febrile%20neutropenia
FEBRILE NEUTROPENIA
Febrile neutropenia is having a fever of ≥38.3 ºC or ≥38 ºC over an hour and neutropenia that is having an absolute neutrophil count (ANC) of <500 neutrophils/mm3 or an ANC <1000 neutrophils/mm3 expected to decline to ≤500 neutrophils/mm3 over the next 48 hours.
The risk of febrile neutropenia is directly proportional to the duration and severity of neutropenia.
Fever is frequently the only indication of infection in the neutropenic patient.

Diagnosis

  • The patient must be examined to determine the potential sites of infection and the causative organisms
  • Frequently, fever is the only indication of infection in the neutropenic patient
  • Complete history should be taken including underlying comorbidities, prior prophylactic antibiotic, concomitant steroid use, recent surgical procedure, exposure to pets, travel, tuberculosis (TB) exposure, etc
  • Thorough physical exam should be done especially at the most commonly infected sites (eg oropharynx, sinuses, skin, lungs, gastrointestinal tract, perineum)

Laboratory Tests

  • Complete blood count (CBC) with differential leukocyte count and platelet count, creatinine, urea nitrogen, electrolytes, hepatic transaminases, total bilirubin
    • Check levels in order to plan supportive care and baseline to monitor for possible occurrence of drug toxicity
  • At least 2 blood cultures (BC) from a peripheral vein site and any indwelling venous catheter, if present
  • Site-specific cultures may be considered
    • Stool: Consider enteric pathogen screen, Clostridium difficile assessment in patients with diarrhea
    • Urine: Perform if patient has urinary catheter, urinary tract infection (UTI) or abnormal urinalysis, or routinely among febrile neutropenic girls
    • Skin: Aspirate or biopsy of skin lesions or wounds
    • Vascular access cutaneous site if inflammation is present (routine, fungal, mycobacterial)
    • Consider viral cultures of mucosal or cutaneous vesicular or ulcerated lesions and of throat or nasopharynx for respiratory symptoms especially during outbreaks
  • Chest X-ray for patients with respiratory symptoms or if outpatient management is planned
  • Consider urinalysis, pulse oximetry
    • In urinalysis, absence of pus cells does not rule out a urinary tract infection in neutropenic patients
  • Tests for viral infection such as polymerase chain reaction- and direct fluorescence antibody-based tests may be considered

Risk Assessment

  • Risk assessment for complications of severe infection is done at the first sign of fever, guiding the type of empirical antibiotic treatment [oral vs intravenous (IV)], treatment setting (outpatient or inpatient), and the duration of antibiotic treatment

Tools Used to Identify Appropriate Site of Care
Talcott's Rules

  • A predictive tool used to identify patients eligible for outpatient management
  • Group I: Inpatients at time of onset of fever
  • Group II: Outpatients with comorbidities requiring in-hospital management
  • Group III: Outpatients without comorbidities but with uncontrolled cancer
  • Group IV: Cancer-free outpatients and with no comorbidities; belongs to low-risk patients

Multinational Association for Supportive Care in Cancer (MASCC) Score

  • Used to identify risk of cancer patients for medical complications and appropriate place of therapy
  • Patient score of ≥21 indicates low risk for complications, and may be a candidate for outpatient management
  • Scoring system dependent on the presence of the following:
     Characteristic  Score
     Burden of illness: No or mild symptoms*  5
     No hypotension (systolic BP >90 mmHg)  5
     No chronic obstructive pulmonary disease  4
     Solid tumor or hematological malignancy with no previous fungal infection  4
     No dehydration requiring IV fluids  3
     Burden of illness: Moderate symptoms*  3
     Outpatient status  3
     Age <60 years  2
    *Burden of febrile neutropenia should be evaluated based on symptom severity: (5) mild or no symptoms; (3) moderate symptoms; (0) severe symptoms/moribund

Clinical Index of Stable Febrile Neutropenia (CISNE)

  • Used for clinically stable patients with solid tumors, history of chemotherapy (mild- to moderate-intensity) and with access to a medical facility to determine the appropriate site of care
  • Scoring depends on the following:
  •  Variable  Score
     Eastern Cooperative Oncology Group (ECOG) performance status ≥2  2
     Chronic obstructive pulmonary disease  1
     Chronic cardiovascular disease  1
     National Cancer Institute Common Toxicity Criteria mucositis grade ≥2  1
     Monocytes <200/μL  1
     Stress-induced hyperglycemia  2
  • CISNE score of 0: Low-risk
  • CISNE score of 1-2: Intermediate-risk
  • CISNE score of ≥3: High-risk

