Suppressor of cytokine signaling-3 expression and its regulation in relation to inflammation in Chronic Obstructive Pulmonary Disease.

Background: The family of Suppressor of Cytokine Signaling (SOCS) acts as a controller of the duration and intensity of cytokine function by negatively regulating the JAK-STAT signaling pathway. SOCS' role in inflammatory diseases in animal models is well demonstrated. However, its role in the development of human disease is still under investigation. SOCS3 plays an important role in tumor development where its downregulation has been implicated in the pathogenesis of various solid tumors such as triple-negative breast cancer. Aim: The aim of this work was to study (1) the expression of SOCS3 in smokers' lungs and its relation to the degree of inflammation and (2) SOCS3 regulation by microRNA (miRNA) in alveolar-macrophage (AM)-derived extracellular vesicles (EVs) in bronchoalveolar lavage (BAL). Methods: Group A: 35 smokers' [19 with COPD (SC) and 16 without COPD (S)] and 9 nonsmokers (NS); SOCS3, TNFα in AM, and CD8+ T cells were quantified by immunohistochemistry, in lung tissue. Group B: additional 9 SC, 11 S, and 5 NS; AM-EVs expressing SOCS3 (CD14+SOCS3+) and SOCS3 suppressors miRNA-19a-3p and 221-3p in EVs were quantified by flow cytometry and PCR, in BAL. Results: The percentage of SOCS3+ AM was higher in SC [68 (6.6-99)%] and S [48 (8-100)%] than in NS [9.6 (1.9-61)%; p = 0.002; p = 0.03] and correlated with % of TNFα+AM (r = 0.48; p = 0.0009) and CD8+ T cells (r = 0.44; p = 0.0029). In BAL, the CD14+SOCS3+ EVs/µL were increased in SC [33 (21-74)] compared to S [16 (8-37); p = 0.03] and NS [9 (7-21); p = 0.003]. Conversely, miRNA-19a-3p and miRNA-221-3p expression were increased in S when compared to SC [19 (2-53) vs. 3 (0.6-8); p = 0.03 and 3 (0.005-9.6) vs. 0.2 (0.08-0.7); p = 0.05]. Conclusions: The suppressor function of SOCS3 in COPD seems to be overridden by other factors and does not follow the animal-model paradigm. Expression of SOCS3 in BAL macrophage-derived EVs might be useful to assess the degree of inflammation and possible progression of COPD. Downregulation of SOCS3, by miRNA, in smokers without COPD might contribute to the risk of developing cancer in these patients.

Update on virus-induced asthma exacerbations.

INTRODUCTION: Viral infections are common triggers for asthma exacerbation. Subjects with asthma are more susceptible to viral infections and develop more severe or long-lasting lower respiratory tract symptoms than healthy individuals owing to impaired immune responses. Of the many viruses associated with asthma exacerbation, rhinovirus (RV) is the most frequently identified virus in both adults and children. AREAS COVERED: We reviewed epidemiological and clinical links and mechanistic studies on virus-associated asthma exacerbations. We included sections on severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), the latest evidence of coronavirus disease 2019 (COVID-19) in asthma patients, and past and future searches for therapeutic and prevention targets. EXPERT OPINION: Early treatment or prevention of viral infections might significantly reduce the rate of asthma exacerbation, which is one of the key points of disease management. Although it is hypothetically possible nowadays to interfere with every step of the infectious cycle of respiratory tract viruses, vaccination development has provided some of the most encouraging results. Future research should proceed toward the development of a wider spectrum of vaccines to achieve a better quality of life for patients with asthma and to reduce the economic burden on the healthcare system.

Extracellular Vesicles (EVs) as Crucial Mediators of Cell-Cell Interaction in Asthma.

