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Impact of Influenza Vaccination on Outcomes of Influenza Infections in Immunocompromised Patients
Abstracts / Biol Blood Marrow Transplant 25 (2019) S290 S442
Wendy M Leisenring PhD3, Janet A Englund MD1, Michael J Boeckh MD, PhD9. 1 Pediatrics, University of Washington, Seattle, WA; 2 Clinical Biostatistics, Fred Hutchinson Cancer Research Center, Seattle, WA; 3 Fred Hutchinson Cancer Research Center, Seattle, WA; 4 Infectious Diseases, Seattle Children's Hospital, Seattle, WA; 5 Laboratory Medicine, University of Washington, Seattle, WA; 6 Janssen Biopharma, Inc., Seattle, WA; 7 Clinical Trial Services, Inc., Covington, WA; 8 Medicine, University of Washington, Seattle, WA; 9 Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, WA Introduction: Bacterial superinfection following moderate to severe respiratory viral infections (RVIs), especially influenza (Flu), is well described in immunocompetent hosts. The clinical impact of preceding RVIs on the development of bacterial superinfection in hematopoietic cell transplant (HCT) recipients may be significant although data are limited. Furthermore, the impact of upper respiratory tract infection (URTI) on this outcome has not been systematically evaluated. Objectives: To investigate whether URTI due to specific respiratory viruses was associated with increased risk of developing bacteremia or bacterial pneumonia post-HCT. Methods: In a longitudinal surveillance study of RVIs among allogeneic HCT recipients conducted from 2005-10, weekly post-HCT nasal washes were collected through day 100. Nasal and bronchoalveolar lavage samples were tested by multiplex PCR for respiratory syncytial virus, parainfluenza viruses (PIV) 1 4, Flu A/B, human metapneumovirus (HMPV), adenovirus, rhinoviruses and coronaviruses. URTI was defined as having respiratory virus detected from nasal samples with respiratory symptoms. Bacteremia and bacterial pneumonia were defined as growth of significant bacteria (e.g., Coagulase-negative staphylococci was defined as insignificant bacteria) from blood and lower respiratory tract samples including bronchoalveolar lavage, respectively. Separate Cox proportional hazards models were used to examine associations between first URTI for individual viruses and the subsequent development of first bacteremia and/or bacterial pneumonia by 100 days post-HCT. Results: We identified 471 HCT recipients (median age: 51 years, range 8 months-75 years). Number of patients for each first outcome event by 100 days post-HCT included the following: Gram-positive bacteremia (n=64), Gram-negative bacteremia (n=53), Gram-positive pneumonia (n=46), Gramnegative pneumonia (n=8), and either bacteremia or pneumonia (n=152). After adjusting for pre-transplant factors only and
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pre- and post-transplant factors, significant URTI variables for outcomes in both models were (1) Flu A for gram-positive bacteremia, (2) HMPV for gram-positive pneumonia, and (3) HMPV for bacteremia or bacterial pneumonia (Figure). The association between PIV URTI and development of bacteremia or pneumonia approached statistical significance. Conclusion: In HCT recipients, URTIs due to Flu A and HMPV are significant risk factors for the development of gram-positive bacteremia and pneumonia, respectively. Further studies are needed to assess whether prevention or early diagnostic and treatment strategies for RVIs can reduce the risk of bacterial infection.
