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Anellovirus Can Be Used to Predict Short- and Long-Term Outcomes in Pediatric Lung Transplant Recipients
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The Journal of Heart and Lung Transplantation, Vol 36, No 4S, April 2017
2( 96) Risk and Outcomes of Pulmonary Fungal Infection in Pediatric Lung Transplant E. Ammerman ,1 L. Danziger-Isakov,1 G.A. Storch,2 M. Fenchel,1 C. Conrad,3 D. Hayes,4 A. Faro,2 S. Goldfarb,5 K. Kesler,6 E. MelicoffPortillo,7 M. Schecter,1 G. Visner,8 N. Williams,9 S.C. Sweet.2 1Children's Hosp Med Ctr, Cincinnati, OH; 2Washington University/St. Louis Children's Hospital, St. Louis, MO; 3Lucile Packard Children's Hospital at Stanford University, Palo Alto, CA; 4Nationwide Children's Hospital, Columbus, OH; 5Children's Hospital of Philadephia, Philadelphia, PA; 6Rho, Inc, Chapel Hill, NC; 7Texas Children's Hospital, Houston, TX; 8Harvard Medical School/Boston Children's Hospital, Boston, MA; 9National Institute of Allergy and Infectious Diseases, Bethesda, MD. Purpose: Pulmonary fungal infection (PFI) occurs after pediatric lung transplant (PLT) but risk factors for and outcomes related to PFI have not been prospectively evaluated. Methods: This NIH-sponsored Clinical Trials in Organ Transplantation in Children (CTOTC-03) enrolled PLT candidates, collecting data prospectively for 2 years post-transplant. Demographics, symptoms, radiology, pathology and microbiology were collected and statistical analyses performed to assess risks for and outcomes related to fungal events. PFI and colonization (COL) were defined by ISHLT criteria. Results: 59 of 61 PLT recipients survived at least 21 days. Pre-transplant fungal COL was reported in 16 (27%) recipients and 6 (10%) donors. Recipient pre-txp COL correlated with cystic fibrosis (CF) (p < 0.01). Twenty-eight (47%) patients developed post-transplant fungal events. Twenty-two (37%) had post-txp COL (median = 67d post, range = 0-750d) with Candida (12), Aspergillus (3), mold (4) or yeast (3). Post-PLT COL was not associated with CF, age or pre-PLT COL. 13 PFIs occurred in 10 (16%) patients, 10 probable and 3 proven per ISHLT criteria. Proven PFIs (3) were Candida while probable PFIs were Candida (3), Aspergillus (3), Penicillium (3), and mold (1).9 PFI occurred within 6 months (m= 126d, r= 0-727d). PFI was preceded by post-PLT COL with the same organism in 4 of 13 PFI (m= 75d, r= 16-172d prior to PFI). Older age at transplant was a risk for PFI (p< 0.01) while recipient pre-PLT COL trended to association (p= 0.10) although pathogens were only the same in one instance. Post-PLT COL was not associated with subsequent PFI (p= 0.14). Prophylaxis agent and duration varied widely. No mortality was attributed to PFI. Conclusion: In PLT, PFI and fungal COL are commonly encountered (16% and 37%, respectively), often occurring within 6 months of PLT but with no associated mortality. CF is associated with pre-PLT COL but not post-PLT COL or PFI. Post-PLT COL did not predict PFI. . PFI prevalence suggested further evaluation to determine optimal prophylaxis strategies are warranted. 2( 97) Anellovirus Can Be Used to Predict Short- and Long-Term Outcomes in Pediatric Lung Transplant Recipients J. Blatter ,1 S. Sweet,1 C. Conrad,2 L.A. Danziger-Isakov,3 A. Faro,4 S.B. Goldfarb,5 D. Hayes Jr.,6 E. Melicoff,7 M. Schecter,8 G. Storch,1 G.A. Visner,9 N.M. Williams,10 D. Wang.11 1Department of Pediatrics, Washington University School of Medicine in St. Louis, Saint Louis, MO; 2Department of Pediatrics, Stanford University School of Medicine, Stanford, CA; 3Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; 4Cystic Fibrosis Foundation, Bethesda, MD; 5Department of Pediatrics, University of Pennsylvania, Philadelphia, PA; 6Department of Pediatrics, The Ohio State University, Columbus, OH; 7Department of Pediatrics, Baylor College of Medicine, Houston, TX; 8Department of Pediatrics, University of Cincinnati, Cincinnati, OH; 9Department of Pediatrics, Harvard Medical School, Boston, MA; 10National Institutes of Health, Bethesda, MD; 11Department of Pathology and Immunology, Department of Molecular Biology, Washington University School of Medicine in St. Louis, Saint Louis, MO. Purpose: Anelloviruses are single-stranded DNA viruses ubiquitously present in human blood. Due to its elevated levels in immunosuppressed patients, including lung transplant recipients, anellovirus levels have been proposed as a functional marker of immune status. We hypothesized that low levels of anellovirus, reflecting relative immunocompetence, would be associated with adverse outcomes in pediatric lung transplant.
