Survival outcomes following urgent lung transplantation in France and the USA.

INTRODUCTION: Lung graft allocation can be based on a score (Lung Allocation Score) as in the USA or sequential proposals combined with a discrete priority model as in France. We aimed to analyse the impact of allocation policy on the outcome of urgent lung transplantation (LT). METHODS: US United Network for Organ Sharing (UNOS) and French Cristal databases were retrospectively reviewed to analyse LT performed between 2007 and 2017. We analysed the mortality risk of urgent LT by fitting Cox models and adjusted Restricted Mean Survival Time. We then compared the outcome after urgent LT in the UNOS and Cristal groups using a propensity score matching. RESULTS: After exclusion of patients with chronic obstructive pulmonary disease/emphysema and redo LT, 3775 and 12 561 patients underwent urgent LT and non-urgent LT in the USA while 600 and 2071 patients underwent urgent LT and non-urgent LT in France. In univariate analysis, urgent LT was associated with an HR for death of 1.24 (95% CI 1.05 to 1.48) in the Cristal group and 1.12 (95% CI 1.05 to 1.19) in the UNOS group. In multivariate analysis, the effect of urgent LT was attenuated and no longer statistically significant in the Cristal database (HR 1.1 (95% CI 0.91 to 1.33)) while it remained constant and statistically significant in the UNOS database (HR 1.12 (95% CI 1.05 to 1.2)). Survival comparison of urgent LT patients between the two countries was significantly different in favour of the UNOS group (1-year survival rates 84.1% (80.9%-87.3%) vs 75.4% (71.8%-79.1%) and 3-year survival rates 66.3% (61.9%-71.1%) vs 62.7% (58.5%-67.1%), respectively). CONCLUSION: Urgent LT is associated with adverse outcome in the USA and in France with a better prognosis in the US score-based system taking post-transplant survival into account. This difference between two healthcare systems is multifactorial.

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.

Paraneoplastic pemphigus uncovers distinct clinical and biological phenotypes of western unicentric Castleman disease.

Unicentric Castleman disease (UCD) is a lymphoproliferative disease of unknown cause. Paraneoplastic pemphigus (PNP) is a major complication shown to be associated with a poor prognosis, with particular severity in patients with bronchiolitis obliterans (BO). This study describes the clinical and biological characteristics of UCD-PNP patients in a large Western cohort. A total of 148 patients diagnosed with UCD were identified, including 14 patients with a defined PNP. PNP was significantly associated with myasthenia gravis (MG) and FDC sarcoma during follow-up (FDCS). PNP was also significantly associated with reduced survival. These data, together with a multivariate analysis by principal components, led to the identification of UCD-PNP as a group at risk of MG, FDCS and death. PDGFRB sequencing performed on UCD lesions from six patients found the gain-of-function p.N666S variant in two. Interestingly, both patients had hyaline-vascular UCD subtype, were in the UCD-PNP subgroup and had FDCS. Sera from 25 UCD-PNP patients and 6 PNP patients without UCD were tested for PNP-associated autoantibodies. Sera from UCD-PNP patients had a strong reactivity against the N-terminal domain of recombinant periplakin (rPPL, 82%) and showed reactivity against at least two domains of rPPL. These features were not found in patients with UCD alone or in the PNP group without UCD. These data indicate that UCD-PNP patients belong to a subgroup sharing strong clinical and biological identity that might help to decipher the different dynamics of UCD natural history.

Risk of Bronchial Complications After Lung Transplantation With Respiratory Corynebacteria. Results From a Monocenter Retrospective Cohort Study.

