile neutropenia 1
• Respiratory viruses including respiratory syncytial virus (RSV), parainfluenza virus, and influenza A and B can cause neutropenic fever 2, 1
• Varicella zoster virus (VZV) may also cause infections in neutropenic patients 1

Clinical Considerations

• The majority of patients (50-60%) who develop fever during neutropenia have an established or occult infection, though many have no identifiable site of infection and no positive culture results 2, 1
• Primary sites of infection are the alimentary tract (mouth, pharynx, esophagus, large and small bowel, rectum), sinuses, lungs, and skin 2, 1
• Approximately 10-20% of patients with neutrophil counts less than 100/mcL will develop a bloodstream infection 2, 1
• The risk of infection is inversely proportional to the neutrophil count, with greatest risk when counts are less than 100/mcL 2, 1
• Duration of neutropenia is a critical factor, with prolonged neutropenia (>10 days) significantly increasing infection risk 2, 1

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
• Mortality rates reach 29.5% in patients with positive radiologic findings 2

Important Caveats

• Signs and symptoms of inflammation may be minimal or absent in severely neutropenic patients 2
• Fever may be the only sign of infection due to attenuated immune response in cancer patients undergoing chemotherapy 3, 4
• Local epidemiology and resistance patterns should guide empiric antibiotic choices 1
• The emergence of resistant microorganisms (MRSA, VRE, carbapenemase-producing gram-negatives) has become a significant problem in neutropenic patients 5

Remember that neutropenic fever is an oncologic emergency requiring prompt recognition and immediate empiric antibiotic therapy to prevent progression to sepsis, septic shock, and death 4, 6.