BACKGROUND:Chronic lung allograft dysfunction (CLAD) leads to declining respiratory function and high mortality, representing the main barrier to long-term survival in lung transplantation (LT). We performed the first genome-wide association study (GWAS) investigating donor's and recipient's genetic factors associated with CLAD. METHOD:We genotyped 392 donor-recipient pairs from the multicentric Cohort in Lung Transplantation. We tested 4.5 million SNPs for association with CLAD using multivariable logistic regression models corrected for age, sex, initial disease and genetic ancestry. Three levels of explanatory variables were separately considered to conduct GWAS: donors-only, recipients-only, and donor-recipient mismatches. We also ran HLA-centric analyses using the same models. RESULTS:Our analysis confirmed the deleterious impact of HLA allelic and epitopic mismatches on CLAD risk, mostly driven by class I HLA (p=0.004). No significant associations with CLAD were found for donors' genotypes or donor-recipient non-HLA mismatches. We highlighted two independent recipient's loci associated with CLAD, including one protective signal (0.39 in CLAD vs 0.66 in non-CLAD recipients, p-value=5.05×10-7, q-value=0.017, OR=0.35) encompassing the PLXDC2 gene, and one risk signal (0.66 in CLAD vs 0.38 in non-CLAD recipients, p-value=9.86×10-7, q-value=0.017, OR=2.83) encompassing the ZNF518A/BLNK genes. These non-coding SNPs are putative regulatory variants of gene expression. Importantly, our single-cell RNA-sequencing showed a down-regulation of PLXDC2 in fibroblasts and lung epithelium in CLAD vs healthy controls. CONCLUSION:This first LT GWAS revealed two candidate loci from the recipient's genome, both biologically relevant for CLAD pathogenesis. Our study calls for larger LT genomic initiatives to increase power for signal discovery.

Background Chronic lung allograft dysfunction (CLAD), the leading cause of death beyond year one post-transplant, encompasses bronchiolitis obliterans syndrome (BOS), restrictive allograft syndrome (RAS), and mixed allograft syndrome (MAS), formalized by the 2019 ISHLT consensus. How thematic priorities have evolved and whether research effort tracks phenotype burden have not been systematically examined. Methods From 1,851 CLAD-related papers (Web of Science, 1990-2025) assembled after AI-assisted relevance screening (validated against blinded expert adjudication), machine learning-based topic modeling using a biomedical language model identified thematic clusters; temporal trajectories were classified by statistical trend analysis; and a phenotype representation index (RI = corpus proportion ÷ clinical prevalence) was computed against 2 reference cohorts with bootstrap confidence intervals. Results Twenty-four thematic clusters were identified (13 declining, 8 stable, 3 rising, 1 emerging). Rising topics included DSA/antibody-mediated rejection (119 papers), restrictive phenotype classification (126 papers), and translational CLAD pathogenesis (143 papers), reflecting momentum predating the 2019 consensus. Donor-derived cell-free DNA was the sole emerging topic (21 papers). Among 950 phenotype-focused papers, BOS was proportionally represented (RI 1.13 vs Leuven; 1.05 vs Toronto). RAS representation was denominator-dependent (RI 0.75-0.99). MAS was substantially under-represented in both cohorts (RI 0.33 vs Leuven; 0.41 vs Toronto). Conclusions Transformer-based topic modeling reveals a directional shift toward immunological mechanisms and phenotype-specific research that classical keyword approaches cannot resolve. Research effort is broadly proportionate to clinical burden for BOS but substantially below for MAS, a gap possibly attributable to pathophysiological differences, diagnostic complexity, limited case volume, and recency of phenotype formalization that multicenter studies may address.

