First use of imlifidase desensitization in a highly sensitized lung transplant candidate: a case report.

Lung transplant candidates who are highly sensitized against human leucocyte antigen present an ongoing challenge with regards to finding immunologically acceptable donors. Desensitization strategies aimed at reducing preformed donor-specific antibodies have a number of limitations. Imlifidase, an IgG-degrading enzyme derived from Streptococcus pyogenes, is a novel agent that has been used to convert positive crossmatches to negative in kidney transplant candidates, allowing transplantation to occur. We present the first case of imlifidase use for antibody depletion in a highly sensitized lung transplant candidate who went on to undergo a successful bilateral lung transplant.

Results of Lung Transplantation for Cystic Fibrosis With Selected Donors Over 65 Years Old.

Lung transplantation is limited by the shortage of suitable donors. Many programs have begun to use extended criteria donors. Donors over 65 years old are rarely reported, especially for young cystic fibrosis recipients. This monocentric study was conducted for cystic fibrosis recipients from January 2005 to December 2019, comparing two cohorts according to lung donor age (<65 years or ≥65 years). The primary objective was to assess the survival rate at 3 years using a Cox multivariable model. Of the 356 lung recipients, 326 had donors under 65 years, and 30 had donors over 65 years. Donors' characteristics did not differ significantly in terms of sex, time on mechanical ventilation before retrieval, and partial pressure of arterial oxygen/fraction of inspired oxygen ratio. There were no significant differences in post-operative mechanical ventilation duration and incidence of grade 3 primary graft dysfunction between the two groups. At 1, 3, and 5 years, the percentage of predicted forced expiratory volume in 1 s (p = 0.767) and survival rate did not differ between groups (p = 0.924). The use of lungs from donors over 65 years for cystic fibrosis recipients allows extension of the donor pool without compromising results. Longer follow-up is needed to assess the long-term effects of this practice.

Blood Lactate During Double-Lung Transplantation: A Predictor of Grade-3 Primary Graft Dysfunction.

OBJECTIVE: Many prognostic factors of grade-3 primary graft dysfunction at postoperative day 3 (PGD3-T72) have been reported, but intraoperative blood lactate level has not been studied. The present retrospective study was done to test the hypothesis that intraoperative blood lactate level (BLL) could be a predictor of PGD3-T72 after double-lung transplantation. DESIGN: Retrospective monocentric cohort study. SETTING: Foch University Hospital, Suresnes, France. PARTICIPANTS: Patients having received a double-lung transplantation between 2012 and 2019. Patients transplanted twice during the study period, having undergone a multiorgan transplantation, or cardiopulmonary bypass, and those under preoperative extracorporeal membrane oxygenation, were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Analysis was performed on a cohort of 449 patients. Seventy-two (16%) patients had a PGD3-T72. Blood lactate level increased throughout surgery to reach a median value of 2.2 (1.6-3.2) mmol/L in the No-PGD3-T72 group and 3.4 (2.3-5.0) mmol/L in the PGD3-T72 group after second lung implantation. The best predictive model for PGD3-T72 was obtained adding a lactate threshold of 2.6 mmol/L at the end of surgery to the clinical model, and the area under the curve was 0.867, with a sensitivity = 76.9% and specificity = 85.4%. Repeated-measures mixed model of BLL during surgery remained significant after adjustment for covariates (F ratio= 4.22, p < 0.001 for interaction). CONCLUSIONS: Blood lactate level increases during surgery and reaches a maximum after the second lung implantation. A value below the threshold of 2.6 mmol/L at the end of surgery has a high negative predictive value for the occurrence of a grade-3 primary graft dysfunction at postoperative day 3.

A virtual crossmatch-based strategy for perioperative desensitisation in lung transplant recipients with pre-formed donor-specific antibodies: 3-year outcome.

