What are the clinical signs and symptoms of febrile neutropenia and how is it diagnosed?

Signs and Symptoms and Diagnosis of Febrile Neutropenia

Definition

Febrile neutropenia is defined as a single oral temperature ≥38.3°C (101°F) or two consecutive readings ≥38.0°C sustained for 1 hour, combined with an absolute neutrophil count (ANC) <500 cells/µL or expected to fall below 500 cells/µL within 48 hours. 1, 2

Temperature Thresholds

• Single oral temperature ≥38.3°C (101°F) constitutes fever 3, 1, 2
• Sustained temperature ≥38.0°C (100.4°F) for ≥1 hour also meets fever criteria 3, 1, 2
• Avoid rectal temperature measurements in neutropenic patients due to risk of mucosal injury and bacteremia 2

Neutropenia Thresholds

• ANC <500 cells/µL at presentation defines neutropenia 3, 1, 2
• Expected decline to <500 cells/µL within 48 hours based on chemotherapy timing also qualifies, even if current ANC is higher 1, 4
• Profound neutropenia (ANC <100 cells/µL) carries the highest infection risk with 10-20% developing bloodstream infections 1
• Duration >7 days significantly increases infection risk and mortality 3, 1

---

Clinical Presentation and Signs

Key Clinical Principle

Fever may be the ONLY sign of serious infection in neutropenic patients because the lack of neutrophils prevents typical inflammatory responses. 1, 2

Attenuated Inflammatory Response

• Symptoms and signs of inflammation are minimal or absent in severely neutropenic patients 3
• Infections present without typical findings: 3
  • Cutaneous infections without cellulitis
  • Pneumonia without infiltrate on chest radiograph
  • Meningitis without CSF pleocytosis
  • Urinary tract infection without pyuria
  • Diminished or absent induration, erythema, and pustulation

Sites to Examine for Subtle Pain or Abnormalities

Even minor findings warrant serious attention. Search for subtle symptoms at these high-risk sites: 3

• Periodontium and oral cavity (mucositis, dental abscesses)
• Pharynx and lower esophagus (odynophagia may indicate esophagitis)
• Lungs (subtle dyspnea, cough)
• Perineum and anus (perirectal pain or tenderness)
• Skin: 3
  • Bone marrow aspiration sites
  • Vascular catheter access sites
  • Tissue around nails
• Eye fundus (fungal endophthalmitis in prolonged neutropenia)

Common Pitfall

Even minor skin lesions can represent serious infections in this population—do not dismiss small areas of erythema, tenderness, or drainage. 1

---

Diagnostic Evaluation

Immediate Actions (Within 2 Hours of Presentation)

All diagnostic specimens must be obtained BEFORE initiating antibiotics, but do not delay antibiotics beyond 2 hours. 1, 2

Blood Cultures

• Two sets of blood cultures from separate sites: 3, 2
  • One from a peripheral vein
  • One from each lumen of any central venous catheter (if present)
• Quantitative blood cultures may help diagnose catheter-related infections when comparing peripheral versus catheter specimens 3
• High-grade bacteremia (≥1,500 cfu/mL) is associated with greater morbidity and mortality 3

Additional Cultures and Specimens

• Urine culture (even without pyuria) 3, 2
• Gram stain and culture of any inflamed or draining catheter site 3
• Stains and cultures for nontuberculous mycobacteria if lesions are persistent or chronic 3
• Respiratory viral screening and viral PCR if respiratory symptoms present 2

Imaging

• Chest radiograph for all patients with respiratory signs/symptoms or if outpatient management is considered 3, 2
• Chest CT if pulmonary symptoms present or fever persists beyond 4-7 days 2

Laboratory Tests

• Complete blood count with differential 2
• Comprehensive metabolic panel (creatinine, blood urea nitrogen, transaminases) 3, 2
• Coagulation panel 2
• C-reactive protein, ferritin, lactate dehydrogenase 2

---

Risk Stratification

High-Risk Features (Require Inpatient IV Therapy)

• Anticipated prolonged neutropenia >7 days 1, 4, 2
• Profound neutropenia (ANC <100 cells/µL) 1, 4
• Underlying hematologic malignancy 4
• Hemodynamic instability 1, 4
• Significant mucositis or serious comorbidities 4
• Allogeneic hematopoietic stem-cell transplant 4

Low-Risk Features (May Be Eligible for Outpatient Oral Therapy)

• Anticipated brief neutropenia <7 days 1, 4
• MASCC score ≥21 1, 4
• No significant comorbidities 4
• Hemodynamically stable 4

---

Microbiology

Bacterial Pathogens

• Gram-positive bacteria currently dominate (historically Gram-negative dominated in the 1970s) 5
• Gram-negative bacteremia carries 18% mortality versus 5% for Gram-positive 1
• 72% of positive blood cultures in one study showed Gram-negative bacteria 6
• Viridans group streptococci are particularly concerning in patients with mucositis 4

Fungal Pathogens

• Risk increases dramatically with neutropenia >7 days 3, 1
• Consider galactomannan or β-D-glucan testing if fever persists 4-7 days 4

Yield of Cultures

• Only 33 of 173 FN episodes (19%) had positive blood cultures in one study 6
• Yield depends on culture systems used and blood volume collected 3
• Microbiology laboratories must stay current with organisms unique to neutropenic hosts 3

---

Clinical Significance and Outcomes

Mortality

• Overall mortality 5% in solid tumors (1% in low-risk patients) 1
• Up to 11% mortality in hematological malignancies 1
• 15% mortality in one tertiary center study 6
• 18% mortality with Gram-negative bacteremia 1
• ANC <100 cells/µL is predictive of increased mortality 6

Morbidity

• 20-30% of patients present complications requiring in-hospital management 5
• Earlier antibiotic administration is associated with fewer complications—delays increase morbidity and mortality 1

---

Critical Pitfalls to Avoid

• Do not wait for ANC to fall below 500 cells/µL before acting—if chemotherapy timing suggests imminent decline, treat as febrile neutropenia 1
• Do not delay antibiotics while awaiting culture results—the 2-hour window from presentation to antibiotic administration is mandatory 1, 2
• Do not dismiss minor symptoms or subtle pain—these may be the only clues to serious infection in the absence of inflammatory response 3, 1
• Do not attribute fever solely to cytokine effects (e.g., from IL-2 therapy) without first ruling out infection 2
• Do not overlook relative hypotension—establish each patient's baseline blood pressure before labeling values as normal 2
• Do not perform rectal examinations in neutropenic patients due to risk of bacteremia 2