Introduction Lung transplantation (LT) remains the only viable therapeutic option for many patients with end-stage lung disease. Over the past decades, the landscape of LT has undergone significant changes. This report presents the first detailed analysis of lung donation and transplantation activity in France. Methods All single and double LTs performed in France in 2024 were included in this analysis. Data were obtained from the national registry of the French organ procurement organisation, encompassing donor, candidate, and recipient characteristics, as well as post-transplant outcomes. Results In 2024, a total of 323 LTs were performed, including 273 from donation after brain death (DBD) and 50 from donation after circulatory death (DCD). This represents an increase from the 288 LTs performed in 2023 but remains below the 2019 level of 384 LTs. The number of DCD procedures doubled compared to 2023, reaching 50, with a lung utilization rate of 90.7%, up from 72.7% in 2023. The primary indications for LT were COPD/emphysema (45.5%) and interstitial lung disease (ILD, 37.6%), while cystic fibrosis (CF)/bronchiectasis accounted for only 4.1% of cases. The median waiting time for candidates was 2.5 months, with a cumulative incidence of transplantation reaching 53% at 3 months, 67% at 6 months, and 81% at 12 months. One-year post-transplant survival was 83.7%, with variations by indication: 89.3% for CF/bronchiectasis recipients, 87.4% for COPD/emphysema, and 80% for ILD. Only 13.7% of candidates were listed under high-urgency status, a decrease from 17% in 2023 and 24.6% in 2022. Over the past five years, the number of CF and bronchiectasis candidates declined from 112 (24%) to 14 (4.1%), while ILD candidates increased from 117 (25%) to 129 (38%). Conclusion France’s LT activity shows gradual recovery, primarily driven by increased DCD procedures, which need to be further developed. LT centers must adapt their surgical and medical strategies to address the evolving distribution of underlying diseases leading to transplantation.

Measuring C-terminal α1-AT peptides before lung transplantation offers a promising approach for early CLAD risk stratification https://bit.ly/4hneqXr.

We present the case of a 57-year-old woman with secondary hypogammaglobulinemia who experienced Clostridioides difficile infection (CDI), with repeated recurrences despite transient clinical responses to standard therapies, including repeated fecal microbiota transplantation. Following the replacement of intravenous immunoglobulin supplementation with immunoglobulin M/immunoglobulin A-enriched immunoglobulin, no recurrence of CDI was observed during the 24-month follow-up period.

Objectives:To analyze the risk factors associated with 1-year overall mortality in patients with nocardiosis. Methods:This retrospective multicenter study was conducted across four university hospitals within the same health care network over 11 years (2014-2024) in Marseille, France. Age-adjusted exact multivariable logistic regression was performed to identify factors associated with 1-year overall mortality. Results:Of the 78 patients with a positive Nocardia spp. sample, 52 (66.7%) had a confirmed infection. Of these patients, 53.8% (28/52) had advanced forms, 34.6% (18/52) had disseminated forms, and 65.4% (34/52) had localized forms. The 1-year mortality rate was 21.2% (11/52), reaching 37.5% (six of 16) in the transplant subgroup and 32.1% (nine of 28) in patients with an advanced form. Severe lymphopenia (<0.5 G/l) was independently associated with 1-year mortality (odds ratio 5.70; 95% confidence interval 1.15-35.23). The main species identified was Nocardia abscessus (16/48, 33%), followed by Nocardia farcinica (9/48, 19%). Neither species was associated with an increased risk of 1-year mortality. All isolates except one were susceptible to imipenem (98%). Ninety-seven percent were susceptible to amikacin, 96.5% to linezolid, and 79% to trimethoprim-sulfamethoxazole. Mortality did not differ according to the adequacy of initial antibiotic therapy, based on antibiotic susceptibility testing or reference charts. Conclusions:Solid organ transplantation and advanced disease were associated with higher crude 1-year mortality rates. In the age-adjusted multivariable analysis, severe lymphopenia (<0.5 G/l) was the only factor independently associated with 1-year mortality.

