Since 2009, IPF patients across Europe are recruited into the eurIPFreg, providing epidemiological data and biomaterials for translational research.

Background: The objectives of the eurIPFreg are to provide clues for IPF phenotype sub-clusters, for triggering factors and co-morbidities, for disease behavior and management. We described data of the 525 IPF subjects recruited from 11/2009 until 10/2016. Methods: Since 2009, eurIPFreg collects longitudinal data of IPF patients across Europe. The registry goes hand in hand with a European IPF Biobank, providing biomaterials for translational research. The clinical phenotype is assessed on the basis of a patient as well as a physician baseline and follow-up questionnaires, overall comprising 1700 parameters. Results: Our cohort showed foll. demographics- 73.7% males, 65.4% previous smokers. Patients seeked medical advice due to insidious dyspnea (90.1%), weakness and latitude (69.2%). FVC was 68.4% +/- 22.6% predicted, DLco ranged at 42.1% +/-17.8% of predicted. Signs of PH were found in 16.8%. Steroids, immunosuppressants and NAC declined in their use since 2009 and were almost quantitatively replaced by the antifibrotics in 2016. The mean survival was 4.89 years (range 0.2-19 years). Patients receiving antifibrotics had a better survival (p= 0,027). Conclusions: Our data provide important insights into characteristics and management changes in European IPF cohort over time. Our patients diverse in age, impairment of lung function, therapeutic regimes and co-morbidities, reflecting changes in the recent diagnostic and therapeutic approach in IPF. Prognostic indicators for IPF patients under antifibrotics have to be established in the future. Our data support the pivotal role of large real-world data registries in recent development of the diagnosis and therapy of IPF.

BACKGROUND: Pulmonary hypertension (pH) is a well-known independent prognostic factor in chronic obstructive pulmonary disease (COPD) and a sufficient criterion for lung transplant candidacy. Limited data are currently available on the hemodynamic and clinical effect of phosphodiesterase 5 inhibitors in patients with severe PH associated with COPD. This study assessed the effect of sildenafil on pulmonary hemodynamics and gas exchange in severe PH associated with COPD.METHODS: After screening, this multicenter, randomized, placebo-controlled double-blind trial randomized patients to receive 20 mg sildenafil or placebo 3 times a day (ratio 2:1) for 16 weeks. The primary end point was the reduction in pulmonary vascular resistance. Secondary end points included BODE (body mass index, airflow obstruction, dyspnea, and exercise capacity) index, 6-minute walk test, and quality of life questionnaire. Changes in the partial pressure of arterial oxygen were evaluated as a safety parameter.RESULTS: The final population included 28 patients, 18 in the sildenafil group and 10 in the placebo group. At 16 week, patients treated with sildenafil had a decrease in pulmonary vascular resistance (mean difference with placebo -1.4 WU; 95% confidence interval, <= -0.05; p = 0.04). Sildenafil also improved the BODE index, diffusion capacity of the lung for carbon monoxide percentage, and quality of life. Change from baseline in the partial pressure of arterial oxygen was not significantly different between the sildenafil and placebo groups.CONCLUSIONS: This pilot study found that treatment with sildenafil reduced pulmonary vascular resistance and improved the BODE index and quality of life, without a significant effect on gas exchange. (C) 2016 International Society for Heart and Lung Transplantation. All rights reserved.

