Pulmonary embolism: yet another cause of hypoxaemic respiratory failure in COVID-19

Pulmonary embolism represents an overlooked cause of worsening respiratory failure in COVID-19. A regular bedside evaluation for atypical features like pleuritic chest pain or pleural effusion could help identify suspected cases for appropriate management

Do Circulating Extracellular Vesicles Strictly Reflect Bronchoalveolar Lavage Extracellular Vesicles in COPD?

Cell-derived extracellular vesicles (EVs) found in the circulation and body fluids contain biomolecules that could be used as biomarkers for lung and other diseases. EVs from bronchoalveolar lavage (BAL) might be more informative of lung abnormalities than EVs from blood, where informa- tion might be diluted. To compare EVs’ characteristics in BAL and blood in smokers with and without COPD. Same-day BAL and blood samples were obtained in 9 nonsmokers (NS), 11 smokers w/o COPD (S), and 9 with COPD (SCOPD) (FEV1: 59 ± 3% pred). After differential centrifugation, EVs (200–500 nm diameter) were identified by flow cytometry and labeled with cell-type specific antigens: CD14 for macrophage-derived EVs, CD326 for epithelial-derived EVs, CD146 for endothelial-derived EVs, and CD62E for activated-endothelial-derived EVs. In BAL, CD14-EVs were increased in S compared to NS [384 (56–567) vs. 172 (115–282) events/μL; p = 0.007] and further increased in SCOPD [619 (224–888)] compared to both S (p = 0.04) and NS (p < 0.001). CD326-EVs were increased in S [760 (48–2856) events/μL, p < 0.001] and in SCOPD [1055 (194–11,491), p < 0.001] when compared to NS [15 (0–68)]. CD146-EVs and CD62E-EVs were similar in the three groups. In BAL, significant differences in macrophage and epithelial-derived EVs can be clearly detected between NS, S and SCOPD, while these differences were not found in plasma. This suggests that BAL is a better medium than blood to study EVs in lung diseases

Pirfenidone for Idiopathic Pulmonary Fibrosis and Beyond

Pirfenidone (PFD) slows the progression of idiopathic pulmonary fibrosis (IPF) by inhibiting the exaggerated fibrotic response and possibly through additional mechanisms, such as anti-inflammatory effects. PFD has also been evaluated in other fibrosing lung diseases. Myocardial fibrosis is a common feature of several heart diseases and the progressive deposition of extracellular matrix due to a persistent injury to cardiomyocytes may trigger a vicious cycle that leads to persistent structural and functional alterations of the myocardium. No primarily antifibrotic medications are used to treat patients with heart failure. There is some evidence that PFD has antifibrotic actions in various animal models of cardiac disease and a phase II trial on patients with heart failure and preserved ejection fraction has yielded positive results. This review summarises the evidence about the possible mechanisms of IPF and modulation by PFD, the main results about IPF or non-IPF interstitial pneumonias and also data about PFD as a potential protective cardiac drug

Effetti della terapia broncodilatatrice sulla tolleranza allo sforzo nel paziente con broncopneumopatia cronica ostruttiva