Corynebacterium spp. are associated with respiratory infections in immunocompromised hosts. A link with bronchial complications after lung transplantation (LTx) has been suggested. We aimed to assess the link between respiratory sampling of Corynebacterium spp. and significant bronchial complication (SBC) after LTx. We performed a single center retrospective study. Inclusion of LTx recipients with at least one respiratory Corynebacterium spp. sample (July 2014 to December 2018). Subjects were matched to unexposed LTx recipients. Primary outcome was SBC occurrence after Corynebacterium spp. isolation. Secondary outcomes were Corynebacterium spp. persistent sampling, chronic lung allograft dysfunction (CLAD) onset and all-cause mortality. Fifty-nine patients with Corynebacterium spp. sampling with 59 without isolation were included. Corynebacterium spp. identification was not associated with SBC occurrence (32.4% vs. 21.6%, p = 0.342). Previous SBC was associated with further isolation of Corynebacterium spp. (OR 3.94, 95% CI [1.72-9.05]). Previous SBC and corticosteroids pulses in the last 3 months were the only factors associated with increased risk of Corynebacterium spp. isolation in multivariate analysis. Corynebacterium spp. sampling was significantly associated with CLAD onset (27.1% vs. 6.9%, p = 0.021). Corynebacterium spp. isolation was not associated with SBC but with higher risk of CLAD. Whether CLAD evolution is affected by Corynebacterium spp. eradication remains to be investigated.

Impact of Culture-Positive Preservation Fluid on Early Morbidity and Mortality After Lung Transplantation.

The prevalence, risk factors and outcomes associated with culture-positive preservation fluid (PF) after lung transplantation (LT) are unknown. From January 2015 to December 2020, the microbiologic analyses of PF used to store the cold ischaemia-placed lung graft(s) of 271 lung transplant patients were retrospectively studied. Culture-positive PF was defined as the growth of any microorganism. Eighty-three (30.6%) patients were transplanted with lung grafts stored in a culture-positive PF. One-third of culture-positive PF were polymicrobial. Staphylococcus aureus and Escherichia coli were the most frequently isolated microorganisms. No risk factors for culture-positive PF based on donor characteristics were identified. Forty (40/83; 48.2%) patients had postoperative pneumonia on Day 0 and 2 (2/83; 2.4%) patients had pleural empyema with at least one identical bacteria isolated in culture-positive PF. The 30-day survival rate was lower for patients with culture-positive PF compared with patients with culture-negative PF (85.5% vs. 94.7%, p = 0.01). Culture-positive PF has a high prevalence and may decrease lung transplant recipient survival. Further studies are required to confirm these results and improve understanding of the pathogenesis of culture-positive PF and their management.

Low HDL-Cholesterol Concentrations in Lung Transplant Candidates are Strongly Associated With One-Year Mortality After Lung Transplantation.

High-density lipoproteins (HDLs), whose main role is the reverse transport of cholesterol, also have pleiotropic anti-inflammatory, antioxidant, anti-apoptotic and anti-infectious properties. During sepsis, HDL cholesterol (HDL-C) concentration is low, HDL particle functionality is altered, and these modifications are correlated with poor outcomes. Based on the protective effects of HDL, we hypothesized that HDL-C levels could be associated with lung transplantation (LT) outcome. We thus looked for an association between basal HDL-C concentration and one-year mortality after LT. In this single-center prospective study including consecutive LTs from 2015 to 2020, 215 patients were included, essentially pulmonary fibrosis (47%) and chronic obstructive pulmonary disease (COPD) (38%) patients. Mortality rate at one-year was 23%. Basal HDL-C concentration stratified nonsurvivors to survivors at one-year (HDL-C = 1.26 [1.12-1.62] mmol/L vs. HDL-C = 1.55 [1.22-1.97] mmol/L, p = 0.006). Multivariate analysis confirmed that HDL-C concentration during the pretransplant assessment period was the only variable inversely associated with mortality. Moreover, mortality at one-year in patients with HDL-C concentrations ≤1.45 mmol/L was significantly higher (log-rank test, p = 0.00085). In conclusion, low basal HDL-C concentrations in candidates for LT are strongly associated with mortality after LT. To better understand this association, further studies in this field are essential and, in particular, a better characterization of HDL particles seems necessary.