Background: Epidemiologic and clinical evidence supports the existence of an obesity-related asthma phenotype. No distinct pathophysiologic elements or specific biomarkers have been identified thus far, but increased oxidative stress has been reported.Objective: We aimed at verifying whether metabolomics of exhaled breath condensate from obese asthmatic (OA) patients, lean asthmatic (LA) patients, and obese nonasthmatic (ONA) subjects could recognize specific and statistically validated biomarkers for a separate "asthma-obesity'' respiratory metabolic phenotype, here defined as "metabotype.''Methods: Twenty-five OA patients, 30 ONA subjects, and 30 mild-to-moderate LA age-matched patients participated in a cross-sectional study. Nuclear magnetic resonance (NMR) profiles were analyzed by using partial least-squares discriminant analysis, and the results were validated with an independent patient set.Results: From NMR profiles, we obtained strong regression models that distinguished OA patients from ONA subjects (quality parameters: goodness-of-fit parameter [R-2] = 0.81 and goodness-of-prediction parameter [Q(2)] = 0.79), as well as OA patients from LA patients (R-2 = 0.91 and Q(2) = 0.89). The allclasses comparison (R-2 = 0.86 and Q(2) = 0.83) indicated that OA patients possess a respiratory metabolic profile fully divergent from those obtained in the other patient groups. We also identified specific biomarkers for between-class separation, which are independent from clinical bias. They are involved in the methane, pyruvate, and glyoxylate and dicarboxylate metabolic pathways.Conclusions: NMR-based metabolomics indicates that OA patients are characterized by a respiratory metabolic fingerprint fully different from that of patients independently affected by asthma or obesity. Such a phenotypic difference strongly suggests unique pathophysiologic pathways involved in the pathogenesis of asthma in adult obese subjects. Furthermore, the OA metabotype could define a strategy for patient stratification based on unbiased biomarkers, with important diagnostic and therapeutic implications.

Background: Fractional concentration of exhaled nitric oxide (FeNO) is a recognized biomarker of the lower respiratory tract, where it is produced by the proximal conducting airways and the expansible peripheral bronchoalveolar compartment. We have previously shown that large increase in body mass decreases FeNO. Here we evaluated bronchial and alveolar components of the NO output of the lower respiratory tract in subjects with severe uncomplicated obesity (OB).Methods: Fifteen OB subjects (BMI 45.3 +/- 5.6 kg/m(2)), 15 healthy controls (HC) (BMI 22.4 +/- 2.4 kg/m(2)) and 10 obese subjects who experienced weight loss after bariatric surgery (OBS) (BMI 31.2 +/- 3.4 kg/m(2)), were examined. Anthropometry and respiratory lung tests were performed. Exhaled NO was assessed using multiple single-breath NO analysis at different constant expiratory flow rates. From the fractional NO concentration measured at each flow-rate, the total NO flux between tissue and gas phase in the bronchial lumen (J'awNO), and the alveolar NO concentration (CANO) were extrapolated.Results: Measured FeNO levels at 50 mL/s were lower in OB compared with HC and OBS (11.6 +/- 2.8 ppb, 18.0 +/- 4.1 ppb and 17.6 +/- 2.9 ppb, respectively, p < 0.05). In OB, both J'awNO and CANO resulted significantly lower than OBS and HC values.Conclusions: Respiratory NO output is decreased in severe uncomplicated obesity for the reduction of both large/central airway maximal NO flux and alveolar NO concentration. The pathophysiological relevance of airway NO abnormalities in severe obese phenotype remains to be investigated. (C) 2015 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

Introduction: Chronic cough is usually defined as a cough that lasts for eight weeks or longer. Its etio-logical diagnosis is not always straightforward, and the measurement of exhaled nitric oxide (FeNO) has been proposed in patients' evaluation. No studies have assessed the usefulness of extended exhaled NO measurement for the evaluation of chronic cough. Therefore, we aimed at evaluating the usefulness of an extended exhaled NO measurement and nasal NO for an initial evaluation of chronic cough.Methods: We studied 52 non-smoker patients with prolonged cough lasting more than eight weeks. Etiologies of cough were identified. Nasal NO and FeNO were assessed using multiple single-breath NO analysis at different constant expiratory flow-rates. From the fractional NO concentration measured at each flow-rate, the total NO flux between tissue and gas phase in the bronchial lumen (J'awNO), and the alveolar NO concentration (CANo) were extrapolated.Results: The patients were classified in four categories: cough variant asthma (CVA), nonasthmatic eosinophilic bronchitis (NAEB), upper airway cough syndrome (UACS) and gastro-esophageal reflux disease (GERD). Compared with UACS and GERD, both exhaled NO and J'awNO were higher in CVA and NAEB, and no differences were found in CANO and nasal NO level among the four groups.Conclusions: Our study suggests a potentially useful role for FeNO measurement in the etiological diagnosis of chronic cough. We did not find any additive value of performing exhaled NO at multiple flow-rates and nasal NO measurements. (C) 2015 Elsevier Ltd. All rights reserved.

