NGF increases Connexin-43 expression and function in pulmonary arterial smooth muscle cells to induce pulmonary artery hyperreactivity.

AIMS: Pulmonary hypertension (PH) is characterised by an increase in pulmonary arterial pressure, ultimately leading to right ventricular failure and death. We have previously shown that nerve growth factor (NGF) plays a critical role in PH. Our objectives here were to determine whether NGF controls Connexin-43 (Cx43) expression and function in the pulmonary arterial smooth muscle, and whether this mechanism contributes to NGF-induced pulmonary artery hyperreactivity. METHODS AND RESULTS: NGF activates its TrkA receptor to increase Cx43 expression, phosphorylation, and localization at the plasma membrane in human pulmonary arterial smooth muscle cells, thus leading to enhanced activity of Cx43-dependent GAP junctions as shown by Lucifer Yellow dye assay transfer and fluorescence recovery after photobleaching -FRAP- experiments. Using both in vitro pharmacological and in vivo SiRNA approaches, we demonstrate that NGF-dependent increase in Cx43 expression and activity in the rat pulmonary circulation causes pulmonary artery hyperreactivity. We also show that, in a rat model of PH induced by chronic hypoxia, in vivo blockade of NGF or of its TrkA receptor significantly reduces Cx43 increased pulmonary arterial expression induced by chronic hypoxia and displays preventive effects on pulmonary arterial pressure increase and right heart hypertrophy. CONCLUSIONS: Modulation of Cx43 by NGF in pulmonary arterial smooth muscle cells contributes to NGF-induced alterations of pulmonary artery reactivity. Since NGF and its TrkA receptor play a role in vivo in Cx43 increased expression in PH induced by chronic hypoxia, these NGF/Cx43-dependent mechanisms may therefore play a significant role in human PH pathophysiology.

Lower airway microbiota compositions differ between influenza, COVID-19 and bacteria-related acute respiratory distress syndromes.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is responsible for 400,000 deaths annually worldwide. Few improvements have been made despite five decades of research, partially because ARDS is a highly heterogeneous syndrome including various types of aetiologies. Lower airway microbiota is involved in chronic inflammatory diseases and recent data suggest that it could also play a role in ARDS. Nevertheless, whether the lower airway microbiota composition varies between the aetiologies of ARDS remain unknown. The aim of this study is to compare lower airway microbiota composition between ARDS aetiologies, i.e. pulmonary ARDS due to influenza, SARS-CoV-2 or bacterial infection. METHODS: Consecutive ARDS patients according to Berlin's classification requiring invasive ventilation with PCR-confirmed influenza or SARS-CoV-2 infections and bacterial infections (> 105 CFU/mL on endotracheal aspirate) were included. Endotracheal aspirate was collected at admission, V3-V4 and ITS2 regions amplified by PCR, deep-sequencing performed on MiSeq sequencer (Illumina®) and data analysed using DADA2 pipeline. RESULTS: Fifty-three patients were included, 24 COVID-19, 18 influenza, and 11 bacterial CAP-related ARDS. The lower airway bacteriobiota and mycobiota compositions (ß-diversity) were dissimilar between the three groups (p = 0.05 and p = 0.01, respectively). The bacterial α-diversity was significantly lower in the bacterial CAP-related ARDS group compared to the COVID-19 ARDS group (p = 0.04). In contrast, influenza-related ARDS patients had higher lung mycobiota α-diversity than the COVID-19-related ARDS (p = 0 < 01). CONCLUSION: Composition of lower airway microbiota (both microbiota and mycobiota) differs between influenza, COVID-19 and bacterial CAP-related ARDS. Future studies investigating the role of lung microbiota in ARDS pathophysiology should take aetiology into account.

COBRAPed cohort: Do sensitization patterns differentiate children with severe asthma from those with a milder disease?