BACKGROUND: Pre-formed donor-specific antibodies (DSAs) are associated with worse outcome after lung transplantation (LTx) and might limit access to LTx. A virtual crossmatch-based strategy for perioperative desensitisation protocol has been used for immunised LTx candidates since 2012 at Foch Hospital (Suresnes, France). We compared the outcome of desensitised LTx candidates with high DSA mean fluorescence intensity and those with low or no pre-formed DSAs, not desensitised. METHODS: For all consecutive LTx recipients (January 2012 to March 2018), freedom from chronic lung allograft dysfunction (CLAD) and graft survival were assessed using Kaplan-Meier analysis and Cox multivariate analysis. RESULTS: We compared outcomes for desensitised patients with high pre-formed DSAs (n=39) and those with no (n=216) or low pre-formed DSAs (n=66). The desensitisation protocol decreased the level of immunodominant DSA (class I/II) at 1, 3 and 6 months post-LTx (p<0.001, p<0.01 and p<0.001, respectively). Freedom from CLAD and graft survival at 3 years was similar in the desensitised group as a whole and other groups. Nevertheless, incidence of CLAD was higher with persistent high-level DSAs than cleared high-level (p=0.044) or no DSAs (p=0.014). Conversely, graft survival was better with cleared high DSAs than persistent high-level, low-level and no pre-formed DSAs (p=0.019, p=0.025 and p=0.044, respectively). On multivariate analysis, graft survival was associated with cleared high DSAs (hazard ratio 0.12, 95% CI 0.02-0.85 versus no DSAs; p=0.035) and CLAD with persistent DSAs (3.04, 1.02-9.17 versus no pre-formed DSAs; p=0.048). CONCLUSION: The desensitisation protocol in LTx recipients with high pre-formed DSAs was associated with satisfactory outcome, with cleared high pre-formed DSAs after desensitisation identified as an independent predictor of graft survival.

Intraoperative Implications of the Recipients' Disease for Double-Lung Transplantation.

OBJECTIVES: To compare intraoperative patterns among patients based on their primary pulmonary disease (cystic fibrosis [CF], chronic obstructive pulmonary disease [COPD]/emphysema [CE], and pulmonary fibrosis [PF]) during double- lung transplantation. The following 3 major outcomes were reported: blood transfusion, extracorporeal membrane oxygenation (ECMO) management, and the possibility of immediate extubation at the end of surgery. DESIGN: Retrospective analysis of a prospectively maintained database, including donor and recipient characteristics and intraoperative variables. SETTING: Foch Hospital, Suresnes, France (academic center performing 60-80 lung transplantations per year). PARTICIPANTS: Patients who underwent double- lung transplantation from 2012-2019. Patients with retransplantation, multiorgan transplantation, or surgery performed with cardiopulmonary bypass were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two hundred forty-six patients had CF, 117 had CE, and 66 had PF. No patient had primary pulmonary arterial hypertension. Blood transfusion was higher in the CF group than in the other 2 groups (red blood cells [p < 0.001], fresh frozen plasma [p = 0.004]). The CF and CE groups were characterized by a lower intraoperative requirement of ECMO (p = 0.002), and the PF group more frequently required postoperative ECMO (p < 0.001). CF and CE patients were more frequently extubated in the operating room than were PF patients (37.4%, 50.4%, and 13.6%, respectively; p < 0.001). CONCLUSIONS: Intraoperative outcomes differed depending on the initial pathology. Such differences should be taken into account in specific clinical studies and in intraoperative management protocols.

Hanging donor lungs give good short-, mid- and long-term results in lung transplantation.

BACKGROUND: Hanging donors are considered as marginal donors and frequently unsuitable for lung transplantation. However, there is no evidence of higher lung transplantation (LTx) morbidity-mortality with lungs providing by hanging donor. METHODS: Between January 2010 and July 2015, we performed a retrospective study at Foch hospital. We aimed to assess whether hanging donor grafts are suitable for lung transplantation. RESULTS: A total of 299 LTx were performed. Subjects were allocated to a hanging group (HG) (n = 20) and a control group (CG) (n = 279). Donor and recipient characteristics did not differ. Primary graft dysfunction (PGD) at 72 hours was comparable in both groups (P = .75). The median duration of postoperative mechanical ventilation (1 [range, 0-84] vs 1 [range, 0-410] day, P = .35), the hospital length of stay (31 days [20-84] vs 32 days [12-435], P = .36) did not differ between the two groups. No statistically significant difference was found in 1-year and 5-year survival between the HG (83% and 78%) and the CG (86% and 75%), P = .85. CONCLUSION: We believe that hanging donors should be considered as conventional donors with particular caution in the final evaluation of the graft and in perioperative management.