525 Impact of Influenza Vaccination on Outcomes of Influenza Infections in Immunocompromised Patients Lea Sacca MPH1, Roy F. Chemaly MD, MPH, FIDSA, FACP2, Marjorie V. Batista MD, TID, PhD3, Ying Jiang MS4, Lynn El Haddad PhD2, Ella J Ariza-Heredia MD2. 1 MPH Health Promotion Behavioral Sciences/Global Health, University of Texas Health Science Center Houston, Houston, TX; 2 Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX; 3 Department of Infectious Diseases, Infection Control & Employee Health, MD Anderson Cancer Center, Houston, TX; 4 Department of Infectious Diseases, Infection Control & Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX Introduction: Patients with cancer are more susceptible to influenza infections than the general population, Hematopoietic Cell Transplant (HCT) recipients in particular. Conflicting data on influenza vaccine effectiveness and a lack of clear recommendations in complex clinical scenarios make the compliance with immunization suboptimal. Methods: We conducted a retrospective study and included both HCT and non-HCT recipients with laboratory-confirmed influenza infection during the previous flu season (September 2017- May 2018). We evaluated 365 patients with hematologic malignancies (85), HCT recipients (138), and patients with various solid tumors (142). We analyzed the impact of influenza vaccination on mortality. Results: Influenza A/H3N2 was the most common type detected during the past season with a total of 251 (69%) patients affected and half of the patients were hospitalized. Amongst the HCT recipients, more patients had an allogeneic than autologous transplant (56% vs. 44%). When compared to HCT recipients who were vaccinated, non-vaccinated HCT recipients had higher mortality rate (21% vs. 6%, p<0.05) and more died from respiratory failure (17% vs. 5%, p<0.05). When stratifying HCT recipients with or without lymphopenia Table 1 Vaccination rates among ST patients, HM patients, and HCT recipients characterized by flu-type groups, administration of oseltamivirtherapy, death, and cause of death
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Abstracts / Biol Blood Marrow Transplant 25 (2019) S290 S442
(lymphocytes count <200) at diagnosis, mortality was higher amongst patients with lymphopenia (26% vs. 6%, p<0.05). Similarly, for patients with hematologic malignancies, the vaccination status was a significant risk factor for mortality (Table). Conclusion: Influenza vaccine administered to HCT and nonHCT recipients prior to a flu infection was effective in reducing overall morbidity and mortality associated with this infection. Although protection from influenza infection was suboptimal, we recommend universal vaccination during the flu season to prevent worse outcomes including mortality, especially amongst HCT recipients.
526 Impact of Post-Transplant High-Dose Cyclophosphamide and Donor Sources on CMV Reactivation. James Michael Martin MD1, Jordan Senchak MD2, Carlyn Rose Tan MD3, Philip A Pancari MD3, Brittany Cael PharmD4, Karthik Devarajan PhD5, Stefan K. Barta MD, MRCP, MS3, Henry C Fung MD3. 1 Hematology/Oncology, Temple University Hospital, Philadelphia, PA; 2 Internal Medicine, Temple University Hospital, Philadelphia, PA; 3 Department of Hematology and Oncology, Fox Chase Cancer Center/Temple University Hospital, Philadelphia, PA; 4 Pharmacy, Fox Chase-Temple Bone Marrow Transplant Program, Philadelphia, PA; 5 Biostatistics and Bioinformatics, Fox Chase Cancer Center, Philadelphia, PA Introduction: Cytomegalovirus (CMV) reactivation remains a common cause of morbidity and mortality following allogeneic hematopoietic cell transplant (HCT) despite attempts at prophylaxis. Following transplantation, surveillance of the peripheral blood CMV viral load with early aggressive treatment is commonly employed and has been an effective strategy at preventing overt infection. While a matched related donor (MRD) is often the preferred transplant type, the use of alternative donors including matched unrelated donors (MUD), mismatched unrelated donors (MMUD) and haploidentical (HI) transplants, has greatly increased over the past several years. The data regarding CMV infection among these alternative donor types is scarce. Objectives: To better characterize the extent and risk factors for CMV reactivation among patients who received an allogeneic HCT for hematologic malignancies, particularly among HI transplant recipients and those who received post-transplant high-dose cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis. Methods: A retrospective analysis was performed on 88 adults with hematologic malignancies who received an allogeneic HCT at our institution from 2012-2017. Only cases with CMV seropositive donors and/or recipients were included. We compared donor types/sources, conditioning regimens, GVHD prophylaxis regimens, and assessed for CMV reactivation utilizing the peripheral blood polymerase chain reaction (PCR) values that are monitored in post-transplant clinic visits. Results: Nineteen (22%) patients received MRD transplants, while the remainder received alternative donor sources, including 17 (19%) HI transplants. Overall, the rate of CMV reactivation was 27% with a significant difference noted between donor sources (p=<0.001). HI transplants had significantly higher rates of CMV reactivation, compared to other donor sources (p=<0.001, OR 8.18, 95% CI 2.56-26.16). There was no difference in the timing of CMV reactivation or the time to CMV PCR clearance among the different donor sources. There was a trend toward higher CMV reactivation among patients who received bone marrow grafts rather than peripheral blood grafts (p=0.173, OR 2.21, CI 0.81-9.12). There was no difference among patients who received myeloablative
conditioning regimens or among those who received PTCy for GVHD prophylaxis. The results are summarized in Table 1. Conclusion: HI HCT transplant recipients are at high risk for CMV reactivation. The use of myeloablative conditioning regimens or PTCy did not affect the rate of CMV reactivation.