BACKGROUND: It is unclear whether sensitization patterns differentiate children with severe recurrent wheeze (SRW)/severe asthma (SA) from those with non-severe recurrent wheeze (NSRW)/non-severe asthma (NSA). Our objective was to determine whether sensitization patterns can discriminate between children from the French COBRAPed cohort with NSRW/NSA and those with SRW/SA. METHODS: IgE to 112 components (c-sIgE) (ImmunoCAP® ISAC) were analyzed in 125 preschools (3-6 years) and 170 school-age children (7-12 years). Supervised analyses and clustering methods were applied to identify patterns of sensitization among children with positive c-sIgE. RESULTS: We observed c-sIgE sensitization in 51% of preschool and 75% of school-age children. Sensitization to house dust mite (HDM) components was more frequent among NSRW than SRW (53% vs. 24%, p < .01). Sensitization to non-specific lipid transfer protein (nsLTP) components was more frequent among SA than NSA (16% vs. 4%, p < .01) and associated with an FEV1/FVC < -1.64 z-score. Among sensitized children, seven clusters with varying patterns were identified. The two broader clusters identified in each age group were characterized by "few sensitizations, mainly to HDM." One cluster (n = 4) with "multiple sensitizations, mainly to grass pollen, HDM, PR-10, and nsLTP" was associated with SA in school-age children. CONCLUSIONS: Although children with wheeze/asthma display frequent occurrences and high levels of sensitization, sensitization patterns did not provide strong signals to discriminate children with severe disease from those with milder disease. These results suggest that the severity of wheeze/asthma may depend on both IgE- and non-IgE-mediated mechanisms.

Non-Contrast-Enhanced Functional Lung MRI to Evaluate Treatment Response of Allergic Bronchopulmonary Aspergillosis in Patients With Cystic Fibrosis: A Pilot Study.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) in cystic fibrosis (CF) patients is associated with severe lung damage and requires specific therapeutic management. Repeated imaging is recommended to both diagnose and follow-up response to treatment of ABPA in CF. However, high risk of cumulative radiation exposure requires evaluation of free-radiation techniques in the follow-up of CF patients with ABPA. PURPOSE: To evaluate whether Fourier decomposition (FD) functional lung MRI can detect response to treatment of ABPA in CF patients. STUDY TYPE: Retrospective longitudinal. POPULATION: Twelve patients (7M, median-age:14 years) with CF and ABPA with pre- and post-treatment MRI. FIELD STRENGTH/SEQUENCE: 2D-balanced-steady-state free-precession (bSSFP) sequence with FD at 1.5T. ASSESSMENT: Ventilation-weighted (V) and perfusion-weighted (Q) maps were obtained after FD processing of 2D-coronal bSSFP time-resolved images acquired before and 3-9 months after treatment. Defects extent was assessed on the functional maps using a qualitative semi-quantitative score (0 = absence/negligible, 1 = <50%, 2 = >50%). Mean and coefficient of variation (CV) of the ventilation signal-intensity (VSI) and the perfusion signal-intensity (QSI) were calculated. Measurements were performed independently by three readers and averaged. Inter-reader reproducibility of the measurements was assessed. Pulmonary function tests (PFTs) were performed within 1 week of both MRI studies as markers of the airflow-limitation severity. STATISTICAL TESTS: Comparisons of medians were performed using the paired Wilcoxon-test. Reproducibility was assessed using intraclass correlation coefficient (ICC). Correlations between MRI and PFT parameters were assessed using the Spearman-test (rho correlation-coefficient). A P-value <0.05 was considered as significant. RESULTS: Defects extent on both V and Q maps showed a significant reduction after ABPA treatment (4.25 vs. 1.92 for V-defect-score and 5 vs. 2.75 for Q-defect-score). VSI_mean was significantly increased after treatment (280 vs. 167). Qualitative analyses reproducibility showed an ICC > 0.90, while the ICCs of the quantitative measurements was almost perfect (>0.99). Changes in VSI_cv and QSI_cv before and after treatment correlated inversely with changes of FEV1%p (rho = -0.68 for both). DATA CONCLUSION: Non-contrast-enhanced FD lung MRI has potential to reproducibly assess response to treatment of ABPA in CF patients and correlates with PFT obstructive parameters. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 3.

The gut-lung axis in the CFTR modulator era.

The advent of CFTR modulators represents a turning point in the history of cystic fibrosis (CF) management, changing profoundly the disease's clinical course by improving mucosal hydration. Assessing changes in airway and digestive tract microbiomes is of great interest to better understand the mechanisms and to predict disease evolution. Bacterial and fungal dysbiosis have been well documented in patients with CF; yet the impact of CFTR modulators on microbial communities has only been partially deciphered to date. In this review, we aim to summarize the current state of knowledge regarding the impact of CFTR modulators on both pulmonary and digestive microbiomes. Our analysis also covers the inter-organ connections between lung and gut communities, in order to highlight the gut-lung axis involvement in CF pathophysiology and its evolution in the era of novel modulators therapies.

Longitudinal Evaluation of Bronchial Changes in Cystic Fibrosis Patients Undergoing Elexacaftor/Tezacaftor/Ivacaftor Therapy Using Lung MRI With Ultrashort Echo-Times.

