High risk of lung cancer in surfactant-related gene variant carriers.

RATIONALE: Several rare surfactant-related genes variants associated with interstitial lung disease are suspected to be associated with lung cancer, but data are missing. OBJECTIVES: We aimed to study the epidemiology and phenotype of lung cancer in an international cohort of surfactant-related gene (SRG) variant carriers. METHODS: We conducted a cross-sectional study of all adults with SRG variants in the OrphaLung network and compared lung cancer risk with telomerase-related gene (TRG) variant carriers. RESULTS: We identified 99 SRG adult variant carriers (SFTPA1 [n=18], SFTPA2 [n=31], SFTPC [n=24], ABCA3 [n=14] and NKX2-1 [n=12]), including 20 (20.2%) with lung cancer (SFTPA1 [n=7]; SFTPA2 [n=8], SFTPC [n=3], NKX2-1 [n=2] and ABCA3 [n=0]). Among SRG variant carriers, the odds of lung cancer was associated with age (odds ratio [OR] 1.04 [95% CI 1.01-1.08]), smoking (OR 20.7 [6.60-76.2]) and SFTPA1/SFTPA2 variants (OR 3.97 [1.39-13.2]). Adenocarcinoma was the only histological type reported, with PDL1 expression≥1% of tumor cells in 3 cases. Cancer staging was localized (I/II) in 8 (40%) individuals, locally advanced (III) in 2 (10%) and metastatic (IV) in 10 (50%). We found no somatic variant eligible for targeted therapy. Seven cancers were surgically removed, 10 received systemic therapy, and 3 received the best supportive care according to their stage and performance status. The median overall survival was 24 months, with stage I/II cancers showing better survival. We identified 233 TRG variant carriers. The comparative risk (subdistribution hazard ratio) for lung cancer in SRG patients versus TRG patients was 18.1 [7.1-44.7]. CONCLUSION: The high risk of lung cancer among SRG variant carriers suggests specific screening and diagnostic and therapeutic challenges. The benefit of regular CT scan follow-up should be evaluated.

Antifibrotic effects of vitamin D3 on human lung fibroblasts derived from patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease. Up to now, no treatment can stop the progression of IPF. Vitamin D3 (VD) reduces experimental lung fibrosis in murine models and depletion of vitamin D3 might be associated with the reduced survival of patients with IPF. In this context, we determined if VD can prevent the pro-fibrotic functions of human lung fibroblasts (HLFs) isolated from patients with IPF. IPF and control HLFs were derived from surgical lung biopsies collected from patients with IPF or with primary lung cancer, respectively. VD (3-100 nM) markedly reduced the basal and PDGF-induced proliferation of HLFs. VD also altered cell cycle by increasing the percentage of IPF HLFs arrested in the G0/G1 phase, and by downregulating the expression of various cell cycle regulatory proteins. In addition, VD barely prevented the TGF-ß1-induced differentiation in HLFs. At 100 nM, VD slightly reduced the expression of the pro-fibrotic marker α-smooth muscle actin, and had no effect on fibronectin and collagen-1 expression. In contrast, 100 nM VD strongly inhibited the aerobic glycolytic metabolism induced by TGF- ß1. Finally, VD reduced both the secretion of lactate, the levels of lactate deshydrogenase mRNA and the activity of intracellular LDH in IPF HLFs. In conclusion, our study shows that VD reduced pro-fibrotic functions of HLFs. These findings suggest that it might be interesting to assess the potential clinical benefits of vitamin D supplementation in patients with IPF, especially on lung function decline.

Anti-fibrotic effects of nintedanib on lung fibroblasts derived from patients with Progressive Fibrosing Interstitial Lung Diseases (PF-ILDs).

