Febrile%20neutropenia Diagnosis

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, time of last chemotherapy session, history of infections in the last 3 months, 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 baseline levels to monitor for possible occurrence of drug toxicity and in order to plan supportive care

At least 2 blood cultures (BC) from a peripheral vein site and any indwelling venous catheter, if present
- In pediatric patients, additional blood cultures from central line during febrile episode are recommended
Site-specific cultures may be considered
- Stool: Consider enteric pathogen screen, Clostridioides (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 pediatric patients
- 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
Risk for chemotherapy-induced febrile neutropenia depends on dose intensity of regimen used, together with patient-specific risk factors and treatment setting

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; belong 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

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

Risk for Medical Complications and Severe Infections

High Risk

Low Risk

MASCC score <21, presence of clinical judgment criteria, CISNE score ≥3, or Talcott's group 1-3
Age ≥60 years old
Presence of comorbidity or clinically unstable
Uncontrolled/progressive cancer
Mucositis grade 3-4
History of allogeneic hematopoietic cell transplant (HCT) or immune/targeted therapies
Inpatient status at time of fever development

MASCC score ≥21, CISNE score <3, or Talcott's group 4
Absence of conditions included in the clinical judgment criteria
Neutropenia <7 days; ANC ≤100 neutrophils/μL; absolute monocyte count ≥100 cell/μL
Malignancy that is in remission, early evidence of bone marrow recovery
Normal X-ray
ECOG performance status 0-1
Near-to-normal renal and hepatic function tests
No IV catheter-site infection
Peak temperature <39°C
Outpatient status at time of fever development

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, pneumonia, 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

Risk Group Based on Chemotherapy Regimen

High-risk group: >20% risk of febrile neutropenia
Intermediate-risk group: 10-20% risk of febrile neutropenia
Low-risk group: <10% risk of febrile neutropenia

Management

Site-of-Care
Outpatient Management

Initial dose of empiric antibiotic therapy should be given in a hospital setting, if feasible
Requirements to be fulfilled to be eligible for outpatient care:
- Residence ≤1 hour or ≤30 miles (48 km) from a medical facility, or with access to a medical facility
- Agreement with primary physician or medical oncologist
- 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
Patient should not have any adverse events from oral antibiotic intake (eg nausea, vomiting) and without history of fluoroquinolone prophylaxis
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

The role of oral antivirals in COVID-19 treatment: Who, when, and how?

Dr. Roger Paredes, Dr. Nicola Petrosillo, Dr. Petrick Periyasamy, 30 Jan 2023

Though most countries have eased pandemic restrictions, there is no room for complacency in managing COVID-19, which continues to cause significant morbidity and mortality.

At a recent symposium, esteemed experts Dr Roger Paredes, Head of Department of Infectious Diseases at the Hospital Universitari Germans Trias i Pujol, Badalona, Catalonia, Spain, and Dr Nicola Petrosillo, Head of the Infection Prevention and Control and Infectious Disease Service at University Hospital Campus Bio-Medico, Rome, Italy, gave global perspectives on the continuing unmet needs in the COVID-19 outpatient landscape and discussed the role of antiviral treatment options in patients at risk of progressing to severe COVID-19. Dr Petrick Periyasamy, Head of Infectious Diseases Unit, Medical Department, UKM Medical Centre, Kuala Lumpur, Malaysia, chaired the session.

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Tackling multidrug-resistant gram-negative bacterial infections in critically ill patients: Challenging the standard approach

Dr. Asok Kurup, Dr. Kenneth Chan, 07 Dec 2020

The rising incidence of infections caused by multidrug-resistant (MDR) gram-negative bacteria has become a serious health threat and a major challenge for intensivists. Against a backdrop of high patient mortality and risk factors for infection in intensive care units (ICU), early adequate therapy is of paramount importance. At a recent Pfizer-sponsored symposium, Dr Asok Kurup, Infectious Disease Physician, Singapore presented the implications of MDR gram-negative infections in critically ill patients in Asia, while Dr Kenneth Chan, Respiratory Physician and Intensivist, Singapore highlighted the role of ceftazidime-avibactam (Zavicefta) and shared published real-world data on ceftazidime-avibactam.