BACKGROUND: Lung magnetic resonance imaging (MRI) with ultrashort echo-times (UTE-MRI) allows high-resolution and radiation-free imaging of the lung structure in cystic fibrosis (CF). In addition, the combination of elexacaftor/tezacaftor/ivacaftor (ETI) has improved CF clinical outcomes such as need for hospitalization. However, the effect on structural disease still needs longitudinal evaluation at high resolution. PURPOSE: To analyze the effects of ETI on lung structural alterations using UTE-MRI, with a focus on bronchiectasis reversibility. STUDY TYPE: Retrospective. POPULATION: Fifty CF patients (mean age 24.3 ± 9.2; 23 males). FIELD STRENGTH/SEQUENCE: 1.5 T, UTE-MRI. ASSESSMENT: All subjects completed both UTE-MRI and pulmonary function tests (PFTs) during two annual visits (M0 and M12), and 30 of them completed a CT scan. They initiated ETI treatment after M0 within a maximum of 3 months from the annual examinations. Three observers scored a clinical MRI Bhalla score on UTE-MRI. Bronchiectasis reversibility was defined as a reduction in both outer and inner bronchial dimensions. Correlations were searched between the Bhalla score and PFT such as the forced expiratory volume in 1 second percentage predicted (FEV1%p). STATISTICAL TESTS: Comparison was assessed using the paired t-test, correlation using the Spearman correlation test with a significance level of 0.05. Concordance and reproducibility were assessed using intraclass correlation coefficient (ICC). RESULTS: There was a significant improvement in MRI Bhalla score after ETI treatment. UTE-MRI demonstrated bronchiectasis reversibility in a subgroup of 18 out of 50 CF patients (36%). These patients with bronchiectasis reversibility were significantly younger, with lower severity of wall thickening but no difference in mucus plugging extent (P = 0.39) was found. The reproducibility of UTE-MRI evaluations was excellent (ICC ≥ 0.95), was concordant with CT scan (N = 30; ICC ≥ 0.90) and significantly correlated to FEV1% at PFT at M0 (N = 50; r = 0.71) and M12 (N = 50; r = 0.72). DATA CONCLUSION: UTE-MRI is a reproducible tool for the longitudinal follow-up of CF patients, allowing to quantify the response to ETI and demonstrating the reversibility of some structural alterations such as bronchiectasis in a substantial fraction of this study population. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY: Stage 2.

The gut microbiota composition is linked to subsequent occurrence of ventilator-associated pneumonia in critically ill patients.

Ventilator-associated pneumonia (VAP) is the most frequent nosocomial infection in critically ill-ventilated patients. Oropharyngeal and lung microbiota have been demonstrated to be associated with VAP occurrence, but the involvement of gut microbiota has not been investigated so far. Therefore, the aim of this study is to compare the composition of the gut microbiota between patients who subsequently develop VAP and those who do not. A rectal swab was performed at admission of every consecutive patient into the intensive care unit (ICU) from October 2019 to March 2020. After DNA extraction, V3-V4 and internal transcribed spacer 2 regions deep-sequencing was performed on MiSeq sequencer (Illumina) and data were analyzed using Divisive Amplicon Denoising Algorithm 2 (DADA2) pipeline. Among 255 patients screened, 42 (16%) patients with invasive mechanical ventilation for more than 48 h were included, 18 (43%) with definite VAP and 24 without (57%). Patients who later developed VAP had similar gut bacteriobiota and mycobiota α-diversities compared to those who did not develop VAP. However, gut mycobiota was dissimilar (ß-diversity) between these two groups. The presence of Megasphaera massiliensis was associated with the absence of VAP occurrence, whereas the presence of the fungal genus Alternaria sp. was associated with the occurrence of VAP. The composition of the gut microbiota, but not α-diversity, differs between critically ill patients who subsequently develop VAP and those who do not. This study encourages large multicenter cohort studies investigating the role of gut-lung axis and oropharyngeal colonization in the development of VAP in ICU patients. Trial registration number: NCT04131569, date of registration: 18 October 2019. IMPORTANCE The composition of the gut microbiota, but not α-diversity, differs between critically ill patients who subsequently develop ventilator-associated pneumonia (VAP) and those who do not. Investigating gut microbiota composition could help to tailor probiotics to provide protection against VAP.

Short-range interactions between fibrocytes and CD8+ T cells in COPD bronchial inflammatory response.

