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.

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.

Prevalence and risk factors of asthma in dairy farmers: Ancillary analysis of AIRBAg.

BACKGROUND: Prolonged occupational agricultural exposure is associated with an increase in asthma diagnosis. This study aimed to identify the prevalence and risk factors for asthma in dairy farmers. METHODS: AIRBAg was a cross-sectional study including 1203 representative dairy farmers. They completed a self-administered questionnaire and underwent a health respiratory check-up. Referral to a pulmonologist was made for any participant with wheezing, dyspnoea, chronic bronchitis, a chronic cough or a FEV1/FEV6 ratio<80%. They underwent further examinations such as spirometry with a reversibility test. Controls (non-asthmatic dairy farmers and non-farm employees) were matched to each asthma case for sex and age (±5 years). The odds ratios (OR) between asthma and different risk factors were estimated using conditional multivariate logistic regression models. RESULTS: Active asthma was diagnosed in 107 (8.9%) farmers. Compared with control dairy farmers, there was a positive association with family history of allergy (OR = 8.68; 95% CI [4.26-17.69]), personal history of eczema (OR = 3.39; 95% CI [1.61-7.13]), hay manipulation (OR = 5.36, 95% CI [1.59-18.01]), and a negative association with farm area (OR = 0.92; 95% CI [0.85-0.99]) and handling treated seeds (OR = 0.47; 95% CI [0.23-0.95]). Compared with control non-farm employees, there was a positive association between asthma and family history of allergy (OR = 95.82, 95% CI [12.55-731.47]). CONCLUSIONS: The prevalence of active asthma in dairy farmers was somewhat higher than the rate observed in the general population but may be controlled by reducing exposure to airborne organic contaminants through occupational adaptions on farms.

Malnutrition and decreased food intake at diagnosis are associated with hospitalization and mortality of idiopathic pulmonary fibrosis patients.

INTRODUCTION AND AIMS: Malnutrition is frequent in patients with idiopathic pulmonary fibrosis (IPF). We examined the relationship between malnutrition at diagnosis and all-cause hospitalization, survival, and acute exacerbation in newly diagnosed IPF patients. METHODS: In this prospective cohort study, the nutritional status of 153 consecutive newly-diagnosed IPF outpatients was evaluated by measuring body mass index (BMI), fat-free mass index (FFMI) with bioelectrical impedance analysis, and food intake with the Self Evaluation of Food Intake (SEFI)®. Diagnosis was taken as the baseline date and malnutrition was defined as an FFMI below 17 (men) or 15 kg/m2 (women). To determine the factors associated with all-cause hospitalization and mortality, univariate Cox regression analyses were performed and variables with P < 0.2 were included in a stepwise multivariable analysis. RESULTS: A quarter (26%; 40/153) of the patients were suffering from malnutrition at baseline, which was more frequent (62%) in patients whose BMI was <25 kg/m2. Patients whose baseline FFMI was low were more likely to be hospitalized (Hazard Ratio (HR) = 1.98 [95% confidence interval, 1.15; 3.41], P = 0.0139) and/or die (HR = 1.79 [1.11; 2.89], P = 0.0165), but their acute exacerbation rate was similar to that of patients with normal FFMIs. Decreased food intake (SEFI®<7) at baseline was associated with all-cause hospitalization (P = 0.003) and mortality (P < 0.0001) during follow-up. Baseline higher gender-age-physiology (GAP) scores (HR = 1.24 [1.01; 1.52], P = 0.0434; HR = 1.71 [1.37; 2.14], P < 0.0001, respectively), lower BMI (HR = 0.89 [0.83; 0.96], P = 0.003; HR = 0.89 [0.82; 0.96], P = 0.003), and decreased food intake (SEFI® score) (HR = 0.81 [0.71; 0.93], P = 0.003; HR = 0.72 [0.64; 0.81], P < 0.0001), but not FFMI, were independently associated with all-cause hospitalization and mortality rates during follow-up. CONCLUSIONS: Malnutrition and decreased food intake at IPF diagnosis are associated with all-cause hospitalization and mortality. Future studies will determine whether dedicated interventions to improve food intake and nutritional status could improve outcomes for IPF patients.