High Risk for Medical Complications and Severe Infections

  • MASCC score <21, presence of clinical judgement criteria, or Talcott's group 1-3
  • Age ≥60 years old
  • Uncontrolled/progressive cancer
  • Mucositis grade 3-4 

Clinical Judgment Criteria

  • Comorbid conditions that predetermine hospital admission in cancer patients with MASCC score of ≥21 and reclassifies patient under high-risk
    • Cardiovascular: Hypotension, accelerated hypertension, presyncope/syncope, uncontrolled heart failure, arrhythmia, angina, bleeding, pericardial effusion
    • Hematologic: ANC ≤100/μL (profound neutropenia) lasting ≥7 days, anemia, deep venous thrombosis, pulmonary embolism
    • Gastrointestinal: Nausea and vomiting, new-onset abdominal pain, diarrhea, inability to swallow oral medications, melena, hematochezia, hematemesis, ascites
    • Neurologic: Altered mental status, seizures, CNS infection, noninfectious meningitis, spinal cord compression, neurologic deficit
    • Renal: Creatinine clearance of <30 mL/min, oliguria, new-onset gross hematuria, urinary obstruction, nephrolithiasis, clinically relevant dehydration/electrolyte abnormalities/acidosis/alkalosis
    • Respiratory: Tachypnea, hypopnea, hypoxemia, hypercarbia, pneumothorax, pleural effusion, chronic lung disease or new pulmonary infiltrates
    • Infectious: Intravascular catheter infection, with clear anatomic site of infection (pneumonia, cellulitis), evidence of sepsis, antimicrobial therapy ≤72 hours prior to consultation, allergy to oral antimicrobials
    • Hepatic: Aminotransferase levels >5x the normal value, worsening aminotransferase levels, bilirubin >2 mg/dL

Low Risk for Severe Infections

  • MASCC score ≥21, absence of conditions included in the clinical judgement criteria, or Talcott's group 4
  • Neutropenia <7 days; ANC ≥100 neutrophils/μL; absolute monocyte count ≥100 cell/μL
  • Expected neutropenia resolution <10 days
  • Malignancy that is in remission, early evidence of bone marrow recovery
  • Normal X-ray
  • Near-to-normal renal and hepatic function tests
  • No IV catheter-site infection
  • Peak temp <39°C
 

Evaluation

Site-of-Care
Outpatient Management
 

  • Initial dose of empiric antibiotic therapy should be given in a hospital setting
  • Requirements to be fulfilled to be eligible for outpatient care:
    • Residence ≤1 hour or ≤30 miles (48 km) from a medical facility
    • Agreement with primary physician
    • Ability to comply with scheduled follow-ups
    • Caregiver or family member is present 24 hours/day
    • With access to transportation and telephone 24 hours/day
    • Without any record of noncompliance with prescribed treatment regimens
  • Patients with neutrophil counts that are recovering are better candidates for outpatient therapy than patients with decreasing counts and no indication of bone marrow recovery
Inpatient Management
  • For low-risk patients, oral therapy may be given to admitted patients instead of IV therapy if:
    • Hemodynamically stable
    • Without acute leukemia or any manifestations of end-organ failure
    • Without pneumonia, indwelling catheter, or severe soft tissue infection
  • All patients at high-risk for complications are recommended to be treated in a hospital setting and closely monitored for instability
  • Other indications for inpatient treatment include:
    • Patients infected with fluoroquinolone-resistant Gram-negative pathogens and resistant to β-lactam/cephalosporin therapy
    • Patients with suspected or confirmed Methicillin-resistant Staphylococcus aureus (MRSA), Vancomycin-resistant organisms (eg enterococci) or Stenotrophomonas maltophilia infection
    • Patients with conditions included in the clinical judgment criteria
Type of Antibiotic Therapy
  • Oral antibiotics are an option for adults at low-risk for complications
    • Should only be considered in patients in whom there is no obvious focus of bacterial infection or any symptom or sign suggesting systemic infection (eg hypotension, rigors) other than fever
    • Patient should have no prior history of fluoroquinolone intake, no nausea or vomiting, and is able to tolerate oral medications
  • Change from IV to oral therapy may be done if oral medications are tolerated and patient is clinically stable
Monotherapy versus Combination Therapy
  • Monotherapy (eg antipseudomonal beta-lactam, carbapenem, or extended-spectrum cephalosporin) may be sufficient treatment for uncomplicated cases
  • Combination therapy (eg a beta-lactam with an aminoglycoside or a fluoroquinolone) is given in complicated infections
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