Asthma is the most common chronic respiratory disorder worldwide and accounts for a huge health and economic burden. Its incidence is rapidly increasing but, in parallel, novel personalized approaches have emerged. Indeed, the improved knowledge of cells and molecules mediating asthma pathogenesis has led to the development of targeted therapies that significantly increased our ability to treat asthma patients, especially in severe stages of disease. In such complex scenarios, extracellular vesicles (EVs i.e., anucleated particles transporting nucleic acids, cytokines, and lipids) have gained the spotlight, being considered key sensors and mediators of the mechanisms controlling cell-to-cell interplay. We will herein first revise the existing evidence, mainly by mechanistic studies in vitro and in animal models, that EV content and release is strongly influenced by the specific triggers of asthma. Current studies indicate that EVs are released by potentially all cell subtypes in the asthmatic airways, particularly by bronchial epithelial cells (with different cargoes in the apical and basolateral side) and inflammatory cells. Such studies largely suggest a pro-inflammatory and pro-remodelling role of EVs, whereas a minority of reports indicate protective effects, particularly by mesenchymal cells. The co-existence of several confounding factors-including technical pitfalls and host and environmental confounders-is still a major challenge in human studies. Technical standardization in isolating EVs from different body fluids and careful selection of patients will provide the basis for obtaining reliable results and extend their application as effective biomarkers in asthma.

Increased risk of emergency department presentations for bronchiolitis in infants exposed to air pollution.

Air pollution has been linked to an increased risk of several respiratory diseases in children, especially respiratory tract infections. The present study aims to evaluate the association between pediatric emergency department (PED) presentations for bronchiolitis and air pollution. PED presentations due to bronchiolitis in children aged less than 1 year were retrospectively collected from 2007 to 2018 in Padova, Italy, together with daily environmental data. A conditional logistic regression based on a time-stratified case-crossover design was performed to evaluate the association between PED presentations and exposure to NO2 , PM2.5, and PM10. Models were adjusted for temperature, relative humidity, atmospheric pressure, and public holidays. Delayed effects in time were evaluated using distributed lag non-linear models. Odds ratio for lagged exposure from 0 to 14 days were obtained. Overall, 2251 children presented to the PED for bronchiolitis. Infants' exposure to higher concentrations of PM10 and PM2.5 in the 5 days before the presentation to the PED increased the risk of accessing the PED by more than 10%, whereas high concentrations of NO2 between 2 and 12 days before the PED presentation were associated with an increased risk of up to 30%. The association between pollutants and infants who required hospitalization was even greater. A cumulative effect of NO2 among the 2 weeks preceding the presentation was also observed. In summary, PM and NO2 concentrations are associated with PED presentations and hospitalizations for bronchiolitis. Exposure of infants to air pollution could damage the respiratory tract mucosa, facilitating viral infections and exacerbating symptoms.

Differences Between Early- and Late-Onset Asthma: Role of Comorbidities in Symptom Control.

BACKGROUND: Asthma can present in early childhood or de novo in adulthood. Our understanding of the burden of comorbidities in adult asthmatic patients stratified by age at onset is incomplete. OBJECTIVES: To evaluate how different comorbidities may affect symptom control in two distinct groups of patients with early- and late-onset asthma (EOA and LOA, respectively) and to explore whether reported comorbidities are associated with lung function and inflammatory parameters. METHODS: We conducted a cross-sectional study of 175 adult asthmatic patients (aged 57.5 ± 17.1 years) recruited at our university asthma clinic. We defined EOA as asthma onset less than 12 years, and LOA as onset greater than 40 years. The primary outcome was symptom control and main comorbidities evaluated were rhinitis, gastroesophageal reflux, obesity, cardiovascular conditions, and bronchiectasis. We used multivariable regression analysis to identify potential predictors of poor control in EOA and LOA. RESULTS: Of 175 subjects, 77 had EOA (44%), 98 had LOA (56%), and comorbidities had a differential impact in the two groups. Rhinitis was more frequent in EOA (76 vs 53%; P = .02) and was associated with uncontrolled asthma (P < .001), reduced FEV1/FVC (P = .01), increased eosinophils (P = .003) and total IgE (P < .01). Conversely, in LOA, rhinitis was associated with more controlled asthma and higher FEV1/FVC (both P < .01). In EOA, only, IgE levels were directly related to blood eosinophils (r = 0.42; P <.001) and inversely to FEV1/FVC (r = -0.35; P = .002). Obesity was present in 20% of patients in both groups, but only in LOA was it associated with uncontrolled disease (P = .009), reduced FEV1/FVC (P = .009), and blood neutrophils (P = .03). In multivariable regression analysis, rhinitis in EOA and obesity in LOA were the risk factors most closely associated with poor control. Gastroesophageal reflux, cardiovascular comorbidities, and bronchiectasis did not affect control. CONCLUSIONS: Early-onset persistent asthma and late-onset asthma are distinct phenotypes with different underlying inflammatory patterns and different comorbidities affecting symptom control.

