What are the differential diagnoses for febrile neutropenia in a patient with a history of cancer or undergoing immunosuppressive therapy?

Differential Diagnoses for Febrile Neutropenia

In patients with febrile neutropenia, bacterial infections are the predominant cause (60-70% of documented infections), followed by fungal pathogens in prolonged neutropenia, and viral pathogens, though 50-60% of cases have no identifiable source despite thorough evaluation. 1, 2

Bacterial Pathogens (Most Common)

Gram-Positive Organisms

• Coagulase-negative staphylococci are among the most frequently isolated gram-positive pathogens in neutropenic patients 1
• Staphylococcus aureus (including MRSA) commonly causes catheter-related infections and skin/soft tissue infections 1
• Viridans group streptococci cause severe infections particularly in patients with chemotherapy-induced mucositis, which disrupts mucosal barriers 1
• Enterococcus species (including VRE) account for >50% of resistant isolates in some centers 1

Gram-Negative Organisms

• Escherichia coli remains a prominent cause and is associated with urinary tract and gastrointestinal sources 1, 2
• Pseudomonas aeruginosa is particularly concerning due to high associated mortality and requires empiric coverage in all cases 1, 2
• Klebsiella, Enterobacter species are common enteric gram-negative pathogens 2

Fungal Pathogens (Emerging with Prolonged Neutropenia)

• Candida species typically cause superficial mucosal infections but can enter the bloodstream through chemotherapy-induced mucositis 1
• Aspergillus species and other filamentous fungi typically emerge after >2 weeks of neutropenia or after the first week of empirical antibiotic therapy, causing life-threatening invasive infections 1, 2
• Fungi are rarely the cause of initial fever early in neutropenia but become increasingly common after 7-10 days of persistent neutropenia 1, 2

Viral Pathogens

• Herpes simplex virus (HSV) commonly causes reactivation disease in seropositive patients 1
• Respiratory viruses including RSV, parainfluenza, and influenza A/B can cause neutropenic fever 1

Non-Infectious Causes

Neutropenic Enterocolitis (Typhlitis)

• Most common cause of acute abdominal pain in neutropenic cancer patients, typically occurring 1-2 weeks after chemotherapy initiation 1, 3
• Presents with neutropenia, fever, bowel wall thickening on imaging, diarrhea, and abdominal pain 1
• Mortality rates reach 29.5% in patients with positive radiologic findings 1
• Requires immediate contrast-enhanced CT scan for diagnosis, as clinical signs are unreliable in immunocompromised patients 3

Drug Fever

• Chemotherapy agents themselves can cause fever without infection 4

Tumor Fever

• Underlying malignancy can cause fever independent of infection 4

Primary Sites of Infection

When infection is identified, the most common anatomic sources are: 1

• Alimentary tract (oral mucositis, esophagitis, enterocolitis)
• Sinuses (particularly in patients with prolonged neutropenia)
• Lungs (pneumonia, often with atypical or minimal radiographic findings)
• Skin and soft tissue (including catheter insertion sites)
• Perianal area (abscesses, cellulitis)

Critical Risk Stratification Factors

Patient-Related Factors Increasing Risk 4

• Age ≥65 years increases infection risk
• ECOG performance status ≥2 significantly increases risk and mortality 4, 5
• Albumin <35 g/L indicates poor nutritional status and higher risk
• Prior FN episode increases risk four-fold in subsequent cycles
• Multiple comorbidities (FN odds increase by 27%, 67%, and 125% for one, two, or three or more comorbidities, respectively)

Neutropenia-Related Factors 4, 1

• Profound neutropenia (ANC <100/mcL) carries the highest risk, with 10-20% developing bloodstream infection
• Duration ≥7 days (protracted neutropenia) significantly increases fungal infection risk
• Risk is inversely proportional to neutrophil count

Cancer-Related Factors 4

• Acute leukemia/MDS has highest FN rates (85-95%)
• High-grade lymphoma (35-71% FN rate)
• Advanced stage disease (≥2) increases risk
• Not in remission or progressive disease increases risk

Clinical Presentation Caveats

A critical pitfall is expecting typical signs of infection - neutropenic patients often have minimal or absent inflammatory signs (redness, swelling, purulence) due to impaired inflammatory response 2. Fever may be the only manifestation of serious infection 4, 2. Some severely neutropenic patients may even present afebrile or hypothermic despite serious infection 4.

Diagnostic Approach Priority

Despite thorough evaluation, 50-60% of febrile neutropenic episodes have no identifiable source and no positive culture results, yet these patients still require immediate empiric broad-spectrum antibiotics within 2 hours of presentation 1, 2. The absence of a documented source does not exclude serious bacterial infection requiring treatment.