The tyrosine kinase inhibitor nintedanib has been recently approved for the treatment of Interstitial Lung Diseases (ILDs) that manifest a progressive fibrosis phenotype other than Idiopathic pulmonary Fibrosis (IPF). Nintedanib reduces the development of lung fibrosis in various animal models resembling features of PF-ILD and in vitro, it inhibits the fibrosing phenotype of human lung fibroblasts (HLFs) isolated from patients with IPF. To get insight on the cellular and molecular mechanisms that drive the clinical efficiency of nintedanib in patients with non-IPF PF-ILD, we investigated its effects on the fibrosing functions of HLFs derived from patients with PF-hypersensitivity pneumonitis (PF-HP, n = 7), PF-sarcoidosis (n = 5) and pleuroparenchymal fibroelastosis (PPFE, n = 4). HLFs were treated with nintedanib (10 nM-1 µM) and then stimulated with PDGF-BB (25-50 ng/ml) or TGF-ß1 (1 ng/ml) for 24-72 h to assess proliferation and migration or differentiation. At nanomolar concentrations, nintedanib reduced the levels of PDGF receptor and ERK1/2 phosphorylation, the proliferation and the migration of PF-HP, PF-sarcoidosis and PPFE HLFs stimulated with PDGF-BB. Moreover, nintedanib also attenuates the myofibroblastic differentiation driven by TGF-ß1 but only when it is used at 1 µM. The drug reduced the phosphorylation of SMAD2/3 and decreased the induction of collagen, fibronectin and α-smooth muscle actin expression induced by TGF-ß1. In conclusion, our results demonstrate that nintedanib counteracts fundamental fibrosing functions of lung fibroblasts derived from patients with PF-HP, PF-sarcoidosis and PPFE, at concentrations previously reported to inhibit control and IPF HLFs. Such effects may contribute to its clinical benefit in patients suffering from these irreversible ILDs.

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.

Early detection of chronic obstructive pulmonary disease in primary care: a randomised controlled trial.

BACKGROUND: Worldwide, chronic obstructive pulmonary disease (COPD) remains largely underdiagnosed. AIM: To assess whether the use of Global Initiative for Chronic Obstructive Lung Disease (GOLD) questions and COPD coordination, either alone or combined, would detect new COPD cases in primary care. DESIGN AND SETTING: GPs in Brittany, France, systematically enrolled patients aged 40-80 years over a 4-month period in this French multicentre cluster randomised controlled study. METHOD: GPs were randomly allocated to one of four groups: control (standard of care), GOLD questions (adapted from symptoms and risk factors identified by GOLD), COPD coordination, and GOLD questions with COPD coordination. New cases of COPD were those confirmed by spirometry: post-bronchodilator forced expiratory volume in 1 second over forced vital capacity of <0.7. RESULTS: In total, 11 430 consultations were conducted by 47 GPs, who enrolled 3162 patients who did not have prior diagnosed asthma or COPD. Among these, 802 (25%) were enrolled in the control, 820 (26%) in the GOLD questions, 802 (25%) in the COPD coordination, and 738 (23%) in the GOLD questions with COPD coordination groups. In the control group, COPD was not evoked, and no spirometry was prescribed. All new cases of COPD diagnosed (n = 24, 0.8%) were in the intervention groups, representing 6.8% of patients who performed spirometry. Statistically significantly more new cases of COPD were detected with COPD coordination (P = 0.01). CONCLUSION: Interventions that can be easily implemented, such as the GOLD questions and COPD coordination, can identify new cases of COPD. Studies are needed to identify the most appropriate case-finding strategies for GPs to detect COPD in primary care for each country.

Prognostic value and predictors of the alteration of the diffusing capacity of the lungs for carbon monoxide in systemic lupus erythematosus.

OBJECTIVES: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by heterogeneous manifestations and severity, with frequent lung involvement. Among pulmonary function tests (PFT), the measure of the diffusing capacity of the lungs for carbon monoxide (DLCO) is a noninvasive and sensitive tool assessing pulmonary microcirculation. Asymptomatic and isolated DLCO alteration has been frequently reported in SLE, but its clinical relevance has not been established. METHODS: This retrospective study focused on 232 SLE patients fulfilling the 2019 EULAR/ACR classification criteria for SLE. Data were collected from the patient's medical record, including demographic, clinical, and immunological characteristics while DLCO was measured when performing PFT as part of routine patient follow-up. RESULTS: At the end of follow-up, DLCO alteration (<70% of predicted value) was measured at least once in 154 patients (66.4%), and was associated with a history of smoking as well as interstitial lung disease (ILD), but was also associated with renal and neurological involvement. History of smoking, detection of anti-nucleosome autoantibodies and clinical lymphadenopathy at diagnosis were independent predictors of DLCO alteration, while early cutaneous involvement with photosensitivity was a protective factor. DLCO alteration, at baseline or anytime during follow-up was predictive of admission in intensive care unit and/or of all-cause death, both mainly due to severe disease flares and premature cardiovascular complications. CONCLUSION: This study suggests a link between DLCO alteration and disease damage, potentially related to SLE vasculopathy, and prognostic value of DLCO on death or ICU admission in SLE.