527 Improving Microbiological Diagnostic Yield of Bronchoalveolar Lavage (BAL) Specimens in Pediatric Allogeneic Hematopoietic Stem Cell Transplant (AlloHSCT) Recipients Jeremy Rosenblum MD1, Nadav Traeger MD2, John Welter MD1, Weihua Huang PhD2, Guiqing Wang PhD2, Changhong Yin MD2, Qiuhu Shi PhD3, John Fallon MD, PhD2, Mitchell S. Cairo MD4. 1 Pediatrics, New York Medical College, Valhalla, NY; 2 Pathology, New York Medical College, Valhalla, NY; 3 Epidemiology and Community Health, New York Medical College, Valhalla, NY; 4 New York Medical College, Valhalla, NY Background: Pulmonary complications, including both infectious and noninfectious etiologies, are a frequent cause of morbidity and mortality in pediatric alloHSCT patients from the immediate post-transplant period to 5 years post-transplant. Early detection and initiation of appropriate antimicrobial therapy improve survival. However, present techniques for identifying infectious organisms are limited by pretreatment with antimicrobial therapies and the need for a priori knowledge of likely viral pathogens, greatly decreasing the yield of BAL. Our group has published the results of 193 pediatric HSCT patients and found a 43% probability of need for BAL in the year following stem cell transplant with only a 40% yield of identifying an infectious organism. Massively parallel sequencing (MPS) has the potential to mitigate these limitations, by identifying the genetic sequence of all DNA or RNA in a sample without the need for viable organisms or microbe specificity. Methods: Pediatric alloHSCT patients with new pulmonary findings on imaging underwent BAL by the pediatric pulmonary service at MFCH as a pilot study (NYMC-181). BAL was performed per standard WMC clinical practice methods and lavage fluid sent for bacterial, fungal, and viral cultures, aspergillus galactomannan, bD-glucan, and PCRs for CMV, EBV, and adenovirus, and other tests as indicated. Excess BAL fluid was preserved in Trizol prior to RNA isolation. cDNA libraries were generated from each sample and sequenced on the Illumina NextSeq platform. Sequence reads were de novo assembled using the Trinity assembler and classified using Kraken and a custom-built database. Results from MPS and clinical testing were compared. Results: 9 patients underwent 10 BALs (1 patient underwent 2 BALs) from July 2016 through December 2017 and had sufficient BAL fluid for inclusion in this study (Figure 1). Clinical microbiological testing identified infections in 6 patients (60%), 3 with bacterial infections (2 Staphylococcus haemolyticus & 1 Streptococcus viridans), 3 with viral pathogens (1 CMV, 1 EBV, and 1 RSV), and 1 fungal infection (Candida). MPS identified infections in 5 patients, one fewer than the clinical testing. Results were wholly concordant in 2 patients (Staph haemolyticus and RSV) and partly concordant in 1 patient (Candida detected, but different viruses found on clinical and sequencing testing). CMV, EBV, S. haemolyticus, and S. viridans (1 patient each) were detected on clinical testing, but not using sequencing. Haemophilus influenza, rhinovirus, and enterovirus (1 patient each) were detected using sequencing, but not clinical testing. Conclusions: RNA based massively parallel sequencing techniques can serve as an adjunct to standard clinical testing of BAL fluid for improved detection of infections (especially polymicrobial) in pediatric recipients of alloHSCT.
