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Pre-formed donor-specific antibodies (DSA) are associated with worse outcome after lung transplantation (LTx) and might limit access to LTx. This limitation to lung-graft allocation might be life-threatening, notably in patient with fibrosis on wait list. A virtual crossmatch (CXM)-based strategy for perioperative desensitization has been used for immunized LTx candidates in a cohort of 321 patients at Foch hospital (2012-2017 period).We analyzed the impact of this desensitization protocol on the access to LTx in candidates with fibrosis with pre-formed DSAs. Among LTx candidates with fibrosis, the access to LTx were compared between 3 groups: Group 1: Candidates with high pre-formed DSA (10005000 were considered unauthorized for the desensitization protocol owing to the reported risk of positive real CXM. Among n=40 LTx candidates with fibrosis during this period, 85% had pre-formed DSA (Single-Ag Luminex assay). Mean calculated panel reactive antibodies (cPRA) was 39% at listing (taking into account all anti-HLA antibodies >500 MFI), and lowered to 6% with a desensitization strategy taking into account only anti-HLA antibodies >5000 (p<0.0001). Mean time on waiting list was 36 days, similar between the 3 groups (p=0.2). In Group 1, a significant decrease of immunodominant pre-formed DSA (class I/II) was observed at 6 months vs day 0 (p<0.001). Survival of the n=40 patients at 1 and 5 years post-LTx was 77% and 64%, respectively, and freedom from CLAD at 1 and 5 years were 96% and 75%, respectively, without significant difference between the 3 groups. A desensitization protocol allowed a satisfactory access to LTx for sensitized LTx candidates with fibrosis, with a post-LTx outcome similar to that of candidates with low-level or no pre-formed DSA. [ABSTRACT FROM AUTHOR]

A strong COVID-19 vaccine campaign is needed to reach the herd immunity and reduce this pandemic infection. In the Foch Hospital, France, in February 2021, 451 healthcare workers were vaccinated by a first dose of AstraZeneca vaccine. Adverse effects were reported to our pharmaco-vigilance circuit, by an online and anonymous questionnaire following the first weeks of the vaccinal campaign to healthcare workers. Two hundred seventy-four (60.8%) of them reported multiple adverse effects. Main adverse effects reported were feverish state/chills (65.7%), fatigue/physical discomfort (62.4%), arthralgia/muscle pain (61.0%) and fever (44.5%). On March 2021 many European countries suspended AstraZeneca vaccine for one week due to safety uncertainty. Thus, confidence in its efficacy is undermined. However, the benefit/risk balance is clearly in favor of vaccination. [ABSTRACT FROM AUTHOR]

Among the rare genetic causes of pulmonary alveolar proteinosis (PAP), some have been evidenced to be linked to methionyl-tRNA synthetase (MARS) mutation. Lung transplantation (LTx) can be offer in case of secondary PAP, but it is admitted that underlying genetic PAP should be ruled out to prevent the recurrence of the disease. Nevertheless, recent investigations have evidenced the defective methionyl-tRNA synthetase (MetRS) activity in MARS-related PAP, and further, its correction with methionine supplementation. Because of significant clinical and imaging pulmonary improvement under methionine supplementation in non-transplanted affected patients, LTx was proposed to 2 patients with life-threatening end-stage MARS-related PAP, associated to an anticipated methionine supplementation following LTx. CASE 1 A 21 years old female underwent a bilateral-LTx in July 2019 for an end-stage PAP. A bridge to Tx had to be performed with ECMO. CASE 2 A 32 years old female underwent a bilateral-LTx in June 2021 for an end-stage PAP associated lung fibrosis, despite methionine supplementation started in December 2019. For both: (i) Diagnosis of a biallelic missense mutation in MARS was performed previously; (ii) Post-operative course was uneventful, with satisfactory graft function at 1095 POD and 455 POD, respectively; (ii) Methionine supplementation was administered each day post-LTx without side effects, (iii) At last follow-up, no PAP recurrence was observed in CT-scan (Figure), and patients had stable lung function. Our 2 LTx cases suggest the feasibility of LTx in MARS-related PAP under methionine supplementation. It suggests that the correction of MetRS activity under methionine supplementation allows functioning alveolar macrophage (AM) in a scenario of replacement of AM from donor by recipient origin. Nevertheless, other scenarios involving inflammatory or cholesterol homeostasis pathways cannot be ruled out. [ABSTRACT FROM AUTHOR]

