Liver disease in germline mutations of telomere-related genes: Prevalence, clinical, radiological, pathological features, outcome, and risk factors.

BACKGROUND AND AIM: Germline mutations of telomere-related genes (TRG) induce multiorgan dysfunction, and liver-specific manifestations have not been clearly outlined. We aimed to describe TRG mutations-associated liver diseases. APPROACH AND RESULTS: Retrospective multicenter analysis of liver disease (transaminases > 30 IU/L and/or abnormal liver imaging) in patients with TRG mutations. Main measurements were characteristics, outcomes, and risk factors of liver disease in a TRG mutations cohort. The prevalence of liver disease was compared to a community-based control group (n = 1190) stratified for age and matched 1:3 for known risk factors of liver disease. Among 132 patients with TRG mutations, 95 (72%) had liver disease, with associated lung, blood, skin, rheumatological, and ophthalmological TRG diseases in 82%, 77%, 55%, 39%, and 30% of cases, respectively. Liver biopsy was performed in 52/95 patients, identifying porto-sinusoidal vascular disease in 48% and advanced fibrosis/cirrhosis in 15%. After a follow-up of 21 months (12-54), ascites, hepato-pulmonary syndrome, variceal bleeding, and HCC occurred in 14%, 13%, 13%, and 2% of cases, respectively. Five-year liver transplantation-free survival was 69%. A FIB-4 score ≥ 3·25 and ≥1 risk factor for cirrhosis were associated with poor liver transplantation-free survival. Liver disease was more frequent in patients with TRG mutations than in the paired control group [80/396, (20%)], OR 12.9 (CI 95%: 7.8-21.3, p < 0.001). CONCLUSIONS: TRG mutations significantly increase the risk of developing liver disease. Although symptoms may be mild, they may be associated with severe disease. Porto-sinusoidal vascular disease and cirrhosis were the most frequent lesions, suggesting that the mechanism of action is multifactorial.

Similarities and differences of interstitial lung disease associated with pathogenic variants in SFTPC and ABCA3 in adults.

BACKGROUND AND OBJECTIVE: Variants in surfactant genes SFTPC or ABCA3 are responsible for interstitial lung disease (ILD) in children and adults, with few studies in adults. METHODS: We conducted a multicentre retrospective study of all consecutive adult patients diagnosed with ILD associated with variants in SFTPC or ABCA3 in the French rare pulmonary diseases network, OrphaLung. Variants and chest computed tomography (CT) features were centrally reviewed. RESULTS: We included 36 patients (median age: 34 years, 20 males), 22 in the SFTPC group and 14 in the ABCA3 group. Clinical characteristics were similar between groups. Baseline median FVC was 59% ([52-72]) and DLco was 44% ([35-50]). An unclassifiable pattern of fibrosing ILD was the most frequent on chest CT, found in 85% of patients, however with a distinct phenotype with ground-glass opacities and/or cysts. Nonspecific interstitial pneumonia and usual interstitial pneumonia were the most common histological patterns in the ABCA3 group and in the SFTPC group, respectively. Annually, FVC and DLCO declined by 1.87% and 2.43% in the SFTPC group, respectively, and by 0.72% and 0.95% in the ABCA3 group, respectively (FVC, p = 0.014 and DLCO , p = 0.004 for comparison between groups). Median time to death or lung transplantation was 10 years in the SFTPC group and was not reached at the end of follow-up in the ABCA3 group. CONCLUSION: SFTPC and ABCA3-associated ILD present with a distinct phenotype and prognosis. A radiologic pattern of fibrosing ILD with ground-glass opacities and/or cysts is frequently found in these rare conditions.

Therapeutic Drug Monitoring of Sputum Voriconazole in Pulmonary Aspergillosis.

Voriconazole is one of the most used antifungal azoles against pulmonary aspergillosis. Therapeutic drug monitoring (TDM) of the voriconazole concentration in plasma is recommended in clinical practice guidelines to prevent treatment failure and toxicity. The aim of this study was to evaluate the feasibility and utility of TDM of the voriconazole concentration in the sputum of patients treated for pulmonary aspergillosis. Fifty sputum and 31 plasma samples were analysed with high-performance tandem mass spectrometry (HPLC-MS/MS) in 24 patients included in the study. The voriconazole concentration was simultaneously assessed in the plasma and sputum in 22 samples. The correlation between the sputum and plasma levels was estimated with a univariate linear regression model, and the observed R2 was 0.86. We determined the following equation, Csputum = 0.45 (Cplasma) + 0.21, which could predict the voriconazole concentration in plasma from sputum. TDM of the voriconazole concentration in sputum is an easy, non-invasive and accurate method with which to evaluate voriconazole exposure in patients with pulmonary aspergillosis.

Amikacin Liposomal Inhalation Suspension in the Treatment of Mycobacterium abscessus Lung Infection: A French Observational Experience.

Background: Mycobacterium abscessus infections remain difficult to manage in both cystic fibrosis (CF) and non-CF patients and reported clinical outcomes are largely unsatisfactory. Clinical trial data are limited and no approved therapies are currently available for the management of M abscessus lung diseases. As an alternative, cohort studies may provide insightful information into the management of M abscessus pulmonary disease. Methods: Based on a retrospective observational cohort study, we investigated the safety and efficacy of amikacin liposome inhaled suspension (ALIS) as an adjunct to a standard antibiotic regimen for M abscessus lung infection in both CF and non-CF patients. We also assessed the association of patient drug compliance with culture conversion and clinical outcomes. Results: Twenty-six patients had long-term follow-up data available. Culture conversion was achieved in 54% (14/26) of the patients with no difference between CF and non-CF patients after an average treatment duration of 10 months. Patient treatment compliance was significantly better in the converter group compared to nonconverters with an odds ratio of 44.78 associated with good compared to poor patient compliance. Overall, 9 patients (35%) experienced an adverse event that led to treatment discontinuation. Conclusions: ALIS appears beneficial in both CF and non-CF populations with M abscessus lung disease.