Prevalence and characteristics of persistent symptoms after non-severe COVID-19: a prospective cohort study.

We performed a prospective cohort study of 311 outpatients with non-severe COVID-19 (187 women, median age 39 years). Of the 214 (68.8%) who completed the 6-week follow-up questionnaire, 115 (53.7%) had recovered. Others mostly reported dyspnea (n = 86, 40.2%), weight loss (n = 83, 38.8%), sleep disorders (n = 68, 31.8%), and anxiety (n = 56, 26.2%). Of those who developed ageusia and anosmia, these symptoms were still present at week 6 in, respectively, 11/111 (9.9%) and 19/114 (16.7%). Chest CT scan and lung function tests found no explanation in the most disabled patients (n = 23). This study confirms the high prevalence of persistent symptoms after non-severe COVID-19.

Use of the COPD Assessment Test (CAT) to screen for COPD in dairy farmers: AIRBAg study.

OBJECTIVES: People at risk of chronic obstructive pulmonary disease (COPD) can benefit from appropriate medical management before severe symptoms appear. This study assesses the value of the COPD Assessment Test (CAT) questionnaire for screening dairy farmers, who tend to be slow or reluctant to seek health care. METHODS: During the time period 2012-2017, 2089 randomly selected dairy farmers in Brittany (France) were invited to complete self-administered questionnaires (including the CAT) and to undergo an occupational health check-up using an electronic mini-spirometer and conventional spirometry. Those showing symptoms suggestive of COPD and/or a ratio FEV1 /FEV6 < 80% were sent to a pulmonologist for a further check-up, including spirometry with a reversibility test. Multivariate logistic models based on CAT scores and socio-demographic or work-related factors were developed to predict COPD. RESULTS: The 1231 farmers who underwent the occupational health check-up included 1203 who met the inclusion/exclusion criteria. Pulmonologist identified 16 (1.3%) cases of COPD. A multivariate logistic regression model (covariates: CAT sum score, on-farm time, BMI, smoking status, free-stall mulching) provided an area under the receiver-operating characteristic curve (AUC) of 0.87 (95% CI: 0.75-0.98). Using a cut-off of 0.007 gave a sensitivity of 93.8% and a specificity of 62.4%. Another model that included CAT breathlessness and the same covariates performed marginally better (AUC = 0.88, 95% CI: 0.77-0.98). CONCLUSION: Our predictive models can both benefit dairy farmers by providing early diagnosis and management of their COPD and avoid unnecessary, costly spirometry during the screening process.

What are the best indicators to assess malnutrition in idiopathic pulmonary fibrosis patients? A cross-sectional study in a referral center.

OBJECTIVES: Little is known about the indicators to assess malnutrition in patients with idiopathic pulmonary fibrosis (IPF). This study aimed to determine the following: 1) the prevalence of malnutrition in IPF patients; 2) the nutritional indicators predictive of low fat-free mass (FFM) as measured by bioimpedance analysis; 3) the IPF patients' characteristics associated with low FFM. METHODS: The IPF patients were consecutively recruited in a referral center for rare pulmonary diseases. Malnutrition was defined as a fat-free mass index (FFMI) = FFM (kg) / (height [m]2) <17 (men) or <15 (women). Nutritional assessment included body mass index (BMI), mid-arm circumference (MAC), triceps skinfold thickness, analogue food intake scale, and serum albumin and transthyretin. The primary endpoint was FFMI. Area under the receiver operating characteristic curve (AUC) assessed low FFMI prediction from nutritional indicators. Multivariable logistic regression determined variables associated with low FFMI. RESULTS: Eighty-one patients were consecutively recruited. Low FFMI prevalence was 28% (23 of 81). BMI AUC was 0.91 (95% confidence interval [CI], 0.84‒0.97) and MAC AUC was 0.85 (0.76‒0.94). Multivariable analysis associated BMI (odds ratio [OR] 0.26 [95% CI, 0.12-0.54], P = 0.0003), male sex (OR 0.02 [0.00-0.33], P = 0.005), and smoking (OR 0.10 [0.01-0.75], P = 0.024) with a lower risk of malnutrition. CONCLUSIONS: Malnutrition occurred in nearly one-third of IPF patients. Malnutrition screening should become systematic based on BMI and MAC, which are good clinical indicators of low FFMI. We propose a practical approach to screen malnutrition in IPF patients.