In humans, obesity plays a critical role in pulmonary inflammation, and is an important risk factor for the development of several inflammatory respiratory diseases. Therefore, understanding the mechanisms that generate mediators in the setting of obesity may help to recognize the link between obesity and chronic respiratory diseases, like the increased incidence and severity of asthma in obese individuals. NMR spectroscopy of exhaled breath condensate (EBC, a non-invasive matrix to access the lung epithelial lining fluid) can unambiguously identify biomarkers characterizing different pulmonary physiopathological states. In this study we aimed at verifying if NMR-based metabolomics of EBC, combined with orthogonal projections to latent structures-discriminant analysis, could possibly recognize specific biomarkers to map the obese metabolic respiratory phenotype. Obese and lean control subjects could be distinguished in a statistical model presenting high quality parameters (R-2 = 0.904 and Q(2) = 0.871). Identified airway metabolites linked to the inflammation processes demonstrate that obesity constitutes a specific inflammatory metabolic phenotype (metabotype). It is concluded that the noninvasive EBC matrix is suitable to selectively investigate the obesity-related lung inflammation.

INTRODUCTION:It has been demonstrated that brief periods of nocturnal continuous positive airway pressure (nCPAP) reduce airway reactivity in animal models and in patients with asthma. The effects of nCPAP in severe uncontrolled non-apneic asthmatic patients are not well known.AIM:In this open pilot study, we aimed to assess the effect nCPAP on peak flow (PEF) variability and asthma control in this type of patients.METHODS:CPAP was applied to 10 patients with severe long-standing asthma without obstructive sleep apnea for seven consecutive nights. CPAP was titrated in auto setting and applied to the patients. Daily PEF, was measured from 2 weeks before the intervention to 2 weeks after the end of nCPAP treatment. PEF amplitude and PEF morning dip (MD) over 24-h periods averaged over 1 week were calculated as indexes of PEF variability. Asthma control test (ACT) and European quality of life (EuroQol) questionnaire were measured at baseline and after 1 month, and at baseline and at the end of CPAP period, respectively.RESULTS:The PEF amplitude significantly decreased both during CPAP period and in the first week after nCPAP discontinuation as compared with the baseline (19.8 ± 7.5%, 23.9 ± 9.1% and 28.9 ± 11.5%, respectively, always P < 0.05). PEF MD significantly decreased during nCPAP in comparison with the baseline (P < 0.001). The ACT and EuroQol significantly improved after nCPAP in comparison with the basal value.CONCLUSIONS:In this preliminary report, brief period of nCPAP reduces PEF variability and improves control in severe non-apneic asthma at a short-term evaluation. Further studies with longer-term evaluation and larger number of patients are warranted.

Exhaled breath condensate (EBC) collection is a noninvasive method to investigate lung diseases. EBC is usually collected with commercial/custom-made condensers, but the optimal condensing temperature is often unknown. As such, the physical and chemical properties of exhaled metabolites should be considered when setting the temperature, therefore requiring validation and standardization of the collecting procedure. EBC is frequently used in nuclear magnetic resonance (NMR)-based metabolomics, which unambiguously recognizes different pulmonary pathological states. Here we applied NMR-based metabolomics to asthmatic and healthy EBC samples collected with two commercial condensers operating at -27.3 and -4.8 °C. Thirty-five mild asthmatic patients and 35 healthy subjects were included in the study, while blind validation was obtained from 20 asthmatic and 20 healthy different subjects not included in the primary analysis. We initially analyzed the samples separately and assessed the within-day, between-day, and technical repeatabilities. Next, samples were interchanged, and, finally, all samples were analyzed together, disregarding the condensing temperature. Partial least-squares discriminant analysis of NMR spectra correctly classified samples, without any influence from the temperature. Input variables were either integral bucket areas (spectral bucketing) or metabolite concentrations (targeted profiling). We always obtained strong regression models (95%), with high average-quality parameters for spectral profiling (R(2) = 0.84 and Q(2) = 0.78) and targeted profiling (R(2) = 0.91 and Q(2) = 0.87). In particular, although targeted profiling clustering is better than spectral profiling, all models reproduced the relative metabolite variations responsible for class differentiation. This warrants that cross comparisons are reliable and that NMR-based metabolomics could attenuate some specific problems linked to standardization of EBC collection.

