Febrile Neutropenia. Laura J. Zitella, MS, RN, ACNP-BC, AOCN Nurse Practitioner Clinical Associate Professor University of California San Francisco

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1 Febrile Neutropenia Laura J. Zitella, MS, RN, ACNP-BC, AOCN Nurse Practitioner Clinical Associate Professor University of California San Francisco

2 What Are The Facts About Febrile Neutropenia (FN)? Fever with neutropenia in patients can represent infection Clinically documented infections occur in only 20-30% of febrile neutropenic episodes Treated with empirical antibiotic therapy Approximately 48% to 60% have an established or occult infection 80% of pathogens from patient s endogenous microbial flora Disease Acute leukemia/mds High Grade Lymphoma Reported Rates of FN 85-95% 35-71% NHL/Myeloma 26% Hodgkin Lymphoma 15% Freifeld et al., 2011; NCCN. Prevention and Treatment of Cancer-Related Infection. v1.2018; Taplitz RA (2018). JCO, 36(14),

3 What is the Human and Healthcare Cost of Febrile Neutropenia? Despite advances in oncology care, infections remain a major cause of morbidity and mortality among patients with cancer and sepsis is a leading cause of death in cancer patients Mortality from infection: ranges from 12% in low-risk patients to 48% in immune compromised patients. In 2012, there were 108,419 cancer-related neutropenia hospitalizations in the United States at a total cost of $2.7 billion Freifeld et al., 2011; NCCN. Prevention and Treatment of Cancer-Related Infection. v1.2018; Tai, E., et al. (2017). Journal of Oncology Practice, 13(6), e552 e561

4 What is the Definition of Neutropenic Fever? Neutropenia ANC <500/μL or ANC <1000/μL and a predicted decline to 500/μL over the next 48 h Fever Oral temperature >38.3 C (single reading) or >38.0 C (>1 h) Fever + neutropenia = febrile neutropenia ANC = absolute neutrophil count. NCCN. Prevention and Treatment of Cancer-Related Infection. v1.2018; Taplitz RA et al. (2018). JCO, 36(14), ; Taplitz RA et al. (2018). JCO, 36(30),

5 What is the Clinical Presentation of Infection in a Neutropenic Patient? Fever is the most important presenting symptom in a neutropenic patient Many normal signs and symptoms of infection may be absent Inflammation may be minimal or absent induration, erythema, and pus normally seen in bacterial skin infections Pneumonia without infiltrate, cough Meningitis without WBCs in CSF UTI without pyuria, etc Flowers et al., 2013; Freifeld et al., 2011; NCCN. Prevention and Treatment of Cancer-Related Infection. v1.2018

6 What are the Common Infectious Organisms Identified in Patients with Febrile Neutropenia? Gram positive coagulase negative staphylococci, staph aureus, enterococcus faecalis Gram negative E. coli, klebsiella pneumoniae, pseudomonas aeruginosa, citrobacter VRE (Vancomycin Resistant Enterococcus) MRSA (Methicillin Resistant Staph Aureus) Fungal aspergillus, candida species, nocardia, cryptococcus neoformans Viral herpes simplex, cytomegalovirus, BK virus C. Diff (Clostridioides difficile)

7 What Considerations are Necessary for the Evaluation of Fever and Neutropenia? History & Physical including: Indwelling catheters/vascular access device Skin Lungs and sinus GI tract (mouth, pharynx, esophagus, bowel, rectum) Perivaginal/perirectal Other considerations: Major comorbid illness Recent surgery, hospitalization Date of last chemotherapy/radiation treatment Prior infections Recent antibiotic therapy/prophylaxis HIV status Medication history Exposures: Others at home with similar symptoms Pets Travel Tuberculosis exposure Recent blood products NCCN. Prevention and Treatment of Cancer-Related Infection. v1.2018

8 What Labs/Radiology are Recommended Prior to the Initiation of Empiric Antibiotic Therapy? Blood cultures x 2 sets (must have minimum of 40 ml for adequate cultures) If central venous catheter present, consider time to positivity culture CBC with differential Comprehensive metabolic panel Chest x-ray, pulse oximetry Urinalysis Lactate Symptom-guided : If diarrhea present, Clostridium difficile assay, GI PCR panel If skin lesions present, obtain biopsy, aspirate, viral DFA, or HSV/VZV PCR of skin lesions If central venous catheter site with erythema or tenderness, obtain site culture If respiratory symptoms present (rhinorrhea, congestion, cough), respiratory PCR for respiratory viruses If abnormal UA or urinary symptoms, urine culture NCCN. Prevention and Treatment of Cancer-Related Infection. v1.2018

