Chapter 47: Fever and Neutropenia

Definitions According to the Infectious Diseases Society of America's Current Recommendations¹

Fever: Single oral temperature ≥38.3°C (≥101°F) or a temperature ≥38.0°C (≥100.4°F) for 1 hour or longer

Neutropenia: Absolute neutrophil count (ANC) of <500 cells/mm³, or a count expected to decrease to <500 cells/mm³ during the next 48 hours

Etiology

In patients with fever and neutropenia:

• 10–20%: Microbiologically documented infection (most commonly bacteremia)

• 20–30%: Clinically documented infection (eg, cellulitis, pneumonia, typhlitis)

• 50–70%: No clinically or microbiologically documented infection

Infectious etiology:

1. Bacteria are the most commonly documented etiology

2. Gram-positive bacteria predominate in recent series; however, the frequency of Gram-negative bacteria is increasing

3. Gram-negative bacteremia may be associated with faster clinical deterioration and death as compared to Gram-positive bacteremia. Hence empirical treatment is targeted to cover Gram-negative pathogens, particularly Pseudomonas aeruginosa

4. Candida and Aspergillus species are the most common causes of invasive fungal infections in neutropenic patients. They are uncommon early or during short episodes of neutropenia but increase in frequency with longer duration of neutropenia

Factors contributing to immune compromise of an individual patient:

1. Corticosteroids, fludarabine, and alemtuzumab (Campath-1H) produce severe defects in cellular immunity

2. Myeloma and CLL are accompanied by defects in humoral immunity

3. Patients without a spleen are at risk of overwhelming sepsis caused by encapsulated bacteria, mainly Streptococcus pneumoniae

4. Obstruction (biliary obstruction, ureteral obstruction, bronchial obstruction) facilitates local infection (cholangitis, pyelonephritis, postobstructive pneumonia)

5. Intravascular devices, drainage tubes, or stents may become colonized and lead to local infection, bacteremia, or fungemia

General Management

1. Expeditious evaluation is mandatory, with special attention to skin, mouth, perianal region, and lungs

2. Cultures of blood^✫, urine, and sputum should be obtained in all patients

3. In case of diarrhea, stool culture with a test to rule out Clostridium difficile (PCR is most sensitive) should be obtained

4. In case of signs or symptoms of upper respiratory tract infection, a nasopharyngeal wash to screen for viruses should be obtained

5. CBC with differential count, chemistry panel, and chest radiograph should be obtained at baseline

6. Antimicrobial treatment should be instituted without delay (for dosage, route of administration, dose adjustment for renal and hepatic impairment of specific agents, see Appendix I)

7. High-risk patients have ANC <100 cells/mm³ and expected duration >7 days, and/or significant comorbidities (hypotension, pneumonia, new-onset abdominal pain, or neurologic changes). They should be admitted and treated with IV antibiotics. Low-risk patients have anticipated brief neutropenia periods and no or few comorbidities, and may be considered for oral or outpatient therapy, provided they have good access to a health care system

Antibiotic Therapy

A flow diagram with suggested antibiotic therapy for inpatients with fever and neutropenia is presented in Figures 47-1 We recommend a systematic approach in which specific questions are answered in order:

1. In a clinically stable patient:

   In a clinically stable patient who does not need vancomycin (uncomplicated fever and neutropenia), intravenous monotherapy with an antipseudomonal β-lactam (cefepime, piperacillin-tazobactam, imipenem, or ...