Blood MMP-9 measured at 2 years after lung transplantation as a prognostic biomarker of chronic lung allograft dysfunction.

BACKGROUND: Long-term outcomes of lung transplantation (LTx) remain hampered by chronic lung allograft dysfunction (CLAD). Matrix metalloproteinase 9 (MMP-9) is a secretory endopeptidase identified as a key mediator in fibrosis processes associated with CLAD. The objective of this study was to investigate whether plasma MMP9 levels may be prognostic of CLAD development. METHODS: Participants were selected from the Cohort in Lung Transplantation (COLT) for which a biocollection was associated. We considered two time points, year 1 (Y1) and year 2 (Y2) post-transplantation, for plasma MMP-9 measurements. We analysed stable recipients at those time points, comparing those who would develop a CLAD within the 2 years following the measurement to those who would remain stable 2 years after. RESULTS: MMP-9 levels at Y1 were not significantly different between the CLAD and stable groups (230 ng/ml vs. 160 ng/ml, p = 0.4). For the Y2 analysis, 129 recipients were included, of whom 50 developed CLAD within 2 years and 79 remained stable within 2 years. MMP-9 plasma median concentrations were higher in recipients who then developed CLAD than in the stable group (230 ng/ml vs. 118 ng/ml, p = 0.003). In the multivariate analysis, the Y2 MMP-9 level was independently associated with CLAD, with an average increase of 150 ng/ml (95% CI [0-253], p = 0.05) compared to that in the stable group. The Y2 ROC curve revealed a discriminating capacity of blood MMP-9 with an area under the curve of 66%. CONCLUSION: Plasmatic MMP-9 levels measured 2 years after lung transplantation have prognostic value for CLAD.

Effect of antifibrotic agents on postoperative complications after lung transplantation for idiopathic pulmonary fibrosis.

BACKGROUND: Antifibrotic agents (AFAs) are now standard-of-care for idiopathic pulmonary fibrosis (IPF). Concerns have arisen about the safety of these drugs in patients undergoing lung transplantation (LTx). METHODS: We performed a multi-centre, nationwide, retrospective, observational study of French IPF patients undergoing LTx between 2011 and 2018 to determine whether maintaining AFAs in the peri-operative period leads to increased bronchial anastomoses issues, delay in skin healing and haemorrhagic complications. We compared the incidence of post-operative complications and the survival of patients according to AFA exposure. RESULTS: Among 205 patients who underwent LTx for IPF during the study period, 58 (28%) had received AFAs within 4 weeks before LTx (AFA group): pirfenidone in 37 (18.0%) and nintedanib in 21 (10.2%). The median duration of AFA treatment before LTx was 13.8 (5.6-24) months. The AFA and control groups did not significantly differ in airway, bleeding or skin healing complications (p = 0.91, p = 0.12 and p = 0.70, respectively). Primary graft dysfunction was less frequent in the AFA than control group (26% vs. 43%, p = 0.02), and the 90-day mortality was lower (7% vs. 18%, p = 0.046). CONCLUSIONS: AFA therapy did not increase airway, bleeding or wound post-operative complications after LTx and could be associated with reduced rates of primary graft dysfunction and 90-day mortality.

Uncovering the Unseen: Bordetella hinzii Emerges in a Lung Transplant Recipient.

Bordetella hinzii (B. hinzii), a Gram-negative bacillus commonly associated with respiratory infections in animals, has garnered attention for its sporadic cases in humans, particularly in immunocompromised individuals. Despite its opportunistic nature, there remains limited understanding regarding its pathogenicity, diagnostic challenges, and optimal treatment strategies, especially in the context of immunosuppression. Herein, we present the first documented case of acute bronchitis caused by B. hinzii in an immunocompromised patient following double-lung transplantation. The patient, a former smoker with sarcoidosis stage IV, underwent transplant surgery and subsequently developed a febrile episode, leading to the identification of B. hinzii in broncho-alveolar lavage samples. Antimicrobial susceptibility testing revealed resistance to multiple antibiotics, necessitating tailored treatment adjustments. Our case underscores the importance of heightened awareness among clinicians regarding B. hinzii infections and the imperative for further research to elucidate its epidemiology and optimal management strategies, particularly in immunocompromised populations.