FGF19 Is Downregulated in Idiopathic Pulmonary Fibrosis and Inhibits Lung Fibrosis in Mice.

Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with limited therapeutic possibilities. FGF19 (fibroblast growth factor 19), an endocrine FGF, was recently shown to decrease liver fibrosis. To ask whether FGF19 had antifibrotic properties in the lung and decipher its effects on common features associated with lung fibrogenesis, we assessed, by ELISA, FGF19 concentrations in plasma and BAL fluids obtained from control subjects and patients with IPF. In vivo, using an intravenously administered adeno11-associated virus, we overexpressed FGF19 at the fibrotic phase of two experimental models of murine lung fibrosis and assessed its effect on lung morphology, lung collagen content, fibrosis markers, and profibrotic mediator expression at mRNA and protein levels. In vitro, we investigated whether FGF19 could modulate the TGF-ß-induced differentiation of primary human lung fibroblasts into myofibroblasts and the apoptosis of murine alveolar type II cells. Although FGF19 was not detected in BAL fluid, FGF19 concentration was decreased in the plasma of patients with IPF compared with control subjects. In vivo, the overexpression of FGF19 was associated with a marked decrease of lung fibrosis and fibrosis markers, with a decrease of profibrotic mediator expression and lung collagen content. In vitro, FGF19 decreased alveolar type 2 epithelial cell apoptosis through the decrease of the proapoptotic BIM protein expression and prevented TGF-ß-induced myofibroblast differentiation through the inhibition of JNK phosphorylation. Altogether, these data identify FGF19 as an antifibrotic molecule with potential therapeutic interest in fibrotic lung disorders.

Impact of ex vivo lung perfusion on brain-dead donor lung utilization: The French experience.

Ex vivo lung perfusion (EVLP) is a valuable method for expanding the lung donor pool. Its indications currently differ across centers. This national retrospective cohort study aimed to describe the profile of donors with lungs transplanted after EVLP and determine the effectiveness of EVLP on lung utilization. We included brain-dead donors with at least one lung offered between 2012 and 2019 in France. Lungs transplanted without or after EVLP were compared with those that were rejected. Donor group phenotypes were determined with multiple correspondence analysis (MCA). The association between donor factors and lung transplantation was assessed with a multivariable multinomial logistic regression. MCA revealed that donors whose lungs were transplanted after EVLP had profiles similar to the donors whose lungs were declined and quite different from those of donors with lungs transplanted without EVLP. Donor predictors of graft nonuse included age ≥50 years, smoking history, PaO2 /FiO2 ratio ≤300 mmHg, abnormal chest imaging, and purulent secretions. EVLP increased utilization of lungs from donors with a smoking history, PaO2 /FiO2 ratio ≤300 mmHg, and abnormal chest imaging.

Favorable, arduous or fatal postoperative pathway within 90 days of lung transplantation.

INTRODUCTION: The maximum gain in quality of life after lung transplantation (LT) is expected between six months and one year after LT, as the occurrence of chronic lung allograft dysfunction may mask the beneficial effects beyond one year. Thus, the postoperative period could be the cornerstone of graft success. We sought to describe the factors present before postoperative admission to the ICU and associated with favorable, arduous or fatal pathway within 90 days of LT. MATERIALS AND METHODS: We conducted a retrospective single-center study between January 2015 and December 2020. Using multinomial regression, we assessed the demographic, preoperative and intraoperative characteristics of patients associated with favorable (duration of postoperative mechanical ventilation < 3 days and alive at Day 90), arduous (duration of postoperative mechanical ventilation ≥ 3 days and alive at Day 90) or fatal (dead at Day 90) pathway within 90 days of LT. RESULTS: A total of 269 lung transplant patients were analyzed. Maximum graft cold ischemic time ≥ 6 h and intraoperative blood transfusion ≥ 3 packed red blood cells were associated with arduous and fatal pathway at Day 90, whereas intraoperative ECMO was strongly associated with fatal pathway. CONCLUSION: No patient demographics influenced the postoperative pathway at Day 90. Only extrinsic factors involving graft ischemia time, intraoperative transfusion, and intraoperative ECMO determined early postoperative pathway.