Women and COPD: do we need more evidence?

The increasingly female face of chronic obstructive pulmonary disease (COPD) prevalence among women has equalled that of men since 2008, due in part to increased tobacco use among women worldwide and exposure to biomass fuels. This finding is supported by a number of characteristics. There is evidence of susceptibility to smoking and other airborne contaminants, along with epidemiological and phenotypic manifestations. COPD has thus become the leading cause of death in women in the USA. The clinical presentation is characterised by increasingly pronounced dyspnoea with a marked tendency towards anxiety and depression, undernutrition, nonsmall cell lung cancer (especially adenocarcinoma) and osteoporosis. Quality of life is also more significantly impacted. The theories advanced to explain these differences involve the role played by oestrogens, impaired gas exchange in the lungs and smoking habits. While these differences require appropriate therapeutic responses (smoking cessation, pulmonary rehabilitation, long-term oxygen therapy), barriers to the treatment of women with COPD include greater under-diagnosis than in men, fewer spirometry tests and medical consultations. Faced with this serious public health problem, we need to update and adapt our knowledge to the epidemiological changes.

Prevalence and risk factors of chronic obstructive pulmonary disease in dairy farmers: AIRBAg study.

BACKGROUND: The AIRBAg study was designed to assess the prevalence of chronic obstructive pulmonary disease (COPD) in dairy farmers and to define its associated risk factors. METHODS: Between March 2012 and February 2017 randomly selected dairy farmers in the French region of Brittany were asked to complete a self-administered questionnaire and undergo an occupational health check-up with electronic mini-spirometry and standard spirometry. Those having one or more of the following features: chronic cough, chronic bronchitis, wheezing, dyspnea and/or a ratio FEV1/FEV6 < 80% were then referred to a pulmonologist for further check-up including spirometry with a reversibility test. Each COPD case was matched with three controls (dairy farmers and non-farm employees), for sex and age ( ±â€¯5 years). Conditional multivariate logistic regression models were used to estimate the odds ratios between COPD occurrence and various risk factors. RESULTS: The 1203 farmers examined included 525 (43.6%) who were "at risk of bronchial obstruction" and 432 (35.9%) of these saw the pulmonologist. This screening identified 16 (1.3%) cases of COPD, including eight non-smokers and five with an FEV1 < 80% of predicted values. Their average age was 54.6 ( ±â€¯7.7) years and 10 of them were men. None complained of illness before the study. Multivariate analyses revealed no significant occupational risk factors for COPD. CONCLUSIONS: This unexpected result may be because Breton dairy farms began to modernize early (1950s), giving rise to conditions with much lower exposure to airborne contaminants.

Role of serum immunoglobulins for predicting sarcoidosis outcome: A cohort study.

