Prevention of Infection in Hematology Patients

Transcription

1 Prevention of Infection in Hematology Patients Laura J. Zitella, MS, RN, ACNP-BC, AOCN Nurse Practitioner Clinical Associate Professor University of California San Francisco

2 Infection in Immunocompromised Hematology Patients Immunocompromised Host Alteration in phagocytic, humoral or cell-mediated immunity Mucositis or Skin Alteration Exposure

3 Innate and Adaptive Immunity Abbas, A. K., Lichtman, A. H., & Pillai, S. (2015). Cellular and Molecular Immunology (8th ed.). Philadelphia, PA: Elsevier Saunders.

4 Severity And Duration Of Neutropenia Increases Risk Of Infection Adapted from Bodey GP, et al. Ann Intern Med. 1966;64: ; Meza L, et al. ASCO Abstract 2840.

5 Definitions of Neutropenia Neutropenia Severe Neutropenia Absolute Neutrophil Count <1000/μL Absolute Neutrophil Count < 500/μL Profound Neutropenia Absolute Neutrophil Count <100/μL Protracted Neutropenia Neutropenia that lasts 7 days Taplitz RA et al. (2018). JCO, 36(14), ; Taplitz RA et al. (2018). JCO, 36(30),

6 What are Common Infections Seen When There is Dysfunction of Neutrophils and Lymphocytes? Cell type Principal functions Examples of Pathogens T lymphocyte B lymphocyte Help B cells and macrophages (CD4+ helper cells), kill infected cells and tumor cells (CD8+ cytotoxic T lymphocytes) Antibody production (B cells develop into plasma cells, which make antibodies) Intracellular pathogens: viral, fungal, mycobacteria, PCP Recurrent bacterial infections with encapsulated organisms; viral infections Neutrophils Phagocytosis and killing of microbes Bacterial infections

7 What Contributes To The Risk Of Infection In Hematology Patients? Balance between microbial colonization and host defenses Phagocytic, humoral and cellular immune defects due to disease or its treatment Neutropenia Altered B- and T-cell function Acute leukemia and lymphoid malignancies Steroids, anti-cd20 monoclonal Ab, and purine analogs Hypogammaglobulinemia Splenectomy Pomakova, D., & Segal, B. H. (2014). Prevention of Infection in Cancer Patients BT - Infectious Complications in Cancer Patients. In V. Stosor & T. R. Zembower (Eds.), (pp ). Cham: Springer International Publishing.

8 What Contributes To The Risk Of Infection In Hematology Patients? Impairment of host defenses in cancer patients Status of malignancy New diagnosis Relapsed or advanced disease Breakdown of normal skin and mucosal barriers Indwelling catheters, mucositis Patient factors Comorbidities, performance status Organ function, bone marrow reserve Treatment factors Intensive therapy, multimodal therapy Pomakova, D., & Segal, B. H. (2014). Prevention of Infection in Cancer Patients BT - Infectious Complications in Cancer Patients. In V. Stosor & T. R. Zembower (Eds.), (pp ). Cham: Springer International Publishing.

9 Disease-Related Factors That Increase Risk Of Infection Disease Infection Risk Cause Hematologic malignancies (Leukemia, lymphoma, MDS, MM) Chronic lymphocytic leukemia, multiple myeloma Leukopenia Encapsulated bacterial infections (S. pneumoniae); recurrent sinopulmonary infections Infiltration of bone marrow Hypogammaglobulinemia NCCN. Prevention and Treatment of Cancer-Related Infection. v1.2018

10 Treatment-Related Factors That Increase Risk Of Infection Treatment Infection Risk Cause Myelosuppressive chemotherapy or radiation to pelvis, spine Neutropenia: bacterial infections Prolonged neutropenia: bacteria, fungi, viruses Chemotherapy or radiation Bacteremia, colitis, candida Mucositis Splenectomy Steroids (Prednisone > 20 mg/d for more than 4 weeks) Purine analogs (e.g. fludarabine, clofarabine, nelarabine, cladribine) Anti-CD20 antibodies (e.g. rituximab, ofatumumab, obinutuzumab) Proteosome inhibitors (e.g bortezomib, carfilzomib, ixazomib) NCCN. Prevention and Treatment of Cancer-Related Infection. v Encapsulated bacterial infections (S. pneumoniae, Neisseria meningitidis, H. influenzae) Bacterial, fungal, viral infections PCP Listeria, mycobacteria, opportunistic fungal and viral infections, PCP Hepatitis B reactivation; Progressive multifocal leukoencephalopathy (PML) due to JC virus VZV reactivation (shingles) Cytotoxic to bone marrow precursors Reduced ability to rapidly produce antibodies Dysfunction of neutrophils, monocytes, and lymphocytes Lymphocytotoxic B- cell deficiency Impaired lymphocyte function