Pleural penetration of amoxicillin and metronidazole during pleural infection: An ambispective cohort study.

OBJECTIVES: The pharmacokinetics of antibiotics in pleural fluid during pleural infections has been poorly described. This study aimed to explore amoxicillin and metronidazole diffusion into the pleural space. METHODS: This was an ambispective, single-centre study that included patients with complicated parapneumonic effusion or pleural empyema managed with repeated therapeutic thoracentesis as first-line treatment between 2014 and 2022. Pleural steady-state or trough concentrations of amoxicillin and metronidazole were measured, with a lower limit of quantification of 5 mg/L. RESULTS: Seventy paired blood and pleural samples were analysed from 40 patients. The median (interquartile range) patient age was 55 years (45-67 years) and 88% were male. The median patient weight was 65.8 kg (57.3-82 kg) and median plasma albumin concentration was 29.7 g/L (23.7-33.9 g/L). Median creatinine clearance was 106 mL/min (95-117 mL/min). Median amoxicillin pleural concentrations in patients treated with oral, bolus and continuous intravenous administrations (6 g/day) were, respectively, 5.2 (<5-6.4), 9.4 (8-13.1) and 10.8 (7.1-13.1) mg/L. Pleural concentrations were <5 mg/L in 5/11 samples (45%) with oral treatment and 6/59 (10%) with intravenous treatment. Median metronidazole pleural concentrations were 18.4 (15.7-22.8) mg/L, with all patients being treated orally (1.5 g/day). CONCLUSIONS: Oral metronidazole (1.5 g/day) and intravenous amoxicillin (6 g/day) achieved therapeutic targets in pleural fluid in most cases, but oral amoxicillin did not.

Infections in autoimmune pulmonary alveolar proteinosis: a large retrospective cohort.

BACKGROUND: Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease, predisposing to an increased risk of infection. A complete picture of these infections is lacking. RESEARCH QUESTION: Describe the characteristics and clinical outcomes of patients diagnosed with aPAP, and to identify risk factors associated with opportunistic infections. METHODS: We conducted a retrospective cohort including all patients diagnosed with aPAP between 2008 and 2018 in France and Belgium. Data were collected using a standardised questionnaire including demographics, comorbidities, imaging features, outcomes and microbiological data. RESULTS: We included 104 patients, 2/3 were men and median age at diagnosis was 45 years. With a median follow-up of 3.4 years (IQR 1.7-6.6 years), 60 patients (58%), developed at least one infection, including 23 (22%) with opportunistic infections. Nocardia spp was the main pathogen identified (n=10). Thirty-five (34%) patients were hospitalised due to infection. In univariate analysis, male gender was associated with opportunistic infections (p=0.04, OR=3.88; 95% CI (1.02 to 22.06)). Anti-granulocyte macrophage colony-stimulating factor antibody titre at diagnosis was significantly higher among patients who developed nocardiosis (1058 (316-1591) vs 580 (200-1190), p=0.01). Nine patients had died (9%), but only one death was related to infection. INTERPRETATION: Patients with aPAP often presented with opportunistic infections, especially nocardiosis, which highlights the importance of systematic search for slow-growing bacteria in bronchoalveolar lavage or whole lung lavage.

SPLF/SMFU/SRLF/SFAR/SFCTCV Guidelines for the management of patients with primary spontaneous pneumothorax.