BACKGROUND: Sarcoidosis is a systemic granulomatous disease which carries variable outcomes. Serum protein electrophoresis is an easily accessible and routinely performed examination at diagnosis, in order to search for hypergammaglobulinemia, which is frequently found, and to rule out other granulomatous diseases such as common variable immunodeficiency. We aimed to assess the impact of baseline immunoglobulin level on the outcome of sarcoidosis. METHODS: We conducted a retrospective cohort-study, at Rennes University Hospital, in which all newly diagnosed patients for whom a serum protein electrophoresis had been performed at baseline were enrolled, from 2006 to 2014. The main outcome was the need for corticosteroid treatment within 2 years from diagnosis, the secondary outcome was the occurrence of relapse among treated patients. RESULTS: Eighty patients were included in the study, and 41.25% of them exhibited an elevated globulins rate. In univariate analysis, an elevated ACE level >70 U/l, Afro-Caribbean origin, and extra-pulmonary involvement, were associated with the need for corticosteroid treatment. In multivariate analysis, only ACE elevation (OR = 1.03, IC95% 1.01-1.05, p = 0.009) and extra-pulmonary involvement (OR = 5.8, IC95% 1.4-24, p = 0.015) were significant. Immunoglobulin level was not associated with the main outcome. Regarding the secondary outcome, none of the studied features were predictive of relapse among the 34 treated patients followed for two years. CONCLUSIONS: There was no relation between the immunoglobulin level at diagnosis and the evolution of sarcoidosis. An elevated ACE level and the presence of initial extra-pulmonary involvement were both associated with a more severe course of the disease necessitating a corticosteroid treatment.

Case-Finding for Persistent Airway Obstruction in Farmers: A Questionnaire With Optimal Diagnosis Criteria.

INTRODUCTION: Appropriate identification of subjects who are candidates for spirometry through case-finding questionnaires may help solve the problem of chronic obstructive pulmonary disease misdiagnosis. The performance of case-finding questionnaires depends at least partially on the characteristics of the population used for their development. The use of an accurate threshold for the forced expiratory volume in 1 second / forced vital capacity ratio to define persistent airway obstruction is also vital in ascertaining chronic obstructive pulmonary disease. METHODS: Using a population examined between October 2012 and May 2013 that included a large subset of agricultural workers both exposed and unexposed to tobacco smoking, the authors aimed to select a combination of items that would identify persons most likely to have persistent airway obstruction defined as forced expiratory volume in 1 second / forced vital capacity less than the lower limit of normal according to the Global Lung Initiative-2012 equations. Two thirds of the population (n=3,397) were randomly selected to develop a questionnaire, and one third (n=1,698) was reserved for questionnaire validation. Statistical analysis was performed in 2016. RESULTS: The selected items were sex, dyspnea, BMI, tobacco smoking habits, age, history of respiratory diseases, and history of occupation at risk. The C-index of the model was 0.84 (95% CI=0.80, 0.88) for the development population and 0.76 (95% CI=0.66, 0.86) for the validation population. Using the selected items in combination, the sensitivity and specificity in identifying persistent airway obstruction were 76% and 77%, respectively, in the development population (and 68% and 73%, respectively, in the validation population) for a threshold value of 2.50%. CONCLUSIONS: This seven-item questionnaire is the first developed from a population comprising a large subset of agricultural workers and using the Global Lung Initiative-2012 equations.

Prevalence and risk factors for COPD in farmers: a cross-sectional controlled study.

There are conflicting data regarding the magnitude and determinants of chronic obstructive pulmonary disease (COPD) risk in farmers.In a cross-sectional study of 917 nonfarming working controls and 3787 farmers aged 40-75 years, we assessed respiratory symptoms, tobacco exposure, job history (without direct exposure measurement) and lung function. COPD was defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criterion (post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) <0.70) and by the Quanjer reference equation (post-bronchodilator FEV1/FVC

Detecting active pelvic arterial haemorrhage on admission following serious pelvic fracture in multiple trauma patients.