Multidimensional 3-Month Follow-Up of Severe COVID-19: Airways beyond the Parenchyma in Symptomatic Patients.

SARS-CoV-2 may lead to a large spectrum of respiratory manifestations, including pulmonary sequelae. We conducted a single-center longitudinal study of survivors from severe COVID-19 cases who underwent a chest CT during hospitalization (CTH). Three months after being discharged, these patients were evaluated by a clinical examination, pulmonary function tests and a chest-CT scan (CTFU). Sixty-two patients were enrolled. At follow-up, 27% complained of exertional dyspnoea and 12% of cough. Dyspnoeic patients had a lower forced expiratory flow (FEF)25-75 (p = 0.015), while a CT scan (p = 0.016 showed that patients with cough had a higher extent of bronchiectasis. Lung volumes and diffusion of carbon monoxide (DLCO) at follow-up were lower in patients who had been invasively ventilated, which correlated inversely with the length of hospitalization and ground-glass extension at CTH. At follow-up, 14.5% of patients had a complete radiological resolution, while 85.5% presented persistence of ground-glass opacities, and 46.7% showed fibrotic-like alterations. Residual ground-glass at CTFU was related to the length of hospitalization (r = 0.48; p = 0.0002) and to the need for mechanical ventilation or high flow oxygen (p = 0.01) during the acute phase. In conclusion, although patients at three months from discharge showed functional impairment and radiological abnormalities, which correlated with a prolonged hospital stay and need for mechanical ventilation, the persistence of respiratory symptoms was related not to parenchymal but rather to airway sequelae.

Symptomatic smokers without COPD have physiological changes heralding the development of COPD.

Background: COPD is a major health problem, mainly due to cigarette smoking. Most studies in COPD are dedicated to fully developed COPD in older subjects, even though development of COPD may start soon after smoking initiation. Therefore, there is a need to diagnose this "early disease" by detecting the initial events responsible for ultimate development of COPD. Methods: Measurement of maximum mid expiratory flow between 25 and 75% of vital capacity (MMEF) in a routine spirometry, which detects small airways disease, was used to investigate if MMEF abnormalities in smokers without COPD (noCOPD) would relate to respiratory symptoms and identify smokers that might progress to COPD. For this purpose we studied 511 smokers, 302 COPD and 209 noCOPD, followed long term with spirometry including MMEF, diffusing capacity of the lung for carbon monoxide (D LCO), 6-min walk test (6MWT), Medical Research Council Dyspnoea Scale and COPD Assessment Test. Three spirometries V1,V2 and V3 (5±2.5 and 10±4 years apart from V1) were performed to assess functional decline and development of COPD. Results: 65% of noCOPD had an abnormal MMEF (<80%) and 38% an abnormal D LCO. The NoCOPD with MMEF <80% group performed worse in the 6MWT (p=0.01), was more dyspnoeic (p=0.01) and had higher prevalence of chronic bronchitis than the noCOPD with MMEF>80% group (p=0.04). 21% of noCOPD with MMEF <80% and 2.7% with MMEF>80% developed COPD by V3 (p=0.0004). Conclusions: The MMEF, a functional test available in a routine spirometry, can detect early lung abnormalities and identify the subset of symptomatic smokers with pathological changes that might lead to COPD.

Air Pollution Exposure Impairs Airway Epithelium IFN-ß Expression in Pre-School Children.