INTRODUCTION: Primary spontaneous pneumothorax (PSP) is the presence of air in the pleural space, occurring in the absence of trauma and known lung disease. Standardized expert guidelines on PSP are needed due to the variety of diagnostic methods, therapeutic strategies and medical and surgical disciplines involved in its management. METHODS: Literature review, analysis of the literature according to the GRADE (Grading of Recommendation, Assessment, Development and Evaluation) methodology; proposals for guidelines rated by experts, patients and organizers to reach a consensus. Only expert opinions with strong agreement were selected. RESULTS: A large PSP is defined as presence of a visible rim along the entire axillary line between the lung margin and the chest wall and ≥ 2 cm at the hilum level on frontal chest X-ray. The therapeutic strategy depends on the clinical presentation: emergency needle aspiration for tension PSP; in the absence of signs of severity: conservative management (small PSP), needle aspiration or chest tube drainage (large PSP). Outpatient treatment is possible if a dedicated outpatient care system is previously organized. Indications, surgical procedures and perioperative analgesia are detailed. Associated measures, including smoking cessation, are described. CONCLUSION: These guidelines are a step towards PSP treatment and follow-up strategy optimization in France.

Benralizumab for eosinophilic granulomatosis with polyangiitis.

BACKGROUND: Benralizumab is effective in the treatment of eosinophilic asthma and is being investigated for the treatment of other eosinophil-associated diseases. Reports on the use of benralizumab for the treatment of eosinophilic granulomatosis with polyangiitis (EGPA) are limited to case reports and small case series. METHODS: We conducted a multicentre, retrospective study including EGPA patients treated with off-label benralizumab. The primary endpoint was the rate of complete response defined as no disease activity (Birmingham Vasculitis Activity Score=0) and a prednisone dose ≤4 mg/day. Partial response was defined as no disease activity and a prednisone dose ≥4 mg/day. RESULTS: Sixty-eight patients were included, including 31 (46%) who had previously received mepolizumab. The use of benralizumab was warranted by uncontrolled asthma in 54 (81%), persistent ear, nose and throat (ENT) manifestations in 27 (40%) and persistent glucocorticoids (GCs) use in 48 (74%) patients. Median (IQR) follow-up after starting benralizumab was 23 (9-34) months. Thirty-three patients (49%) achieved a complete response, 24 (36%) achieved a partial response and 10 (15%) did not respond. Among the 57 patients who initially responded, 10 (18%) eventually required further line treatments. GCs were discontinued in 23 patients (38%). Prior mepolizumab use was associated with a higher rate of primary failure (26.7% vs 5.4%, p=0.034) and less frequent GCs discontinuation (14.8% vs 55.9%, p=0.001). Vasculitis flares occurred in 7 patients (11%) and were associated with histological evidence of vasculitis and/or antineutrophil cytoplasmic antibodies positivity at benralizumab initiation (p=0.004). CONCLUSIONS: Benralizumab appears to be an effective treatment for refractory asthma or ENT manifestations in EGPA and allows GC-sparing. However, its efficacy was lower after prior failure of mepolizumab.

Risk of Malnutrition in Patients With Systemic Sclerosis-Associated Interstitial Lung Disease Treated With Nintedanib in the Randomized, Placebo-Controlled SENSCIS Trial.

OBJECTIVE: To assess adverse events (AEs) in relation to baseline body mass index (BMI) and the risk of malnutrition in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) treated with nintedanib. METHODS: Among patients with SSc-ILD randomized to receive nintedanib or placebo in the SENSCIS trial, we assessed AEs in subgroups by baseline BMI ≤20 kg/m2 and BMI >20 kg/m2 , and the risk of malnutrition using a modified version of the Malnutrition Universal Screening Tool (MUST), over 52 weeks. RESULTS: The AE profile of nintedanib was similar between subgroups with a baseline BMI ≤20 kg/m2 (n = 61) and a baseline BMI >20 kg/m2 (n = 515). In these subgroups, respectively, AEs led to treatment discontinuation in 16.7% and 15.9% of the nintedanib group and 13.5% and 8.0% of the placebo group, respectively. Based on the modified MUST, the proportions of patients who had a low risk of malnutrition at baseline and at their last assessment were 74.0% in the nintedanib group and 78.1% in the placebo group, while the proportions who were classified as at low risk at baseline but at high risk by their last assessment were 4.5% in the nintedanib group and 1.0% in the placebo group. CONCLUSION: In the SENSCIS trial, most patients with SSc-ILD remained at low risk of malnutrition over 52 weeks, but the proportion at high risk was higher in patients who received treatment with nintedanib compared to those who received placebo. Management of disease manifestations and AEs that may be associated with weight loss is important to reduce the risk of malnutrition in patients with SSc-ILD.