Circovirus Hepatitis Infection in Heart-Lung Transplant Patient, France.

In March 2022, a 61-year-old woman in France who had received a heart-lung transplant sought treatment with chronic hepatitis mainly characterized by increased liver enzymes. After ruling out common etiologies, we used metagenomic next-generation sequencing to analyze a liver biopsy sample and identified an unknown species of circovirus, tentatively named human circovirus 1 (HCirV-1). We found no other viral or bacterial sequences. HCirV-1 shared 70% amino acid identity with the closest known viral sequences. The viral genome was undetectable in blood samples from 2017-2019, then became detectable at low levels in September 2020 and peaked at very high titers (1010 genome copies/mL) in January 2022. In March 2022, we found >108 genome copies/g or mL in the liver and blood, concomitant with hepatic cytolysis. We detected HCirV-1 transcripts in 2% of hepatocytes, demonstrating viral replication and supporting the role of HCirV-1 in liver damage.

Efficacy of three COVID-19 vaccine doses in lung transplant recipients: a multicentre cohort study.

QUESTION ADDRESSED BY THE STUDY: Do three coronavirus disease 2019 (COVID-19) vaccine doses induce a serological response in lung transplant recipients? METHODS: We retrospectively included 1071 adults (551 (52%) males) at nine transplant centres in France. Each had received three COVID-19 vaccine doses in 2021, after lung transplantation. An anti-spike protein IgG response, defined as a titre >264 BAU·mL-1 after the third dose (median (interquartile range (IQR)) 3.0 (1.7-4.1) months), was the primary outcome and adverse events were the secondary outcomes. Median (IQR) age at the first vaccine dose was 54 (40-63) years and median (IQR) time from transplantation to the first dose was 64 (30-110) months. RESULTS: Median (IQR) follow-up after the first dose was 8.3 (6.7-9.3) months. A vaccine response developed in 173 (16%) patients. Factors independently associated with a response were younger age at vaccination, longer time from transplantation to vaccination and absence of corticosteroid or mycophenolate therapy. After vaccination, 51 (5%) patients (47 non-responders (47/898 (5%)) and four (4/173 (2%)) responders) experienced COVID-19, at a median (IQR) of 6.6 (5.1-7.3) months after the third dose. No responders had severe COVID-19 compared with 15 non-responders, including six who died of the disease. CONCLUSIONS: Few lung transplant recipients achieved a serological response to three COVID-19 vaccine doses, indicating a need for other protective measures. Older age and use of mycophenolate or corticosteroids were associated with absence of a response. The low incidence of COVID-19 might reflect vaccine protection via cellular immunity and/or good adherence to shielding measures.

Determinants of survival after lung transplantation in telomerase-related gene mutation carriers: A retrospective cohort.

Carriers of germline telomerase-related gene (TRG) mutations can show poor prognosis, with an increase in common hematological complications after lung transplantation (LT) for pulmonary fibrosis. The aim of this study was to describe the outcomes after LT in recipients carrying a germline TRG mutation and to identify the predictors of survival. In a multicenter cohort of LT patients, we retrospectively reviewed those carrying pathogenic TRG variations (n = 38; TERT, n = 23, TERC, n = 9, RTEL1, n = 6) between 2009 and 2018. The median age at LT was 54 years (interquartile range [IQR] 46-59); 68% were male and 71% had idiopathic pulmonary fibrosis. During the diagnosis of pulmonary fibrosis, 28 (74%) had a hematological disease, including eight with myelodysplasia. After a median follow-up of 26 months (IQR 15-46), 38 patients received LT. The overall post-LT median survival was 3.75 years (IQR 1.8-NA). The risk of death after LT was increased for patients with myelodysplasia (HR 4.1 [95% CI 1.5-11.5]) or short telomere (HR 2.2 [1.0-5.0]) before LT. After LT, all patients had anemia, 66% had thrombocytopenia, and 39% had neutropenia. Chronic lung allograft dysfunction frequency was 29% at 4 years. The present findings support the use of LT in TRG mutation carriers without myelodysplasia. Hematological evaluation should be systematically performed before LT.