Background Despite major advances in targeted therapies, lung transplantation remains a key option for selected patients with end-stage pulmonary arterial hypertension (PAH) but is associated with substantial clinical and organizational challenges. Our aim was to describe the impact of changes in advanced PAH management and referral strategies on the profile of transplanted patients and outcomes. Methods All patients with PAH (except congenital heart disease), who underwent lung or heart–lung transplantation between 2008 and 2023 were retrospectively studied in France. Data were obtained from the National PAH and Transplant Registries. Patient characteristics, transplant strategies, and outcomes were compared between 2008–2015 (period 1) and 2016–2023 (period 2). Results Overall, 241 PAH patients underwent transplantation. The proportion of patients aged ≥50 years increased from 30% to 44% (p=0.04). Time from diagnosis to transplantation tended to increase (39 vs. 46 months, p=0.2). Pre-operative extracorporeal membrane oxygenation (ECMO) as a bridge to transplantation increased from 6% to 14% (p=0.05), while post-operative ECMO use remained stable (35% vs. 36%). Three-month post-transplant survival was 85% (95% CI 78–92%) and 91% (95% CI 86–96%) in periods 1 and 2, respectively. In the PAH population aged <65 years, the ratio of deaths without transplantation to transplantations performed exceeded 5:1, with marked heterogeneity across aetiologies. Conclusion Advances in severe PAH management have enabled transplantation in older and more intensively treated patients without compromising short-term outcomes. However, major disparities in access to transplantation persist across PAH aetiologies, underscoring the persistent challenges in advanced PAH management.

Introduction Les grossesses chez les femmes transplantées pulmonaires sont considérées à haut risque du fait de la fréquence élevée d’hypertension artérielle, de diabète et d’infections. Il existe par ailleurs un risque certain d’allo-immunisation HLA lié à la grossesse, pouvant potentiellement aboutir chez les patientes greffées à un rejet humoral. Quelques cas ont été décrits chez des femmes transplantées rénales, hépatiques et cardiaques, mais ce risque n’avait jamais été étudié en transplantation pulmonaire. L’objectif de notre étude est d’étudier le risque d’apparition d’un rejet humoral dans l’année suivant la grossesse, celui-ci associant l’apparition d’anticorps anti-HLA dirigés contre le donneur (Donnor Specific Antibodies, DSA) et une dégradation de la fonction respiratoire. Méthodes Il s’agit d’une étude rétrospective multicentrique menée dans les 11 centres de transplantation pulmonaire français. Elle concernait les femmes transplantées pulmonaires ayant présenté une grossesse, aboutie ou non, entre le 1er janvier 2012 et le 31 décembre 2021. Résultats Soixante-seize grossesses ont été incluses chez 52 patientes. Il s’agissait principalement de femmes transplantées bi-pulmonaires (n=43 ; 82,7 %), sur mucoviscidose (n=40 ; 76,9 %) ou hypertension pulmonaire (n=11 ; 21 %), dont l’âge moyen à la transplantation était de 24±5 ans, et au début de la grossesse de 31±5 ans. Sur l’ensemble des grossesses, 43 (56,6 %) ont abouti à la naissance d’enfants, dont une grossesse gémellaire, tandis que les autres ont mené à une interruption de grossesse (n=8 ; 10,5 %) ou une fausse couche (n=25 ; 32,9 %). Cinq rejets humoraux (6,6 %) ont été identifiés dans l’année suivant la grossesse, avec un délai moyen de survenue de 6,24±6,02 mois. Deux des 5 grossesses ont abouti à la naissance d’un nouveau-né et 3 à une interruption de grossesse. Ces 5 rejets humoraux ont abouti à la perte du greffon avec 2 décès et 3 retransplantations. Concernant les critères de jugements secondaires, 17 grossesses (22,4 %) ont entraîné une allo-immunisation de novo et 2 autres (2,6 %) une majoration d’une allo-immunisation préexistante. Quand les anticorps anti-HLA étaient des DSA de novo (n=5), un rejet humoral apparaissait dans tous les cas. Trois grossesses ont été suivies d’un rejet aigu cellulaire sans rejet humoral et une grossesse suivie d’un rejet réversible neutrophilique. Aucun facteur de risque de développer un rejet humoral n’a été identifié. Une analyse de survie exploratoire n’a pas montré de différence significative dans une situation d’allo-immunisation. Conclusion La grossesse chez les femmes transplantées pulmonaires semble être à risque d’allo-immunisation HLA et d’apparition de rejet humoral dans l’année qui la suit. Le rejet humoral post grossesse a été responsable d’une perte du greffon pulmonaire dans 100 % des cas de notre étude. Le suivi des anticorps anti-HLA doit donc être rapproché et prolongé durant l’année suivant la grossesse. Une évaluation du risque de rejet humoral par un typage HLA du père en préconceptionnel comparé à celui du greffon peut se discuter. Un typage HLA de l’enfant sur sang ombilical peut également être proposé afin de renforcer l’immunosuppression en cas d’antigènes HLA communs entre le greffon et l’enfant.