Bronchi of chronic obstructive pulmonary disease (COPD) are the site of extensive cell infiltration, allowing persistent contact between resident cells and immune cells. Tissue fibrocytes interaction with CD8+ T cells and its consequences were investigated using a combination of in situ, in vitro experiments and mathematical modeling. We show that fibrocytes and CD8+ T cells are found in the vicinity of distal airways and that potential interactions are more frequent in tissues from COPD patients compared to those of control subjects. Increased proximity and clusterization between CD8+ T cells and fibrocytes are associated with altered lung function. Tissular CD8+ T cells from COPD patients promote fibrocyte chemotaxis via the CXCL8-CXCR1/2 axis. Live imaging shows that CD8+ T cells establish short-term interactions with fibrocytes, that trigger CD8+ T cell proliferation in a CD54- and CD86-dependent manner, pro-inflammatory cytokines production, CD8+ T cell cytotoxic activity against bronchial epithelial cells and fibrocyte immunomodulatory properties. We defined a computational model describing these intercellular interactions and calibrated the parameters based on our experimental measurements. We show the model's ability to reproduce histological ex vivo characteristics, and observe an important contribution of fibrocyte-mediated CD8+ T cell proliferation in COPD development. Using the model to test therapeutic scenarios, we predict a recovery time of several years, and the failure of targeting chemotaxis or interacting processes. Altogether, our study reveals that local interactions between fibrocytes and CD8+ T cells could jeopardize the balance between protective immunity and chronic inflammation in the bronchi of COPD patients.

Generating High-Resolution Synthetic CT from Lung MRI with Ultrashort Echo Times: Initial Evaluation in Cystic Fibrosis.

Background Lung MRI with ultrashort echo times (UTEs) enables high-resolution and radiation-free morphologic imaging; however, its image quality is still lower than that of CT. Purpose To assess the image quality and clinical applicability of synthetic CT images generated from UTE MRI by a generative adversarial network (GAN). Materials and Methods This retrospective study included patients with cystic fibrosis (CF) who underwent both UTE MRI and CT on the same day at one of six institutions between January 2018 and December 2022. The two-dimensional GAN algorithm was trained using paired MRI and CT sections and tested, along with an external data set. Image quality was assessed quantitatively by measuring apparent contrast-to-noise ratio, apparent signal-to-noise ratio, and overall noise and qualitatively by using visual scores for features including artifacts. Two readers evaluated CF-related structural abnormalities and used them to determine clinical Bhalla scores. Results The training, test, and external data sets comprised 82 patients with CF (mean age, 21 years ± 11 [SD]; 42 male), 28 patients (mean age, 18 years ± 11; 16 male), and 46 patients (mean age, 20 years ± 11; 24 male), respectively. In the test data set, the contrast-to-noise ratio of synthetic CT images (median, 303 [IQR, 221-382]) was higher than that of UTE MRI scans (median, 9.3 [IQR, 6.6-35]; P < .001). The median signal-to-noise ratio was similar between synthetic and real CT (88 [IQR, 84-92] vs 88 [IQR, 86-91]; P = .96). Synthetic CT had a lower noise level than real CT (median score, 26 [IQR, 22-30] vs 42 [IQR, 32-50]; P < .001) and the lowest level of artifacts (median score, 0 [IQR, 0-0]; P < .001). The concordance between Bhalla scores for synthetic and real CT images was almost perfect (intraclass correlation coefficient, ≥0.92). Conclusion Synthetic CT images showed almost perfect concordance with real CT images for the depiction of CF-related pulmonary alterations and had better image quality than UTE MRI. Clinical trial registration no. NCT03357562 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Schiebler and Glide-Hurst in this issue.

Development and external validation of a prediction model for the transition from mild to moderate or severe form of COVID-19.