Extracorporeal membrane oxygenation for grade 3 primary graft dysfunction after lung transplantation: Long-term outcomes.

INTRODUCTION: Extracorporeal membrane oxygenation (ECMO) is an efficient and innovative therapeutic tool for primary graft dysfunction (PGD). However, its effect on survival and long-term lung function is not well known. This study evaluated those parameters in patients with PGD requiring ECMO. METHOD: This single-center, retrospective study included patients who underwent LTx at our institute between January 2007 and December 2013. Patients and disease characteristics, survival, and pulmonary function tests were recorded. RESULTS: A total of 309 patients underwent LTx during the study period and 211 were included. The patients were predominantly male (53.5%), the median age was 39 years, and the primary pathology was suppurative disease (53.1%). ECMO for PGD was mandatory in 24 (11.7%) cases. Mortality at 3 months in the ECMO group was 50% (N = 12). However, long-term survival after PGD did not correlate with ECMO. Forced expiratory volume and vital capacity were significantly reduced in patients with PGD requiring ECMO, especially those with idiopathic pulmonary fibrosis. CONCLUSION: Veno-arterial ECMO appears to be suitable for management of PGD after LTx. Patients with PGD requiring ECMO show increased initial mortality; however, long-term survival was comparable with that of other patients in the study. Lung function does not appear to be related to PGD requiring ECMO.

Prognostic value of the PaO2 /FiO2 ratio determined at the end-surgery stage of a double-lung transplantation.

INTRODUCTION: We evaluated the prognostic role of the arterial oxygen partial pressure/fractional inspired oxygen ratio (PaO2 /FiO2 ratio) measured at the end of double-lung transplantation (DLT). METHODS: This was a monocentric cohort study of all consecutive DLT patients between January 1, 2012, and January 1, 2016, except patients with preoperative extracorporeal membrane oxygenation (ECMO), intraoperative cardiopulmonary bypass, postoperative ECMO, large patent foramen ovale, redo transplantation during the study period, and multiorgan transplantation. RESULTS: A total of 164 patients were included in the study; 45 had a PaO2 /FiO2 ratio <200, 39 a ratio in the range 200-300, and 80 a ratio >300. The risk of being in the lower ratio group is positively related to body mass index, preoperative pulmonary hypertension, and fibrosis. It is negatively related to emergency surgery, age, and intraoperative institution of ECMO. There was a trend for more grade 3 pulmonary graft dysfunction at day 3 in the worst PaO2 /FiO2 ratio group. Mortality at 1000 days was similar for all patients and even after exclusion of patients who had required intraoperative ECMO. CONCLUSION: PaO2 /FiO2 ratio measured at the end of DLT does not forecast 1000-day mortality.

Inhaled nitric oxide dependency at the end of double-lung transplantation: a boosted propensity score cohort analysis.

Inhaled nitric oxide (iNO) is usually used during lung transplantation despite controversial postoperative benefits. Our group chose to administer iNO systematically during the procedure and stop at the end of surgery. This study aims to describe the features of patients who cannot be weaned from iNO, the reasons for this and its impact on postoperative outcomes. This is a monocentric cohort study comprised all consecutive patients who underwent double-lung transplantation (DLT) between 1 January 2012 and 1 January 2016. The impact of iNO dependency on postoperative outcomes was estimated using a boosted inverse probability of treatment weighting estimator. A total of 9.8% of the 173 patients included in the study could not be weaned from iNO at end-surgery stage. Body mass index (OR = 2.03, 95% CI = 1.14-3.29, P = 0.02) and intraoperative extracorporeal membrane oxygenation (OR = 1.80, 95% CI = 1.02-2.72, P = 0.04) were risk factors for iNO dependency In the weighted population, iNO dependency was associated with an increased prevalence of grade 3 primary graft dysfunction (adjusted RR = 4.20, 95% CI = 1.75-10.09, P < 0.001) and decreased postoperative survival during the first 1500 days of follow-up (adjusted HR = 5.0, 95% CI = 1.86-13.48, P < 0.001). Inhaled nitric oxide dependency is an early marker of a poor prognosis following DLT.