BACKGROUND:The diagnosis of pulmonary antibody-mediated rejection (AMR) remains challenging with lack of specific defining features. This study evaluated the diagnostic and prognostic significance of intragraft anti human leukocyte antigen (HLA) donor-specific antibodies (gDSA) in pulmonary AMR. METHODS:This multicenter prospective study enrolled adult lung transplant recipients (LTR) with serum anti-HLA DSA (sDSA) >1,000 Luminex mean fluorescence intensity (MFI). Transbronchial biopsies (TBBx) were obtained for both standard histologic analysis and cryopreservation to detect anti-HLA class I and II gDSA, using Luminex single-antigen beads assay. Clinical follow-up was conducted over 24 months. An expert pathologist reviewed all TBBx using a predefined checklist. A blinded adjudication panel categorized clinical diagnoses as possible, probable, or definite AMR and non-AMR conditions. The primary objective was to assess gDSA sensitivity and specificity for AMR diagnosis. Additionally, we compared graft outcomes between gDSA+ vs gDSA- patients. RESULTS:Seventy-seven LTR from 5 centers were included from August 2019 to July 2022. Twenty-nine patients were classified as probable or definite clinical/subclinical AMR. Among the cohort, 13 had positive gDSA. gDSA sensitivity, specificity, and positive predictive value for AMR diagnosis were 34.4%, 93.7%, and 76.9%, respectively. gDSA diagnostic performance for AMR was better than sDSA ≥12,500 MFI (sensitivity 37.9%, specificity 85.4%, and positive predictive value 61.1%). Event-free survival analysis (10% forced expiratory volume in 1 second decline or graft loss) showed no significant differences by gDSA positivity. Limited biopsy sampling and spatial heterogeneity may have biased sensitivity and prognostic performances of the technique. CONCLUSIONS:gDSA might offer a specific complementary support for the clinical diagnosis of AMR following lung transplantation.

Introduction: Ultrasound-guided trans-thoracic needle biopsy (US-TTNB) is a method of choice for the diagnostic management of peripheral lung lesions and pleural masses for pulmonologists. If complication risk factors and diagnostic yield have been well reported for CT-guided biopsies, publications for US-TTNB in this fi eld are very scarce. Methods: The primary objective of this study was to describe the diagnostic yield of US-TTNB carried out by pulmonologists defined by a definitive histopathological diagnosis. Secondary objectives were to identify factors that may influence diagnostic yield and to describe complications of this procedure. Between September 2015 and December 2022, charts of consecutive patients presenting peripheral lesion with pleural contact and having undergone US-TTNB were retrospectively analyzed. ROC curves were performed to assess the probability of having a contributing biopsy (definitive histology) depending on scannographic measurements and the number of punctures. Univariate and then multivariate analyses were performed to look for variables associated with complications. Results: One hundred and fifty-nine patients were enrolled in this study. Among them, diagnosis was obtained for 140 patients (88% success rate). The histology was in favor of a neoplastic process in 96% of cases (135/140). Analysis of the ROC curves showed that the depth of the lesion (AUC 75%; 95% CI: 65-85; cut-off 3.0 cm), the width of the lesion (AUC 73%; 95% CI: 63-86; cut-off 3.9 cm), the pleural contact (AUC 68%; 95% CI: 57-80; cut-off 3.8 cm), and the number of biopsies (AUC 70%; 95% CI: 59-81; cut-off 3 biopsies) were the variables associated with diagnostic yield. Complications occurred for 27 patients (17%), mainly pneumothorax (6%), hemoptysis (6%), and sepsis (6%). Univariate analysis showed a significant association between pneumothorax and lesion depth (OR 0.68; 95% CI: 0.65-0.92; p = 0.03) with a predicted probability > 5% for a depth < 4 cm according to general linear model analysis. Univariate and multivariate analysis revealed a significant association between the number of biopsies and the risk of sepsis (OR 1.90; 95% CI: 1.19-3.26; p = 0.01) with a predicted probability > 5% for more than 4 biopsies. Conclusion: US-TTNB is a reliable diagnostic procedure that can be performed by pulmonologists. The depth, width, pleural contact of the lesion, and the number of biopsies are key variables associated with diagnostic yield. The depth of the lesion is associated with the risk of pneumothorax, and the number of biopsies with the risk of pulmonary sepsis. (c) 2024 S. Karger AG, Basel