Lung transplantation for interstitial lung disease in idiopathic inflammatory myositis: A cohort study.

In patients with interstitial lung disease (ILD) complicating classical or amyopathic idiopathic inflammatory myopathy (IIM), lung transplantation outcomes might be affected by the disease and treatments. Here, our objective was to assess survival and prognostic factors in lung transplant recipients with IIM-ILD. We retrospectively reviewed data for 64 patients who underwent lung transplantation between 2009 and 2021 at 19 European centers. Patient survival was the primary outcome. At transplantation, the median age was 53 [46-59] years, 35 (55%) patients were male, 31 (48%) had classical IIM, 25 (39%) had rapidly progressive ILD, and 21 (33%) were in a high-priority transplant allocation program. Survival rates after 1, 3, and 5 years were 78%, 73%, and 70%, respectively. During follow-up (median, 33 [7-63] months), 23% of patients developed chronic lung allograft dysfunction. Compared to amyopathic IIM, classical IIM was characterized by longer disease duration, higher-intensity immunosuppression before transplantation, and significantly worse posttransplantation survival. Five (8%) patients had a clinical IIM relapse, with mild manifestations. No patient experienced ILD recurrence in the allograft. Posttransplantation survival in IIM-ILD was similar to that in international all-cause-transplantation registries. The main factor associated with worse survival was a history of muscle involvement (classical IIM). In lung transplant recipients with idiopathic inflammatory myopathy, survival was similar to that in all-cause transplantation and was worse in patients with muscle involvement compared to those with the amyopathic disease.

An emerging phenotype of pulmonary arterial hypertension patients carrying SOX17 variants.

BACKGROUND: The phenotype of pulmonary arterial hypertension (PAH) patients carrying SOX17 pathogenic variants remains mostly unknown. METHODS: We report the genetic analysis findings, characteristics and outcomes of patients with heritable PAH carrying SOX17 variants from the French Pulmonary Hypertension Network. RESULTS: 20 patients and eight unaffected relatives were identified. The median (range) age at diagnosis was 17 (2-53) years, with a female:male ratio of 1.5. At diagnosis, most of the patients (74%) were in New York Heart Association Functional Class III or IV with severe haemodynamic compromise, including a median pulmonary vascular resistance of 14.0 (4.2-31.5) WU. An associated congenital heart disease (CHD) was found in seven PAH patients (35%). Patients with CHD-associated PAH were significantly younger at diagnosis than PAH patients without CHD. Four patients (20%) suffered from recurrent haemoptysis requiring repeated arterial embolisations. 13 out of 16 patients (81%) for whom imaging was available displayed chest computed tomography abnormalities, including dilated, tortuous pulmonary vessels, ground-glass opacities as well as anomalies of the bronchial and nonbronchial arteries. After a median (range) follow-up of 47 (1-591) months, 10 patients underwent lung transplantation and one patient benefited from a heart-lung transplantation due to associated CHD. Histopathological analysis of lung explants showed a congested lung architecture with severe pulmonary arterial remodelling, subpleural vessel dilation and numerous haemorrhagic foci. CONCLUSIONS: PAH due to SOX17 pathogenic variants is a severe phenotype, frequently associated with CHD, haemoptysis and radiological abnormalities. Pathological assessment reveals severe pulmonary arterial remodelling and malformations affecting pulmonary vessels and thoracic systemic arteries.

Lung transplantation for acute respiratory distress syndrome: a retrospective European cohort study.