Wendy M Leisenring PhD3, Janet A Englund MD1, Michael J Boeckh MD, PhD9. 1 Pediatrics, University of Washington, Seattle, WA; 2 Clinical Biostatistics, Fred Hutchinson Cancer Research Center, Seattle, WA; 3 Fred Hutchinson Cancer Research Center, Seattle, WA; 4 Infectious Diseases, Seattle Children's Hospital, Seattle, WA; 5 Laboratory Medicine, University of Washington, Seattle, WA; 6 Janssen Biopharma, Inc., Seattle, WA; 7 Clinical Trial Services, Inc., Covington, WA; 8 Medicine, University of Washington, Seattle, WA; 9 Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, WA Introduction: Bacterial superinfection following moderate to severe respiratory viral infections (RVIs), especially influenza (Flu), is well described in immunocompetent hosts. The clinical impact of preceding RVIs on the development of bacterial superinfection in hematopoietic cell transplant (HCT) recipients may be significant although data are limited. Furthermore, the impact of upper respiratory tract infection (URTI) on this outcome has not been systematically evaluated. Objectives: To investigate whether URTI due to specific respiratory viruses was associated with increased risk of developing bacteremia or bacterial pneumonia post-HCT. Methods: In a longitudinal surveillance study of RVIs among allogeneic HCT recipients conducted from 2005-10, weekly post-HCT nasal washes were collected through day 100. Nasal and bronchoalveolar lavage samples were tested by multiplex PCR for respiratory syncytial virus, parainfluenza viruses (PIV) 1 4, Flu A/B, human metapneumovirus (HMPV), adenovirus, rhinoviruses and coronaviruses. URTI was defined as having respiratory virus detected from nasal samples with respiratory symptoms. Bacteremia and bacterial pneumonia were defined as growth of significant bacteria (e.g., Coagulase-negative staphylococci was defined as insignificant bacteria) from blood and lower respiratory tract samples including bronchoalveolar lavage, respectively. Separate Cox proportional hazards models were used to examine associations between first URTI for individual viruses and the subsequent development of first bacteremia and/or bacterial pneumonia by 100 days post-HCT. Results: We identified 471 HCT recipients (median age: 51 years, range 8 months-75 years). Number of patients for each first outcome event by 100 days post-HCT included the following: Gram-positive bacteremia (n=64), Gram-negative bacteremia (n=53), Gram-positive pneumonia (n=46), Gramnegative pneumonia (n=8), and either bacteremia or pneumonia (n=152). After adjusting for pre-transplant factors only and
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pre- and post-transplant factors, significant URTI variables for outcomes in both models were (1) Flu A for gram-positive bacteremia, (2) HMPV for gram-positive pneumonia, and (3) HMPV for bacteremia or bacterial pneumonia (Figure). The association between PIV URTI and development of bacteremia or pneumonia approached statistical significance. Conclusion: In HCT recipients, URTIs due to Flu A and HMPV are significant risk factors for the development of gram-positive bacteremia and pneumonia, respectively. Further studies are needed to assess whether prevention or early diagnostic and treatment strategies for RVIs can reduce the risk of bacterial infection.