Introduction: Air pollution is a risk factor for respiratory infections and asthma exacerbations. We previously reported impaired Type-I and Type-III interferons (IFN-ß/λ) from airway epithelial cells of preschool children with asthma and/or atopy. In this study we analyzed the association between rhinovirus-induced IFN-ß/λ epithelial expression and acute exposure to the principal outdoor air pollutants in the same cohort. Methods: We studied 34 children (17asthmatics/17non-asthmatics) undergoing fiberoptic bronchoscopy for clinical indications. Bronchial epithelial cells were harvested by brushing, cultured and experimentally infected with Rhinovirus Type 16 (RV16). RV16-induced IFN-ß and λ expression was measured by quantitative real time PCR, as was RV16vRNA. The association between IFNs and the mean exposure to PM10, SO2 and NO2 in the day preceding bronchoscopy was evaluated using a Generalized Linear Model (GLM) with Gamma distribution. Results: Acute exposure to PM10 and NO2 was negatively associated to RV16-induced IFNß mRNA. For each increase of 1ug/m3 of NO2 we found a significative decrease of 2.3x103 IFN-ß mRNA copies and for each increase of 1ug/m3 of PM10 a significative decrease of 1x103 IFN-ß mRNA copies. No significant associations were detected between IFN-λ mRNA and NO2 nor PM10. Increasing levels of NO2 (but not PM10) were found to be associated to increased RV16 replication. Conclusions: Short-term exposure to high levels of NO2 and PM10 is associated to a reduced IFN-ß expression by the airway epithelium, which may lead to increased viral replication. These findings suggest a potential mechanism underlying the link between air pollution, viral infections and asthma exacerbations.

Pneumothorax and/or Pneumomediastinum Worsens the Prognosis of COVID-19 Patients with Severe Acute Respiratory Failure: A Multicenter Retrospective Case-Control Study in the North-East of Italy.

Pneumothorax (PNX) and pneumomediastinum (PNM) are potential complications of COVID-19, but their influence on patients' outcomes remains unclear. The aim of the study was to assess incidence, risk factors, and outcomes of severe COVID-19 complicated with PNX/PNM. METHODS: A retrospective multicenter case-control analysis was conducted in COVID-19 patients admitted for respiratory failure in intermediate care units of the Treviso area, Italy, from March 2020 to April 2021. Clinical characteristics and outcomes of patients with and without PNX/PNM were compared. RESULTS: Among 1213 patients, PNX and/or PNM incidence was 4.5%. Among these, 42% had PNX and PNM, 33.5% only PNX, and 24.5% only PNM. COVID-19 patients with PNX/PNM showed higher in-hospital (p = 0.02) and 90-days mortality (p = 0.048), and longer hospitalization length (p = 0.002) than COVID-19 patients without PNX/PNM. At PNX/PNM occurrence, one-third of subjects was not mechanically ventilated, and the respiratory support was similar to the control group. PNX/PNM occurrence was associated with longer symptom length before hospital admission (p = 0.005) and lower levels of blood lymphocytes (p = 0.017). CONCLUSION: PNX/PNM are complications of COVID-19 associated with a worse prognosis in terms of mortality and length of hospitalization. Although they are more frequent in ventilated patients, they can occur in non-ventilated, suggesting that mechanisms other than barotrauma might contribute to their presentation.

Risk Factors for Development and Severity of COVID-19 in COPD Patients.

The impact that COVID-19 could have on patients with COPD is a real concern. In this study we evaluated, in a cohort of longitudinally followed COPD subjects, the incidence of COVID-19, seeking for possible risk factors and prognostic factors predicting the clinical outcome. In our cohort of 370 patients (followed for 5.3 ± 2.7 years), 22 developed COVID-19 (COPD/COVID-19+) between February/November 2020 (5.9%). Cardio-metabolic conditions (hypertension, dyslipidemia, obesity, diabetes) but not respiratory abnormalities (FEV1, DLCO, emphysema and exacerbation history), were risk factors for development of COVID-19 in COPD patients. Out of the 22 COPD/COVID-19+ patients, 10 needed intensive care. Low DLCO and emphysema, but also metabolic comorbidities, were related to the need for intensive care.

Critical Review of the Evolution of Extracellular Vesicles' Knowledge: From 1946 to Today.

Extracellular vesicles (EVs) are a family of particles/vesicles present in blood and body fluids, composed of phospholipid bilayers that carry a variety of molecules that can mediate cell communication, modulating crucial cell processes such as homeostasis, induction/dampening of inflammation, and promotion of repair. Their existence, initially suspected in 1946 and confirmed in 1967, spurred a sharp increase in the number of scientific publications. Paradoxically, the increasing interest for EV content and function progressively reduced the relevance for a precise nomenclature in classifying EVs, therefore leading to a confusing scientific production. The aim of this review was to analyze the evolution of the progress in the knowledge and definition of EVs over the years, with an overview of the methodologies used for the identification of the vesicles, their cell of origin, and the detection of their cargo. The MISEV 2018 guidelines for the proper recognition nomenclature and ways to study EVs are summarized. The review finishes with a "more questions than answers" chapter, in which some of the problems we still face to fully understand the EV function and potential as a diagnostic and therapeutic tool are analyzed.