La Broncopneumopatia Cronica Ostruttiva (BPCO) è una malattia dell’apparato respiratorio caratterizzata dalla presenza di dispnea, deterioramento della qualità della vita e ridotta tolleranza all’esercizio, che si può valutare con il test da sforzo cardiopolmonare incrementale e con il test da sforzo cardiopolmonare a carico costante. La terapia broncodilatatrice può aumentare la capacità all’esercizio in questi pazienti. Scopo della tesi. Lo scopo di questa tesi è valutare, mediante uno studio in crossover in singolo cieco, l’efficacia di un pretrattamento in acuto con broncodilatatatori nebulizzati (anticolinergici e β2agonisti) associati a cortisonici inalatori (CSI), in confronto con placebo (soluzione fisiologica) sul tempo di endurance (endurance time, ET), sul consumo massimo di ossigeno (VO2/kg), sulla frequenza cardiaca massima (FC) e sulla capacità inspiratoria (IC) valutata nel test cardiopolmonare a carico costante in pazienti affetti da BPCO. Soggetti e metodi. Sono stati studiati 17 soggetti (15 maschi e 2 femmine, età: 68,35 5,85 anni, fumatori o ex-fumatori con 57 41 pack-years) affetti da BPCO di grado moderato (FEV1: 53,5% 16,7% pred), in fase di stabilità clinica e sottoposti a regolare terapia farmacologica. Tutti hanno eseguito inizialmente: test da sforzo cardiopolmonare incrementale a rampa, Prove di Funzionalità Respiratoria (PFR e DLCO), EGA a riposo, valutazione della qualità della vita mediante Saint George’s Respiratory Questionnaire, test del cammino in 6 minuti (6MWT). Successivamente, in due giorni diversi, i soggetti hanno eseguito un test cardiopolmonare a carico costante (pari all’80% del wattaggio massimo raggiunto nel test incrementale) preceduto da inalazione di una combinazione di broncodilatatori (salbutamolo ed ipratropio) e con CSI (B+CSI), o da placebo (soluzione fisiologica, SF). Risultati. Il pretrattamento con broncodilatatori e CSI non ha prodotto un cambiamento statisticamente significativo del tempo di endurance (ET), del consumo massimo di ossigeno (VO2/kg), della frequenza cardiaca ad isotime (FCiso) e nella capacità inspiratoria (IC) alla fine dello sforzo a carico costante. La IC basale risultava lievemente maggiore dopo B+CSI rispetto a SF (2,71 L vs 2,44 L, rispettivamente). La FC massima alla fine del test a carico costante dopo B+CSI era significativamente maggiore rispetto alla SF (109 bpm vs 105 bpm; p: 0,046). Un sottogruppo di 7 soggetti mostrava un aumento di almeno 30 secondi del tempo di endurance dopo B+CSI (responders). Questi pazienti presentavano, rispetto ai 10 che non miglioravano l’ET dopo trattamento attivo (non responders), un peggiore indice BODE (3,33 vs 1,70; p < 0,05), una peggiore DLCO (49,4% vs 76,3%; p<0,05), un minore wattaggio al test incrementale (71,7 W vs 98,5 W, p<0,05), una maggiore differenza fra IC al massimo dello sforzo ed IC a riposo nel test dopo SF (-0,40 L vs -0,04 L, p<0,05), una maggiore slope del cambiamento della IC durante l’endurance con SF ([ICmax-ICrest]/endurance time) (– 2,91 mL/sec vs – 0,36 mL/sec), una minore variazione frequenza cardiaca durante l’endurance con SF [(FCmax-FCrest)/FCrest x 100)] (+25,7% vs +40,5%), un minore incremento della ventilazione durante endurance con SF [(VEmax-VErest)/VErest x 100)] (+30% vs +130%). Infine è stata osservata una correlazione tra VO2/kg al test incrementale ed indice BODE (R: -0,639), distanza percorsa nel 6MWT (R: 0,519), il volume residuo (% pred., R: -0,535), e il punteggio SGRQ-attività (R: -0,718). Conclusioni. Queste osservazioni preliminari non permettono di confermare che una dose aggiuntiva di broncodilatatori e corticosteroidi immediatamente prima dello sforzo in pazienti con BPCO già in trattamento regolare è capace di determinare un miglioramento della tolleranza allo sforzo. Tuttavia esiste una sottopopolazione di soggetti (quelli con maggiore gravità della malattia) che sembrano giovarsi di un incremento acuto della terapia broncodilatatrice. Inoltre queste osservazioni confermano che la tolleranza all’esercizio fisico è ben correlata ad altri indici funzionali che esprimono le limitazioni nella vita quotidiana imposte dalla malattia BPCO

Expression Analysis of Muscle-Specific miRNAs in Plasma-Derived Extracellular Vesicles from Patients with Chronic Obstructive Pulmonary Disease