Pulmonary Hypertension (PH) associated to chronic respiratory diseases is currently classified in the 3rd group, as a mild to moderate form of pre-capillary PH that progressively complicates the prognosis of associated pulmonary disease. In clinical practice, however, some unresolved issues in the respiratory PH should be considered: 1) the PH heterogeneity in some respiratory diseases, such as Chronic Obstructive Pulmonary Disease (COPD), where the prevalence of unrecognized left heart disease, or chronic pulmonary thromboembolism may change the clinical classification; 2) the combining form of severe PH which often is not correlated to chronic ventilator impairment, while outcome is strictly related to pulmonary haemodynamics. The recognition of out of proportion respiratory PH in several chronic respiratory diseases which include COPD, Idiopathic Pulmonary Fibrosis (IPF), Combined Pulmonary Fibrosis and Emphysema, Obstructive Sleep Apnea (OSA), Obesity Hypoventilation Syndrome (OHS) may be important for a comprehensive clinical classification of severe respiratory PH, as well as, for the inclusion of these patients in randomized clinical trials on PH targeted therapy.

The use of nasal nitric oxide (nNO) in sinonasal disease has recently been advocated as a potential tool to explore upper inflammatory airway disease. However, it is currently hampered by some factors including the wide range of measurement methods, the presence of various confounding factors and the heterogeneity of the study population. The contribution of nasal airway and paranasal sinuses communicating with the nose through the ostia represents the main confounding factor. There is accumulating evidence that nasal humming (which is the production of a tone without opening the lips or forming words) during nNO measurement increases nNO levels due to a rapid gas exchange in the paranasal sinuses. The aim of this review is to discuss the basic concepts and clinical applications of nNO assessment during humming, which represents a simple and noninvasive method to approach sinonasal disease.

The prevalence of asthma and allergic diseases has increased dramatically during the past few decades not only in industrialized countries. Urban air pollution from motor vehicles has been indicated as one of the major risk factors responsible for this increase. Although genetic factors are important in the development of asthma and allergic diseases, the rising trend can be explained only in changes occurred in the environment. Despite some differences in the air pollution profile and decreasing trends of some key air pollutants, air quality is an important concern for public health in the cities throughout the world. Due to climate change, air pollution patterns are changing in several urbanized areas of the world, with a significant effect on respiratory health. The observational evidence indicates that recent regional changes in climate, particularly temperature increases, have already affected a diverse set of physical and biological systems in many parts of the world. Associations between thunderstorms and asthma morbidity in pollinosis subjects have been also identified in multiple locations around the world. Allergens patterns are also changing in response to climate change and air pollution can modify the allergenic potential of pollens especially in presence of specific weather conditions. The underlying mechanisms of all these interactions are not well known yet. The consequences on health vary from decreases in lung function to allergic diseases, new onset of diseases, and exacerbation of chronic respiratory diseases. Factor clouding the issue is that laboratory evaluations do not reflect what happens during natural exposition, when atmospheric pollution mixtures in polluted cities are inhaled. In addition, it is important to recall that an individual’s response to pollution exposure depends on the source and components of air pollution, as well as meteorological conditions. Indeed, some air pollution-related incidents with asthma aggravation do not depend only on the increased production of air pollution, but rather on atmospheric factors that favour the accumulation of air pollutants at ground level. Considering these aspects governments worldwide and international organizations such as the World Health Organization and the European Union are facing a growing problem of the respiratory effects induced by gaseous and particulate pollutants arising from motor vehicle emissions.