11 NCCN Guidelines: Infection Risk Stratification NCCN. Prevention and Treatment of Cancer-Related Infection. v1.2018

12 What Guides Your Decision Making About Infection Prophylaxis? 1. Risk of infection 2. Potential severity of infection and the likelihood of response to therapy 3. Safety and efficacy of antimicrobial prophylaxis

13 What Is The Role Of Colony Stimulating Factors (CSF) To Prevent Neutropenia? CSF used for primary prevention decreases the risk of febrile neutropenia by 50% CSFs reduce: Neutropenia and febrile neutropenia Infection Infection-related and overall mortality Duration of hospitalization Duration of parenteral antibiotics CSFs maintain dose intensity Aapro et al., 2011; Kuderer et al., 2007; Lyman et al., 2010; NCCN. Myeloid Growth Factors. V2.2018; Sung et al., 2007

14 Consensus Guidelines for Colony Stimulating Factors (CSFs): ASCO, EORTC, ESMO, NCCN Assess risk of febrile neutropenia (FN) associated with the chemotherapy regimen FN risk 20% CSF Recommended FN Risk 10-20% Consider CSF FN Risk < 10% CSF Not Indicated CSFs not routinely recommended for: Patients undergoing radiation AML induction Hodgkin lymphoma treated with ABVD Aapro et al., 2011; Crawford et al., 2010; Kuderer et al., 2007; Lyman et al., 2011; ; NCCN. Myeloid Growth Factors. V2.2018; Smith et al., 2006

15 Antibiotic Prophylaxis During Neutropenia Neutropenia increases risk of severe bacterial infections High risk: ANC < 100 for more than 7 days Intermediate risk: ANC < 1000 for more than 7 days Low risk: ANC < 500 for less than 7 days Optimal antibacterial prophylaxis targets bacterial gut decontamination of gram (-) organisms while maintaining anaerobic bacteria considered important to maintain resistance to C. difficile and other pathogenic organisms Drugs of Choice: Levofloxacin 500 mg PO daily (preferred) Ciprofloxacin 500 mg PO twice daily Cullen et al., 2005 ; Freifeld et al., 2011; Gafter-Gvili et al., 2012; NCCN. Prevention and Treatment of Cancer-Related Infection. v1.2018; Taplitz RA et al. (2018). JCO, 36(14), ; Tomblyn et al., 2009

16 When Is It Appropriate To Use Antibiotic Prophylaxis During Neutropenia? Recommended for high risk neutropenic patients expected to have ANC 100/mcl for 7 days (e.g. acute leukemia/hct): Reduces overall mortality and infection-related mortality Monitor for antibiotic resistance or adverse effects May consider for intermediate risk patients Not recommended for low risk patients Has not been proven to decrease mortality Results in treating large numbers of patients with antibiotics to prevent small number of infections Risk of antibiotic resistance or adverse effects was not statistically significant in the clinical trials, but there remains significant clinical concern as resistance rates have increased over past decade Cullen et al., 2005 ; Freifeld et al., 2011; Gafter-Gvili et al., 2012; NCCN. Prevention and Treatment of Cancer-Related Infection. v1.2018; Taplitz RA et al. (2018). JCO, 36(14), ; Tomblyn et al., 2009

17 Febrile Episodes (%) Is Antibiotic Prophylaxis Necessary in Addition to CSFs? Levofloxacin Placebo P =.001 P =.01 Pegfilgrastim Placebo P <.001 Ciprofloxacin Filgrastim Pegfilgrastim Pegfilgrastim and ciprofloxacin P < Cullen et al., 2005 Bucaneve et al., 2005 Vogel et al., 2005 von Minckwitz et al., 2008 Bucaneve et al., 2005; Cullen et al., 2005; Vogel et al., 2005; von Minckwitz et al., 2008