OBJECTIVES: COVID-19 pandemic seems to be under control. However, despite the vaccines, 5 to 10% of the patients with mild disease develop moderate to critical forms with potential lethal evolution. In addition to assess lung infection spread, chest CT helps to detect complications. Developing a prediction model to identify at-risk patients of worsening from mild COVID-19 combining simple clinical and biological parameters with qualitative or quantitative data using CT would be relevant to organizing optimal patient management. METHODS: Four French hospitals were used for model training and internal validation. External validation was conducted in two independent hospitals. We used easy-to-obtain clinical (age, gender, smoking, symptoms' onset, cardiovascular comorbidities, diabetes, chronic respiratory diseases, immunosuppression) and biological parameters (lymphocytes, CRP) with qualitative or quantitative data (including radiomics) from the initial CT in mild COVID-19 patients. RESULTS: Qualitative CT scan with clinical and biological parameters can predict which patients with an initial mild presentation would develop a moderate to critical form of COVID-19, with a c-index of 0.70 (95% CI 0.63; 0.77). CT scan quantification improved the performance of the prediction up to 0.73 (95% CI 0.67; 0.79) and radiomics up to 0.77 (95% CI 0.71; 0.83). Results were similar in both validation cohorts, considering CT scans with or without injection. CONCLUSION: Adding CT scan quantification or radiomics to simple clinical and biological parameters can better predict which patients with an initial mild COVID-19 would worsen than qualitative analyses alone. This tool could help to the fair use of healthcare resources and to screen patients for potential new drugs to prevent a pejorative evolution of COVID-19. CLINICAL TRIAL REGISTRATION: NCT04481620. CLINICAL RELEVANCE STATEMENT: CT scan quantification or radiomics analysis is superior to qualitative analysis, when used with simple clinical and biological parameters, to determine which patients with an initial mild presentation of COVID-19 would worsen to a moderate to critical form. KEY POINTS: • Qualitative CT scan analyses with simple clinical and biological parameters can predict which patients with an initial mild COVID-19 and respiratory symptoms would worsen with a c-index of 0.70. • Adding CT scan quantification improves the performance of the clinical prediction model to an AUC of 0.73. • Radiomics analyses slightly improve the performance of the model to a c-index of 0.77.

OP2113, a new drug for chronic hypoxia-induced pulmonary hypertension treatment in rat.

BACKGROUND AND PURPOSE: Pulmonary hypertension (PH) is a cardiovascular disease characterised by an increase in pulmonary arterial (PA) resistance leading to right ventricular (RV) failure. Reactive oxygen species (ROS) play a major role in PH. OP2113 is a drug with beneficial effects on cardiac injuries that targets mitochondrial ROS. The aim of the study was to address the in vivo therapeutic effect of OP2113 in PH. EXPERIMENTAL APPROACH: PH was induced by 3 weeks of chronic hypoxia (CH-PH) in rats treated with OP2113 or its vehicle via subcutaneous osmotic mini-pumps. Haemodynamic parameters and both PA and heart remodelling were assessed. Reactivity was quantified in PA rings and in RV or left ventricular (LV) cardiomyocytes. Oxidative stress was detected by electron paramagnetic resonance and western blotting. Mitochondrial mass and respiration were measured by western blotting and oxygraphy, respectively. KEY RESULTS: In CH-PH rats, OP2113 reduced the mean PA pressure, PA remodelling, PA hyperreactivity in response to 5-HT, the contraction slowdown in RV and LV and increased the mitochondrial mass in RV. Interestingly, OP2113 had no effect on haemodynamic parameters, both PA and RV wall thickness and PA reactivity, in control rats. Whereas oxidative stress was evidenced by an increase in protein carbonylation in CH-PH, this was not affected by OP2113. CONCLUSION AND IMPLICATIONS: Our study provides evidence for a selective protective effect of OP2113 in vivo on alterations in both PA and RV from CH-PH rats without side effects in control rats.

Bridging gut microbiota composition with extended-spectrum beta-lactamase Enterobacteriales faecal carriage in critically ill patients (microbe cohort study).

BACKGROUND: The worldwide dissemination of extended spectrum beta-lactamase producing Enterobacteriales (ESBL-E) is of major concern. Microbiota may play a role in the host resistance to colonization with ESBL-E, but the underlying mechanisms remain unknown. We aimed to compare the gut microbiota composition between ESBL-producing E. coli or K. pneumoniae carriers and ESBL-E non-carriers according to the bacterial species. RESULTS: Among 255 patients included, 11 (4,3%) were colonized with ESBL-producing E. coli and 6 (2,4%) with ESBL-producing K. pneumoniae, which were compared with age- and sex-matched ESBL-E non carriers. While no significant differences were found between ESBL-producing E. coli carriers and non-carriers, gut bacteriobiota α-diversity was decreased in ESBL-K. pneumoniae faecal carriers compared both with non-carriers (p = 0.05), and with ESBL-producing E. coli carriers. The presence of Sellimonas intestinalis was associated with the absence of ESBL-producing E. coli fecal carriage. Campylobacter ureolyticus, Campylobacter hominis, bacteria belonging to Clostridium cluster XI and Saccharomyces sp. were associated with the absence of ESBL-producing K. pneumoniae faecal carriage. CONCLUSIONS: The composition of the gut microbiota differs between ESBL-producing E. coli and K. pneumoniae faecal carriers suggesting that microbial species should be taken into account when investigating the role of gut microbiota in resistance to gut colonization with ESBL-E. TRIAL REGISTRATION NUMBER: NCT04131569, date of registration: October 18, 2019.