Prognostic stratification in pulmonary arterial hypertension (PAH) relies on clinical assessment and invasive hemodynamic measurements. However, right ventricular (RV) dilatation and function, assessed by cardiac magnetic resonance (CMR), have been demonstrated to predict survival independent of invasive indices. Soluble ST2 (sST2),a marker of cardiomyocyte stress related to the IL33/IL1-receptor system, increases in heart failure, especially when RV overload is present. Aim of this study was to explore sST2 and IL-33 levels in PAH, and to evaluate their possible correlation with cardiac remodeling as assessed by CMR 25 patients with PAH underwent contrast-enhanced CMR and measurement of serum sST2, IL-33 and NT-proBNP levels.10 age-matched healthy individuals with a negative echocardiogram served as controls. PAH patients showed increased sST2 levels compared with controls. Patients with sST2 levels above and below the median differed significantly in terms of WHO class, walking distance, RV diastolic and systolic volume indices, and ejection fraction. Analysis of CMR data showed strong correlation of sST2 levels with right ventricular end-systolic volume and NT-proBNP, as well as a significant negative correlation with RV ejection fraction. Regression analysis suggested independent predictive value of the two biomarkers with respect to RV function. Serum sST2 levels are elevated in patients with PAH, and they are strictly correlated with the severity of right heart remodeling and dysfunction. sST2 appears as a promising novel biomarker and a potentially useful tool for the non- invasive assessment of RV dysfunction.

We studied the discriminating capacity of NMR spectroscopy-based metabolomics of exhaled breath condensate (EBC) in asthma and COPD patients, who were either steroid-naive or treated with inhaled corticosteroids (ICS) [fluticasone (500-1000 μg/day) for at least 2 months], and healthy subjects. Twenty-seven steroid-naive COPD patients (21/6, males/females, age 67±2 years, mean±SEM, FEV1 68±2.9% predicted value), 20 COPD patients on ICS (16/4, males/females, age 70±2 years, FEV1 73±4.2% predicyed value), 21 steroid-naive asthmatics (16/5, males/females, age 32±3.9 years, FEV1 99±4.9% predicted value), 19 asthmatics on ICS (14/5, males/females, age 31±4.0 years, FEV1 85±5.0% predicted value), and 15 healthy subjects (8/7, males/females, age 28±1 years, FEV1 116±2.6% predicted value) were included in a cross-sectional study. Asthma and healthy subjects were nonsmokers, COPD patients were exsmokers. EBC was collected after 20 min of tidal breathing (Ecoscreen, Jaeger, Hoechberg, Germany). 1H-NMR spectra (Bruker Avance spectrometer) were data reduced to buckets (AMIX 3.6 package, Bruker Biospin, Rheinstetten, Germany) and normalized to total spectral area. Good reproducibility and no salivary contamination was previously reported (Montuschi P et al, Thorax, 2012). PLS-DA showed all study groups were separated (R2=0.79, Q2=0.80), suggesting an effect of ICS on EBC metabolites which has to be investigated in prospective controlled studies. ![Figure][1] [1]: pending:yes

Chronic Obstructive Pulmonary Disease (COPD) is a chronic inflammatory lung disease which may be complicated by development of co-morbidities including metabolic disorders. Metabolic disorders commonly associated with this disease contribute to lung function impairment and mortality. Systemic inflammation appears to be a major factor linking COPD to metabolic alterations. Adipose tissue seems to interfere with systemic inflammation in COPD patients by producing a large number of proteins, known as "adipokines", involved in various processes such as metabolism, immunity and inflammation. There is evidence that adiponectin is an important modulator of inflammatory processes implicated in airway pathophysiology. Increased serum levels of adiponectin and expression of its receptors on lung tissues of COPD patients have recently highlighted the importance of the adiponectin pathway in this disease. Further, in vitro studies have demonstrated an anti-inflammatory activity for this adipokine at the level of lung epithelium. This review focuses on mechanisms by which adiponectin is implicated in linking COPD with metabolic disorders.

