Pleural clinic: where thoracic ultrasound meets respiratory medicine.

Thoracic ultrasound (TUS) has become an essential procedure in respiratory medicine. Due to its intrinsic safety and versatility, it has been applied in patients affected by several respiratory diseases both in intensive care and outpatient settings. TUS can complement and often exceed stethoscope and radiological findings, especially in managing pleural diseases. We hereby aimed to describe the establishment, development, and optimization in a large, tertiary care hospital of a pleural clinic, which is dedicated to the evaluation and monitoring of patients with pleural diseases, including, among others, pleural effusion and/or thickening, pneumothorax and subpleural consolidation. The clinic was initially meant to follow outpatients undergoing medical thoracoscopy. In this scenario, TUS allowed rapid and regular assessment of these patients, promptly diagnosing recurrence of pleural effusion and other complications that could be appropriately managed. Over time, our clinic has rapidly expanded its initial indications thus becoming the place to handle more complex respiratory patients in collaboration with, among others, thoracic surgeons and oncologists. In this article, we critically describe the strengths and pitfalls of our "pleural clinic" and propose an organizational model that results from a synergy between respiratory physicians and other professionals. This model can inspire other healthcare professionals to develop a similar organization based on their local setting.

Extracellular Vesicles in Pulmonary Hypertension: A Dangerous Liaison?

The term pulmonary hypertension (PH) refers to different conditions, all characterized by increased pressure and resistance in the pulmonary arterial bed. PH has a wide range of causes (essentially, cardiovascular, pulmonary, or connective tissue disorders); however, idiopathic (i.e., without a clear cause) PH exists. This chronic, progressive, and sometimes devastating disease can finally lead to right heart failure and eventually death, through pulmonary vascular remodeling and dysfunction. The exact nature of PH pathophysiology is sometimes still unclear. Extracellular vesicles (EVs), previously known as apoptotic bodies, microvesicles, and exosomes, are small membrane-bound vesicles that are generated by almost all cell types and can be detected in a variety of physiological fluids. EVs are involved in intercellular communication, thus influencing immunological response, inflammation, embryogenesis, aging, and regenerative processes. Indeed, they transport chemokines, cytokines, lipids, RNA and miRNA, and other biologically active molecules. Although the precise functions of EVs are still not fully known, there is mounting evidence that they can play a significant role in the pathophysiology of PH. In this review, after briefly recapping the key stages of PH pathogenesis, we discuss the current evidence on the functions of EVs both as PH biomarkers and potential participants in the distinct pathways of disease progression.

Clinical Applications of Endobronchial Ultrasound (EBUS) Scope: Challenges and Opportunities.

Endobronchial Ultrasound (EBUS) has been widely used to stage lung tumors and to diagnose mediastinal diseases. In the last decade, this procedure has evolved in several technical aspects, with new tools available to optimize tissue sampling and to increase its diagnostic yield, like elastography, different types of needles and, most recently, miniforceps and cryobiopsy. Accordingly, the indications for the use of the EBUS scope into the airways to perform the Endobronchial Ultrasound-TransBronchial Needle Aspiration (EBUS-TBNA) has also extended beyond the endobronchial and thoracic boundaries to sample lesions from the liver, left adrenal gland and retroperitoneal lymph nodes via the gastroesophageal tract, performing the Endoscopic UltraSound with Bronchoscope-guided Fine Needle Aspiration (EUS-B-FNA). In this review, we summarize and critically discuss the main indication for the use of the EBUS scope, even the more uncommon, to underline its utility and versatility in clinical practice.

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.

Extracellular Vesicles in Lung Cancer: Bystanders or Main Characters?