Air Pollution Relates to Airway Pathology in Children with Wheezing.

Rationale: Outdoor air pollution contributes to asthma development and exacerbations, yet its effects on airway pathology have not been defined in children. Objectives: To explore the possible link between air pollution and airway pathology, we retrospectively examined the relationship between environmental pollutants and pathological changes in bronchial biopsy specimens from children undergoing a clinically indicated bronchoscopy. Methods: Structural and inflammatory changes (basement membrane [BM] thickness, epithelial loss, eosinophils, neutrophils, macrophages, mast cells, and lymphocytes) were quantified in biopsy specimens by using immunohistochemistry. The association between exposure to particulate matter less than 10 µm in aerodynamic diameter (PM10), SO2 and NO2 and biopsy findings was evaluated by using a generalized additive model with Gamma family to allow for overdispersion, adjusted for atmospheric pressure, temperature, humidity, and wheezing. Results: Overall, 98 children were included (age 5.3 ± 2.9 yr; 53 with wheezing/45 without wheezing). BM thickness increased with prolonged exposure to PM10 (rate ratio [RR], 1.29; 95% confidence interval [CI], 1.09-1.52), particularly in children with wheezing. Prolonged exposure to PM10 was also associated with eosinophilic inflammation in children with wheezing (RR, 3.16; 95% CI, 1.35-7.39). Conversely, in children without wheezing, increased PM10 exposure was associated with a reduction of eosinophilic inflammation (RR, 0.12; 95% CI, 0.02-0.6) and neutrophilic inflammation (RR, 0.36; 95% CI, 0.14-0.89). Moreover, NO2 exposure was also linked to reductions in neutrophil infiltration (RR, 0.57; 95% CI, 0.34-0.93) and eosinophil infiltration (RR, 0.33; 95% CI, 0.14-0.77). Conclusions: Different patterns of association were observed in children with wheezing and in children without wheezing. In children without wheezing, exposure to PM10 and NO2 was linked to reduced eosinophilic and neutrophilic inflammation. Conversely, in children with wheezing, prolonged exposure to PM10 was associated with increased BM thickness and eosinophilic inflammation, suggesting that it might contribute to asthma development by promoting airway remodeling and inflammation.

Low-Blood Lymphocyte Number and Lymphocyte Decline as Key Factors in COPD Outcomes: A Longitudinal Cohort Study.

BACKGROUND: Smokers with and without chronic obstructive pulmonary disease (COPD) are at risk of severe outcomes like exacerbations, cancer, respiratory failure, and decreased survival. The mechanisms for these outcomes are unclear; however, there is evidence that blood lymphocytes (BL) number might play a role. OBJECTIVE: The objective of this study is to investigate the relationship between BL and their possible decline over time with long-term outcomes in smokers with and without COPD. METHODS: In 511 smokers, 302 with COPD (COPD) and 209 without COPD (noCOPD), followed long term, we investigated whether BL number and BL decline over time might be associated with long-term outcomes. Smokers were divided according to BL number in high-BL (≥1,800 cells/µL) and low-BL (<1,800 cells/µL). Clinical features, cancer incidence, and mortality were recorded during follow-up. BL count in multiple samples and BL decline over time were calculated and related to outcomes. RESULTS: BL count was lower in COPD (1,880 cells/µL) than noCOPD (2,300 cells/µL; p < 0.001). 43% of COPD and 23% of noCOPD had low-BL count (p < 0.001). BL decline over time was higher in COPD than noCOPD (p = 0.040). 22.5% of the whole cohort developed cancer which incidence was higher in low-BL subjects and in BL decliners than high-BL (31 vs. 18%; p = 0.001) and no decliners (32 vs. 19%; p = 0.002). 26% in the cohort died during follow-up. Furthermore, low-BL count, BL decline, and age were independent risk factors for mortality by Cox regression analysis. CONCLUSION: BL count and BL decline are related to worse outcomes in smokers with and without COPD, which suggests that BL count and decline might play a mechanistic role in outcomes deterioration. Insights into mechanisms inducing the fall in BL count could improve the understanding of COPD pathogenesis and point toward new therapeutic measures.