Main Pathogenic Mechanisms and Recent Advances in COPD Peripheral Skeletal Muscle Wasting.

Chronic obstructive pulmonary disease (COPD) is a worldwide prevalent respiratory disease mainly caused by tobacco smoke exposure. COPD is now considered as a systemic disease with several comorbidities. Among them, skeletal muscle dysfunction affects around 20% of COPD patients and is associated with higher morbidity and mortality. Although the histological alterations are well characterized, including myofiber atrophy, a decreased proportion of slow-twitch myofibers, and a decreased capillarization and oxidative phosphorylation capacity, the molecular basis for muscle atrophy is complex and remains partly unknown. Major difficulties lie in patient heterogeneity, accessing patients' samples, and complex multifactorial process including extrinsic mechanisms, such as tobacco smoke or disuse, and intrinsic mechanisms, such as oxidative stress, hypoxia, or systemic inflammation. Muscle wasting is also a highly dynamic process whose investigation is hampered by the differential protein regulation according to the stage of atrophy. In this review, we report and discuss recent data regarding the molecular alterations in COPD leading to impaired muscle mass, including inflammation, hypoxia and hypercapnia, mitochondrial dysfunction, diverse metabolic changes such as oxidative and nitrosative stress and genetic and epigenetic modifications, all leading to an impaired anabolic/catabolic balance in the myocyte. We recapitulate data concerning skeletal muscle dysfunction obtained in the different rodent models of COPD. Finally, we propose several pathways that should be investigated in COPD skeletal muscle dysfunction in the future.

Adherence, reliability, and variability of home spirometry telemonitoring in cystic fibrosis.

Introduction: Forced spirometry is the gold standard to assess lung function, but its accessibility may be limited. By contrast, home spirometry telemonitoring allows a multi-weekly lung function follow-up but its real-life adherence, reliability, and variability according to age have been poorly studied in patients with CF (PwCF). We aimed to compare real-life adherence, reliability and variability of home spirometry between children, teenagers and adults with CF. Methods: This real-life observational study included PwCF followed for six months in whom lung function (i.e, forced expiratory volume maximum in 1 s (FEV1), forced vital capacity (FVC), forced mid-expiratory flow (FEF) and FEV1/FVC ratio) was monitored by both conventional and home spirometry between July 2015 and December 2021. The adherence, reliability and variability of home spirometry was assessed in all PwCF and compared between children (<12years old), teenagers (12-18 years old) and adults. Results: 174 PwCF were included (74 children, 43 teenagers and 57 adults). Home spirometry was used at least one time per week by 64.1 ± 4.9% PwCF, more frequently in children and teenagers than in adults (79.4 ± 2.9%, 69.2 ± 5.5% and 40.4 ± 11.5% respectively). The reliability to conventional lung function testing was good for all assessed parameters (e.g., FEV1: r = 0.91, p < 0.01) and the variability over the 6 months of observation was low (FEV1 coefficient of variation = 11.5%). For each parameter, reliability was better, and the variability was lower in adults than in teenagers than in children. Conclusion: Home spirometry telemonitoring appears to be a reliable tool for multi-weekly lung function follow-up of PwCF.

Lung Mycobiota α-Diversity Is Linked to Severity in Critically Ill Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) affects more than 200 million people worldwide. The chronic course of COPD is frequently worsened by acute exacerbations (AECOPD). Mortality in patients hospitalized for severe AECOPD remains dramatically high, and the underlying mechanisms are poorly understood. Lung microbiota is associated with COPD outcomes in nonsevere AECOPD, but no study specifically investigated severe AECOPD patients. The aim of this study is thus to compare lung microbiota composition between severe AECOPD survivors and nonsurvivors. Induced sputum or endotracheal aspirate was collected at admission from every consecutive severe AECOPD patient. After DNA extraction, the V3-V4 and ITS2 regions were amplified by PCR. Deep-sequencing was performed on a MiSeq sequencer (Illumina); the data were analyzed using DADA2 pipeline. Among 47 patients admitted for severe AECOPD, 25 (53%) with samples of sufficient quality were included: 21 of 25 (84%) survivors and 4 of 25 (16%) nonsurvivors. AECOPD nonsurvivors had lower α-diversities indices than survivors for lung mycobiota but not for lung bacteriobiota. Similar results were demonstrated comparing patients receiving invasive mechanical ventilation (n = 13 [52%]) with those receiving only noninvasive ventilation (n = 12 [48%]). Previous systemic antimicrobial therapy and long-term inhaled corticosteroid therapy could alter the lung microbiota composition in severe AECOPD patients. In acidemic AECOPD, lower lung mycobiota α-diversity is linked to the severity of the exacerbation, assessed by mortality and the requirement for invasive mechanical ventilation, whereas lung bacteriobiota α-diversity is not. This study encourages a multicenter cohort study investigating the role of lung microbiota, especially fungal kingdom, in severe AECOPD. IMPORTANCE In AECOPD with acidemia, more severe patients-i.e., nonsurvivors and patients requiring invasive mechanical ventilation-have lower lung mycobiota α-diversity than survivors and patients receiving only noninvasive ventilation, respectively. This study encourages a large multicenter cohort study investigating the role of lung microbiota in severe AECOPD and urges investigation of the role of the fungal kingdom in severe AECOPD.