Lung cancer still represents the main cause of cancer death worldwide. The poor survival is mainly related to the diagnosis which is often obtained in advanced stages when the disease is unresectable and characterized by the worst prognosis. Only in the last decades have great discoveries led to the development of new therapies targeted to oncogenes and to boost the host immune response against the tumor. Tumor identification and molecular/immunological characterization rely on bioptic samples which represent the gold standard for diagnosis. Nonetheless, less invasive procedures providing small samples will be more and more common in the future. Extracellular vesicles (EV), submicron particles released by any cell type, are candidates for diagnostic and prognostic biomarkers. EV are mediators of intercellular communication and can convey cytokines, miRNAs, antigens, and many other factors of tumorigenesis. This review summarizes the most appealing findings on lung-cancer-related EV, debating the evidence on circulating versus airway EV as potential biomarkers in disease management and the main studies on the role of these particles on lung cancer pathogenesis. Overall, the available results point toward a wide range of possible applications, supported by the promising achievements of genotyping on BAL fluid EV and proteomic analysis on pleural effusion EV. Nonetheless, the study of lung EV is still affected by remarkable methodological issues, especially when in vitro evidence is translated into humans. Whether EV still represent an "information fog" or can be useful in lung cancer management will be discussed, with possible hints on how to improve their usage.

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.

Chronic Bronchitis Affects Outcomes in Smokers without Chronic Obstructive Pulmonary Disease (COPD).

BACKGROUND: Chronic bronchitis (CB) importantly affects outcomes in smokers with COPD, but the effects on smokers without COPD are less well known and less emphasized. The aim of our study was to investigate the possible effects of CB on clinical outcomes in smokers without COPD (noCOPD) and compare them with the effects in smokers with COPD (COPD). METHODS: For that purpose, we studied 511 smokers, 302 with and 209 without COPD, followed for 10 years in an academic COPD ambulatory setting. Chronic bronchitis was defined as the presence of cough and sputum production for at least 3 months in each of two consecutive years. All subjects underwent clinical and functional examination with spirometry, diffusion capacity (DLco), 6-min walking test (6MWT), mMRC Dyspnoea Scale, COPD Assessment Test (CAT), and recording of annual frequency of exacerbations. All-cause mortality during follow-up was recorded. RESULTS: 27% of noCOPD and 45% of COPD had CB. noCOPD with CB had lower FEV1 and DLco, worse 6MWT, more dyspnoea, a higher number of exacerbations and lower survival than noCOPD without CB. CB did not affect FEV1 decline in noCOPD but it significantly did in COPD. CONCLUSIONS: The presence of chronic bronchitis in smokers without COPD will significantly affect symptoms, quality of life, and survival, underlining the importance of recognizing the condition and managing it accordingly.

Revealing the pathogenic and ageing-related mechanisms of the enigmatic idiopathic pulmonary fibrosis (and chronic obstructive pulmonary disease).

PURPOSE OF REVIEW: Growing evidence suggests that ageing-associated alterations occur in both idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). Here, we review the most recent literature on dysregulated ageing pathways in IPF and COPD and discuss how they may contribute to disease pathogenesis. RECENT FINDINGS: Recent studies have shown that alveolar epithelial type II (ATII) cells undergo premature senescence under stress and that senescent ATII cells promote lung fibrogenesis. Some studies have explored the role of mitochondrial dysfunction in IPF. They have provided evidence that dysfunctional mitochondria are important contributors to fibrogenesis through release of damaged DNA and excessive formation of reactive oxygen species, whereas restoration of mitochondrial homeostasis may attenuate lung fibrosis. Insufficient autophagy has been shown to promote epithelial-to-mesenchymal transition and aberrant epithelial-fibroblast crosstalk, suggesting that autophagy augmentation may represent a potential therapeutic strategy. A number of studies have also explored the role of cellular senescence, mitochondrial homeostasis and autophagy in COPD. SUMMARY: Several ageing mechanisms are dysregulated in the lungs of patients with IPF and COPD, although how they contribute to disease development and progression remains elusive. Genetic or pharmacologic attenuation of senescence-related pathways and elimination of senescent cells may represent a promising therapeutic strategy.

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.

Brief communication: Chest radiography score in young COVID-19 patients: Does one size fit all?

During the SARS-CoV-2 pandemic, chest X-Ray (CXR) scores are essential to rapidly assess patients' prognoses. This study evaluates a published CXR score in a different national healthcare system. In our study, this CXR score maintains a prognostic role in predicting length of hospital stay, but not disease severity. However, our results show that the predictive role of CXR score could be influenced by socioeconomic status and healthcare system.

