Successful lung transplantation in genetic methionyl-tRNA synthetase-related alveolar proteinosis/lung fibrosis without recurrence under methionine supplementation: Medium-term outcome in 4 cases.

Pulmonary alveolar proteinosis (PAP) results from the accumulation of lipoproteinaceous material in the alveoli and alveolar macrophages, and can be associated with pulmonary fibrosis, with a need for lung transplantation (LTx). Causes of PAP are autoimmune (90%-95%), secondary (5%), or hereditary (<1%). Patients with hereditary PAP are generally not considered for isolated LTx, due to the high probability of recurrence after LTx, and only a challenging scenario with sequential LTx followed by hematopoietic stem cell transplantation (HSCT) was reported as successful. Recently, a new genetic cause of PAP linked to mutations in the methionyl-tRNA synthetase (MARS) gene has been reported, with a highly variable clinical presentation. Because clinical correction of the defective MARS activity with methionine supplementation has been reported in nontransplanted children, we reassessed the feasibility of LTx for candidates with MARS-related PAP/fibrosis. We report 3 cases of LTx performed for MARS-related pulmonary alveolar proteinosis-pulmonary fibrosis without recurrence under methionine supplementation, whereas another fourth case transplanted without supplementation had fatal PAP recurrence. These results suggest the effectiveness of methionine in correcting defective MARS activity and also looking for this very rare diagnosis in case of unclassified PAP/fibrosis. It argues for not excluding the feasibility of isolated LTx in patients with MARS mutation.

The French Compassionate Program of elexacaftor-tezacaftor-ivacaftor in people with cystic fibrosis with advanced lung disease and no F508del CFTR variant.

BACKGROUND: The European Medicines Agency has approved the cystic fibrosis transmembrane conductance regulator (CFTR) modulator combination elexacaftor-tezacaftor-ivacaftor (ETI) for people with cystic fibrosis (pwCF) carrying at least one F508del variant. The United States Food and Drug Administration (FDA) also approved ETI for pwCF carrying one of 177 rare variants. METHODS: An observational study was conducted to evaluate the effectiveness of ETI in pwCF with advanced lung disease that were not eligible to ETI in Europe. All patients with no F508del variant and advanced lung disease (defined as having a percent predicted forced expiratory volume (ppFEV1)<40 and/or being under evaluation for lung transplantation) and enrolled in the French Compassionate Program initiated ETI at recommended doses. Effectiveness was evaluated by a centralized adjudication committee at 4-6 weeks in terms of clinical manifestations, sweat chloride concentration and ppFEV1. RESULTS: Among the first 84 pwCF included in the program, ETI was effective in 45 (54%) and 39 (46%) were considered to be non-responders. Among the responders 22/45 (49%) carried a CFTR variant that is not currently approved by FDA for ETI eligibility. Important clinical benefits, including suspending the indication for lung transplantation, a significant decrease in sweat chloride concentration by a median [IQR] -30 [-14;-43]mmol·l-1 (n=42; p<0.0001) and an improvement in ppFEV1 by+10.0 [6.0; 20.5] (n=44, p<0.0001), were observed in those for whom treatment was effective. CONCLUSION: Clinical benefits were observed in a large subset of pwCF with advanced lung disease and CFTR variants not currently approved for ETI.

Molecular profile of non-small cell lung cancer in reunion Island.

BACKGROUND: In recent years, the discovery of predictive biomarkers has enabled the development of targeted therapies that have improved the prognosis of patients with non-small cell lung cancer (NSCLC). No data are available at present on the molecular profile of NSCLC in Reunion Island, a French overseas department located in the Indian Ocean and characterized by an ethnically-mixed population. METHOD: This observational, retrospective, and multicenter study included all patients who were diagnosed with NSCLC in Reunion Island during 2 years and whose tumor specimens were sent for molecular analysis at Bordeaux University Hospital. The aim of the study was to determine the molecular profile of NSCLC in the Reunionese population, including the frequency of epidermal growth factor receptor (EGFR) mutation. RESULTS: A total of 310 patients with NSCLC were screened for genetic mutations. Of these, 281 (91%) had adenocarcinoma, 207 (66%) were born in Reunion Island, 79 (25%) were never-smokers, and 109 (35%) were women. One hundred and seventy-eight (57%) patients had a genetic mutation. An EGFR mutation was detected in 69 patients (22%) of the 310 included patients. This mutation was detected in 23% of patients with adenocarcinoma, 40% of women, 55% of never-smokers, and 23% of patients born in Reunion Island. CONCLUSION: The frequency of EGFR mutation is high in the Reunionese population. This frequency is similar to that reported in Asia and may be explained by the history of migrations and ethnic mixing in Reunion Island. These findings suggest complex interactions between genetic and environmental factors in the carcinogenesis of NSCLC.