18 Who Should Be Treated With Antivirals To Prevent HSV/VZV Reactivation? HSV seropositive patients: Autologous or allogeneic HCT Acute leukemia Lymphoma Multiple myeloma CLL Treatment with proteasome inhibitors (e.g bortezomib), alemtuzumab, or purine analogs (e.g fludarabine) GVHD treated with steroids Prior HSV reactivation during treatment Drugs of choice: Valacyclovir 500 mg PO QD-BID (HSV) or BID-TID (VZV) Acyclovir mg PO BID (HSV) or 800 mg PO BID (VZV) Famciclovir 250 mg PO BID (HSV/VZV) Freifeld et al., 2011; NCCN. Prevention and Treatment of Cancer-Related Infection. v1.2018; Taplitz RA et al. (2018). JCO, 36(14), ; Tomblyn et al., 2009

19 Hepatitis B Virus (HBV) Reactivation 30% of world population has been infected with HBV 350 million people worldwide with chronic HBV Transmitted by perinatal, percutaneous, and sexual exposure and by close person-to-person contact (presumably by open cuts and sores, especially among children in hyperendemic area) In endemic areas, major source of transmission is perinatal Patients undergoing HCT or immunosuppressive therapy may lose immune control of HBV Incidence of HBV reactivation during anticancer treatment is 20-50% Two-fold higher risk with rituximab-chemo vs chemo alone HBV reactivation can lead to fulminant hepatitis and death Dong et al., 2013; EASL, 2012; Lok & McMahon, 2009; NCCN. Prevention and Treatment of Cancer-Related Infection. v1.2018; Terrault et al Hepatology, 67(4)

20 Who Should Be Tested for Hepatitis B? High risk patients Endemic areas: Africa; North, Southeast, East Asia; South Pacific; Middle East; Eastern Europe; Parts of Western Europe; North America (Alaskan natives and indigenous populations of Northern Canada); Parts of Central and South America; Caribbean Persons who have ever injected drugs Men who have sex with men or persons who are not in a long-term, mutually monogamous relationship Persons with HIV, chronic liver disease, end-stage renal disease Patients undergoing anti-cd20 therapy Patients undergoing hematopoietic cell transplantation. More than 40% of patients with HBV do not have obvious risk factors Hwang JP et al. 2015, JCO, 33(19), ; NCCN. Prevention and Treatment of Cancer-Related Infection. v1.2018; Tomblyn et al., 2009

21 Who Should Be Treated With Antivirals To Prevent HBV Reactivation? All Hepatitis B surface Ag positive patients Hepatitis B surface Ag negative/hepatitis B core Ab positive patients who: Are undergoing allo HCT Are being treated with anti-cd20 therapy or alemtuzumab Antivirals: Entecavir 0.5 mg PO daily (preferred) Tenofovir 300 mg PO daily Adefovir 10 mg PO daily Telbivudine 600 mg PO daily Lamivudine 100 mg PO daily (not recommended due to higher rate of resistance than other choices) Monitor HBV DNA every 1-3 months Continue antiviral until at least 6-12 months after cessation of therapy NCCN. Prevention and Treatment of Cancer-Related Infection. v1.2018; Hwang & Lok, 2014; Lok & McMahon, 2009; Taplitz RA et al. (2018). JCO, 36(14), ; Tomblyn et al., 2009

22 Antifungal Prophylaxis Major types of fungal infections are yeasts (e.g Candida) and molds (e.g. Aspergillus) Azoles Fluconazole Effective against candida, no activity against molds Mold-active azoles: voriconazole, posaconazole, isavuconazole Effective against both yeast and molds Echinocandins: caspofungin, micafungin, anidulafungin Effective against both yeast and molds NCCN. Prevention and Treatment of Cancer-Related Infection. v1.2018; Taplitz RA et al. (2018). JCO, 36(14),