Clinical and histopathologic predictors of therapeutic response to bronchial thermoplasty in severe refractory asthma.

BACKGROUND: Phenotypes and endotypes predicting optimal response to bronchial thermoplasty (BT) in patients with severe asthma remain elusive. OBJECTIVE: Our aim was to compare the clinical characteristics and hallmarks of airway inflammation and remodeling before and after BT in responder and partial responder patients with severe asthma refractory to oral steroids and to omalizumab. METHODS: In all, 23 patients with severe refractory asthma were divided into BT responders (n = 15) and BT partial responders (n = 8), according to the decrease in asthma exacerbations at 12 months after BT. Clinical parameters were compared at baseline and 12 months after BT, and hallmarks of airway inflammation and remodeling were analyzed by immunohistochemistry in bronchial biopsy specimens before and 3 months after BT. RESULTS: At baseline, the BT responders were around 8 years younger than the BT partial responders (P = .02) and they had a greater incidence of atopy, higher numbers of blood eosinophils (both P = .03) and IgE levels, higher epithelial IFN-α expression, and higher numbers of mucosal eosinophils and IL-33-positive cells (P ≤ .05). A reduction in blood eosinophil count, serum IgE level, type 2 airway inflammation, and numbers of mucosal IL-33-positive cells and mast cells associated with augmented epithelial MUC5AC and IFN-α/ß immunostaining was noted after BT in responders, whereas the numbers of mucosal IL-33-positive cells were augmented in BT partial responders. Most of these changes were correlated with clinical parameters. Subepithelial membrane thickening and airway smooth muscle area were similar in the 2 patient groups at baseline and after BT. CONCLUSION: By reducing allergic type 2 inflammation and increasing epithelial MUC5AC and anti-viral IFN-α/ß expression, BT may enhance host immune responses and thus attenuate exacerbations and symptoms in BT responders. Instead, targeting IL-33 may provide a clinical benefit in BT partial responders.

Specific Genomic Alterations in High-Grade Pulmonary Neuroendocrine Tumours with Carcinoid Morphology.

INTRODUCTION: High-grade lung neuroendocrine tumours with carcinoid morphology have been recently reported; they may represent the thoracic counterparts of grade 3 digestive neuroendocrine tumours. We aimed to study their genetic landscape including analysis of tumoral heterogeneity. METHODS: Eleven patients with high-grade (>20% Ki-67 and/or >10 mitoses) lung neuroendocrine tumours with a carcinoid morphology were included. We analysed copy number variations, somatic mutations, and protein expression in 16 tumour samples (2 samples were available for 5 patients allowing us to study spatial and temporal heterogeneity). RESULTS: Genomic patterns were heterogeneous ranging from "quiet" to tetraploid, heavily rearranged genomes. Oncogene mutations were rare and most genetic alterations targeted tumour suppressor genes. Chromosomes 11 (7/11), 3 (6/11), 13 (4/11), and 6-17 (3/11) were the most frequently lost. Altered tumour suppressor genes were common to both carcinoids and neuroendocrine carcinomas, involving different pathways including chromatin remodelling (KMT2A, ARID1A, SETD2, SMARCA2, BAP1, PBRM1, KAT6A), DNA repair (MEN1, POLQ, ATR, MLH1, ATM), cell cycle (RB1, TP53, CDKN2A), cell adhesion (LATS2, CTNNB1, GSK3B) and metabolism (VHL). Comparative spatial/temporal analyses confirmed that these tumours emerged from clones of lower aggressivity but revealed that they were genetically heterogeneous accumulating "neuroendocrine carcinoma-like" genetic alterations through progression such as TP53/RB1 alterations. CONCLUSION: These data confirm the importance of chromatin remodelling genes in pulmonary carcinoids and highlight the potential role of TP53 and RB1 to drive the transformation in more aggressive high-grade tumours.