The Role of Bronchoscopy in the Diagnosis and Management of Patients with SARS-Cov-2 Infection.

Bronchoscopy has several major diagnostic and therapeutic indications in pulmonology. However, it is an aerosol-generating procedure that places healthcare providers at an increased risk of infection. Now more than ever, during the spread of the coronavirus disease 2019 (COVID-19) pandemic, the infectious risk during bronchoscopy is significantly raised, and for this reason its role in diagnostic management is debated. In this review, we summarized current evidence regarding the indications for bronchoscopy and the measures that should be applied to decrease risk exposure. Indeed, seeing the long-lasting period of the pandemic, resuming standard of care for all patients is required.

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.

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.

Microvesicles in bronchoalveolar lavage as a potential biomarker of COPD.

Microvesicles (MVs) released from almost all cells are recognized as cell communication tools. MVs have been investigated in several inflammatory diseases but poorly in biological fluids like bronchoalveolar lavage (BAL) of smokers. The purpose of this study was to investigate the presence and source of MVs in BAL of smokers with and without chronic obstructive pulmonary disease (COPD) compared with nonsmoking controls. Using flow cytometry in BAL, we detected endothelial and alveolar macrophage (AM)-derived MVs and found a higher number of AM-MVs in the BAL of smokers with COPD than in smokers without COPD and nonsmokers, which correlated with the pack-years (r = 0.46; P = 0.05) and with the degree of airway obstruction measured by the forced expiratory volume in 1 s percent predicted (r = -0.56; P = 0.01). Endothelial and alveolar macrophage-derived MVs are present and measurable in human BAL fluid. In response to smoking and to the development of COPD, inflammatory signals in AM-derived MVs can be quantified, and their numbers are related to the pack-years and the decrease in lung function. These results open the opportunity for future investigation of these microvesicles as biomarkers and possible mechanistic guides in COPD.

Multiple pulmonary nodules presenting a difficult diagnostic challenge.

We describe the case of a 56 years-old man with a subacute onset of symptoms mimicking a granulomatosis with polyangiitis. He was admitted to our hospital with acute respiratory failure requiring oxygen therapy, fever and crusted rhinitis. Despite initial improvement in radiological and clinical features with a steroids therapy, his condition worsened rapidly and he was re admitted to our department with ARDS. Despite antibiotic, antiviral and antifungal therapy, an endotracheal intubation was necessary and ultimately the patient passed away. Only a histological examination on autopsy had shown the presence of a diffuse Anaplastic Large Cell Lymphoma (ALCL), a rare type of non-Hodgkin lymphoma (NHL) originated from mature post-thymic T cells. It represents 1-3% of NHL. Different subtypes have been described: Kinase (ALK)-negative ALCL, ALK-positive ALCL and breast implantassociated ALCL. ALK-negative ALCL affects mainly old males and has the worst prognosis.

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.

Reassessing the Role of Eosinophils as a Biomarker in Chronic Obstructive Pulmonary Disease.

Blood eosinophils measurement, as proxy for tissue eosinophils, has become an important biomarker for exacerbation risk and response to inhaled corticosteroids (ICS) in Chronic Obstructive Pulmonary Disease (COPD). Its use to determine the pharmacological approach is recommended in the latest COPD guidelines. The potential role of blood eosinophils is mainly based on data derived from post-hoc and retrospective analyses that showed an association between increased blood eosinophils and risk of exacerbations, as well as mitigation of this risk with ICS. Yet other publications, including studies in real life COPD, do not confirm these assumptions. Moreover, anti-eosinophil therapy targeting interleukin (IL)-5 failed to reduce exacerbations in COPD patients with high blood eosinophils, which casts significant doubts on the role of eosinophils in COPD. Furthermore, a reduction of eosinophils might be harmful since COPD patients with relatively high eosinophils have better pulmonary function, better life quality, less infections and longer survival. These effects are probably linked to the role of eosinophils in the immune response against pathogens. In conclusion, in COPD, high blood eosinophils are widely used as a biomarker for exacerbation risk and response to ICS. However, much is yet to be learned about the reasons for the high eosinophil counts, their variations and their controversial effects on the fate of COPD patients.