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Respiratory Viral Infections in Pediatric Lung Transplant Recipients Are Not Associated with BOS, Retransplant or Death
Abstracts S119 2( 93) Long-Term Outcomes After Living-Donor Lobar Lung Transplantation Using a Single Donor S. Ueda , T.F. Chen-Yoshikawa, H. Motoyama, M. Hamaji, K. Hijiya, A. Aoyama, H. Date. Thoracic Surgery, Kyoto University Hospital, Kyoto, Japan. Purpose: In standard living-donor lobar lung transplantation (LDLLT), two separate donors are required for each individual recipient. However, in selected cases, LDLLT is performed by using a lower lobe from a single donor because of donor shortage or size-matching. We investigated long-term outcomes of such single LDLLT. Methods: Between 2008 and 2016, 77 LDLLTs were performed in Kyoto University Hospital. Among them, 13 single LDLLTs (16.9%) were performed in 12 patients. Retrospective chart review was conducted on our institutional database. Results: Recipients were 3 male and 9 female patients, including 10 children (< 15 years old). The median age was 10.5 years (range, 6-43). The diagnoses of recipients were 7 pulmonary complications after hematopoietic stem cell transplantation, 2 idiopathic pulmonary fibrosis, 1 bronchiolitis obliterans after Stevens-Johnson syndrome, 1 pulmonary veno-occlusive disease, and 1 pulmonary hypertension after surgical correction of congenital heart disease (transposition of the great arteries). Single right LDLLT using a right lower lobe (n= 10) and a right lower basal segment (n= 1) from a donor was performed in 11 patients, including 2 patients with concomitant left pneumonectomy for oversized donor graft. In the remaining 1 patient, right-to-left inverted LDLLT was performed by transplanting a right lower lobe in the left thorax and sparing the native right lung, which was less damaged. One patient underwent single LDLLT using a right lower lobe from his father, which eventually developed primary graft dysfunction. Seventeen days later, he underwent single LDLLT using a left lower lobe from his mother. The median follow-up period was 54 months, ranging from 2 weeks to 100 months. Fiveyear survival was 83.9%. Two patients died of primary graft dysfunction 2 weeks and 3 months after LDLLT, respectively. Three patients suffered from bronchiolitis obliterans syndrome. Nine out of 10 surviving patients are alive without oxygen requirement and only one patient is currently on the waiting list for cadaveric lung transplantation. Conclusion: Despite small number of cases, LDLLT using a single donor was performed with acceptable outcomes. Although surgical procedures are challenging, LDLLT using a single donor might be considered as one of the surgical treatment options in countries with severe donor shortage like Japan. 2( 94) Respiratory Viral Infections in Pediatric Lung Transplant Recipients Are Not Associated with BOS, Retransplant or Death S.C. Sweet ,1 R. Buller,1 H. Chin,2 C. Conrad,3 A. Faro,4 S. Goldfarb,5 D. Hayes,6 P. Heeger,7 D. Ikle,2 K. Kesler,2 E. Melicoff-Portillo,8 T. Mohanakumar,9 M. Schecter,10 G. Storch,1 G. Visner,11 N. Williams,12 L. Danziger-Isakov.10 1Washington University, St. Louis, MO; 2Rho, Inc., Chapel Hill, NC; 3Lucille Packard Children’s Hospital, Palo Alto, CA; 4Cystic Fibrosis Foundation, Bethesda, MD; 5Children's Hospital of Philadephia, Philadephia, PA; 6Nationwide Children's Hospital, Columbus, OH; 7Mount Sinai School of Medicine, New York, NY; 8Texas Children's Hospital, Houston, TX; 9St. Joseph's Hospital & Medical Center, Phoenix, AZ; 10Cincinnati Children's Hosp Med Ctr, Cincinnati, OH; 11Boston Children's Hospital, Boston, MA; 12National Institutes of Health, Bethesda, MD. Purpose: Multiple retrospective studies in adult lung transplant recipients (LTR) have shown community acquired respiratory viral (CARV) infections to be a risk factor bronchiolitis obliterans syndrome (BOS) or bronchiolitis obliterans (OB). We hypothesized that exposure to respiratory viral infections would be associated with late allograft dysfunction in pediatric LTR. Methods: The NIH-sponsored Clinical Trials in Organ Transplantation in Children (CTOTC-03) study collected clinical data from pediatric lung transplant candidates (LTC) at 6 United States centers. Pediatric LTR were followed for at least 2 years or until reaching a composite primary endpoint (PE) of BOS/OB, retransplantation or death. Blood, bronchoalveolar lavage (BAL) and nasopharyngeal (NP) specimens were obtained at standard of care visits during the first 2 years post-transplant. NP specimens were
