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Cytotoxic T Cells Early after Lung Transplantation Precede the Restrictive Allograft Syndrome
S406
The Journal of Heart and Lung Transplantation, Vol 38, No 4S, April 2019
of such mismatches, particularly from male donor organs transplanted into female recipients, are unclear. Methods: A review of the United Network of Organ Sharing (UNOS) database was conducted from 10/1987 to 12/2016. Recipient and graft survivals, and the incidences of acute rejection (AR)-related hospitalization and bronchiolitis obliterans syndrome (BOS), were determined across four groups: male donor-male recipient (dMrM, n = 12095), female donor-female recipient (dFrF, n=7444), female donor-male recipient (dFrM, n=3962) and male donor-female recipient (dMrF, n = 5766). Results: AR-related hospitalization was specifically increased only in the dMrF group (p=0.006). In addition, severe BOS (Grade 3) was specifically increased only in the dMrF group (p <0.0001). However, despite the fact that female recipients had higher rates of AR and BOS (see Table), these data did not translate to diminished graft or patient survival. Conclusion: In clinical lung transplantation, female recipients of male allografts specifically exhibited significantly increased rates of AR and BOS. These findings are consistent with well-established immunological concepts and evidence, and have implications for donor-recipient matching in order to achieve optimal outcomes.
Immunological Outcomes of Lung Transplantation as functions of Donor-Recipient Sex Matching AR-related hospitalization and Grade 3 BOS as functions of donor-recipient sex matching Donor-Recipient Acute Rejection Severe BOS Sex Matching Groups Related Hospitalization (Grade 3) dMrM dFrF dFrM dMrF
25.2% 24.8% 23.6% 27.8%
3.88% 3.96% 3.94% 4.46%
1024 Diagnosis of Restrictive Allograft Syndrome (RAS) in Single-Lung Transplantation Using PFTs and CT-Scan Volumetry and Score O. Brugiere,1 Q. Philippot,1 R. Bun,2 C. Couffignal,3 J. Frijat,4 V. Bunel,1 L. Morer,1 G. Mourin,1 G. Jebrak,1 Y. Castier,5 G. Dauriat,1 P. Mordant,5 H. Mal,1 and M. Debray.6 1Transplantation Pulmonaire, Hopital Bichat, Paris, France; 2Departement Biostatistique, Hopital Bichat, Paris, France; 3Departement Biostatistique, Hopital Bichat, Paris, France; 4Explorations Fonctionnelles Respiratoires, Hopital Bichat, Paris, France; 5Chirurgie Thoracique, Hopital Bichat, Paris, France; and the 6 Radiologie, Hopital Bichat, Paris, France. Purpose: Restrictive allograft syndrome (RAS) has been identified as a chronic lung allograft dysfunction (CLAD) with the worst prognosis after lung transplantation (LTx). Diagnostic criteria of RAS have been proposed in double-LTx (DLTx), but how to apply these criteria in single (S)-LTx remain debatable. Hence, there is a need to validate and refine these criteria in SLTx. Our aim was to investigate functional, allosensitization, and CTscan abnormalities patterns in SLTx recipients with RAS, as compared to single LTx with BOS or in stable condition. Methods: We retrospectively reviewed data from all SLTx recipients during the 2009-2015 period at Bichat hospital. Among them, RAS phenotype in SLTx was identified using criteria defined in BLTx, including both PFTs (FVC ≤ 80% of baseline or FEV1 ≤ 80% of baseline with FEV1/ FVC > 0.7) and CT-scan with persistent opacities suggestive of RAS. These SLTx with RAS were compared with SLTx with BOS and stable patients. We compared outcome of PFTs (FVC, FEV1, FEV1/FVC), repeated CT-scan (both CT-volumetry and CT parenchymal score), and DSA between the 3 groups at the following 4 time points with available CT-scan: (1) at the date of best post-Tx functional status, (2) at the date of CLAD onset, defined at first irreversible decline of PFTs or graft CT-volume, or first onset of pleuroparenchymal abnormalities reflected by RAS parenchymal score; (3) at last available CT-scan; (4) at an average time between 2 and 3. Results: 17 SLTx were identified with RAS diagnosis, and compared to 17 SLTx with BOS and 17 stable SLTx. In RAS patients, outcome of FVC,