Cellular interplay in skeletal muscle regeneration and wasting: insights from animal models.

Skeletal muscle wasting, whether related to physiological ageing, muscle disuse or to an underlying chronic disease, is a key determinant to quality of life and mortality. However, cellular basis responsible for increased catabolism in myocytes often remains unclear. Although myocytes represent the vast majority of skeletal muscle cellular population, they are surrounded by numerous cells with various functions. Animal models, mostly rodents, can help to decipher the mechanisms behind this highly dynamic process, by allowing access to every muscle as well as time-course studies. Satellite cells (SCs) play a crucial role in muscle regeneration, within a niche also composed of fibroblasts and vascular and immune cells. Their proliferation and differentiation is altered in several models of muscle wasting such as cancer, chronic kidney disease or chronic obstructive pulmonary disease (COPD). Fibro-adipogenic progenitor cells are also responsible for functional muscle growth and repair and are associated in disease to muscle fibrosis such as in chronic kidney disease. Other cells have recently proven to have direct myogenic potential, such as pericytes. Outside their role in angiogenesis, endothelial cells and pericytes also participate to healthy muscle homoeostasis by promoting SC pool maintenance (so-called myogenesis-angiogenesis coupling). Their role in chronic diseases muscle wasting has been less studied. Immune cells are pivotal for muscle repair after injury: Macrophages undergo a transition from the M1 to the M2 state along with the transition between the inflammatory and resolutive phase of muscle repair. T regulatory lymphocytes promote and regulate this transition and are also able to activate SC proliferation and differentiation. Neural cells such as terminal Schwann cells, motor neurons and kranocytes are notably implicated in age-related sarcopenia. Last, newly identified cells in skeletal muscle, such as telocytes or interstitial tenocytes could play a role in tissular homoeostasis. We also put a special focus on cellular alterations occurring in COPD, a chronic and highly prevalent respiratory disease mainly linked to tobacco smoke exposure, where muscle wasting is strongly associated with increased mortality, and discuss the pros and cons of animal models versus human studies in this context. Finally, we discuss resident cells metabolism and present future promising leads for research, including the use of muscle organoids.

Bronchial Remodeling-based Latent Class Analysis Predicts Exacerbations in Severe Preschool Wheezers.

Rationale: Children with preschool wheezing represent a very heterogeneous population with wide variability regarding their clinical, inflammatory, obstructive, and/or remodeling patterns. We hypothesized that assessing bronchial remodeling would help clinicians to better characterize severe preschool wheezers. Objectives: The main objective was to identify bronchial remodeling-based latent classes of severe preschool wheezers. Secondary objectives were to compare cross-sectional and longitudinal clinical and biological data between classes and to assess the safety of bronchoscopy. Methods: This double-center prospective study (NCT02806466) included severe preschool wheezers (1-5 yr old) requiring fiberoptic bronchoscopy. Bronchial remodeling parameters (i.e., epithelial integrity, reticular basement membrane [RBM] thickness, mucus gland, fibrosis and bronchial smooth muscle [BSM] areas, the density of blood vessels, and RBM-BSM distance) were assessed and evaluated by latent class analysis. An independent cohort of severe preschool wheezers (NCT04558671) was used to validate our results. Measurements and Main Results: Fiberoptic bronchoscopy procedures were well tolerated. A two-class model was identified: Class BR1 was characterized by increased RBM thickness, normalized BSM area, the density of blood vessels, decreased mucus gland area, fibrosis, and RBM-BSM distance compared with Class BR2. No significant differences were found between classes in the year before fiberoptic bronchoscopy. By contrast, Class BR1 was associated with a shorter time to first exacerbation and an increased risk of both frequent (3 or more) and severe exacerbations during the year after bronchoscopy in the two cohorts. Conclusions: Assessing bronchial remodeling identified severe preschool wheezers at risk of frequent and severe subsequent exacerbations with a favorable benefit to risk ratio.