Methods: We used 135 extracted blood samples from the Clinical Trials in Organ Transplantation in Children (CTOT-C) multicenter study. These samples were collected from approximately two weeks to six months following transplant from 57 pediatric lung transplant recipients (age 8mos to 18yrs). Quantitative polymerase chain reaction (PCR) assays selective for alpha- and betatorquevirus, two common anellovirus genera, were applied. Each patient's two-week, six-week, and six-month anellovirus levels, as available, were categorized as high or low based on being above or below the median copy number at the respective time point. Long-term outcomes were analyzed both individually and as a "composite" (death, chronic rejection, or retransplant within two years). Results: Patients with low alphatorquevirus levels at approximately two weeks following transplant were more likely to develop an episode of acute cellular rejection (ACR) within the first three months following transplant (p= 0.013). All patients who died within two years after transplant had low betatorquevirus levels at six weeks following transplant (p= 0.047). Low betatorquevirus levels at six months following transplant were associated with the development of the composite outcome (p= 0.017). Conclusion: There is an association between low anellovirus levels and the development of adverse outcomes in pediatric lung transplant patients. Alphatorquevirus levels are associated with short-term outcome (i.e., ACR) while betatorquevirus levels are associated with long-term outcome (i.e., death, or composite outcome within two years). These observations suggest that anelloviruses can serve as useful biomarkers of immune status and predictors of adverse outcomes. Future research is needed to explore whether anelloviruses play a functional role in modulating the post-transplant immune milieu or contribute directly to adverse outcomes.
2( 98) Extracorporeal Life Support in Pediatric Lung Transplant: A Single Center Experience R.D. Vanderlaan ,1 M. Cypel,2 H. Grassmann,3 O. Honjo,4 T. Humpl,5 C.A. Caldarone,4 M. Solomon,3 R. Casas,3 S. Azad,2 A. Gueguerian,6 S. Keshavjee.2 1Cardiac Surgery, University of Toronto, Toronto, ON, Canada; 2Thoracic Surgery, Lung Transplant Program, University Health Network, Toronto, ON, Canada; 3Respiratory Medicine, Lung Transplant Program, Hospital for Sick Children, Toronto, ON, Canada; 4Cardiovascular Surgery, Hospital for Sick Children, Toronto, ON, Canada; 5Cardiology, Hospital for Sick Children, Toronto, ON, Canada; 6Critical Care Medicine, Hospital for Sick Children, Toronto, ON, Canada. Purpose: There is a paucity of literature surrounding the use and outcomes of extracorporeal life support (ECLS) in pediatric lung transplant (LTx) patients. Therefore, we sought to describe ECLS use and outcomes in pediatric LTx patients at our institution. Methods: We retrospective reviewed all pediatric LTx (0-18 years) between 2000-2016. We collected patient, ECLS, operative and post- operative variables and long term outcomes. Results: At our institution, 47 LTx were preformed between 2000-2016, with two patients undergoing retransplant. 98% had a bilateral LTx and the most common indications for transplant were: cystic fibrosis (CF) (53%) and pulmonary hypertension (15%). ECLS was used in 34% (16/47) patients: 6% (3/47) patients required both pre and post-LTx ECLS, 13% (6/47) of patients required only pre-LTx ECLS and 15% (7/47) patients required post-LTx ECLS. NovalungR as a bridge to transplant was used in 67% (6/9) of patients requiring pre-LTx ECLS, and the median duration of support was 86 (38-142) days. Those patients requiring ECLS post-LTx were primarily supported by VA ECMO (70%, 7/10) and had a diagnosis of CF (60%, 6/10). The overall median survival in our pediatric lung transplant cohort was 5.5 years. The median survival in patients who received ECLS was 3.8 years compared to 6.9 years for those who did not require ECLS (p= 0.15). Compared to LTx patients who did not require ECLS, need for post-LTx ECLS was associated with a higher risk of mortality (HR 2.6, 0.8-7.7; p= 0.02) (Fig 1). Conclusion: The use of ECLS in children is more prevalent than in adults in our program. Novalung can be used as a successful bridge to LTx in pediatric patients, while the use of ECLS post-LTx is associated with increased mortality. ECLS is an important adjunct to pediatric lung transplant and further understanding of factors associated with poor outcomes will aid risk stratification.