MicroRNAs (miRNAs) are a class of short non-coding RNAs involved in the regulation of gene expression and the control of several cellular processes at physiological and pathological levels. Furthermore, extracellular vesicles (EV), which are small membrane-bound vesicles secreted by cells in the extracellular environment, contain functional miRNAs. The remarkable deregulation of many miRNAs has been demonstrated in respiratory diseases. Among them, miR-206, miR-133a-5p, and miR-133a-3p are striated muscle-specific miRNAs (myo-miRNA), related to skeletal muscle dysfunction, one of the commonest systemic manifestations in patients with chronic obstructive pulmonary disease (COPD). Nevertheless, their circulating expression in COPD patients is not demonstrated. For these reasons, we performed a pilot study to analyze the expression profiles of myo-miRNAs in plasma-derived EV from patients with COPD. We analyzed the expression profiles of selected myo-miRNAs in plasma-derived EV from COPD. Receiver operating characteristic analyses were carried out to evaluate whether selected plasma miRNAs were able to discriminate between different groups of COPD patients. We found EV-embedded myo-miRNAs in the bloodstream of COPD patients. Specifically, miR-206, miR-133a-5p and miR-133a-3p were significantly upregulated in group B patients. Receiver operating characteristic analyses of the combination of these selected miRNAs showed their high capacity to discriminate group B from other COPD patients. Our data provide evidence that myo-miRNA are present in EV in the plasma of COPD patients and their expression (miR-206, miR-133a-5p, and miR-133a-3p) can discriminate group B from group C patients. The future analysis of a larger number of patients should allow us to obtain more refined correlations

An observation of prescription behaviors and adherence to guidelines in patients with COPD: real world data from October 2012 to September 2014

Introduction: GOLD guideline recommendations are currently the “gold standard” for the treatment of COPD patients. Objectives: The objective of this analysis was to evaluate compliance with GOLD guidelines in managing COPD patients’ treatment by general practitioners (GPs) and pulmonologists. Since inhaled corticosteroid (ICS) use is defined as inappropriate in mild and moderate COPD patients, special attention was paid to ICS therapy use in these classes. Methods: The study was based on the Italian GP database IMS Health Longitudinal Patient Database (IMS Health LPD) and on the Patient Analyzer specialist IMS Health database. The observed cohort included all patients with a diagnosis of COPD, aged 40 years or more, with at least one ATC R03 class prescription, visited by GPs and pulmonologists during four timeframes: October 2012 – March 2013 (cohort 1), April 2013 – September 2013 (cohort 2), October 2013 – March 2014 (cohort 3); April 2014 – September 2014 (cohort 4). Patients were classified into disease severity groups following 2008 GOLD guidelines, based on FEV1 value. Results: Cohorts were quite similar in size (about two thousand patients per cohort). Pulmonologists visited more severe patients than GPs. About 50% of GPs’ mild and moderate patients received treatments containing inhaled corticosteroids. Pulmonologists were more adherent to guidelines, with smaller percentages of mild patients treated with therapies containing ICS (ranging from 19.0% to 30.1%). An improvement in adherence was observed during the four time periods, with a decrease in the use of therapies containing ICS in mild and moderate patients. In absolute terms, it emerged that GPs more often prescribe ICS improperly to patients in the mild and moderate severity classes than pulmonologists. Conclusion: Real world data indicate that adherence to GOLD guidelines is only partially met by GPs in their general practice and shows higher prescription appropriateness by pulmonologists

Cell-derived microparticles and the lung

Cell-derived microparticles are small (0.1–1 μm) vesicles shed by most eukaryotic cells upon activation or during apoptosis. Microparticles carry on their surface, and enclose within their cytoplasm, molecules derived from the parental cell, including proteins, DNA, RNA, microRNA and phospholipids. Microparticles are now considered functional units that represent a disseminated storage pool of bioactive effectors and participate both in the maintenance of homeostasis and in the pathogenesis of diseases. The mechanisms involved in microparticle generation include intracellular calcium mobilisation, cytoskeleton rearrangement, kinase phosphorylation and activation of the nuclear factor-κB. The role of microparticles in blood coagulation and inflammation, including airway inflammation, is well established in in vitro and animal models. The role of microparticles in human pulmonary diseases, both as pathogenic determinants and biomarkers, is being actively investigated. Microparticles of endothelial origin, suggestive of apoptosis, have been demonstrated in the peripheral blood of patients with emphysema, lending support to the hypothesis that endothelial dysfunction and apoptosis are involved in the pathogenesis of the disease and represent a link with cardiovascular comorbidities. Microparticles also have potential roles in patients with asthma, diffuse parenchymal lung disease, thromboembolism, lung cancer and pulmonary arterial hypertension