Trans-bronchial lung cryobiopsy in patients at high-risk of complications.

BACKGROUND: The surgical lung biopsy (SLB) is the recommended sampling technique when the pathological analysis of the lung is required in the work-up of an interstitial lung disease (ILD) but trans-bronchial lung cryobiopsy (TBLC) is increasingly recognized as an alternative approach. As TBLCs have lower mortality and morbidity risks than SLB, this study aimed to investigate the safety of TBLCs in patients at higher risk of complications and for whom SLB was not considered as an alternative. METHOD: This prospective study was conducted in two hospitals in which TBLCs were performed in patients with body mass index (BMI) > 35, and/or older than 75 years, and/or with severely impaired lung function (FVC < 50% or DLCO < 30%), and/or systolic pulmonary artery pressure > 45 mmHg, and/or a clinically significant cardiac disease. Patients with any of these risk factors constituted the high-risk group. Clinical outcomes were compared with those obtained in patients without these risk factors (low-risk group). RESULTS: Ninety-six patients were included between April 2015 and April 2020, respectively 38 and 58 in the high-risk or the low-risk group. No statistically significant difference was observed between both groups in terms of severity and rate of bleeding, pneumothorax, or duration of hospital stay (p value ranging from 0.419 to 0.914). CONCLUSION: This preliminary study on a limited number of patients suggests that TBLC appears safe in those in whom lung biopsy is at high-risk of complications according to their age, BMI, lung impairment, and cardiac comorbidities.

High Prevalence of Nontuberculous Mycobacteria in Cystic Fibrosis Patients in Tropical French Reunion Island.

BACKGROUND: Reunion Island is a French overseas department located in a tropical area, where cystic fibrosis incidence is high. Cystic fibrosis (CF) patients are at risk of developing nontuberculous mycobacteria (NTM) infection. Epidemiologic studies are lacking in Reunion Island. METHODS: From 2002 to 2015, a retrospective review was performed in university hospitals on Reunion Island. All CF patients having at least 1 positive NTM isolate were included. Clinical, radiologic, and microbiologic data were collected from patient records. RESULTS: Fifty-one CF patients were included. The overall estimated prevalence of NTM was 26.4% in total CF population and 36.9% in patients over 12 years of age. Mycobacterium abscessus and Mycobacterium avium were the most frequently identified species found in 31 patients (60.8%) and 14 patients (27.4%), respectively. A rare NTM species: Mycobacterium simiae was found in 4 patients (7.8%). Twenty-nine patients (56.9%) met the American Thoracic Society (ATS) criteria for infection. They were more likely younger with a low body mass index and more frequently infected by Mycobacterium abscessus (22/29). CONCLUSION: The overall prevalence of NTM in tropical Reunion Island is 3 times higher than in metropolitan France. A different environmental exposure in a tropical climate or risk factors related to cystic fibrosis or its treatment in Reunion patients could explain it.

Functional assessment and phenotypic heterogeneity of SFTPA1 and SFTPA2 mutations in interstitial lung diseases and lung cancer.

INTRODUCTION: Interstitial lung diseases (ILDs) can be caused by mutations in the SFTPA1 and SFTPA2 genes, which encode the surfactant protein (SP) complex SP-A. Only 11 SFTPA1 or SFTPA2 mutations have so far been reported worldwide, of which five have been functionally assessed. In the framework of ILD molecular diagnosis, we identified 14 independent patients with pathogenic SFTPA1 or SFTPA2 mutations. The present study aimed to functionally assess the 11 different mutations identified and to accurately describe the disease phenotype of the patients and their affected relatives. METHODS: The consequences of the 11 SFTPA1 or SFTPA2 mutations were analysed both in vitro, by studying the production and secretion of the corresponding mutated proteins and ex vivo, by analysing SP-A expression in lung tissue samples. The associated disease phenotypes were documented. RESULTS: For the 11 identified mutations, protein production was preserved but secretion was abolished. The expression pattern of lung SP-A available in six patients was altered and the family history reported ILD and/or lung adenocarcinoma in 13 out of 14 families (93%). Among the 28 SFTPA1 or SFTPA2 mutation carriers, the mean age at ILD onset was 45 years (range 0.6-65 years) and 48% underwent lung transplantation (mean age 51 years). Seven carriers were asymptomatic. DISCUSSION: This study, which expands the molecular and clinical spectrum of SP-A disorders, shows that pathogenic SFTPA1 or SFTPA2 mutations share similar consequences for SP-A secretion in cell models and in lung tissue immunostaining, whereas they are associated with a highly variable phenotypic expression of disease, ranging from severe forms requiring lung transplantation to incomplete penetrance.