Nuclear magnetic resonance (NMR)-based metabolomics separates exhaled breath condensate (EBC) profiles of patients affected by pulmonary disease from those of healthy subjects. Here we show the discriminatory ability of NMR-based metabolomics in separating patients exposed to the same risk factor, namely, smoking habit in smoking-related diseases. Fifty duplicated EBC samples from a cohort of current smokers without chronic obstructive pulmonary disease (COPD, henceforth HS), COPD smokers, and subjects with established pulmonary Langerhans cell histiocytosis (PLCH) were analyzed by means of NMR spectroscopy followed by principal component analysis (PCA) and projection to latent structures discriminant analysis (PLS-DA). Clusterization of EBC spectra was disease-specific. COPD and PLCH samples present a profile different from that of HS, showing acetate increase and 1-methylimidazole reduction. An inverse behavior of 2-propanol and isobutyrate characterized COPD with respect to PLCH (high/low in COPD, low/high in PLCH). Both the 2-component and the 3-component PLS-DA models showed a 96% cross-validated accuracy, presenting R(2) and Q(2) values in the ranges of 0.97-0.87 and 0.91-0.78, respectively, and R(2) = 0.87 and Q(2) = 0.78, indicating that data variation is well explained by each model (R(2)), with a good predictivity (Q(2)). NMR spectra of EBC discriminate COPD and PLCH patients from HS and between them, with well-defined metabolic profiles for each class. The specificity of EBC profiles suggests that disease itself drives metabolic separation overwhelming the "common background" due to smoking habit. EBC-NMR investigation offers a powerful tool for assessing the evolution of airway diseases even in the presence of a strong common factor.

Pulmonary arterial hypertension (PAH) is a rare disease characterized by a dramatic, progressive rise of pulmonary vascular resistance (PVR), leading to elevated pulmonary artery pressures, right ventricular (RV) overload, and, eventually, failure. Current evaluation of PAH is based on invasive hemodynamics (RHC), exercise capacity, echocardiography, and N-terminal pro brain natriuretic peptide (NT-proBNP) levels [ [1] Task Force for Diagnosis and Treatment of Pulmonary Hypertension of European Society of Cardiology (ESC) European Respiratory Society (ERS) International Society of Heart and Lung Transplantation (ISHLT) et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J. 2009; 34: 1219-1263 Crossref PubMed Scopus (1091) Google Scholar ]; although published survival data support a strong clinical role for cardiac magnetic resonance imaging (CMR) of the RV, this technique is still underused [ [2] Bradlow W.M. Gibbs J.S. Mohiaddin R.H. Cardiovascular magnetic resonance in pulmonary hypertension. J Cardiovasc Magn Reson. 2012; 14: 6 Crossref PubMed Scopus (53) Google Scholar ]. Much research is currently focusing on the exploration of candidate soluble biomarkers of RV dysfunction and prognosis.

Adiponectin (Acrp30) exerts protective functions on metabolic and cellular processes as energy metabolism, cell proliferation and differentiation by two widely expressed receptors, AdipoR1 and AdipoR2. To date, the biological role of Acrp30 in lung has not been completely assessed but altered levels of Acrp30 and modulated expression of both AdipoRs have been related to establishment and progression of chronic obstructive pulmonary disease (COPD) and lung cancer. Here, we investigated the effects of Acrp30 on A549, a human alveolar epithelial cell line, showing how, in a time and dose-dependent manner, it decreases cell viability and increases apoptosis through ERK1/2 and AKT. Furthermore, we examined the effects of Acrp30 on A549 cells exposed to TNFa and/or IL-1ß, two potent lung inflammatory cytokines. We showed that Acrp30, in dose- and time-dependent manner, reduces cytotoxic effects of TNFa and/or IL-1ß improving cell viability and decreasing apoptosis. In addition, Acrp30 inhibits NF-?B nuclear trans-activation and induces the expression of the anti-inflammatory IL-10 cytokine without modifying that of pro-inflammatory IL-6, IL-8, and MCP-1 molecules via ERK1/2 and AKT. Finally, specifically silencing AdipoR1 or AdipoR2, we observed that NF-?B inhibition is mainly mediated by AdipoR1. Taken together, our data provides novel evidence for a direct effect of Acrp30 on the proliferation and inflammation status of A549 cells strongly supporting the hypothesis for a protective role of Acrp30 in lung. Further studies are needed to fully elucidate the Acrp30 lung effects in vivo but our results confirm this adipokine as a promising therapeutic target in lung diseases.