BACKGROUND: The published experience of lung transplantation in acute respiratory distress syndrome (ARDS) is limited. The aim of this study was to investigate the contemporary results of lung transplantation attempts in ARDS in major European centres. METHODS: We conducted a retrospective multicentre cohort study of all patients listed for lung transplantation between 2011 and 2019. We surveyed 68 centres in 22 European countries. All patients admitted to the waitlist for lung transplantation with a diagnosis of "ARDS/pneumonia" were included. Patients without extracorporeal membrane oxygenation (ECMO) or mechanical ventilation were excluded. Patients were followed until 1 October 2020 or death. Multivariable analysis for 1-year survival after listing and lung transplantation was performed. RESULTS: 55 centres (81%) with a total transplant activity of 12 438 lung transplants during the 9-year period gave feedback. 40 patients with a median age of 35 years were identified. Patients were listed for lung transplantation in 18 different centres in 10 countries. 31 patients underwent lung transplantation (0.25% of all indications) and nine patients died on the waitlist. 90% of transplanted patients were on ECMO in combination with mechanical ventilation before lung transplantation. On multivariable analysis, transplantation during 2015-2019 was independently associated with better 1-year survival after lung transplantation (OR 10.493, 95% CI 1.977-55.705; p=0.006). 16 survivors out of 23 patients with known status (70%) returned to work after lung transplantation. CONCLUSIONS: Lung transplantation in highly selected ARDS patients is feasible and outcome has improved in the modern era. The selection process remains ethically and technically challenging.

Airway complications in lung transplant recipients with telomere-related interstitial lung disease.

INTRODUCTION: Patients with short telomere-related interstitial lung disease (ILD) have worse outcomes after lung transplantation. We hypothesized that post-transplant airway complications, including dehiscence and bronchial stenosis, would be more common in the short telomere ILD lung transplant population. METHODS: We conducted a multi-institutional (Brigham and Women's Hospital, Groupe de Transplantation de la SPLF) retrospective cohort study of 63 recipients between 2009 and 2019 with ILD and short telomeres, compared to 4359 recipients from the Scientific Registry of Transplant Recipients with ILD and no known telomeropathy. RESULTS: In the short telomere cohort, six recipients (9.5%) developed dehiscence and nine recipients (14.3%) developed stenosis, compared to 60 (1.4%) and 149 (3.4%) in the control, respectively. After adjusting for age, sex, and bilaterality, the presence of short telomeres was associated with higher odds of dehiscence (odds ratio (OR) = 8.24, 95% confidence interval (CI) = 3.34 20.29, p < .001) and stenosis (OR = 4.63, 95% CI 2.21 9.69, p < .001). CONCLUSION: The association between the presence of short telomeres and post-transplant dehiscence and stenosis suggest that airway complications may be a contributor to increased morbidity and mortality in patients with telomere-related ILD.

Transplantation for pulmonary arterial hypertension with congenital heart disease: Impact on outcomes of the current therapeutic approach including a high-priority allocation program.

Patients with end-stage pulmonary arterial hypertension due to congenital heart disease have limited access to heart-lung transplantation or double-lung transplantation. We aimed to assess the effects of a high-priority allocation program established in France in 2007. We conducted a retrospective study to compare waitlist and posttransplantation outcomes before versus after implementation of the high-priority allocation program. We included 67 consecutive patients (mean age at listing, 33.2 ± 10.5 years) with pulmonary arterial hypertension due to congenital heart disease listed for heart-lung transplantation or double-lung transplantation from 1997 to 2016. At one month, the incidences of transplantation and death before transplantation were 3.5% and 24.6% in 1997-2006, 4.8% and 4.9% for patients on the regular list in 2007-2016, and 41.2% and 7.4% for patients listed under the high-priority allocation program (p < .001 and p = .0001, respectively). Overall survival was higher in patients listed in 2007-2016 (84.2% and 61.2% at 1 and 10 years vs. 36.8% and 22.1%, p = .0001). Increased incidence of transplantation, decreased waiting list mortality, and improved early and long-term outcomes were observed in patients with pulmonary arterial hypertension due to congenital heart disease listed for transplantation in the recent era, characterized by implementation of a high-priority allocation program.