Background: We reviewed our experience with tracheal extubation in the operating room (E-OR) among cystic fibrosis patients requiring bilateral lung transplantation to evaluate safety and determine predictive factors of E-OR.Methods: The charts of 89 recipients (from May 2007 to June 2013) were analysed. Patients were divided into E-OR and E-ICU (intensive care unit extubation) groups. Data are expressed as numbers (percentages) or medians [25th-75th percentiles].Results: There were 41 patients in the E-OR group (46%). Donor and recipient characteristics were similar between groups. Intraoperative complications occurred less frequently in the E-OR group, and fluid and transfusion requirements were lower. Postoperative courses were different in the E-OR group, including a lower rate of grade 3 primary graft dysfunction (0 compared with 19 patients, P<0.0001) and shorter ICU (5.0 [3.7-7.2] compared with 11.5 [7.0-15.5] days) and hospital stays (22.0 [18.0-25.5] compared with 33.0 [25.0-56.5] days, respectively; P<0.0001 for both). The 1 yr survival rates were similar: 95% in the E-OR group and 98% in the E-ICU group. A statistical model built on a development cohort of 60 randomly selected patients predicted 95% of E-OR instances in this cohort and 82% of E-OR instances in the validation cohort (28 patients). Predictive factors were complications during single-lung ventilation (second graft implantation), complications during bipulmonary ventilation (end of surgery), and the ratio of arterial partial pressure of oxygen to fractional inspired oxygen (end of surgery).Conclusions: Our protocol allowed for extubation of 46% of bilateral lung transplant patients without increased postoperative risks. [ABSTRACT FROM AUTHOR]

Pre-formed donor-specific antibodies (pf-DSA) are associated with worse outcome after lung transplantation (LTx) and might limit access to LTx. A virtual crossmatch (CXM)-based strategy for perioperative desensitization protocol has been used for immunized LTx candidates since 2012 at Foch hospital. We compared the outcome of desensitized LTx candidates with high pf-DSA mean fluorescence intensity (MFI) and those with low or no pf-DSA, not desensitized. For all consecutive LTx recipients (January 2012-March 2018), freedom from CLAD and graft survival were assessed by Kaplan-Meier analysis and Cox proportional-hazards multivariate analysis. We compared outcomes for desensitized patients with high pf-DSA (n=39) and those with no (n=216) or low pf-DSAs (n=66). The desensitization protocol decreased the level of immunodominant pf-DSA (class I/II) at 1, 3, and 6 month post-LTx (p<0.001, p<0.01, p<0.001, respectively). Freedom from CLAD and graft survival at 3 years was similar in the desensitized group as a whole and other groups. Nevertheless, incidence of CLAD was higher with persistent high- than cleared high-level (p=0.044) or no pf-DSAs (p=0.014). Conversely, graft survival was better with cleared high pf-DSA than persistent high-, low-level, and no pf-DSAs(p= 0.019, p=0.025, and p=0.044, respectively). On multivariate analysis, graft survival was associated with cleared high pf-DSA (HR:0.12 [95%CI 0.02-0.85] vs no DSAs, p=0.035) and CLAD with persistent pf-DSA (HR: 3.04 [1.02-9.17] vs no pf-DSA, p=0.048). The desensitization protocol in LTx recipients with high pf-DSAs was associated with satisfactory outcome, with cleared high pf-DSAs after desensitization identified as an independent predictor of graft survival. [ABSTRACT FROM AUTHOR]