Prognostic role of MUC5B rs35705950 genotype in patients with idiopathic pulmonary fibrosis (IPF) on antifibrotic treatment.

BACKGROUND: A common variant located in the promoter region of MUC5B (rs35705950) is the strongest risk factor for sporadic and familiar IPF, as well as a predictor of outcome. However, there are no data on the effect of MUC5B rs35705950 genotype on the prognosis of IPF patients on antifibrotic treatment. The aim of this study is to determine, in a phenotypically well-characterized population of patients with IPF treated with antifibrotics, the impact of MUC5B rs35705950 genotype on disease progression and survival. METHODS: 88 IPF patients on antifibrotic treatment were followed-up from 2014 until transplantation, death or end of follow-up (December 2019). Disease progression was defined as a forced vital capacity (FVC) loss ≥ 5% per year. All patients were genotyped for MUC5B rs35705950 by PCR amplification and Sanger sequencing. RESULTS: Out of 88 patients, 61 (69%) carried the mutant T allele (TT or TG) and 27 (31%) did not (GG). Carriage of the MUC5B rs35705950 T allele was not associated with a faster decline in FVC. Conversely, at the end of the follow-up, overall survival in carriers of the TT/TG genotype was longer compared to that of the GG genotype carriers. FVC (L) at baseline and time to respiratory failure at rest were independent predictors of worse prognosis. CONCLUSIONS: In IPF patients on antifibrotic treatment, carriage of the MUC5B rs35705950 T allele is associated with longer survival, highlighting the usefulness of MUC5B genetic data in clinical decision making.

Influence of Cell Quality on Inflammatory Biomarkers in COPD Sputum Supernatant.

PURPOSE: We recently introduced a sputum cell quality score to rate how cell morphology, cellular debris and squamous cell contamination influence inflammatory cell identification during microscopic evaluation. However, sputum cell quality is generally not considered for the interpretation of sputum fluid phase biomarkers. Therefore, we compared the soluble protein concentrations between sputum samples with different cell quality. The impact of cell quality was compared to other factors potentially affecting soluble biomarker concentrations. METHODS: A comprehensive sputum dataset from 154 clinically stable COPD patients was used to analyse the differences and the variability of sputum supernatant concentrations for 23 proteins between low, medium, and high sputum cell quality samples. A model was developed and tested to compare the impact of different factors on sputum supernatant protein levels. RESULTS: Mean percentages of sputum macrophages, neutrophils, eosinophils, monocytes and lymphocytes showed no significant differences between low, medium and high cell quality levels. The mean percentage of squamous cells were lower, while total cell count/mL sputum and cell viability were significantly higher in sputum samples with higher cell quality. The concentrations of Interleukin-6, Interleukin-8 and Tumor Necrosis Factor Receptor 2 were significantly increased in sputum samples of higher cell quality. The variability of most protein concentrations declined with increasing cell quality levels. Sixteen proteins showed significantly negative correlations with the percentage of squamous cells. For 14 proteins we observed a positive correlation with cell number/mL sputum. Multiple regression analysis shows that generally less than 30% of the protein variability can be explained by the included factors. CONCLUSION: Sputum cell quality has a significant impact on some soluble biomarker concentrations in sputum supernatant. Sputum samples with low sputum cell quality show a higher variability of fluid phase proteins in comparison to medium and high sputum cell quality levels.

CA 19-9 serum levels in patients with end-stage idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases (ILDs): Correlation with functional decline.