FEV1, CT-volume, and CT-score showed all a significant decrease from time-point of CT baseline to last CT-scan (p< 0.001, p<0.001, p<0.001, p<0.001, respectively for the 4 parameters). Interestingly, CT-scan score showed the earlier significant increased value to identify RAS diagnosis at the date of CT-onset (p<0.05 for CT-score ≥ 3), as compared no significant decline for FVC, FEV1, CT volumetry (p=ns). Criteria of RAS based only on spirometry lacked of specificity, since 35 % of BOS SLTx patients also had FVC < 80% of baseline during follow-up. Conclusion: RAS diagnosis remains challenging in SLTx. We observed that the increase of a CT score ≥3 may lead to earlier identification of RAS patients in this population, as compared to standard criteria of RAS initially defined in DLTx. 1025 Cytotoxic T Cells Early after Lung Transplantation Precede the Restrictive Allograft Syndrome T. Nakagiri, A. Kn€ofel, W. Sommer, J. Salman, T. Siemeni, M. Avsar, F. Ius, P. Zardo, I. Tudorache, A. Haverich and G. Warnecke. Cardiothoracic, Transplantation, and Vascular Surgery, Hannover Medical School, Hannover, Germany. Purpose: The outcome after lung transplantation is limited by chronic lung allograft dysfunction (CLAD), subclassified into bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS). RAS tends to an earlier, more severe and more rapid course as compared to BOS. Underlying differences of the immunologic phenotype, potentially unveiling therapeutic targets, have not yet been well-defined. Methods: From June 2013 to August 2015, we collected whole blood samples from 142 consecutively transplanted patients 3 weeks after lung transplantation, excluding only those patients with missing blood samples or who did not consent to have the samples drawn. The samples were analyzed by flow cytometry. CD3+ CD8+ T cells were defined as cytotoxic T cells. Follow up ended as of 09/2018 and full data was available from 138 patients. CLAD diagnosis was made according to ISHLT consensus criteria based on a persistent >20% decline of FEV1 in spirometry. RAS was diagnosed in the presence of a >20% decline of FEV1 concomitant with a >10% decline of the total lung capacity and confirmed by CT scans. Results: In this cohort, 115 patients did not develop CLAD at the end of follow up (control group). BOS was observed in 18 patients, whereas RAS was observed in 5 patients. In the BOS group, 7 patients were graded 1, 1 patient was graded 2, and 10 patients were graded 3. There was no significant difference in the percentage of CD8 T cells amongst lymphocytes between the control and the CLAD group (5.2§8.2% vs. 5.7§7.1%, respectively: p=0.40), three weeks after transplantation. In addition, there was also no significant difference between the control and the BOS subgroup (5.2§8.2% vs. 3.9§5.8%, respectively: p=0.27). However, a significant difference was detected between the BOS and RAS groups (3.9§5.8 vs. 12.0§8.6%, respectively: p<0.05). Moreover, the difference was also significant between grade 3 BOS patients and the RAS group (2.4§2.5% vs. 12.0§8.6%, respectively, p<0.01). Conclusion: The development of the most severe and frequently early subtype of chronic lung rejection, the restrictive allograft syndrome, is preceeded by a high frequency of cytotoxic effector CD8+ T cells in peripheral blood as early as three weeks post transplantation. Cytotoxic T cells are also known to contribute to acute rejections and might be targeted by multiple immunosuppressive treatments.