BACKGROUND: The early diagnosis of pelvic arterial haemorrhage is challenging for initiating treatment by transcatheter arterial embolization (TAE) in multiple trauma patients. We use an institutional algorithm focusing on haemodynamic status on admission and on a whole-body CT scan in stabilized patients to screen patients requiring TAE. This study aimed to assess the effectiveness of this approach. METHODS: This retrospective cohort study included 106 multiple trauma patients admitted to the emergency room with serious pelvic fracture [pelvic abbreviated injury scale (AIS) score of 3 or more]. RESULTS: Of the 106 patients, 27 (25%) underwent pelvic angiography leading to TAE for active arterial haemorrhage in 24. The TAE procedure was successful within 3h of arrival in 18 patients. In accordance with the algorithm, 10 patients were directly admitted to the angiography unit (n=8) and/or operating room (n=2) for uncontrolled haemorrhagic shock on admission. Of the remaining 96 stabilized patients, 20 had contrast media extravasation on pelvic CT scan that prompted pelvic angiography in 16 patients leading to TAE in 14. One patient underwent a pelvic angiography despite showing no contrast media extravasation on pelvic CT scan. All 17 stabilized patients who underwent pelvic angiography presented a more severely compromised haemodynamic status on admission, and they required more blood products during their initial management than the 79 patients who did not undergo pelvic angiography. The incidence of unstable pelvic fractures was however comparable between the two groups. Overall, haemodynamic instability and contrast media extravasation on the CT-scan identified 26 out of the 27 patients who required subsequent pelvic angiography leading to TAE in 24. CONCLUSIONS: An algorithm focusing on haemodynamic status on arrival and on the whole-body CT scan in stabilized patients may be effective at triaging multiple trauma patients with serious pelvic fractures.

On-site screening of farming-induced chronic obstructive pulmonary disease with the use of an electronic mini-spirometer: results of a pilot study in Brittany, France.

PURPOSE: Dairy farming is a risk factor for the development of chronic obstructive pulmonary disease (COPD). We assessed the prevalence of farming-induced COPD (FI-COPD) using a new screening device, and we analyzed symptoms and occupational risk factors. METHODS: We performed on-site screening study of bronchial obstruction using an electronic mini-spirometer (EMS) on an entire population of dairy farmers (n = 147) from two villages in Brittany, France. Suspected bronchial obstruction (FEV1/FEV6 <0.8) was confirmed with standardized lung function tests (FEV1/FVC ≤0.7). We assessed past medical histories, respiratory symptoms, and occupational tasks of subjects with bronchial obstruction; asthmatics were defined as atopic and/or reversible; smoking-induced COPD patients were defined as non-reversible, non-atopic with smoking histories (≥5 PY); and FI-COPD patients were defined as non-reversible, non-atopic, and non-smokers. RESULTS: Using the EMS, 30.6% (n = 45) of dairy farmers were suspected of bronchial obstruction and underwent standardized spirometry. The FEV1/FEV6 ratio and FEV1/FVC ratio were in good agreement (r² = 0.66, P < 0.0001). The prevalence of confirmed bronchial obstruction was 9.5% (n = 14), which included 4 asthmatics, 3 smoking-induced COPD subjects, and 7 FI-COPD subjects. All the COPD patients were GOLD Stage II, and none were aware of their respiratory disease. Foddering duration was significantly higher in FI-COPD subjects compared with non-obstructive subjects, with 44 versus 17 min/day, respectively. CONCLUSIONS: The EMS was a convenient mean of screening for bronchial obstruction, especially in on-site settings, and allowed us to diagnose FI-COPD in a non-spontaneously complaining dairy farmer population. Foddering was considered a significant risk factor.

Increased extracellular matrix metalloproteinase inducer (EMMPRIN) expression in pulmonary fibrosis.

Extracellular matrix metalloproteinase inducer (EMMPRIN) was examined on bronchoalveolar lavage fluids (BALFs) and lung tissue from patients with fibrosis (usual interstitial pneumonia-idiopathic pulmonary fibrosis [UIP-IPF], n = 15; diffuse parenchymal lung diseases without IPF characteristics on computerized tomography scan, n = 8) and without fibrosis (n = 6). In UIP-IPF, EMMPRIN staining was increased in areas of fibrosis, mainly in macrophages and in epithelial cells. EMMPRIN was also found in the extracellular medium with significant levels in patients with lung fibrosis compared to subjects without fibrosis. Moreover, macrophages from patients with lung fibrosis spontaneously produce EMMPRIN. These findings show that EMMPRIN is increased in lung fibrosis.