525 Impact of Influenza Vaccination on Outcomes of Influenza Infections in Immunocompromised Patients Lea Sacca MPH1, Roy F. Chemaly MD, MPH, FIDSA, FACP2, Marjorie V. Batista MD, TID, PhD3, Ying Jiang MS4, Lynn El Haddad PhD2, Ella J Ariza-Heredia MD2. 1 MPH Health Promotion Behavioral Sciences/Global Health, University of Texas Health Science Center Houston, Houston, TX; 2 Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX; 3 Department of Infectious Diseases, Infection Control & Employee Health, MD Anderson Cancer Center, Houston, TX; 4 Department of Infectious Diseases, Infection Control & Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX Introduction: Patients with cancer are more susceptible to influenza infections than the general population, Hematopoietic Cell Transplant (HCT) recipients in particular. Conflicting data on influenza vaccine effectiveness and a lack of clear recommendations in complex clinical scenarios make the compliance with immunization suboptimal. Methods: We conducted a retrospective study and included both HCT and non-HCT recipients with laboratory-confirmed influenza infection during the previous flu season (September 2017- May 2018). We evaluated 365 patients with hematologic malignancies (85), HCT recipients (138), and patients with various solid tumors (142). We analyzed the impact of influenza vaccination on mortality. Results: Influenza A/H3N2 was the most common type detected during the past season with a total of 251 (69%) patients affected and half of the patients were hospitalized. Amongst the HCT recipients, more patients had an allogeneic than autologous transplant (56% vs. 44%). When compared to HCT recipients who were vaccinated, non-vaccinated HCT recipients had higher mortality rate (21% vs. 6%, p<0.05) and more died from respiratory failure (17% vs. 5%, p<0.05). When stratifying HCT recipients with or without lymphopenia Table 1 Vaccination rates among ST patients, HM patients, and HCT recipients characterized by flu-type groups, administration of oseltamivirtherapy, death, and cause of death
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Abstracts / Biol Blood Marrow Transplant 25 (2019) S290 S442
(lymphocytes count <200) at diagnosis, mortality was higher amongst patients with lymphopenia (26% vs. 6%, p<0.05). Similarly, for patients with hematologic malignancies, the vaccination status was a significant risk factor for mortality (Table). Conclusion: Influenza vaccine administered to HCT and nonHCT recipients prior to a flu infection was effective in reducing overall morbidity and mortality associated with this infection. Although protection from influenza infection was suboptimal, we recommend universal vaccination during the flu season to prevent worse outcomes including mortality, especially amongst HCT recipients.
526 Impact of Post-Transplant High-Dose Cyclophosphamide and Donor Sources on CMV Reactivation. James Michael Martin MD1, Jordan Senchak MD2, Carlyn Rose Tan MD3, Philip A Pancari MD3, Brittany Cael PharmD4, Karthik Devarajan PhD5, Stefan K. Barta MD, MRCP, MS3, Henry C Fung MD3. 1 Hematology/Oncology, Temple University Hospital, Philadelphia, PA; 2 Internal Medicine, Temple University Hospital, Philadelphia, PA; 3 Department of Hematology and Oncology, Fox Chase Cancer Center/Temple University Hospital, Philadelphia, PA; 4 Pharmacy, Fox Chase-Temple Bone Marrow Transplant Program, Philadelphia, PA; 5 Biostatistics and Bioinformatics, Fox Chase Cancer Center, Philadelphia, PA Introduction: Cytomegalovirus (CMV) reactivation remains a common cause of morbidity and mortality following allogeneic hematopoietic cell transplant (HCT) despite attempts at prophylaxis. Following transplantation, surveillance of the peripheral blood CMV viral load with early aggressive treatment is commonly employed and has been an effective strategy at preventing overt infection. While a matched related donor (MRD) is often the preferred transplant type, the use of alternative donors including matched unrelated donors (MUD), mismatched unrelated donors (MMUD) and haploidentical (HI) transplants, has greatly increased over the past several years. The data regarding CMV infection among these alternative donor types is scarce. Objectives: To better characterize the extent and risk factors for CMV reactivation among patients who received an allogeneic HCT for hematologic malignancies, particularly among HI transplant recipients and those who received post-transplant high-dose cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis. Methods: A retrospective analysis was performed on 88 adults with hematologic malignancies who received an allogeneic HCT at our institution from 2012-2017. Only cases with CMV seropositive donors and/or recipients were included. We compared donor types/sources, conditioning regimens, GVHD prophylaxis regimens, and assessed for CMV reactivation utilizing the peripheral blood polymerase chain reaction (PCR) values that are monitored in post-transplant clinic visits. Results: Nineteen (22%) patients received MRD transplants, while the remainder received alternative donor sources, including 17 (19%) HI transplants. Overall, the rate of CMV reactivation was 27% with a significant difference noted between donor sources (p=<0.001). HI transplants had significantly higher rates of CMV reactivation, compared to other donor sources (p=<0.001, OR 8.18, 95% CI 2.56-26.16). There was no difference in the timing of CMV reactivation or the time to CMV PCR clearance among the different donor sources. There was a trend toward higher CMV reactivation among patients who received bone marrow grafts rather than peripheral blood grafts (p=0.173, OR 2.21, CI 0.81-9.12). There was no difference among patients who received myeloablative
conditioning regimens or among those who received PTCy for GVHD prophylaxis. The results are summarized in Table 1. Conclusion: HI HCT transplant recipients are at high risk for CMV reactivation. The use of myeloablative conditioning regimens or PTCy did not affect the rate of CMV reactivation.