Management of neutropenia, the main side effect of Valganciclovir, may affect final transplant results. The main objective of this study is to evaluate the safety of Valganciclovir in D+/R- patients. The secondary objectives are to assess the impact of neutropenia and Mycophenolate Mofetil (MMF) daily dosage modification on the outcomes of the transplant. We performed a single-center retrospective study from 01/01/2010 to 12/31/2018 including 531 consecutive lung transplant patients. 59 of the 108 D+/R- patients (55%) experienced at least one episode of neutropenia during the first posttransplant year leading to its premature withdrawal for 31 patients (29%). Among D+/R- patients, subgroup of premature vGCV withdrawal experienced significantly more neutropenia and reduction of MMF in comparison with complete vGCV treatment subgroup (87% vs 42%, p < 0.0001; 90% vs 44%, p = 0.001). Premature vGCV withdrawal subgroup patients are also more likely to develop late onset CMV event (74% vs 43%, p = 0.05). In comparison with non D+/R- patients, D+/R- are significantly more concerned by neutropenia as well as MMF dosage reduction (55% vs 27% and 48% vs 20%, p< 0.0001). In multivariate analysis, concerning the transplant population, neither the neutropenia event nor the reduction of MMF or the occurrence of CMV event are associated with increased alloimmunization, chronic lung allograft dysfunction (CLAD) or graft loss. However, in the D+/R- subgroup, neutropenia is a protective factor for CLAD in multivariate analysis (HR 0.12 [0.03-0.49], p < 0.001) while longer length of Valganciclovir exposure or reduction of MMF dosage events are identified as independant risk factors (HR 1.31 [1.01-1.70], p = 0.04; HR 7.82 [2.02-30.27], p <0.001). Considering adverse effects associated with Valganciclovir one-year treatment may have a negative impact on the outcomes of the transplant, an alternative should be proposed. [ABSTRACT FROM AUTHOR]

Data on outcomes in lung transplant recipients with SARS-CoV-2 infection remains limited. Given the potential higher COVID-19 severity in lung recipients, the Agence de la biomedecine has limited the transplant program to patients with high-urgency status during the first epidemic wave. The program has been fully restored where possible during the second epidemic wave. This study aimed to assess the impact of COVID-19 on lung recipient mortality in France. All lung recipients with COVID-19 reported in the French national registry CRISTAL between February 1st and September 30th 2020 were included in the study. Patient characteristics were extracted from CRISTAL. Cumulative number of cases by month since February (Figure 1) and case fatality rate (CFR) were calculated. Mortality rates from February to September in the whole 2019 and 2020 recipient cohorts were compared. Survival curves were estimated using Kaplan-Meier method and compared using the log-rank test. Of the 46 patients (median age (IQR) 51 years (39-60), 54% female, median time from transplantation 3.5 years (0.8-7.1)) 88% required hospitalization including 21% in ICU. Eight patients died (CFR: 17.4%). No difference in 3-month survival was observed between 2020 and 2019 recipient cohorts (98.6% 95%CI [98.0%-99.0%] vs 98.4% [97.8%-98.8%], respectively) (Figure 2). COVID-19 was associated with lower fatality rate in lung recipients than in other organ transplant recipients and did not result in an excess mortality. These findings suggest that continuing lung transplant activity during the COVID-19 pandemic was a reasonable option. [ABSTRACT FROM AUTHOR]

Highly sensitized lung transplant candidates undergo transplant at a significantly lower rate than unsensitized candidates. We conducted a survey to understand the approach to waitlist and peri-operative management of these candidates across programs worldwide. Lung transplant programs were invited to complete the survey either online or by telephone. Survey questions pertained to programs' method of human leukocyte antigen (HLA) antibody detection, characterization of HLA antibody risk, incorporation of virtual (VCM) and actual crossmatch (ACM) results in organ allocation decisions, and use of pre or peri-operative desensitization therapy between January 2018 and October 2019. 57 adult (39/57), pediatric (4/57), and combined (14/57) lung transplant programs were surveyed. Respondents were transplant physicians (46/57), surgeons (3/57), or several multi-disciplinary team members (8/57) from programs in North America (39/57), Europe (11/57), Asia (3/57), Australia (3/57), and Africa (1/57). Regarding organ allocation, 32/57 programs decline offers for candidates who are highly sensitized/critically ill on the basis of an unacceptable VCM. A high degree of sensitization is a contraindication to transplant at 12/57 programs, and a contraindication to using mechanical support as bridge-to-transplant at 19/57. At 19/57 programs, offers are accepted regardless of positive VCM results if the prospective flow crossmatch (4/19) or complement-dependent cytotoxicity crossmatch (15/19) is negative, either for all candidates (9/19) or only for those who are highly sensitized/critically ill (10/19). A minority of programs (8/57) accept offers regardless of positive VCM or ACM results, either for all candidates (1/8) or only for those who are highly sensitized/critically ill (7/8). All of these programs use plasmapheresis, intravenous immune globulin, thymoglobulin, and/or rituximab peri-operatively. Currently, 13/57 programs treat highly sensitized candidates on the waitlist with various desensitization therapies to improve their likelihood of receiving an acceptable offer. There is significant variation in the management of sensitized lung transplant candidates across programs. Further research and international consensus are needed to improve access to transplant for these patients. [ABSTRACT FROM AUTHOR]