23 Which Patients Benefit from Antifungal Prophylaxis? Oral azole or parenteral echinocandin recommended for patients at high risk for profound, protracted neutropenia AML, MDS: posaconazole ALL: fluconazole or micafungin HCT patients (auto with mucositis or allo): fluconazole or micafungin Significant GVHD: posaconazole Patients with grade III or IV mucositis (high risk for candidiasis): fluconazole Risk of invasive aspergillosis > 6%: mold-active triazole NCCN. Prevention and Treatment of Cancer-Related Infection. v1.2018; Taplitz RA et al. (2018). JCO, 36(14),

24 Indications for Pneumocystis Prophylaxis Patients at high risk (>3.5% risk for pneumonia from Pneumocystis jirovecii): Autologous/allogeneic HCT ALL Treatment with alemtuzumab, purine analogs (e.g fludarabine), or PI3K inhibitors (e.g. idelalisib) Prolonged corticosteroid use ( 20 mg/day prednisone for 4 weeks) Temozolomide in combination with radiation CD4 count < 200 cells/mcl Examples of Medications Trimethoprim/sulfamethoxazole DS (800/160) on M,W,F Trimethoprim/sulfamethoxazole SS (400/80) daily Alternative: Atovaquone 1500 mg PO/d (suspension) taken with food Dapsone 100 mg PO/d Inhaled (aerosolized) pentamadine 300 mg/month Freifeld et al., 2011; NCCN. Prevention and Treatment of Cancer-Related Infection. v1.2018; Neumann et al., 2013; Taplitz RA et al. (2018). JCO, 36(14), ; Tomblyn et al., 2009

25 Summary of Antimicrobial Prophylaxis Infection Risk Low Intermediate High Antimicrobial Prophylaxis Bacterial - None Fungal - None Viral - None unless prior HSV episode Bacterial - Consider fluoroquinolone prophylaxis during neutropenia Fungal - Consider fluconazole during neutropenia and for anticipated mucositis; consider PCP prophylaxis for at risk patients Viral - During neutropenia and at least 30d after auto HCT Bacterial Consider fluoroquinolone prophylaxis during neutropenia Fungal Consider antifungal prophylaxis during neutropenia; consider PCP prophylaxis for at risk patients Viral- HSV/VZV during neutropenia and at least 30d after allo HCT; pre-emptive CMV screening for allo HCT and alemtuzumab; HBV screening and prophylaxis for at risk patients Freifeld et al., 2011; NCCN. Prevention and Treatment of Cancer-Related Infection. v1.2018; Taplitz RA et al. (2018). JCO, 36(14), ; Tomblyn et al., 2009

26 Miguel is very worried about getting an infection. He asks you what is the most effective strategy to prevent infection? A. Fluoroquinolone prophylaxis B. Colony stimulating factors C. Handwashing D. HEPA-filtered room

27 Handwashing The single most effective method to prevent the transmission of infection is hand hygiene Alcohol-based hand rub or soap and water Must use soap and water if: Hands are visibly soiled or contaminated with blood or body fluids While caring for a patient with C. difficile WHO 5 Moments for Hand Hygiene Boyce & Pittet, 2002;

28 Should I Be On A Special Diet? In 70s, observations that fresh fruits and vegetables with high microbial counts; concern for bacterial translocation through disrupted mucosa Low microbial or neutropenic diet: NO fresh fruits and vegetables There are NO studies that show that dietary restrictions decrease the risk of infection. Most notable studies: RCT of ~ 150 AML induction pts at MDACC Retrospective study of ~ 700 HCT pts at NMH Restriction of fresh fruits and vegetables is not recommended by any professional cancer organization Standard food safety recommended: additional specific recommendations for HCT patients Freifeld et al., 2011; Gardner et al., 2008; Taplitz RA et al. (2018). JCO, 36(14), ; Trifilio et al., 2012; Zitella, Gobel, & O Leary, 2009

29 USDA/FDA Food Safety Guidelines for People with Cancer Clean Hands, surface areas, fruits and vegetables Separate Keep raw meat, poultry, seafood, eggs, and their juices away from other food Cook Cook foods to the proper temperatures Chill Keep refrigerator 40 F and freezer 0 F.