Late viral or bacterial respiratory infections in lung transplanted patients: impact on respiratory function.

BACKGROUND: Respiratory infections are a major threat for lung recipients. We aimed to compare with a monocentric study the impact of late viral and bacterial respiratory infections on the graft function. METHODS: Patients, who survived 6 months or more following lung transplantation that took place between 2009 and 2014, were classified into three groups: a viral infection group (VIG) (without any respiratory bacteria), a bacterial infection group (BIG) (with or without any respiratory viruses), and a control group (CG) (no documented infection). Chronic lung allograft dysfunction (CLAD) and acute rejection were analysed 6 months after the inclusion in the study. RESULTS: Among 99 included lung recipients, 57 (58%) had at least one positive virological respiratory sample during the study period. Patients were classified as follows: 38 in the VIG, 25 in the BIG (among which 19 co-infections with a virus) and 36 in the CG. The BIG presented a higher initial deterioration in lung function (p = 0.05) than the VIG. But 6 months after the infection, only the VIG presented a median decrease of forced expiratory volume in 1 s; - 35 mL (IQR; - 340; + 80) in the VIG, + 140 mL (+ 60;+ 330) in the BIG and + 10 (- 84;+ 160) in the CG, p < 0.01. Acute rejection was more frequent in the VIG (n = 12 (32%)), than the BIG (n = 6 (24%)) and CG (n = 3 (8%)), p < 0.05, despite presenting no more CLAD (p = 0.21). CONCLUSIONS: Despite a less severe initial presentation, single viral respiratory infections seem to lead to a greater deterioration in lung function, and to more acute rejection, than bacterial infections.

Treatment and outcome of Unicentric Castleman Disease: a retrospective analysis of 71 cases.

We retrospectively analysed 71 cases of Unicentric Castleman disease, a rare, usually asymptomatic, benign lymphoproliferative disorder presenting as a unique nodal mass. Although surgery is considered as the gold standard therapy, only 38 patients (54%) underwent initial surgical resection and 95% were cured. An additional 9 patients had surgery after an attempt at medical reduction. Reduction therapy was used in 21 patients with a 55% response rate, but without evidence for an optimal regimen. Radiotherapy was limited to 8 patients because of associated toxicity. Watch and wait was considered in 13 asymptomatic patients and 11 of these remained stable for up to 17 years.

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.

Human airway trypsin-like protease exerts potent, antifibrotic action in pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is characterized by the deposition of excessive extracellular matrix and the destruction of lung parenchyma, resulting from an aberrant wound-healing response. Although IPF is often associated with an imbalance in protease activity, the mechanisms underlying the sustained repair mechanisms are not fully understood. Here, we addressed the role of the recently identified, membrane-anchored serine protease human airway trypsin-like protease (HAT). In the present study, we show that both HAT expression and activity were up-regulated in human IPF specimens. Next, adenoviral overexpression of HAT before bleomycin challenge attenuated lung injury as well as extracellular matrix deposition in the bleomycin-induced pulmonary fibrosis model. In vitro, HAT prevented specific fibrosis-associated responses in primary human pulmonary fibroblasts and induced the expression of mediators associated with the prostaglandin E2 pathway. Altogether, our findings suggested that HAT could have a protective role in IPF and other fibrotic lung disorders.-Menou, A., Flajolet, P., Duitmen, J., Justet, A., Moog, S., Jaillet, M., Tabèze, L., Solhonne, B., Garnier, M., Mal, H., Mordant, P., Castier, Y., Cazes, A., Sallenave, J.-M., Mailleux, A. A., Crestani, B. Human airway trypsin-like protease exerts potent, antifibrotic action in pulmonary fibrosis.