Rituximab and mycophenolate mofetil combination in patients with interstitial lung disease (EVER-ILD): a double-blind, randomised, placebo-controlled trial.

BACKGROUND: Standard of care for interstitial lung disease (ILD) with a nonspecific interstitial pneumonia (NSIP) pattern proposes mycophenolate mofetil (MMF) as one of the first-step therapies while rituximab is used as rescue therapy. METHODS: In a randomised, double-blind, two-parallel group, placebo-controlled trial (NCT02990286), patients with connective tissue disease-associated ILD or idiopathic interstitial pneumonia (with or without autoimmune features) and a NSIP pattern (defined on NSIP pathological pattern or on integration of clinicobiological data and a NSIP-like high-resolution computed tomography pattern) were randomly assigned in a 1:1 ratio to receive rituximab (1000 mg) or placebo on day 1 and day 15 in addition to MMF (2 g daily) for 6 months. The primary end-point was the change in percent predicted forced vital capacity (FVC) from baseline to 6 months analysed by a linear mixed model for repeated measures analysis. Secondary end-points included progression-free survival (PFS) up to 6 months and safety. FINDINGS: Between January 2017 and January 2019, 122 randomised patients received at least one dose of rituximab (n=63) or placebo (n=59). The least-squares mean change from baseline to 6 months in FVC (% predicted) was +1.60 (se 1.13) in the rituximab+MMF group and -2.01 (se 1.17) in the placebo+MMF group (between-group difference 3.60, 95% CI 0.41-6.80; p=0.0273). PFS was better in the rituximab+MMF group (crude hazard ratio 0.47, 95% CI 0.23-0.96; p=0.03). Serious adverse events occurred in 26 (41%) patients of the rituximab+MMF group and in 23 (39%) of the placebo+MMF group. Nine infections were reported in the rituximab+MMF group (five bacterial infections, three viral infections, one other) and four bacterial infections in the placebo+MMF group. INTERPRETATION: Combination of rituximab and MMF was superior to MMF alone in patients with ILD and a NSIP pattern. The use of this combination must take into consideration the risk of viral infection.

SPLF/SMFU/SRLF/SFAR/SFCTCV Guidelines for the management of patients with primary spontaneous pneumothorax: Endorsed by the French Speaking Society of Respiratory Diseases (SPLF), the French Society of Emergency Medicine (SFMU), the French Intensive Care Society (SRLF), the French Society of Anesthesia & Intensive Care Medicine (SFAR) and the French Society of Thoracic and Cardiovascular Surgery (SFCTCV).

INTRODUCTION: Primary spontaneous pneumothorax (PSP) is the presence of air in the pleural space, occurring in the absence of trauma and known lung disease. Standardized expert guidelines on PSP are needed due to the variety of diagnostic methods, therapeutic strategies and medical and surgical disciplines involved in its management. METHODS: Literature review, analysis of literature according to the GRADE (Grading of Recommendation Assessment, Development and Evaluation) methodology; proposals for guidelines rated by experts, patients, and organizers to reach a consensus. Only expert opinions with strong agreement were selected. RESULTS: A large PSP is defined as presence of a visible rim along the entire axillary line between the lung margin and the chest wall and ≥2 cm at the hilum level on frontal chest x-ray. The therapeutic strategy depends on the clinical presentation: emergency needle aspiration for tension PSP; in the absence of signs of severity: conservative management (small PSP), needle aspiration or chest tube drainage (large PSP). Outpatient treatment is possible if a dedicated outpatient care system is previously organized. Indications, surgical procedures and perioperative analgesia are detailed. Associated measures, including smoking cessation, are described. CONCLUSION: These guidelines are a step towards PSP treatment and follow-up strategy optimization in France.

A case report of Covid-19 in an autoimmune pulmonary alveolar proteinosis: An association in tune with the times!