Long-term efficacy of dupilumab in asthma with or without chronic rhinosinusitis and nasal polyps.

BACKGROUND: Coexisting chronic rhinosinusitis and nasal polyps (CRS-NPs) substantially increases the disease burden of asthma. Dupilumab, a fully human monoclonal antibody, has established efficacy and an acceptable safety profile in asthma and CRS with NP. OBJECTIVE: To evaluate long-term dupilumab efficacy in TRAVERSE (NCT02134028) patients with uncontrolled, moderate-to-severe (QUEST) or oral corticosteroid (OCS)-dependent (VENTURE) asthma with or without coexisting CRS-NP. METHODS: In TRAVERSE, 317 of 1530 (21%) QUEST and 61 of 187 (48%) VENTURE patients had self-reported CRS-NP; they received subcutaneous 300 mg dupilumab every 2 weeks up to 96 weeks. Patients were categorized by parent study treatment group (placebo/dupilumab, dupilumab/dupilumab). End points included annualized asthma exacerbation rates and mean change from parent study baseline in prebronchodilator forced expiratory volume in 1 second, Asthma Control Questionnaire 5 score, Asthma Quality of Life Questionnaire score, and OCS dose. RESULTS: Patients with coexisting CRS-NP had higher OCS dose and a history of more exacerbations. Concluding TRAVERSE, exacerbation rates decreased from 2.39 to 0.32 and 2.32 to 0.35 in dupilumab/dupilumab and 2.36 to 0.41 and 2.36 to 0.45 in placebo/dupilumab by week 96 from QUEST and VENTURE baselines, respectively. Non-CRS-NP results were similar. Improvements in forced expiratory volume in 1 second, Asthma Control Questionnaire 5 score, and Asthma Quality of Life Questionnaire score during parent studies were maintained in TRAVERSE; placebo/dupilumab patients achieved similar improvements to dupilumab/dupilumab by week 48. By week 96, 71% and 39% of OCS-dependent patients with CRS-NP and 83% and 47% without CRS-NP treated with dupilumab/dupilumab and placebo/dupilumab, respectively, stopped OCS. CONCLUSION: Long-term dupilumab efficacy was maintained in patients with asthma with or without self-reported coexisting CRS-NP, including OCS-sparing effects observed in OCS-dependent severe asthma. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT02528214, NCT02414854, and NCT02134028.

Proteomic profiling of serum identifies a molecular signature that correlates with clinical outcomes in COPD.

OBJECTIVE: Novel biomarkers related to main clinical hallmarks of Chronic obstructive pulmonary disease (COPD), a heterogeneous disorder with pulmonary and extra-pulmonary manifestations, were investigated by profiling the serum levels of 1305 proteins using Slow Off-rate Modified Aptamers (SOMA)scan technology. METHODS: Serum samples were collected from 241 COPD subjects in the multicenter French Cohort of Bronchial obstruction and Asthma to measure the expression of 1305 proteins using SOMAscan proteomic platform. Clustering of the proteomics was applied to identify disease subtypes and their functional annotation and association with key clinical parameters were examined. Cluster findings were revalidated during a follow-up visit, and compared to those obtained in a group of 47 COPD patients included in the Melbourne Longitudinal COPD Cohort. RESULTS: Unsupervised clustering identified two clusters within COPD subjects at inclusion. Cluster 1 showed elevated levels of factors contributing to tissue injury, whereas Cluster 2 had higher expression of proteins associated with enhanced immunity and host defense, cell fate, remodeling and repair and altered metabolism/mitochondrial functions. Patients in Cluster 2 had a lower incidence of exacerbations, unscheduled medical visits and prevalence of emphysema and diabetes. These protein expression patterns were conserved during a follow-up second visit, and substanciated, by a large part, in a limited series of COPD patients. Further analyses identified a signature of 15 proteins that accurately differentiated the two COPD clusters at the 2 visits. CONCLUSIONS: This study provides insights into COPD heterogeneity and suggests that overexpression of factors involved in lung immunity/host defense, cell fate/repair/ remodelling and mitochondrial/metabolic activities contribute to better clinical outcomes. Hence, high throughput proteomic assay offers a powerful tool for identifying COPD endotypes and facilitating targeted therapies.