Role of C1q-binding anti-HLA antibodies as a predictor of lung allograft outcome.

Presence of anti-human leukocyte antigen donor-specific antibodies (DSAs) is associated with poor outcome after lung transplantation. Currently, DSAs are detected using the Luminex technique, which may be overly sensitive. The new C1q assay allows for the exclusive detection of complement (C1q)-binding antibodies, involved in antibody-mediated rejection. We investigated whether early detection of complement-binding DSAs is associated with chronic lung allograft dysfunction (CLAD) and survival.From 2009 to 2012, lung transplant recipients from three transplantation centres were screened for the presence of DSA and their complement-binding capacity during the 6-12 months post-transplantation in a stable condition.The analysis included 168 patients. The 3-year rates of freedom from CLAD and graft survival were lower for patients with complement-binding DSAs (33.6% and 53.7%, respectively), as compared with patients with non-complement-binding DSAs (61.9% and 77.4%, respectively) and patients without DSA (70% and 84.9%, respectively) (p<0.001 and p=0.001, respectively). Detection of complement-binding DSA was associated with a risk of graft loss that was nearly tripled after adjustment for clinical, functional, histological and immunological factors (hazard ratio 2.98, 95% CI 1.33-6.66; p=0.008).Assessment of the C1q-binding capacity of DSA appears to be useful in identifying stable lung transplant recipients at high risk of lung allograft loss.

Donor-specific HLA antibody-mediated complement activation is a significant indicator of antibody-mediated rejection and poor long-term graft outcome during lung transplantation: a single center cohort study.

Complement-mediated allograft injury, elicited by donor-specific HLA antibodies (DSA), is a defining pathophysiological characteristic of allograft damage. We aimed to study DSA-induced complement activation as a diagnostic marker of antibody-mediated rejection (AMR) and a risk stratification tool for graft loss in the context of lung transplantation (LT). We identified 38 DSA-positive patients whose serum samples were submitted for C3d deposition testing via the C3d assay. Among these 38 patients, 15 had AMR (DSAPos AMRPos ). Results were reported for each patient as the C3d ratio for each DSA, the immunodominant DSA, and the C3d ratio for all DSA present in a sample (C3d ratioSUM ). DSAPos AMRPos patients had higher C3d ratioSUM values (58.66 (-1.32 to 118.6) vs. 1.52 (0.30 to 2.74), P = 0.0016) and increased immunodominant C3d ratios (41.87 (1.72 to 82.02) vs. 0.69 (0.21 to 1.19), P = 0.001) when compared with DSAPos AMRNeg patients. Specificity and calculated positive predictive value of the immunodominant C3d ratio and BCMsum tests for AMR diagnosis were both 100% (CI = 17.4-100) in this cohort. Worst graft survival was associated with both immunodominant C3d ratio ≥4 or C3d ratioSUM ≥10 or BCMsum >7000, suggesting that the antibody composition and/or strength are the principal determinants of an HLA DSA's capacity to activate complement.

High Emergency Lung Transplantation: dramatic decrease of waiting list death rate without relevant higher post-transplant mortality.

Many candidates for lung transplantation (LT) die on the waiting list, raising the question of graft availability and strategy for organ allocation. We report the experience of the new organ allocation program, "High Emergency Lung Transplantation" (HELT), since its implementation in our center in 2007. Retrospective analysis of 201 lung transplant patients, of whom 37 received HELT from 1st July 2007 to 31th May 2012. HELT candidates had a higher impairment grade on respiratory status and higher Lung Allocation Score (LAS). HELT patients had increased incidence of perioperative complications (e.g., perioperative bleeding) and extracorporeal circulatory assistance (75% vs. 36.6%, P = 0.0005). No significant difference was observed between HELT and non-HELT patients in mechanical ventilation duration (15.5 days vs. 11 days, P = 0.27), intensive care unit length of stay (15 days vs. 10 days, P = 0.22) or survival rate at 12 (81% vs. 80%), and 24 months post-LT (72.9% vs. 75.0%). Lastly, mortality on the waiting list was spectacularly reduced from 19% to 2% when compared to the non-HELT 2004-2007 group. Despite a more severe clinical status of patients on the waiting list, HELT provided similar results to conventional LT. These results were associated with a dramatic reduction in the mortality rate of patients on the waiting list.