also obtained when patients developed symptoms suggestive of respiratory viral infection. Sera were analysed for antibodies to donor mismatched HLA (DSA), self-antigens k-alpha-tubulin (kAT) and collagen V (ColV), and alloand auto-reactivity by Elispot. Multiplex PCR was used to interrogate BAL and NP specimens for 17 CARV. Results: Of 78 pediatric LTC, 61 received transplants. All were followed until meeting the PE or for at least 2 years. Of the 28 patients meeting the PE, the triggering criterion was BOS grade ≥ 0-p in 13, OB in 4, death in 10 and re-transplant in one. Of 397 BAL and 480 NP specimens, CARV was detected in 156. Of these 121 (85%) were rhinovirus. Although a Chi-square test suggested that patients with CARV in BAL or NP were less likely to meet the PE (p = 0.05), a Cox proportional hazard model with time-varying covariates analysis showed the cohorts were not significantly different (p = 0.34). No association was observed between CARV recovery from BAL or NP and mechanistic endpoints, including the development of DSA, kAT and ColV Ab and Elispot responses. Conclusion: In this prospective study of pediatric LTR, identification of CARV in NP or BAL was not predictive of meeting a composite endpoint of BOS, retransplant or death and was not associated with increase in alloor autoimmune responses. Further study is needed to clarify the difference between these findings in pediatric LTR and the retrospective association of CARV with BOS and OB in adult LTR.
2( 95) Autotransplantation of the Left Lung for the Treatment of Recurrent Life Threatening Pulmonary Hemorrhage Related to Pulmonary Vascular Malformation: A Novel Treatment Approach & a Unique Chance to Study Ischemia/Reperfusion Injury C. Falk ,1 N. Schwerk,2 C. Mueller,2 W. Sommer,3 K. Daeman,1 J. Keil,1 C. Neudörfl,1 G. Hansen,2 A. Haverich,3 G. Warnecke,3 I. Tudorache.3 1Institute of Transplant Immunology, IFB-Tx, Hannover Medical School, Hannover, Germany; 2Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany; 3Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany. Purpose: Ischemia reperfusion injury (IRI) remains a major clinical problem in lung transplantation. We report an IRI after left lung autotransplantation in an adolescent for recurrent life threatening pulmonary bleedings from extra-anatomic peribronchial systemic arteries. Explantation of the left lung removed all extra-anatomic vessels. Postoperatively the patient has remained asymptomatic. This is the first described case of autotransplantation of a single lung for such an indication. Furthermore, this procedure was a unique chance to investigate isolated IRI as there was no alloreactivity. Methods: Left and right lobe broncheoalveolar lavage (BAL) and blood samples were collected at several time points before, intra and post-transplantation. Luminex-based multiplex assays were used for cytokines, chemokines, growth factors and serum proteases analysis, and flow cytometry for leukocyte subsets. Results: The left lung BAL showed a significant increase in 78 cytokines and chemokines, characterizing IRI. The fastest response was with innate signals like IL-6, IL1RA, IL-18 and IL-16 and chemokines recruiting monocytes and neutrophils like CXCL8, CCL2, CCL4 and CCL5. This was also seen in BAL from the untreated right lung and systemically in plasma but time-delayed and less intensively. In contrast, typical T and NK cell derived cytokines and activation markers were neither elevated in BAL nor plasma. Several BAL cytokine and chemokine levels decreased 24hrs after autotransplantation (IL-6, CCL2, CCL4, TNF-α and IFN-γ ), others later (IL1RA, IL-18, IL-16 and CXCL8). There was also a tissue response of epithelial, endothelial or stroma cells to IRI, indicated by high levels of sICAM-1, sVCAM, sTie-2, VEGF, Ang-2, and HGF levels immediately in left lung BAL but delayed in right lung BAL and plasma. Conclusion: These results indicate that isolated IRI in the absence of alloreactivity can induce a strong cytokine/chemokine response, mainly by monocytes and neutrophils as well as non-immune cells, such as endothelial, epithelial and stroma cells. This strong inflammatory response was not restricted to the re-implanted left lung, since it was also detected time-delayed in the untreated right lung and in part systemically.