1026 Decreased Serum Levels of Irisin are Associated with the Development of Chronic Lung Allograft Dysfunction after Bilateral Living-Donor Lobar Lung Transplantation T. Shiotani, S. Sugimoto, H. Yamamoto, T. Kurosaki, S. Otani, M. Okazaki, M. Yamane, S. Toyooka and T. Oto. Department of General Thoracic Surgery, Organ Transplant Center, Okayama University, Okayama, Japan. Purpose: Irisin is a skeletal muscle cell-derived myokine associated with physical activity. Recently, decreased serum irisin levels have been shown
The Journal of Heart and Lung Transplantation, Vol 38, No 4S, April 2019
of such mismatches, particularly from male donor organs transplanted into female recipients, are unclear. Methods: A review of the United Network of Organ Sharing (UNOS) database was conducted from 10/1987 to 12/2016. Recipient and graft survivals, and the incidences of acute rejection (AR)-related hospitalization and bronchiolitis obliterans syndrome (BOS), were determined across four groups: male donor-male recipient (dMrM, n = 12095), female donor-female recipient (dFrF, n=7444), female donor-male recipient (dFrM, n=3962) and male donor-female recipient (dMrF, n = 5766). Results: AR-related hospitalization was specifically increased only in the dMrF group (p=0.006). In addition, severe BOS (Grade 3) was specifically increased only in the dMrF group (p <0.0001). However, despite the fact that female recipients had higher rates of AR and BOS (see Table), these data did not translate to diminished graft or patient survival. Conclusion: In clinical lung transplantation, female recipients of male allografts specifically exhibited significantly increased rates of AR and BOS. These findings are consistent with well-established immunological concepts and evidence, and have implications for donor-recipient matching in order to achieve optimal outcomes.
Immunological Outcomes of Lung Transplantation as functions of Donor-Recipient Sex Matching AR-related hospitalization and Grade 3 BOS as functions of donor-recipient sex matching Donor-Recipient Acute Rejection Severe BOS Sex Matching Groups Related Hospitalization (Grade 3) dMrM dFrF dFrM dMrF
25.2% 24.8% 23.6% 27.8%
3.88% 3.96% 3.94% 4.46%
1024 Diagnosis of Restrictive Allograft Syndrome (RAS) in Single-Lung Transplantation Using PFTs and CT-Scan Volumetry and Score O. Brugiere,1 Q. Philippot,1 R. Bun,2 C. Couffignal,3 J. Frijat,4 V. Bunel,1 L. Morer,1 G. Mourin,1 G. Jebrak,1 Y. Castier,5 G. Dauriat,1 P. Mordant,5 H. Mal,1 and M. Debray.6 1Transplantation Pulmonaire, Hopital Bichat, Paris, France; 2Departement Biostatistique, Hopital Bichat, Paris, France; 3Departement Biostatistique, Hopital Bichat, Paris, France; 4Explorations Fonctionnelles Respiratoires, Hopital Bichat, Paris, France; 5Chirurgie Thoracique, Hopital Bichat, Paris, France; and the 6 Radiologie, Hopital Bichat, Paris, France. Purpose: Restrictive allograft syndrome (RAS) has been identified as a chronic lung allograft dysfunction (CLAD) with the worst prognosis after lung transplantation (LTx). Diagnostic criteria of RAS have been proposed in double-LTx (DLTx), but how to apply these criteria in single (S)-LTx remain debatable. Hence, there is a need to validate and refine these criteria in SLTx. Our aim was to investigate functional, allosensitization, and CTscan abnormalities patterns in SLTx recipients with RAS, as compared to single LTx with BOS or in stable condition. Methods: We retrospectively reviewed data from all SLTx recipients during the 2009-2015 period at Bichat hospital. Among them, RAS phenotype in SLTx was identified using criteria defined in BLTx, including both PFTs (FVC ≤ 80% of baseline or FEV1 ≤ 80% of baseline with FEV1/ FVC > 0.7) and CT-scan with persistent opacities suggestive of RAS. These SLTx with RAS were compared with SLTx with BOS and stable patients. We compared outcome of PFTs (FVC, FEV1, FEV1/FVC), repeated CT-scan (both CT-volumetry and CT parenchymal score), and DSA between the 3 groups at the following 4 time points with available CT-scan: (1) at the date of best post-Tx functional status, (2) at the date of CLAD onset, defined at first irreversible decline of PFTs or graft CT-volume, or first onset of pleuroparenchymal abnormalities reflected by RAS parenchymal score; (3) at last available CT-scan; (4) at an average time between 2 and 3. Results: 17 SLTx were identified with RAS diagnosis, and compared to 17 SLTx with BOS and 17 stable SLTx. In RAS patients, outcome of FVC,