Autoimmune pulmonary alveolar proteinosis (PAP) is a rare disease characterized by the alveoli accumulation of surfactants proteins and lipids, which diagnosis is confirmed by the presence of GM-CSF antibodies in serum. PAP can be evoked when its characteristic images on chest computed-tomography (CT) are present: bilateral and multifocal ground-glass opacities and crazy-paving appearance. Patients with PAP are at an increased risk of opportunistic infections caused by Nocardia, mycobacteria and fungal pathogens due to impaired processing of pulmonary surfactant. We here report a typical case of newly diagnosed autoimmune PAP, with initial indication to realize a whole-lung lavage. Despite this treatment the patient presented a marked clinical worsening, with increasing need for oxygen and finally the need for mechanical ventilation. The chest CT was controlled and found to be typical of PAP, while the search for opportunistic infections remained negative. Finally, SARS-CoV-2 PCR was performed on bronchoalveolar lavage fluid, and was positive, whereas it had previously been negative twice. Our case report highlights the difficulty of distinguishing SARS-CoV-2 infection in the context of PAP, as the chest CT features are similar. We believe that a SARS-CoV-2 RT-PCR should be systematically realized in case of respiratory deterioration in PAP patients.

Weight loss and outcomes in subjects with progressive pulmonary fibrosis: data from the INBUILD trial.

BACKGROUND: Lower body mass index (BMI) and weight loss have been associated with worse outcomes in some studies in patients with pulmonary fibrosis. We analyzed outcomes in subgroups by BMI at baseline and associations between weight change and outcomes in subjects with progressive pulmonary fibrosis (PPF) in the INBUILD trial. METHODS: Subjects with PPF other than idiopathic pulmonary fibrosis were randomized to receive nintedanib or placebo. In subgroups by BMI at baseline (< 25, ≥ 25 to < 30, ≥ 30 kg/m2), we analyzed the rate of decline in FVC (mL/year) over 52 weeks and time-to-event endpoints indicating disease progression over the whole trial. We used a joint modelling approach to assess associations between change in weight and the time-to-event endpoints. RESULTS: Among 662 subjects, 28.4%, 36.6% and 35.0% had BMI < 25, ≥ 25 to < 30 and ≥ 30 kg/m2, respectively. The rate of decline in FVC over 52 weeks was numerically greater in subjects with baseline BMI < 25 than ≥ 25 to < 30 or ≥ 30 kg/m2 (nintedanib: - 123.4, - 83.3, - 46.9 mL/year, respectively; placebo: - 229.5; - 176.9; - 171.2 mL/year, respectively). No heterogeneity was detected in the effect of nintedanib on reducing the rate of FVC decline among these subgroups (interaction p = 0.83). In the placebo group, in subjects with baseline BMI < 25, ≥ 25 to < 30 and ≥ 30 kg/m2, respectively, 24.5%, 21.4% and 14.0% of subjects had an acute exacerbation or died, and 60.2%, 54.5% and 50.4% of subjects had ILD progression (absolute decline in FVC % predicted ≥ 10%) or died over the whole trial. The proportions of subjects with these events were similar or lower in subjects who received nintedanib versus placebo across the subgroups. Based on a joint modelling approach, over the whole trial, a 4 kg weight decrease corresponded to a 1.38-fold (95% CI 1.13, 1.68) increase in the risk of acute exacerbation or death. No association was detected between weight loss and the risk of ILD progression or the risk of ILD progression or death. CONCLUSIONS: In patients with PPF, lower BMI at baseline and weight loss may be associated with worse outcomes and measures to prevent weight loss may be required. TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT02999178 .

Patients with worsening fibrosis (scarring) of the lungs may lose weight. This study suggests that the course of disease may be worse in patients who lose weight. Measures to prevent weight loss may be needed in these patients.