Post-approval studies in France, challenges facing medical devices.

Medical devices are characterized notably by a wide heterogeneity (from tongue depressors to hip prostheses, and from non-implantable to invasive devices), a short life cycle with recurrent incremental innovations (from 18 months to 5 years), and an operator-dependent nature. The objective of the current round table was to develop proposals and recommendations concerning the prerequisites needed in order to meet the French health authorities expectations concerning requests for post-approval studies for medical devices, required in cases where short and long-term consequences are unknown. These studies, which are the responsibility of the manufacturer or the distributor of the medical device, are designed to confirm the role of the medical device in the therapeutic management strategy in a real-life setting. There are currently approximately 150 post-approval studies underway, mainly concerning class III devices, and the majority face difficulties implementing the study or meeting the study objectives. In light of this, the round table endeavored to clearly identify the conditions for implementation of post-approval studies specific to the characteristics of medical devices. Various areas of progress have been envisaged to improve the performance of these studies, and by consequence, the efficiency of reimbursement of medical devices by the national health insurance. These include providing manufacturers with the opportunity to better anticipate post-approval requirements, defining a study-specific primary objective, integrating a phase allowing dialogue between the manufacturer, the health authorities and the scientific committee, and increasing awareness and training of health professionals on the impact of post-approval clinical studies in terms of the reimbursement of medical devices by the national insurance.

Scientific evaluation and pricing of medical devices and associated procedures in France.

Medical devices are many and various, ranging from tongue spatulas to implantable or invasive devices and imaging machines; their lifetimes are short, between 18 months and 5 years, due to incessant incremental innovation; and they are operator-dependent: in general, the clinical user performs a fitting procedure (hip implant or pacemaker), a therapeutic procedure using a non-implantable invasive device (arrhythmic site ablation probe, angioplasty balloon, extension spondyloplasty system, etc.) or follow-up of an active implanted device (long-term follow-up of an implanted cardiac defibrillator or of a deep brain stimulator in Parkinson's patients). A round-table held during the XXVIII(th) Giens Workshops meeting focused on the methodology of scientific evaluation of medical devices and the associated procedures with a view to their pricing and financing by the French National Health Insurance system. The working hypothesis was that the available data-set was sufficient for and compatible with scientific evaluation with clinical benefit. Post-registration studies, although contributing to the continuity of assessment, were not dealt with. Moreover, the focus was restricted to devices used in health establishments, where the association between devices and technical medical procedures is optimally representative. An update of the multiple regulatory protocols governing medical devices and procedures is provided. Issues more specifically related to procedures as such, to non-implantable devices and to innovative devices are then dealt with, and the proposals and discussion points raised at the round-table for each of these three areas are presented.

Conversion to belatacept after lung transplantation: Report of 10 cases.

BACKGROUND: Calcineurin inhibitors (CNIs) remain the cornerstone of maintenance immunosuppression (IS) after lung transplantation (LTx), although CNI-related life-threatening toxic effects may occur. Belatacept, a novel immunosuppressant that blocks a T-cell co-stimulation pathway, is a non-nephrotoxic drug indicated as an alternative to CNIs in kidney Tx. In LTx, there are only a few reports of belatacept conversion as a CNI-free or CNI-sparing IS treatment. METHODS: We reviewed a series of 10 LTx recipients with conversion to a CNI-free belatacept IS regimen within the first year post-LTx (n = 7) or a belatacept/low-dose CNI combination after the first year (n = 3). RESULTS: Use of belatacept was triggered by severe renal failure in 9 patients and under-IS with previous other IS-related toxicities in 1 patient. Mean estimated glomerular filtration rate after starting belatacept significantly improved at 6 months after initiation and at the last-follow-up (p = 0.006, and p = 0.002 respectively). The incidence of recurrent and/or severe acute cellular rejection (ACR) episodes was high in patients with CNI-free belatacept-based IS (n = 4/7). Chronic graft allograft dysfunction developed in 2 of 9 recipients under belatacept IS. Belatacept was stopped in 6 patients because of recurrent/severe ACR (n = 3), recurrent opportunistic infections (n = 1), center modified policy (n = 1), or other cause (n = 1). CONCLUSION: Early conversion to CNI-free belatacept-based IS improved renal function in this series but was counterbalanced by a high incidence of recurrent ACR, including life-threatening episodes. Other studies are needed to better determine the indications for its use after LTx, possibly with lower immunological risk IS regimens, such as CNI-sparing belatacept.