Lung transplantation for sarcoidosis: outcome and prognostic factors.

STUDY QUESTION: In patients with sarcoidosis, past and ongoing immunosuppressive regimens, recurrent disease in the transplant and extrapulmonary involvement may affect outcomes of lung transplantation. We asked whether sarcoidosis lung phenotypes can be differentiated and, if so, how they relate to outcomes in patients with pulmonary sarcoidosis treated by lung transplantation. PATIENTS AND METHODS: We retrospectively reviewed data from 112 patients who met international diagnostic criteria for sarcoidosis and underwent lung or heart-lung transplantation between 2006 and 2019 at 16 European centres. RESULTS: Patient survival was the main outcome measure. At transplantation, median (interaquartile range (IQR)) age was 52 (46-59) years; 71 (64%) were male. Lung phenotypes were individualised as follows: 1) extended fibrosis only; 2) airflow obstruction; 3) severe pulmonary hypertension (sPH) and airflow obstruction; 4) sPH, airflow obstruction and fibrosis; 5) sPH and fibrosis; 6) airflow obstruction and fibrosis; 7) sPH; and 8) none of these criteria, in 17%, 16%, 17%, 14%, 11%, 9%, 5% and 11% of patients, respectively. Post-transplant survival rates after 1, 3, and 5 years were 86%, 76% and 69%, respectively. During follow-up (median (IQR) 46 (16-89) months), 31% of patients developed chronic lung allograft dysfunction. Age and extended lung fibrosis were associated with increased mortality. Pulmonary fibrosis predominating peripherally was associated with short-term complications. ANSWER TO THE STUDY QUESTION: Post-transplant survival in patients with pulmonary sarcoidosis was similar to that in patients with other indications for lung transplantation. The main factors associated with worse survival were older age and extensive pre-operative lung fibrosis.

Urgent desensitization in patients bridged to heart transplantation under extracorporeal membrane oxygenation support: A preliminary experience.

Antihuman leukocyte antigen (HLA) antibodies restrict the access to cardiac allografts. Desensitization therapy is a major challenge in patients with cardiogenic shock waiting for urgent heart transplantation (HT). We retrospectively reviewed six patients (mean age of 37.5 years [16-70]) who underwent plasmapheresis (PP) under extracorporeal membrane oxygenation (ECMO) before transplant between January 2017 and September 2018. The average duration of follow-up was 25 months [20-32]. Mean fluorescence intensity (MFI) of HLA-specific antibodies was reported as follows: score 4 for MFI < 1000, score 6 for 1000 < MFI < 3000 and score 8 for MFI > 3000. The mean duration of ECMO support was 29 days [1-74] and 6.8 [1-29] PP sessions were performed per patient before transplant. The mean number of HLA-specific antibodies before HT was 9.6 for score 6 [4-13] and 5.8 for score 8 [1-12]. Four patients had major complications after transplantation (2 hemorrhagic shocks, 5 infectious events). Mean MFI reduction rate was 94% [79-100] for Class I and 44.2% for Class II [0-83]. Hospital survival was 100%, and early antibody-mediated rejection was diagnosed in one patient at 7 days after HT. Plasmapheresis under ECMO support was associated with favorable early outcomes in highly sensitized candidates for urgent heart transplantation.

Worldwide clinical practices in perioperative antibiotic therapy for lung transplantation.