Effects of Ruxolitinib on fibrosis in preclinical models of systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune fibrotic disorder notably characterized by the production of antinuclear autoantibodies, which have been linked to an excess of apoptotic cells, normally eliminated by a macrophagic efferocytosis. As interferon (IFN) signature and phosphorylation of JAK-STAT proteins are hallmarks of SSc tissues, we tested the hypothesis that a JAK inhibitor, ruxolitinib, targeting the IFN signaling, could improve efferocytosis of IFN-exposed human macrophages in vitro as well as skin and lung fibrosis. In vivo, BLM- and HOCl-induced skin thickness and fibrosis is associated with an increase of caspase-3 positive dermal cells and a significant increase of IFN-stimulated genes expression. In BLM-SSc model, ruxolitinib prevented dermal thickness, fibrosis and significantly decreased the number of cleaved caspase-3 cells in the dermis. Ruxolitinib also improved lung architecture and fibrosis although IFN signature was not entirely decreased by ruxolitinib. In vitro, ruxolitinib improves efferocytosis capacity of human monocyte-differentiated macrophages exposed to IFN-γ or IFN-ß. In human fibroblasts derived from lung (HLF) biopsies isolated from patients with idiopathic pulmonary fibrosis, the reduced mRNA expression of typical TGF-ß-activated markers by ruxolitinib was associated with a decrease of the phosphorylation of SMAD2 /3 and STAT3. Our finding supports the anti-fibrotic properties of ruxolitinib in a systemic SSc mouse model and in vitro in human lung fibroblasts.

COVID-19 in patients with pulmonary alveolar proteinosis: a European multicentre study.

Adult PAP patients experience similar #COVID19 rates to the general population, and high rates of hospitalisation and deaths, underscoring their vulnerability and the need for measures to prevent infection. The impact of iGM-CSF must be considered. https://bit.ly/3M0wKnZ.

French practical guidelines for the diagnosis and management of idiopathic pulmonary fibrosis - 2021 update. Full-length version.

BACKGROUND: Since the latest 2017 French guidelines, knowledge about idiopathic pulmonary fibrosis has evolved considerably. METHODS: Practical guidelines were drafted on the initiative of the Coordinating Reference Center for Rare Pulmonary Diseases, led by the French Language Pulmonology Society (SPLF), by a coordinating group, a writing group, and a review group, with the involvement of the entire OrphaLung network, pulmonologists practicing in various settings, radiologists, pathologists, a general practitioner, a health manager, and a patient association. The method followed the "Clinical Practice Guidelines" process of the French National Authority for Health (HAS), including an online vote using a Likert scale. RESULTS: After a literature review, 54 guidelines were formulated, improved, and then validated by the working groups. These guidelines addressed multiple aspects of the disease: epidemiology, diagnostic procedures, quality criteria and interpretation of chest CT scans, lung biopsy indication and procedures, etiological workup, methods and indications for family screening and genetic testing, assessment of the functional impairment and prognosis, indication and use of antifibrotic agents, lung transplantation, management of symptoms, comorbidities and complications, treatment of chronic respiratory failure, diagnosis and management of acute exacerbations of fibrosis. CONCLUSION: These evidence-based guidelines are intended to guide the diagnosis and practical management of idiopathic pulmonary fibrosis.

Tracheobronchopathia osteochondroplastica: clinical, bronchoscopic, and comorbid features in a case series.

BACKGROUND: Tracheobronchopathia osteochondroplastica (TO) is a rare condition of unknown etiology. TO is characterized by submucosal nodules, with or without calcifications, protruding in the anterolateral walls of the trachea and proximal bronchi. The objective of this study was to describe TO features and associated comorbidities in a series of patients. METHODS: Patients suffering from TO were retrospectively included by investigators from the Groupe d'Endoscopie Thoracique et Interventionnelle Francophone (GETIF). Demographic, clinical, comorbidities, bronchoscopic, functional, and radiological characteristics, and outcomes were recorded and analyzed. RESULTS: Thirty-six patients were included (69% male with a mean of 65 ± 12 years). Chronic symptoms were described by 81% of patients including cough (74%) and dyspnea on exertion (74%). TO was associated with COPD in 19% of the cases and gastroesophageal reflux disease in 6%. A mild to severe airflow obstruction was present in 55% of the cases. CT scan showed tracheal submucosal nodules in 93% of patients and tracheal stenosis in 17%. Bronchoscopy identified TO lesions in the trachea in 65% of the cases, and 66% of them were scattered. A bronchoscopic reevaluation was performed in 7 cases, 9 ± 14 months [1-56] after initial diagnosis, and showed the stability of lesions in all cases. Three patients underwent interventional bronchoscopic treatment. CONCLUSION: The diagnosis of TO relies on typical bronchoscopic findings and can be evoked on a CT scan. Histologic diagnosis can be useful in atypical cases for differential diagnosis. Given its low consequences in terms of symptoms, lung functions, and evolution, no treatment is usually required.