BACKGROUND:Lung cancer (LC) after lung transplantation (LTx) is a rare but severe complication whose treatment and outcomes remain unclear. METHODS:This multicenter retrospective observational cohort study included consecutive patients diagnosed between 2000 and 2023 with primary LC after LTx or heart-LTx. Patient characteristics, cancer stage, treatment modalities, and outcomes were analyzed. Survival was assessed using Kaplan-Meier methods. We compared the cohort to control recipients without post-transplantation LC. RESULTS:Of 7,313 recipients, 143 (2%) developed LC, after a median interval of 5.3 years. Fifty-five cancers (37%) were stage I disease and 53 (35%) were metastatic disease. In 60 (42%) patients, curative-intent surgery, predominantly via a thoracotomy (79%), was performed and achieved R0 resection in 53 of 57 (93%) patients. Day-90 mortality was 5% after lobectomy and 33% after pneumonectomy. Of the 31 (21%) patients given curative-intent radiotherapy, 3 developed radiation-induced grade 3 or 4 lung toxicity. Median overall survival in patients with stage I, II, III, and IV disease was 83, 16, 10, and 6 months, respectively. Compared to controls, patients with LC were older at transplantation, had greater donor and recipient smoking exposure, and more often received single LTx (43% vs 16%). Of the 62 single-LTx recipients, 52 (84%) had LC in the native lung. CONCLUSIONS:Curative-intent surgical resection, when avoiding pneumonectomy, and radiotherapy yield good long-term survival in early-stage post-transplantation LC. The dramatic survival differences between early and advanced stages emphasize the critical importance of routine low-dose computed tomography screening in all recipients, notably after single LTx.

Background:Chronic lung allograft dysfunction (CLAD) is the main cause of death following lung transplantation (LT). Its pathophysiology and risk factors remain poorly understood. Donor or recipient genetic characteristics could be involved. MUC5B promoter rs35705950 polymorphism is one of the major genetic factors associated with pulmonary fibrosis. We aimed to correlate the MUC5B genotype of recipients and donors with LT outcomes. Methods:Recipient and donor blood samples from the Cohort in Lung Transplantation biobank were used. MUC5B status was determined by quantitative PCR using probes for rs35705950 polymorphism. CLAD occurrence and phenotype were blindly adjudicated. Results:210 recipient-donor pairs were analysed. At 5 years, 68 patients (32.4%) had CLAD. The MUC5B rs35705950 polymorphism, whether in the donor or the recipient, was not associated with CLAD at 5 years (OR 1.07 (95% CI 0.53-2.11), p=0.8, and OR 0.79 (95% CI 0.37-1.60), p=0.5, respectively), CLAD-free survival or CLAD phenotype. The prevalence of the recipients' T allele differed among underlying respiratory diseases (20.0% in interstitial lung disease, 8.4% in emphysema, 13.4% in cystic fibrosis and 5.6% for others, p=0.03). Risk of antibody-mediated rejection (AMR) was independent of the donor MUC5B polymorphism genotype, whereas the presence of the T allele in the recipient was associated with a reduced occurrence of AMR (OR 0.26 (95% CI 0.08-0.69), p=0.015). Conclusion:MUC5B rs35705950 polymorphism in the donor or the recipient does not affect LT outcomes. The significant association between the recipients' polymorphism and reduced AMR occurrence has yet to be confirmed.