Idiopathic pulmonary fibrosis presents a progressive and heterogeneous functional decline. CA 19-9 has been proposed as biomarker to predict disease course, but its role remains unclear. We assessed CA 19-9 levels and clinical data in end-stage ILD patients (48 IPF and 20 non-IPF ILD) evaluated for lung transplant, to correlate these levels with functional decline. Patients were categorized based on their rate of functional decline as slow (n = 20; ΔFVC%pred ≤ 10%/year) or rapid progressors (n = 28; ΔFVC%pred ≥ 10%/year). Nearly half of the entire patients (n = 32; 47%) had CA 19-9 levels ≥37kU/L. CA 19-9 levels in IPF were not different from non-IPF ILD populations, however, the latter group had a median CA 19-9 level above the normal cut-off value of 37 KU/l (60 [17-247] kU/L). Among IPF patients, CA 19-9 was higher in slow than in rapid progressors with a trend toward significance (33vs17kU/L; p = 0.055). In the whole population, CA19-9 levels were inversely related with ΔFVC/year (r = -0.261; p = 0.03), this correlation remained in IPF patients, particularly in rapid progressors (r = -0.51; p = 0.005), but not in non. Moreover, IPF rapid progressors with normal CA 19-9 levels showed the greater ΔFVC/year compared to those with abnormal CA 19-9 (0.95 vs. 0.65 L/year; p = 0.03). In patients with end-stage ILD, CA 19-9 may represent a marker of disease severity, whereas its level is inversely correlated with functional decline, particularly among IPF rapid progressors.

Heart Failure is Highly Prevalent and Difficult to Diagnose in Severe Exacerbations of COPD Presenting to the Emergency Department.

BACKGROUND: Some 20% of patients with stable Chronic Obstructive Pulmonary Disease (COPD) might have heart failure (HF). HF contribution to acute exacerbations of COPD (AECOPD) presenting to the emergency department (ED) is not well established. AIMS: To assess (1) the HF incidence in patients presenting to the ED with AECOPD; (2) the concordance between ED and respiratory ward (RW) diagnosis; (3) the factors associated with risk of death after hospital discharge. METHODS: Retrospective chart review of 119 COPD patients presenting to ED for acute exacerbation of respiratory symptoms and then admitted to RW where a final diagnosis of AECOPD, AECOPD and HF and AECOPD and OD (other diagnosis), was obtained. ED and RW diagnosis were then compared. Factors affecting survival at follow-up were investigated. RESULTS: At RW, 40.3% of cases were diagnosed of AECOPD, 40.3% of AECOPD and HF and 19.4% of AECOPD and OD, with ED diagnosis coinciding with RW's in 67%, 23%, and 57% of cases respectively. At RW, 60% of patients in GOLD1 had HF, of which 43% were diagnosed at ED, while 40% in GOLD4 had HF that was never diagnosed at ED. Lack of inclusion in a COPD care program, HF, and early readmission for AECOPD were associated with mortality. CONCLUSIONS: HF is highly prevalent and difficult to diagnose in patients in all GOLD stages presenting to the ED with severe AECOPD, and along with lack of inclusion in a COPD care program, confers a high risk for mortality.

Airway inflammatory profile is correlated with symptoms in stable COPD: A longitudinal proof-of-concept cohort study.

BACKGROUND AND OBJECTIVE: Symptoms negatively impact the quality of life and long-term prognosis of patients with chronic obstructive pulmonary disease (COPD). Little is known about the relationship linking airway inflammation and symptoms in stable COPD. In this study, we evaluated whether respiratory symptoms in COPD are related to sputum inflammatory cellular profile and whether symptom changes are associated with changes in airway inflammation. METHODS: A total of 40 patients with stable COPD with moderate-to-severe airflow obstruction were enrolled. Patients were visited weekly over 4 weeks. At each visit, patients underwent clinical assessments, lung function tests and sputum induction. Patients recorded daily dyspnoea, sputum and cough scores. RESULTS: The changes between two consecutive visits in the percent of sputum neutrophils and eosinophils were related to the changes in the cough (P < 0.001; r = 0.63) and dyspnoea scores (P < 0.001; r = 0.58) of the prior week. Furthermore, using regression analyses, we were able to demonstrate that changes in the cough score were specifically associated to the change in neutrophils, while changes in the dyspnoea score and use of rescue medications were associated with changes in eosinophils numbers. CONCLUSION: Our study showed an association between symptoms and the sputum inflammatory profile. In particular, changes in symptoms (cough and dyspnoea) were correlated with changes in the specific sputum inflammatory cell components of airway inflammation (neutrophils and eosinophils, respectively), providing novel information on the mechanisms of disease manifestation.