FEV1, CT-volume, and CT-score showed all a significant decrease from time-point of CT baseline to last CT-scan (p< 0.001, p<0.001, p<0.001, p<0.001, respectively for the 4 parameters). Interestingly, CT-scan score showed the earlier significant increased value to identify RAS diagnosis at the date of CT-onset (p<0.05 for CT-score ≥ 3), as compared no significant decline for FVC, FEV1, CT volumetry (p=ns). Criteria of RAS based only on spirometry lacked of specificity, since 35 % of BOS SLTx patients also had FVC < 80% of baseline during follow-up. Conclusion: RAS diagnosis remains challenging in SLTx. We observed that the increase of a CT score ≥3 may lead to earlier identification of RAS patients in this population, as compared to standard criteria of RAS initially defined in DLTx. 1025 Cytotoxic T Cells Early after Lung Transplantation Precede the Restrictive Allograft Syndrome T. Nakagiri, A. Kn€ofel, W. Sommer, J. Salman, T. Siemeni, M. Avsar, F. Ius, P. Zardo, I. Tudorache, A. Haverich and G. Warnecke. Cardiothoracic, Transplantation, and Vascular Surgery, Hannover Medical School, Hannover, Germany. Purpose: The outcome after lung transplantation is limited by chronic lung allograft dysfunction (CLAD), subclassified into bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS). RAS tends to an earlier, more severe and more rapid course as compared to BOS. Underlying differences of the immunologic phenotype, potentially unveiling therapeutic targets, have not yet been well-defined. Methods: From June 2013 to August 2015, we collected whole blood samples from 142 consecutively transplanted patients 3 weeks after lung transplantation, excluding only those patients with missing blood samples or who did not consent to have the samples drawn. The samples were analyzed by flow cytometry. CD3+ CD8+ T cells were defined as cytotoxic T cells. Follow up ended as of 09/2018 and full data was available from 138 patients. CLAD diagnosis was made according to ISHLT consensus criteria based on a persistent >20% decline of FEV1 in spirometry. RAS was diagnosed in the presence of a >20% decline of FEV1 concomitant with a >10% decline of the total lung capacity and confirmed by CT scans. Results: In this cohort, 115 patients did not develop CLAD at the end of follow up (control group). BOS was observed in 18 patients, whereas RAS was observed in 5 patients. In the BOS group, 7 patients were graded 1, 1 patient was graded 2, and 10 patients were graded 3. There was no significant difference in the percentage of CD8 T cells amongst lymphocytes between the control and the CLAD group (5.2§8.2% vs. 5.7§7.1%, respectively: p=0.40), three weeks after transplantation. In addition, there was also no significant difference between the control and the BOS subgroup (5.2§8.2% vs. 3.9§5.8%, respectively: p=0.27). However, a significant difference was detected between the BOS and RAS groups (3.9§5.8 vs. 12.0§8.6%, respectively: p<0.05). Moreover, the difference was also significant between grade 3 BOS patients and the RAS group (2.4§2.5% vs. 12.0§8.6%, respectively, p<0.01). Conclusion: The development of the most severe and frequently early subtype of chronic lung rejection, the restrictive allograft syndrome, is preceeded by a high frequency of cytotoxic effector CD8+ T cells in peripheral blood as early as three weeks post transplantation. Cytotoxic T cells are also known to contribute to acute rejections and might be targeted by multiple immunosuppressive treatments.
1026 Decreased Serum Levels of Irisin are Associated with the Development of Chronic Lung Allograft Dysfunction after Bilateral Living-Donor Lobar Lung Transplantation T. Shiotani, S. Sugimoto, H. Yamamoto, T. Kurosaki, S. Otani, M. Okazaki, M. Yamane, S. Toyooka and T. Oto. Department of General Thoracic Surgery, Organ Transplant Center, Okayama University, Okayama, Japan. Purpose: Irisin is a skeletal muscle cell-derived myokine associated with physical activity. Recently, decreased serum irisin levels have been shown