Clinical evaluation of medical devices: main constraints and specificities.

The purpose of the Giens round table no. 1 was to make proposals and recommendations regarding the clinical evaluation of medical devices. First, the European and French regulatory rules were examined and compared with the US FDA approach. Thereafter, the main specificities and constraints of the MD sector were underlined and their impact in clinical evaluation described and analyzed. Two areas, cumulating most of these constraints, were consecutively analyzed for concrete case study. Considering a patient-centered approach, the RT issued eight recommendations directed to manufacturers, physicians and policymakers in order to improve clinical evaluation in the medical device field.

Trans-arterial embolization for hemoptysis in lung transplant recipients.

INTRODUCTION: Hemoptysis isn't rare in lung transplant recipients (LTR). Yet, trans-arterial embolization (TAE) in LTR has been rarely reported in the literature. The aim of the study was to present the feasibility and outcomes of TAE for hemoptysis in LTR. MATERIALS AND METHODS: Retrospective study of all LTR who underwent TAE for hemoptysis in our single institution between 2005 and 2020. RESULTS: A total of 787 patients underwent lung transplantation between 2005 and 2020. Fifteen LTR underwent 21 TAE for hemoptysis in a median delay of 42 days after LT. TAE was performed within a year after LT in 13 patients (86.7%) with 12 of those patients having concomitant severe ischemic airway injury with necrosis and anastomotic dehiscence. Bronchoscopy confirmed bronchial anastomoses has being the source of the bleeding in 11 LTR (84.6%). Restoration of bronchial vascularization was highlighted in 13 patients (87%). Despite TAE, bronchial anastomosis healing was observed in all surviving patients with anastomotic dehiscence in a median delay of 43 days. CONCLUSION: In our experience, hemoptysis requiring TAE in LTR was rare, frequently occurring in the first weeks after LT, and seemed associated with anastomotic ischemia and dehiscence. Bleeding mainly originated from ischemic bronchial anastomosis through the restoration of the bronchial artery circulation. Our results suggest that bronchial arteriography should be routinely proposed in such patients in the event of hemoptysis.

Operating room extubation: A predictive factor for 1-year survival after double-lung transplantation.

BACKGROUND: Operating room (OR) extubation has been reported after lung transplantation (LT) in small cohorts. This study aimed to evaluate the prognosis of OR-extubated patients. The secondary objectives were to evaluate the safety of this approach and to identify its predictive factors. METHODS: This retrospective single-center cohort study included patients undergoing double lung transplantation (DLT) from January 2012 to June 2019. Patients undergoing multiorgan transplantation, repeat transplantation, or cardiopulmonary bypass during the study period were excluded. OR-extubated patients were compared with intensive care unit (ICU)-extubated patients. RESULTS: Among the 450 patients included in the analysis, 161 (35.8%) were extubated in the OR, and 4 were reintubated within 24 hours. Predictive factors for OR extubation were chronic obstructive pulmonary disease (COPD)/emphysema (p = .002) and cystic fibrosis (p = .005), recipient body mass index (p = .048), and the PaO2/FiO2 ratio 10 minutes after second graft implantation (p < .001). OR-extubated patients had a lower prevalence of grade 3 primary graft dysfunction at day 3 (p < .001). Eight (5.0%) patients died within the first year after OR extubation, and 49 (13.5%) patients died after ICU extubation (log-rank test; p = .005). After adjustment for OR extubation predictive factors, the multivariate Cox regression model showed that OR extubation was associated with greater one-year survival (adjusted hazard ratio = 0.40 [0.16-0.91], p = .028). CONCLUSIONS: OR extubation was associated with a favorable prognosis after DLT, but the association should not be interpreted as causality. This fast-track protocol was made possible by a team committed to developing a comprehensive strategy to enhance recovery.