BACKGROUND: Infection is the most common cause of mortality within the first year after lung transplantation (LTx). The management of perioperative antibiotic therapy is a major issue, but little is known about worldwide practices. METHODS: We sent by email a survey dealing with 5 daily clinical vignettes concerning perioperative antibiotic therapy to 180 LTx centers around the world. The invitation and a weekly reminder were sent to lung transplant specialists for a single consensus answer per center during a 3-month period. RESULTS: We received a total of 99 responses from 24 countries, mostly from Western Europe (n = 46) and the USA (n = 34). Systematic screening for bronchial recipient colonization before LTx was mostly performed with sputum samples (72%), regardless of the underlying lung disease. In recipients without colonization, antibiotics with activity against gram-negative bacteria resistant strains (piperacillin / tazobactam, cefepime, ceftazidime, carbapenems) were reported in 72% of the centers, and antibiotics with activity against methicillin-resistant Staphylococcus aureus (mainly vancomycin) were reported in 38% of the centers. For these recipients, the duration of antibiotics reported was 7 days (33%) or less (26%) or stopped when cultures of donor and recipients were reported negatives (12%). In recipients with previous colonization, antibiotics were adapted to the susceptibility of the most resistant strain and given for at least 14 days (67%). CONCLUSION: Practices vary widely around the world, but resistant bacterial strains are mostly targeted even if no colonization occurs. The antibiotic duration reported was longer for colonized recipients.

Impact of donor, recipient and matching on survival after high emergency lung transplantation in France.

INTRODUCTION: Since July 2007, the French high emergency lung transplantation (HELT) allocation procedure prioritises available lung grafts to waiting patients with imminent risk of death. The relative impacts of donor, recipient and matching on the outcome following HELT remain unknown. We aimed at deciphering the relative impacts of donor, recipient and matching on the outcome following HELT in an exhaustive administrative database. METHODS: All lung transplantations performed in France were prospectively registered in an administrative database. We retrospectively reviewed the procedures performed between July 2007 and December 2015, and analysed the impact of donor, recipient and matching on overall survival after the HELT procedure by fitting marginal Cox models. RESULTS: During the study period, 2335 patients underwent lung transplantation in 11 French centres. After exclusion of patients with chronic obstructive pulmonary disease/emphysema, 1544 patients were included: 503 HELT and 1041 standard lung transplantation allocations. HELT was associated with a hazard ratio for death of 1.41 (95% CI 1.22-1.64; p<0.0001) in univariate analysis, decreasing to 1.32 (95% CI 1.10-1.60) after inclusion of recipient characteristics in a multivariate model. A donor score computed to predict long-term survival was significantly different between the HELT and standard lung transplantation groups (p=0.014). However, the addition of donor characteristics to recipient characteristics in the multivariate model did not change the hazard ratio associated with HELT. CONCLUSIONS: This exhaustive French national study suggests that HELT is associated with an adverse outcome compared with regular allocation. This adverse outcome is mainly related to the severity status of the recipients rather than donor or matching characteristics.

Perspectives on Scedosporium species and Lomentospora prolificans in lung transplantation: Results of an international practice survey from ESCMID fungal infection study group and study group for infections in compromised hosts, and European Confederation of Medical Mycology.

BACKGROUND: Scedosporium species and Lomentospora prolificans (S/L) are the second most common causes of invasive mold infections following Aspergillus in lung transplant recipients. METHODS: We assessed the current practices on management of S/L colonization/infection of the lower respiratory tract before and after lung transplantation in a large number of lung transplant centers through an international practice survey from October 2016 to March 2017. RESULTS: A total of 51 respondents from 45 lung transplant centers (17 countries, 4 continents) answered the survey (response rate 58%). S/L colonization was estimated to be detected in candidates by 48% of centers. Only 18% of the centers used a specific medium to detect S/L colonization. Scedosporium spp. colonization was a contraindication to transplantation in 10% of centers whereas L prolificans was a contraindication in 31%; 22% of centers declared having had 1-5 recipients infected with S/L in the past 5 years. CONCLUSIONS: This survey gives an overview of the current practices regarding S/L colonization and infection in lung transplant centers worldwide and underscores the need of S/L culture procedure standardization before implementing prospective studies.

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.