Introduction Ventilator-delivered pressures and patient efforts during assisted mechanical ventilation leave patients at risk of lung injury. Electrical diaphragm activity can provide continuous diaphragm monitoring because it provides an electromyographic measure of diaphragmatic effort. However, it is uncertain whether this can be used to assess respiratory effort of lung distending pressure during spontaneous breathing. Objectives Our primary objective was to establish the validity of using electrical diaphragm activity (Edi) to total lung-distending pressure (ΔPL,dyn). We then applied this method to a longitudinal cohort study to describe the distribution and magnitude of ΔPL,dyn during assisted mechanical ventilation. Methods We performed a secondary analysis based on two published studies. Pocc and Edi were measured in 16 mechanically ventilated patients. ΔPes was measured and observed ΔPL,dyn was computed. Similarly, ΔPes, ΔPL,dyn, Pocc, Edi,occ, and Edi,open were measured in an additional 12 mechanically ventilated patients.Estimated ΔPL,dyn for non-occluded breaths was computed as ΔPaw – Pocc/Edi,occ [asterisk] 2/3 [asterisk] Edi,open. The estimated ΔPL,dyn was validated against observed ΔPL,dyn via Pearson's correlation and Bland-Altman analysis. This method was then applied to 45 patients where ΔPaw, Edi,open, and Pocc were measured. Results The validation analysis was performed using 98 recordings obtained in 28 subjects. We found that the median ΔPL,dyn was 19cm H2O (15-23 cm H2O) and estimated ΔPL,dyn had a median of 20 cm H2O (IQR 16-25 cm H2O). The measured and predicted ΔPL,dyn, showed a moderate correlation (R2=0.70, p<0.0001) with a bias of 6% and limits of agreement approximating 28% – 40%. In the longitudinal cohort with 45 patients and 4508 study-hours, we computed the distribution of estimated ΔPL,dyn during assisted ventilation. Estimated ΔPL,dyn was elevated ( >25 cm H2O) in 21% of hours with spontaneous breathing and 35 patients had ≥1 hour of ΔPL,dyn >25 cm H2O. When estimated ΔPL,dyn exceeded 25 cm H2O, the contribution of respiratory effort to total lung-distending pressure was a median of 71% (IQR 58-82%). Conclusion Dynamic transpulmonary driving pressure, a measure of lung stress during spontaneous breathing, can be estimated by monitoring Edi and Pocc. Excessive respiratory effort may be an important and frequent contributor to excess lung stress and strain during mechanical ventilation.

INTRODUCTION:Usual interstitial pneumonia (UIP) is a key pattern of interstitial lung disease (ILD), most commonly linked to idiopathic pulmonary fibrosis (IPF). Identifying underlying autoimmune conditions such as myositis is clinically relevant, yet guidelines provide limited recommendations regarding myositis antibody (MSA) screening. METHODS:We retrospectively analyzed patients with UIP who underwent systematic MSA screening at our center. Clinical and serological characteristics were compared between MSA-positive (MSA+) and MSA-negative (MSA-) groups. Logistic regression was used to identify predictive factors. RESULTS:Among 134 patients, 15 (11 %) were MSA+. Compared with MSA- patients, MSA+ cases were more likely to present with autoimmune disease (p = 0.03), ANA ≥ 1:320 (p < 0.001), and positive rheumatoid factor (p = 0.04). A four-parameter profile combining ANA < 1:320, absence of rheumatoid factor, no hypergammaglobulinemia, and no Raynaud's phenomenon strongly predicted MSA negativity with excellent specificity (100 %), modest sensitivity (35 %), and good overall discriminative ability (AUC = 0.82). DISCUSSION:In patients with UIP, a simple four-parameter profile (ANA < 1:320, absence of rheumatoid factor, absence of hypergammaglobulinemia, and absence of Raynaud's phenomenon) strongly predicts negative MSA status. These findings support a more targeted approach to MSA screening, potentially improving diagnostic accuracy, guiding treatment decisions, and reducing unnecessary testing in UIP.