The Journal of Heart and Lung Transplantation, Vol 36, No 4S, April 2017
2( 96) Risk and Outcomes of Pulmonary Fungal Infection in Pediatric Lung Transplant E. Ammerman ,1 L. Danziger-Isakov,1 G.A. Storch,2 M. Fenchel,1 C. Conrad,3 D. Hayes,4 A. Faro,2 S. Goldfarb,5 K. Kesler,6 E. MelicoffPortillo,7 M. Schecter,1 G. Visner,8 N. Williams,9 S.C. Sweet.2 1Children's Hosp Med Ctr, Cincinnati, OH; 2Washington University/St. Louis Children's Hospital, St. Louis, MO; 3Lucile Packard Children's Hospital at Stanford University, Palo Alto, CA; 4Nationwide Children's Hospital, Columbus, OH; 5Children's Hospital of Philadephia, Philadelphia, PA; 6Rho, Inc, Chapel Hill, NC; 7Texas Children's Hospital, Houston, TX; 8Harvard Medical School/Boston Children's Hospital, Boston, MA; 9National Institute of Allergy and Infectious Diseases, Bethesda, MD. Purpose: Pulmonary fungal infection (PFI) occurs after pediatric lung transplant (PLT) but risk factors for and outcomes related to PFI have not been prospectively evaluated. Methods: This NIH-sponsored Clinical Trials in Organ Transplantation in Children (CTOTC-03) enrolled PLT candidates, collecting data prospectively for 2 years post-transplant. Demographics, symptoms, radiology, pathology and microbiology were collected and statistical analyses performed to assess risks for and outcomes related to fungal events. PFI and colonization (COL) were defined by ISHLT criteria. Results: 59 of 61 PLT recipients survived at least 21 days. Pre-transplant fungal COL was reported in 16 (27%) recipients and 6 (10%) donors. Recipient pre-txp COL correlated with cystic fibrosis (CF) (p < 0.01). Twenty-eight (47%) patients developed post-transplant fungal events. Twenty-two (37%) had post-txp COL (median = 67d post, range = 0-750d) with Candida (12), Aspergillus (3), mold (4) or yeast (3). Post-PLT COL was not associated with CF, age or pre-PLT COL. 13 PFIs occurred in 10 (16%) patients, 10 probable and 3 proven per ISHLT criteria. Proven PFIs (3) were Candida while probable PFIs were Candida (3), Aspergillus (3), Penicillium (3), and mold (1).9 PFI occurred within 6 months (m= 126d, r= 0-727d). PFI was preceded by post-PLT COL with the same organism in 4 of 13 PFI (m= 75d, r= 16-172d prior to PFI). Older age at transplant was a risk for PFI (p< 0.01) while recipient pre-PLT COL trended to association (p= 0.10) although pathogens were only the same in one instance. Post-PLT COL was not associated with subsequent PFI (p= 0.14). Prophylaxis agent and duration varied widely. No mortality was attributed to PFI. Conclusion: In PLT, PFI and fungal COL are commonly encountered (16% and 37%, respectively), often occurring within 6 months of PLT but with no associated mortality. CF is associated with pre-PLT COL but not post-PLT COL or PFI. Post-PLT COL did not predict PFI. . PFI prevalence suggested further evaluation to determine optimal prophylaxis strategies are warranted. 2( 97) Anellovirus Can Be Used to Predict Short- and Long-Term Outcomes in Pediatric Lung Transplant Recipients J. Blatter ,1 S. Sweet,1 C. Conrad,2 L.A. Danziger-Isakov,3 A. Faro,4 S.B. Goldfarb,5 D. Hayes Jr.,6 E. Melicoff,7 M. Schecter,8 G. Storch,1 G.A. Visner,9 N.M. Williams,10 D. Wang.11 1Department of Pediatrics, Washington University School of Medicine in St. Louis, Saint Louis, MO; 2Department of Pediatrics, Stanford University School of Medicine, Stanford, CA; 3Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; 4Cystic Fibrosis Foundation, Bethesda, MD; 5Department of Pediatrics, University of Pennsylvania, Philadelphia, PA; 6Department of Pediatrics, The Ohio State University, Columbus, OH; 7Department of Pediatrics, Baylor College of Medicine, Houston, TX; 8Department of Pediatrics, University of Cincinnati, Cincinnati, OH; 9Department of Pediatrics, Harvard Medical School, Boston, MA; 10National Institutes of Health, Bethesda, MD; 11Department of Pathology and Immunology, Department of Molecular Biology, Washington University School of Medicine in St. Louis, Saint Louis, MO. Purpose: Anelloviruses are single-stranded DNA viruses ubiquitously present in human blood. Due to its elevated levels in immunosuppressed patients, including lung transplant recipients, anellovirus levels have been proposed as a functional marker of immune status. We hypothesized that low levels of anellovirus, reflecting relative immunocompetence, would be associated with adverse outcomes in pediatric lung transplant.