also obtained when patients developed symptoms suggestive of respiratory viral infection. Sera were analysed for antibodies to donor mismatched HLA (DSA), self-antigens k-alpha-tubulin (kAT) and collagen V (ColV), and alloand auto-reactivity by Elispot. Multiplex PCR was used to interrogate BAL and NP specimens for 17 CARV. Results: Of 78 pediatric LTC, 61 received transplants. All were followed until meeting the PE or for at least 2 years. Of the 28 patients meeting the PE, the triggering criterion was BOS grade ≥ 0-p in 13, OB in 4, death in 10 and re-transplant in one. Of 397 BAL and 480 NP specimens, CARV was detected in 156. Of these 121 (85%) were rhinovirus. Although a Chi-square test suggested that patients with CARV in BAL or NP were less likely to meet the PE (p = 0.05), a Cox proportional hazard model with time-varying covariates analysis showed the cohorts were not significantly different (p = 0.34). No association was observed between CARV recovery from BAL or NP and mechanistic endpoints, including the development of DSA, kAT and ColV Ab and Elispot responses. Conclusion: In this prospective study of pediatric LTR, identification of CARV in NP or BAL was not predictive of meeting a composite endpoint of BOS, retransplant or death and was not associated with increase in alloor autoimmune responses. Further study is needed to clarify the difference between these findings in pediatric LTR and the retrospective association of CARV with BOS and OB in adult LTR.
2( 95) Autotransplantation of the Left Lung for the Treatment of Recurrent Life Threatening Pulmonary Hemorrhage Related to Pulmonary Vascular Malformation: A Novel Treatment Approach & a Unique Chance to Study Ischemia/Reperfusion Injury C. Falk ,1 N. Schwerk,2 C. Mueller,2 W. Sommer,3 K. Daeman,1 J. Keil,1 C. Neudörfl,1 G. Hansen,2 A. Haverich,3 G. Warnecke,3 I. Tudorache.3 1Institute of Transplant Immunology, IFB-Tx, Hannover Medical School, Hannover, Germany; 2Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany; 3Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany. Purpose: Ischemia reperfusion injury (IRI) remains a major clinical problem in lung transplantation. We report an IRI after left lung autotransplantation in an adolescent for recurrent life threatening pulmonary bleedings from extra-anatomic peribronchial systemic arteries. Explantation of the left lung removed all extra-anatomic vessels. Postoperatively the patient has remained asymptomatic. This is the first described case of autotransplantation of a single lung for such an indication. Furthermore, this procedure was a unique chance to investigate isolated IRI as there was no alloreactivity. Methods: Left and right lobe broncheoalveolar lavage (BAL) and blood samples were collected at several time points before, intra and post-transplantation. Luminex-based multiplex assays were used for cytokines, chemokines, growth factors and serum proteases analysis, and flow cytometry for leukocyte subsets. Results: The left lung BAL showed a significant increase in 78 cytokines and chemokines, characterizing IRI. The fastest response was with innate signals like IL-6, IL1RA, IL-18 and IL-16 and chemokines recruiting monocytes and neutrophils like CXCL8, CCL2, CCL4 and CCL5. This was also seen in BAL from the untreated right lung and systemically in plasma but time-delayed and less intensively. In contrast, typical T and NK cell derived cytokines and activation markers were neither elevated in BAL nor plasma. Several BAL cytokine and chemokine levels decreased 24hrs after autotransplantation (IL-6, CCL2, CCL4, TNF-α and IFN-γ ), others later (IL1RA, IL-18, IL-16 and CXCL8). There was also a tissue response of epithelial, endothelial or stroma cells to IRI, indicated by high levels of sICAM-1, sVCAM, sTie-2, VEGF, Ang-2, and HGF levels immediately in left lung BAL but delayed in right lung BAL and plasma. Conclusion: These results indicate that isolated IRI in the absence of alloreactivity can induce a strong cytokine/chemokine response, mainly by monocytes and neutrophils as well as non-immune cells, such as endothelial, epithelial and stroma cells. This strong inflammatory response was not restricted to the re-implanted left lung, since it was also detected time-delayed in the untreated right lung and in part systemically.