9 How Do You Assess Risk for a Patient with Febrile Neutropenia? HIGH RISK PATIENT: Inpatient at time of development of fever Significant medical comorbidity/clinically unstable Anticipated prolonged severe neutropenia (ANC 100 for 7 days) Hepatic insufficiency (transaminases > 5X ULN) Renal insufficiency (CrCL < 30 ml/min) Uncontrolled/progressive cancer Pneumonia or other complex infection at presentation Alemtuzumab-treated Mucositis grade 3-4 MASCC score <21 LOW RISK PATIENT: Outpatient at time of development of fever No comorbidities or concurrent illness Anticipated short duration of severe neutropenia (ANC 100 for <7days) ECOG performance status 0-1 No hepatic/renal insufficiency MASCC risk score 21 NCCN. Prevention and Treatment of Cancer-Related Infection. v1.2018

10 The Multinational Association for Supportive Care in Cancer Risk-Index Score (MASCC) For Neutropenic Complications Characteristic Weight Burden of febrile neutropenia with no or mild symptoms 5 No hypotension (systolic blood pressure >90 mmhg) 5 No chronic obstructive pulmonary disease 4 Solid tumor or hematologic malignancy w/ no previous fungal infxn 4 No dehydration requiring parenteral fluids 3 Burden of febrile neutropenia with moderate symptoms 3 Outpatient status 3 Age <60 years 2 Burden of febrile neutropenia refers to general clinical status as influenced by the febrile neutropenic episode. It is evaluated in accordance with the following scale: no symptoms (5), mild symptoms (5), moderate symptoms (3), severe symptoms (0), moribund (0). Chronic obstructive pulmonary disease means active chronic bronchitis, emphysema, decrease in FEVs, need for oxygen therapy and/or steroids and/or bronchodilators. Previous fungal infection means demonstrated fungal infection or empirically treated suspected fungal infection.

11 What Is An Easy Way To Calculate The MASCC Score? Use the online MASCC Febrile Neutropenia Risk Score calculator to determine MASCC score

12 How Can I Safely Treat A Patient With Low Risk Febrile Neutropenia As An Outpatient? Consider appropriateness for home therapy with daily clinic follow up: 24 hour home caregiver available Access to emergency facilities and clinic Observation period as outpatient Confirm status as low-risk and patient in stable condition MASCC score 21 Lactate < 2 Afebrile Normal blood pressure and heart rate No alteration in mental status Prescription for oral antibiotics: Ciprofloxacin 500 mg PO BID and Augmentin 875 mg PO BID x 7 days If PCN allergy, moxifloxacin 400 mg PO daily x 7 days RN provides patient with discharge instructions/education Re-assess patient the following day NCCN. Prevention and Treatment of Cancer-Related Infection. v1.2018

13 What is Appropriate Initial Empiric Therapy for High Risk Febrile Neutropenia? Intravenous antibiotic monotherapy Extended-spectrum antipseudomonal Cefepime Piperacillin-tazobactam Meropenem (favored if concern for ESBL organisms) NCCN. Prevention and Treatment of Cancer-Related Infection. v1.2018

14 What Is The Role Of Vancomycin In Febrile Neutropenia? Indicated for: Clinically apparent, serious catheter-related infection (covers coagulase-negative staphylococcal infections and MRSA) Gram-positive bacteremia (until final ID and sensitivity which informs antibiotic choice) Known colonization with MRSA or PCN/cephalosporin-resistant pneumococci Clinical instability (hypotension or shock) Soft tissue infection Not recommended for: Routine initial therapy for febrile neutropenia Routine addition for persistent fevers Routine use for patients with central lines that don t appear infected Routine use in setting of mucositis Use of vancomycin should be re-assessed after 2-3 days and discontinued if no evidence of resistant gram-positive infection NCCN. Prevention and Treatment of Cancer-Related Infection. v1.2018

15 Infection, Systemic Inflammatory Reaction (SIRS), Sepsis: What does it all mean? Bone, R., Balk, R., Cerra, F., Dellinger, R., Fein, A., Knaus, W., Schein, R., et al. (1992). Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest, 101(6),