Methods: We used 135 extracted blood samples from the Clinical Trials in Organ Transplantation in Children (CTOT-C) multicenter study. These samples were collected from approximately two weeks to six months following transplant from 57 pediatric lung transplant recipients (age 8mos to 18yrs). Quantitative polymerase chain reaction (PCR) assays selective for alpha- and betatorquevirus, two common anellovirus genera, were applied. Each patient's two-week, six-week, and six-month anellovirus levels, as available, were categorized as high or low based on being above or below the median copy number at the respective time point. Long-term outcomes were analyzed both individually and as a "composite" (death, chronic rejection, or retransplant within two years). Results: Patients with low alphatorquevirus levels at approximately two weeks following transplant were more likely to develop an episode of acute cellular rejection (ACR) within the first three months following transplant (p= 0.013). All patients who died within two years after transplant had low betatorquevirus levels at six weeks following transplant (p= 0.047). Low betatorquevirus levels at six months following transplant were associated with the development of the composite outcome (p= 0.017). Conclusion: There is an association between low anellovirus levels and the development of adverse outcomes in pediatric lung transplant patients. Alphatorquevirus levels are associated with short-term outcome (i.e., ACR) while betatorquevirus levels are associated with long-term outcome (i.e., death, or composite outcome within two years). These observations suggest that anelloviruses can serve as useful biomarkers of immune status and predictors of adverse outcomes. Future research is needed to explore whether anelloviruses play a functional role in modulating the post-transplant immune milieu or contribute directly to adverse outcomes.
2( 98) Extracorporeal Life Support in Pediatric Lung Transplant: A Single Center Experience R.D. Vanderlaan ,1 M. Cypel,2 H. Grassmann,3 O. Honjo,4 T. Humpl,5 C.A. Caldarone,4 M. Solomon,3 R. Casas,3 S. Azad,2 A. Gueguerian,6 S. Keshavjee.2 1Cardiac Surgery, University of Toronto, Toronto, ON, Canada; 2Thoracic Surgery, Lung Transplant Program, University Health Network, Toronto, ON, Canada; 3Respiratory Medicine, Lung Transplant Program, Hospital for Sick Children, Toronto, ON, Canada; 4Cardiovascular Surgery, Hospital for Sick Children, Toronto, ON, Canada; 5Cardiology, Hospital for Sick Children, Toronto, ON, Canada; 6Critical Care Medicine, Hospital for Sick Children, Toronto, ON, Canada. Purpose: There is a paucity of literature surrounding the use and outcomes of extracorporeal life support (ECLS) in pediatric lung transplant (LTx) patients. Therefore, we sought to describe ECLS use and outcomes in pediatric LTx patients at our institution. Methods: We retrospective reviewed all pediatric LTx (0-18 years) between 2000-2016. We collected patient, ECLS, operative and post- operative variables and long term outcomes. Results: At our institution, 47 LTx were preformed between 2000-2016, with two patients undergoing retransplant. 98% had a bilateral LTx and the most common indications for transplant were: cystic fibrosis (CF) (53%) and pulmonary hypertension (15%). ECLS was used in 34% (16/47) patients: 6% (3/47) patients required both pre and post-LTx ECLS, 13% (6/47) of patients required only pre-LTx ECLS and 15% (7/47) patients required post-LTx ECLS. NovalungR as a bridge to transplant was used in 67% (6/9) of patients requiring pre-LTx ECLS, and the median duration of support was 86 (38-142) days. Those patients requiring ECLS post-LTx were primarily supported by VA ECMO (70%, 7/10) and had a diagnosis of CF (60%, 6/10). The overall median survival in our pediatric lung transplant cohort was 5.5 years. The median survival in patients who received ECLS was 3.8 years compared to 6.9 years for those who did not require ECLS (p= 0.15). Compared to LTx patients who did not require ECLS, need for post-LTx ECLS was associated with a higher risk of mortality (HR 2.6, 0.8-7.7; p= 0.02) (Fig 1). Conclusion: The use of ECLS in children is more prevalent than in adults in our program. Novalung can be used as a successful bridge to LTx in pediatric patients, while the use of ECLS post-LTx is associated with increased mortality. ECLS is an important adjunct to pediatric lung transplant and further understanding of factors associated with poor outcomes will aid risk stratification.