[Autochthonous hydatid cyst of the lung]. / Kyste hydatique pulmonaire autochtone.

Cystic echinococcosis, or hydatidosis, also known as hydatid cyst, is a cosmopolitan parasitosis mainly present in breeding areas. This anthropozoonosis is related to the tissue development of an hydatid of an echinococcus tænia, Echinococcus granulosus, found in the digestive tract of canids, at the adult state. In France, this larval cestosis is essentially an import disease developed by patients from endemic areas such as East and North Africa, South America or Asia. However, autochtonous forms, although rare, still persist. Here we describe the case of a 39-year-old non-smoking patient from Paris, admitted in the emergency department for chest pain associated with sweating and chills. The clinical examination found the notion of a right lower lobar pulmonary nodule discovered 20 years ago, on a chest X-ray, but never explored. Thoracic computed tomography shows two large cystic opacities with endocystic flaky images, including one ruptured in the pleura with right pleural effusion. This radiological suspicion of fissured cystic echinococcosis was confirmed by positive hydatidosis serology. The multidisciplinary meeting retained the indication of right basal segmentectomy enlarged to a diaphragmatic patch, associated with treatment by albendazole. The diagnosis was confirmed by parasitological and pathological data. In this article, we will deal with the macroscopic and microscopic features of this rare parasitosis in metropolitan France and we will discuss the elements of management of a fresh resected specimen during macroscopic examination to prevent parasite swarming.

Penetration of the Human Pulmonary Epithelium by Aspergillus fumigatus Hyphae.

Background: The airway epithelium is the first barrier interacting with Aspergillus fumigatus conidia after their inhalation, suggesting that this structure functions as point of entry of this fungus to initiate pulmonary aspergillosis. Methods: To study epithelial entry by A fumigatus, primary human reconstituted pseudostratified epithelium cultured in air-liquid interface as well as bronchial epithelial cell monolayers were infected with conidia. Results: Under these experimental conditions, we found that A fumigatus hyphae traversed the bronchial epithelium through a mechanism involving the recruitment of actin, which formed a tunnel that allows hyphae to enter the cells without disturbing their integrity. Conclusions: These findings describe a new mechanism by which A fumigatus hyphae penetrate the airway epithelial barrier and can infect its human host.

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.

FGF9 prevents pleural fibrosis induced by intrapleural adenovirus injection in mice.

Fibroblast growth factor 9 (FGF9) is necessary for fetal lung development and is expressed by epithelium and mesothelium. We evaluated the role of FGF9 overexpression on adenoviral-induced pleural injury in vivo and determined the biological effects of FGF9 on mesothelial cells in vitro. We assessed the expression of FGF9 and FGF receptors by mesothelial cells in both human and mouse lungs. Intrapleural injection of an adenovirus expressing human FGF9 (AdFGF9) or a control adenovirus (AdCont) was performed. Mice were euthanized at days 3, 5, and 14 Expression of FGF9 and markers of inflammation and myofibroblastic differentiation was studied by qPCR and immunohistochemistry. In vitro, rat mesothelial cells were stimulated with FGF9 (20 ng/ml), and we assessed its effect on proliferation, survival, migration, and differentiation. FGF9 was expressed by mesothelial cells in human idiopathic pulmonary fibrosis. FGF receptors, mainly FGFR3, were expressed by mesothelial cells in vivo in humans and mice. AdCont instillation induced diffuse pleural thickening appearing at day 5, maximal at day 14 The altered pleura cells strongly expressed α-smooth muscle actin and collagen. AdFGF9 injection induced maximal FGF9 expression at day 5 that lasted until day 14 FGF9 overexpression prevented pleural thickening, collagen and fibronectin accumulation, and myofibroblastic differentiation of mesothelial cells. In vitro, FGF9 decreased mesothelial cell migration and inhibited the differentiating effect of transforming growth factor-ß1. We conclude that FGF9 has a potential antifibrotic effect on mesothelial cells.