16 Febrile neutropenia

17 Evolution of Definitions of Sepsis 1991, 2001, 2004, 2008, 2012 CONSENSUS Sepsis Known or suspected infection AND Systemic Inflammatory Response Syndrome (SIRS) Temp > 38 or < 36 HR > 90 RR > 20 or PaCO2 < 32 WBC > 12 or < 4 or Bands > 10% Severe Sepsis Sepsis AND organ dysfunction e.g. hypoperfusion, hypotension, acute lung injury, encephalopathy, acute kidney injury, coagulopathy Septic Shock Sepsis AND hypotension after adequate fluid resuscitation (30 ml/kg) 2016 CONSENSUS Sepsis: Life-threatening organ dysfunction caused by dysregulated host response to infection Suspected or documented infection qsofa 2 Septic Shock: subset of sepsis in which underlying circulatory, cellular and metabolic abnormalities are associated with a greater risk of mortality than sepsis alone Sepsis Vasopressors required to keep MAP 65 mmhg Lactate > 2 despite adequate fluid resuscitation Severe sepsis and the SIRS criteria are no longer a component of the updated definition Bone RC, Balk RA, Cerra FB, et al. AACP/SCCM Consensus Conference: definitions for sepsis and organ failure. Crit Care Med. 1992;20(6): ; Levy MM, Fink MP, Marshall JC, et al; 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive Care Med. 2003;29(4): ; Singer M et al. JAMA. 2016;315(8):

18 Do You Know The Current Sepsis Criteria? Sepsis Life-threatening organ dysfunction caused by dysregulated host response to infection Suspected or documented infection qsofa 2 Septic Shock Subset of sepsis with circulatory and cellular/metabolic dysfunction associated with higher risk of mortality Sepsis Vasopressors required to keep MAP 65 mmhg Lactate > 2 despite adequate fluid resuscitation qsofa: quick Sequential (Sepsis-Related) Organ Failure Assessment Three simple tests to identify patients at risk for sepsis Alteration in mental status Systolic blood pressure of less than 100 mm Hg Respiration rate greater than 22 breaths/min Singer M et al. JAMA. 2016;315(8):

19 Singer M et al. JAMA. 2016;315(8): qsofa : quick SOFA; MAP, mean arterial pressure.

20 Management of Sepsis Early Diagnosis Early Source Control Early Antibiotics Early Fluid Resuscitation Vasopressors qsofa Draw 2 sets of blood cultures (aerobic and anaerobic). If central line, draw 1 set from central line and 1 set peripherally. Draw cultures before antimicrobials CBC with diff, CMP, lactate Other diagnostic tests as indicated Identify or exclude specific anatomic diagnosis of infection requiring emergent source control (e.g.abscess) Intervention to control source (e.g drain) Administer within 1 h Empiric broadspectrum antimicrobial therapy 2 antibiotics recommended for septic shock Combination therapy not recommended for neutropenic sepsis For hypoperfusion: 30ml/kg of intravenous crystalloid fluid be given within the first 3 hours Target mean arterial pressure (MAP): 65 mmhg Repeat lactate 3 hours later Use lactate to guide resuscitation (goal lactate <2) First choice: Norepinephrine Add vasopressin (up to 0.03 U/min) or epinephrine to reach MAP target May use vasopressin (up to 0.03 U/min) to decrease norepinephrine dosage Rhodes A. et al. Crit Care Med 2017; 45:

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22 Elevated Lactate Predicts Mortality in Sepsis Patients Lactate Marker of cellular hypoxia and metabolic acidosis Normal level < 2 Levels > 4 associated with increased mortality With serial testing, decreasing lactate is a marker of improved perfusion, reduced mortality, and better prognosis rising lactate levels suggests the opposite. Mortality Risk Relative to Lactate Level Howell et al., 2007; Shapiro et al., 2008

23 Antimicrobial Therapy for Sepsis Combination therapy should not be routinely used for on-going treatment of most other serious infections, including bacteremia and sepsis without shock. Combination therapy is not recommended for the routine treatment of neutropenic sepsis/bacteremia. Narrow antimicrobial therapy once pathogen identification and sensitivities are established and/or adequate clinical improvement achieved Continue antimicrobial treatment for 7-10 days for most serious infections associated with sepsis and septic shock. Assess daily assessment for de-escalation of antimicrobial therapy in patients with sepsis and septic shock. Consider measurement of procalcitonin levels to support shortening the duration of antimicrobial therapy in sepsis patients. Rhodes A. et al. Crit Care Med 2017; 45:

24 CSF Use in Febrile Neutropenia CSFs can shorten duration of neutropenia but NOT duration of fever or decrease infection mortality Routine use not recommended; often used in practice No role for filgrastim if patient received pegfilgrastim Consider CSF in severely neutropenic patients w/ documented infections that do not respond to appropriate treatment, or when prolonged delay in marrow recovery is anticipated

25 Persistent Fever in FN The response to treatment is defined by resolution of fever Median time-to-defervescence for high-risk patients treated with appropriate empirical antibacterial regimens is 5-7 d Continue initial antibiotic regimen for at least 3-4 d in stable patients, regardless of persistent fever Antifungals added after 4-7 d of febrile neutropenia unresponsive to initial therapy CT chest may be performed for high risk patients with prolonged neutropenia to evaluate for evidence of invasive mold infection The most important factor for resolution of infection is neutrophil count recovery Bow et al., 2006; Freifeld et al., 2011; NCCN. Prevention and Treatment of Cancer-Related Infection. v1.2018

26 Why Add Anti-Fungals for Persistent Neutropenic Fevers? Neutropenic pts are known to be at risk for invasive fungal infections which can result in high rates of morbidity and mortality Infection mostly due to Candida and Aspergillus species Early studies suggest: Up to 20% of pts will develop an invasive fungal infection by D20 of neutropenia ~60% of pts will develop an invasive fungal infection by D35 of neutropenia Clinical exam and cultures lack sensitivities for detection of fungal infections One study showed only ~50% of patients with autopsy-proven disseminated candidasis had positive blood cultures Another study showed high prevalence (~30%) of invasive fungal infection at autopsy, but less than 1/3 were diagnosed while patient was still alive Berenguer et al., Diag Micro 1993; 17:103-9; Chamilos et al., Haematologica 2006; 986-9; Wingard et al. CID 2004;39:S38-43

27 Central Line Associated Bloodstream Infections (CLABSI) Central line should be removed for bacteremia due to: Staphylococcus Aureus Gram negative bacilli ( e.g. Pseudomonas spp., Stenotrophomonas spp.) Fungi (e.g Candida spp) Mycobacteria If patient is stable, may retain central line and treat with systemic antibiotics x 7-14d for: Coagulase-negative staphylococcus Enterococcus Freifeld et al., 2011; Mermel et al., 2009

28 Drug-Resistant Gram-Negative Bacteria Extended spectrum beta-lactamase (ESBL) producing gram-negative bacteria ESBLs are enzymes that mediate resistance to extended-spectrum cephalosporins and and monobactams (e.g., aztreonam) Most common ESBL-producing isolates: Klebsiella pneumoniae, K. oxytoca, or Escherichia coli Treatment: carbapenem (meropenem) Carbapenem-resistant Enterobacteriaceae (CRE) Most common: Klebsiella pneumoniae carbapenemase (KPC)-producing bacteria Treatment: combination therapy with polymyxin and carbapenem Freifeld et al., 2011; NCCN. Prevention and Treatment of Cancer-Related Infection. v1.2018

29 Drug-Resistant Gram-Positive Bacteria Vancomycin-resistant enterococcus (VRE) Treatment: linezolid, daptomycin, tigecycline Methicillin-resistant Staphylococcus Aureus (MRSA) Treatment: vancomycin, linezolid, daptomycin, tigecycline Other interventions for drug-resistant infections: Private room or cohort patients Contact isolation Judicious use of antimicrobials Surveillance Freifeld et al., 2011; NCCN. Prevention and Treatment of Cancer-Related Infection. v1.2018; Siegel et al., 2007

30 Clinical Pearls About Serious Infections Infection associated with hypotension or respiratory failure carries a poorer prognosis. Infection with gram negative organisms has a greater risk of septic shock than gram positive organisms. Abdominal source of sepsis is more fatal than any other source. The longer a person is ill, hospitalized, or immune compromised, the greater their chance of developing significant sepsis.

31 Summary Patients with febrile neutropenia need prompt assessment and intervention Risk assessment is critical to identify patients that can safely be treated outpatient and those that require admission Early identification of sepsis is critical Lactate is a marker of mortality and response to therapy Aggressively administer IV fluids and antibiotics

32 Evidence-Based Practice Resources for Oncology Nurses Oncology Nursing Society National Comprehensive Cancer Network The Cochrane Library Up To Date Centers for Disease Control and Prevention Infectious Diseases Society of America American Society of Clinical Oncology