30 Do Protective Environments Or Protective Gear Reduce The Risk Of Infection? HEPA filtration Protective against molds in high risk patients Antiseptic bathing Evidence overall contradictory Recent studies showed benefit in HCT and critical care patients Laminar airflow Value unclear; doesn t decrease mortality Protective clothing (e.g. gowns, surgical masks, shoe covers) Not proven to reduce the risk of infection Antiseptic Bathing Climo et al., 2013; Freifeld et al., 2011; Mank et al., 2003; NCCN. Prevention and Treatment of Cancer-Related Infection. v1.2018; Pallotto C et al Clin Micro Inf: Taplitz RA et al. (2018). JCO, 36(14),

31 Additional Recommendations from ASCO Guidelines to Prevent Infection All health care workers should comply with hand hygiene and respiratory hygiene/cough etiquette guidelines to reduce the risk for aerosol- and direct or indirect contact based transmission of pathogenic microorganisms in the health care setting Outpatients with neutropenia from cancer therapy should avoid prolonged contact with environments that have high concentrations of airborne fungal spores (eg, construction and demolition sites, intensive exposure to soil through gardening or digging, or household renovation) Taplitz RA et al. (2018). JCO, 36(14),

32 Can Cancer Patients Receive Vaccines? Recommended Vaccines Vaccines Used For Specific Circumstances Vaccines to Avoid Influenza annually (inactivated vaccine) Pneumococcal vaccine PCV13 followed by dose of PPSV23 at least 8 weeks later and 5 y after the first dose Tetanus, diphtheria, and acellular pertussis (Td/Tdap): Tdap to previously unvaccinated adults < 65 y Then Td every 10 years Hepatitis B vaccine Splenectomy, splenic irradiation or functional asplenia: Administer at least two weeks prior to splenectomy or splenic irradiation Pneumococcal polysaccharide vaccine (PCV13 followed by dose of PPSV23 at least 8 weeks later and 5 y after the first dose) Meningococcal conjugate vaccine quadrivalent (MCV4) and 2 months later and then every 5 y Haemophilus influenzae type b (Hib) vaccine Live, attenuated virus vaccines: Influenza live vaccine (FluMist ) Smallpox Measles, mumps, rubella vaccine (MMR) Varicella zoster Rotavirus Yellow fever Oral typhoid vaccine (TY21a) BCG Oral poliovirus vaccine Vaccines can be deferred in patients unlikely to respond: patients who have received anti-b-cell antibodies within the past 6 months or patients with acute leukemia treated with induction/consolidation chemotherapy CDC, 2018; NCCN. Prevention and Treatment of Cancer-Related Infection. v1.2018; Taplitz RA et al. (2018). JCO, 36(14),

33 John is a 63 y/o with Stage III diffuse large B cell lymphoma with PMH of HTN and DM. He is treated with RCHOP. He does not have a central line. Should John receive prophylactic antibiotics so he does not develop febrile neutropenia? No. Prophylactic antibiotics are not recommended for intermediate risk neutropenic patients who have an anticipated duration of neutropenia less than 7-10 days. Should John receive myeloid growth factors? Yes. Since he is over age 60, the risk of febrile neutropenia after RCHOP is > 20%. Should John be tested for hepatitis B? Yes. He is going to be treated with rituximab.

34 Miguel is a 33 y/o with AML who is treated with 7+3 induction chemotherapy. He has a PICC line. Should Miguel receive prophylactic antibiotics so he does not develop febrile neutropenia? Yes. Patients with AML have an anticipated duration of neutropenia(anc < 100) for more than 7-10 days and are at high risk for infection. Should Miguel receive growth factors? No. Growth factors are not recommended during induction therapy for AML. What other prophylactic medications do you recommend? Antifungal and antiviral.

35 Summary Risk assessment informs recommendations for infection prophylaxis For high risk patients, antimicrobial and antifungal prophylaxis should be considered Antiviral prophylaxis recommended for patients at high risk of reactivation Hand washing is a key element of infection control and prevention Restriction of fresh fruits/vegetables and protective isolation have not been shown to decrease infection

36 Resources NCCN Guideline for Prevention and Treatment of Cancer-Related Infections ONS Putting Evidence into Practice: Prevention of Infection For patients: The CDC s Division of Cancer Prevention and Control: Prevent Cancer Infections USDA Food Safety for Cancer Patients