Radial-EBUS and virtual bronchoscopy planner for peripheral lung cancer diagnosis: How it became the first-line endoscopic procedure.

BACKGROUND: Various advanced bronchoscopy methods have been developed to reach peripheral lung lesions (PLL). In a large cohort, we aimed to assess a standardized procedure of first-line radial-endobronchial ultrasound (r-EBUS) and virtual bronchoscopy planner for the diagnosis of peripheral lung cancer. METHODS: This retrospective, single center study included patients who had r-EBUS-guided bronchoscopy for the diagnosis of a PLL between 2008 and 2019. Cases without a final diagnosis of cancer or follow-up were excluded. RESULTS: Between 2008 and 2019, 2735 patients had a r-EBUS procedure, among whom 1627 had a final diagnosis of cancer and were included in the present study. Over the 12-year study period, r-EBUS became the first-line endoscopic procedure to assess PLL (25% as first-line bronchoscopy in 2008 vs. 92% in 2019). The frequency of the bronchus sign decreased from 2009 to 2019 (100% to 80%; p = 0.001), whereas US visualization of the lesion remained stable (88%). The median number of biopsies increased from two (2008 to 2014) to four (2015 to 2019) (p < 0.0001), with the same diagnostic efficiency (74% total and 80% when a bronchus sign was present). Of the 651 adenocarcinomas, molecular analysis was possible in 86%. PD-L1 expression analysis was possible in 81% of cases. During the study period, the lifetime of the radial probe increased from 57 procedures to 77 procedures/probe. CONCLUSION: Because r-EBUS and VB planner is easy to perform under local anesthesia, inexpensive and efficient it can be used as a first-line procedure to assess peripheral lung cancer.

Virtual Bronchoscopy Planner and Radial-EBUS Guided Biopsy for Organizing Pneumonia Diagnosis.

BACKGROUND: The diagnosis of organizing pneumonia (OP) often requires histological confirmation. The aim of this retrospective study was to evaluate the diagnostic yield and complication rate of radial endobronchial ultrasound (r-EBUS) for OP. METHODS: All patients who had r-EBUS as a first diagnostic procedure for a peripheral pulmonary lesion at Rouen University Hospital, France, between April 2008 and December 2020 were included. Cases without a final diagnosis of OP or follow-up were excluded. Patients, lesions, and r-EBUS characteristics were retrospectively analyzed. RESULTS: 2735 r-EBUS procedures were performed, and 33 cases with final OP could be analyzed. Procedures were performed under local anesthesia in 28/33 cases (85%). Among the 33 final OP cases, 17 were considered cryptogenic, and 16 secondary. The lesions were patchy alveolar opacities in 23 cases (70%), masses or pulmonary nodules in 8 cases (24%), and diffuse infiltrative opacities in 2 cases (6%). A bronchus sign on CT scan was found in all cases. In 22 cases (67%), a histopathological diagnosis was obtained from the r-EBUS samples. In 4 cases (12%), histopathological diagnosis was made by surgery, and in 7 cases (21%) the diagnosis was made based on clinical, radiological, and evolution features. An ultrasound image was found in 100% (22/22) of cases in the r-EBUS positive (r-EBUS+) group vs. 60% (6/10) in the r-EBUS negative (r-EBUS-) group, respectively (p < 0.002). The diagnostic yield of r-EBUS for OP was 67% and increased to 79% (22/28) when an ultrasound image was obtained. The median time between CT scan and r-EBUS procedure was 14 days (3-94): 11.5 days in the r-EBUS+ group and 22 days in the r-EBUS- group (p < 0.0001). No severe complications were reported. CONCLUSION: r-EBUS, when performed shortly after a CT scan showing a bronchus sign, is an efficient and safe technique for OP diagnosis.

Impact of CYP2C19 genetic polymorphisms on voriconazole dosing and exposure in adult patients with invasive fungal infections.

Voriconazole (VCZ) use is limited by its narrow therapeutic range and significant interpatient variability in exposure. This study aimed to assess (i) the impact of CYP2C19 genotype on VCZ exposure and (ii) the doses required to achieve the therapeutic range in adult patients with invasive fungal infections (IFIs). Therapeutic drug monitoring (TDM) of VCZ, based on trough concentration measurement, and CYP2C19 genotyping were used to guide VCZ dosing in Caucasian patients with IFIs. The two common polymorphisms in Caucasians (CYP2C19*2 and *17), associated with decreased or increased CYP2C19 activity, respectively, were correlated with the daily VCZ dose, pharmacokinetic parameters and concentration-to-dose ratio. In total, 111 trough concentration measurements from 35 genotyped patients were analysed using linear mixed-effect models. The mean VCZ doses required to achieve target concentrations were significantly higher in CYP2C19*17 carriers compared with CYP2C19*1/*1 individuals (P<0.001): 2.57±0.25mg/kg twice daily in CYP2C19*1/*1 patients versus 3.94±0.39mg/kg and 6.75±0.54mg/kg in *1/*17 and *17/*17 patients, respectively. In addition, exposure to VCZ correlated with the CYP2C19*17 variant. Indices of exposure for CYP2C19*2 carriers were in line with the functional effect of this polymorphism compared with CYP2C19*1/*1 individuals, however comparisons of doses required to achieve target concentrations were not statistically different. The CYP2C19*17 allele predicted both VCZ exposure and dose required to achieve effective and non-toxic concentrations. CYP2C19 genotyping appears useful to guide VCZ initial dosing when coupled with TDM and to explain subtherapeutic concentrations frequently observed in clinical practice.