527 Improving Microbiological Diagnostic Yield of Bronchoalveolar Lavage (BAL) Specimens in Pediatric Allogeneic Hematopoietic Stem Cell Transplant (AlloHSCT) Recipients Jeremy Rosenblum MD1, Nadav Traeger MD2, John Welter MD1, Weihua Huang PhD2, Guiqing Wang PhD2, Changhong Yin MD2, Qiuhu Shi PhD3, John Fallon MD, PhD2, Mitchell S. Cairo MD4. 1 Pediatrics, New York Medical College, Valhalla, NY; 2 Pathology, New York Medical College, Valhalla, NY; 3 Epidemiology and Community Health, New York Medical College, Valhalla, NY; 4 New York Medical College, Valhalla, NY Background: Pulmonary complications, including both infectious and noninfectious etiologies, are a frequent cause of morbidity and mortality in pediatric alloHSCT patients from the immediate post-transplant period to 5 years post-transplant. Early detection and initiation of appropriate antimicrobial therapy improve survival. However, present techniques for identifying infectious organisms are limited by pretreatment with antimicrobial therapies and the need for a priori knowledge of likely viral pathogens, greatly decreasing the yield of BAL. Our group has published the results of 193 pediatric HSCT patients and found a 43% probability of need for BAL in the year following stem cell transplant with only a 40% yield of identifying an infectious organism. Massively parallel sequencing (MPS) has the potential to mitigate these limitations, by identifying the genetic sequence of all DNA or RNA in a sample without the need for viable organisms or microbe specificity. Methods: Pediatric alloHSCT patients with new pulmonary findings on imaging underwent BAL by the pediatric pulmonary service at MFCH as a pilot study (NYMC-181). BAL was performed per standard WMC clinical practice methods and lavage fluid sent for bacterial, fungal, and viral cultures, aspergillus galactomannan, bD-glucan, and PCRs for CMV, EBV, and adenovirus, and other tests as indicated. Excess BAL fluid was preserved in Trizol prior to RNA isolation. cDNA libraries were generated from each sample and sequenced on the Illumina NextSeq platform. Sequence reads were de novo assembled using the Trinity assembler and classified using Kraken and a custom-built database. Results from MPS and clinical testing were compared. Results: 9 patients underwent 10 BALs (1 patient underwent 2 BALs) from July 2016 through December 2017 and had sufficient BAL fluid for inclusion in this study (Figure 1). Clinical microbiological testing identified infections in 6 patients (60%), 3 with bacterial infections (2 Staphylococcus haemolyticus & 1 Streptococcus viridans), 3 with viral pathogens (1 CMV, 1 EBV, and 1 RSV), and 1 fungal infection (Candida). MPS identified infections in 5 patients, one fewer than the clinical testing. Results were wholly concordant in 2 patients (Staph haemolyticus and RSV) and partly concordant in 1 patient (Candida detected, but different viruses found on clinical and sequencing testing). CMV, EBV, S. haemolyticus, and S. viridans (1 patient each) were detected on clinical testing, but not using sequencing. Haemophilus influenza, rhinovirus, and enterovirus (1 patient each) were detected using sequencing, but not clinical testing. Conclusions: RNA based massively parallel sequencing techniques can serve as an adjunct to standard clinical testing of BAL fluid for improved detection of infections (especially polymicrobial) in pediatric recipients of alloHSCT.