Lung transplantation (LT) is limited by the shortage of suitable donors. To overcome this problem, many programs have begun to use extended criteria donors. However, the use lung donors over 65 years old is rarely reported especially among a population of young cystic fibrosis (CF) recipient. We report a single center experience of lung transplantations for CF recipients between January 2005 and september 2019. Two cohorts were built and compared according to lung donor age <65 years or ≥ 65 years. Among this period, 378 bilateral lung transplantations (BLT) for CF were performed. 344 BLT were done with donors aged < 65 years, and 34 BLT with donors aged ≥65 years. Donor characteristics did not differ in sex, donor time on mechanical ventilation before retrieval, or donor partial pressure of arterial oxygen/fraction of inspired oxygen ratio. Older donors group was significantly less often smoker (12% vs 41%, p=0.001). Recipients receiving donor lungs aged <65years were younger than those receiving older donor lungs (28 [IQR 24-34] vs 32 [IQR 26-41] years, p=0.022). Post-operative mechanical ventilation duration (1 [IQR 0-6] vs 1 [IQR 0-6] days p=0,742) and incidence of sever primary graft dysfunction (grade 3) at 72h (9% vs 6% p=0.285) did not differ significantly between the two groups. The percentage predicted forced expiratory volume in 1 second after one year did not differ significantly between the two groups (76 [IQR 58-89] vs 74 [IQR 51-92] %, p=0,796). 1-year and 3-years survival were not significantly different, with respectively 90 vs 94% and 83 vs 85% (p=0.684). Use of donor lungs over 65 years for CF recipients allows donor pool extension without compromising early and midterm results. However, longer follow up is needed to appreciate long term results. [ABSTRACT FROM AUTHOR]

Objectives PHT is the main manifestation of liver disease in adults CF patients. The risk of hepatic decompensation after isolated LT is unknown. The model for end-stage liver disease (MELD) score is not relevant for the indication to combined lungs-liver transplantation. We presented the postoperative outcome of isolated lung transplantation in CF patients with asymptomatic PHT. Methods From 2008 to 2014, 14 isolated LT (over 299) were proceeded over CF patients with PHT. Results All Patients had asymptomatic liver disease before LT but all had PHT on the CT scan: splenomegaly (14–19 cm) in 10 patients, portosystemic collaterals in 8, all had portal vein dilatation >14 (diameter 17±2.3 mm). The liver stiffness measurement (LMS) was elevated 18±8 kPa when in our adult CF center median LSM was 5.9 kPa in 241 CF patients. Thirteen patients had normal liver and renal function. Gastroesophageal varices were absents in 10 screened patients. After LT, 4 patients required ECMO, 6 developed easy to treat ascites associated with transient renal insufficiency (4) or intestinal complications (2). One developed transient ascitis 7 months after LT associated with sepsis and renal dysfunction. Hepatocellular function remain normal in all patients. Every patient is still alive (mean time 42±22 months). Conclusion Carefully selected CF patients with end-stage lung disease and portal hypertension can tolerate isolated lung transplantation. The non-invasive evaluation of the severity of PHT has to be evaluated. Prospective multicentric study is need to clearly define the indications of combined lung–liver transplantation. [ABSTRACT FROM AUTHOR]