The visual perception of artworks at the National Museum of San Matteo (Pisa, Italy)

This study aimed to investigate how different light sources, their particular settings and the contrast they create between the artworks on display and their backgrounds affect the visual perception of art and space and visitors preference when it comes to lighting arrangements. The study involved a psychophysical experiment that was performed in two exhibition rooms at the National Museum of San Matteo in Pisa (Italy), using two artworks from its permanent collection, namely a panel painting and a marble sculpture. The experiment was carried out by 55 people, who were asked to assess and evaluate different lighting configurations for the two artworks and compare them in terms of contrast, enhancement of the characteristics of the artworks and, finally, personal preference. The purpose of the study was to find out whether there are correlations between the three aforementioned parameters and, especially, whether contrast and enhancement have a tangible effect on personal preference. The final goal was to identify and define lighting configurations that offer the best impression of the artworks, in terms of both faithfulness to the original message of the artist and enjoyment of the exhibition for visitors to the museum. In addition, the experiment was designed to investigate whether viewers prefer lighting configurations that enhance the artworks or whether personal preference is actually driven by other factors, such as individual feelings and specific messages communicated by the artworks. The experiment involved various lighting configurations: three traditional configurations, created using spotlights and wallwashers with warm light, and one configuration made by mixing smaller spotlights with different CCTs, which tested the so-called Monza Method. ARCOS LED expert spotlights, ARCOS wallwashers and SUPERSYSTEM II spotlights were installed to realise the multiple test lighting configurations, which featured combinations of the various luminaires and different settings, optics and lenses. The study found that the observers generally preferred more neutral configurations, which created an intermediate contrast ratio between the exhibits and their backgrounds. Furthermore, the lighting solutions that were described as relaxing and simple were rated as the most pleasant and interesting, while more uniform scenarios were seen as being boring and not suitable for the enhancement of the artworks

Fluticasone furoate, umeclidinium bromide, and vilanterol as a combination therapy for chronic obstructive pulmonary disease

Introduction: Triple therapy with two bronchodilators (LABA plus LAMA) and an inhaled corticosteroid (ICS) is recommended for patients suffering from severe chronic obstructive pulmonary disease (COPD). Areas covered: All 12–52 week-long studies comparing triple therapy with umeclidinium (UM) added to either fluticasone furoate/vilanterol (FF/VI) or fluticasone propionate/salmeterol (FP/SAL) vs. other comparators in COPD patients of group B or D (2011 GOLD classification) were considered. When UM was added to ICS/LABA with separate devices or within a single device, triple combination was more effective than comparators (usually, ICS/LABA combinations) regarding improvements to pulmonary function, symptoms, quality of life and, in the longer studies, rate of moderate-severe exacerbations. The IMPACT study (a large trial comparing UM/FF/VI with both FF/VI and UM/VI combinations) showed that triple therapy had a greater effect compared to dual therapies in reducing the rate of moderate-severe exacerbations, improving trough FEV1 and improving quality of life. The safety profile was good, without excess cardiovascular effects or pneumonia, however, the presence of comorbidities was frequent. Expert commentary: UM/FF/VI combination represents a good option for severe COPD patients who remain symptomatic and/or with frequent exacerbations despite dual therapies. Once daily administration with a simple and effective device may increase adherence and efficacy of the treatment

The Emerging Role of Extracellular Vesicles Detected in Different Biological Fluids in COPD

The pathogenesis of chronic obstructive pulmonary disease (COPD) is characterized by complex cellular and molecular mechanisms, not fully elucidated so far. It involves inflammatory cells (monocytes/macrophages, neutrophils, lymphocytes), cytokines, chemokines and, probably, new players yet to be clearly identified and described. Chronic local and systemic inflammation, lung aging and cellular senescence are key pathological events in COPD development and progression over time. Extracellular vesicles (EVs), released by virtually all cells both as microvesicles and exosomes into different biological fluids, are involved in intercellular communication and, therefore, represent intriguing players in pathobiological mechanisms (including those characterizing aging and chronic diseases); moreover, the role of EVs as biomarkers in different diseases, including COPD, is rapidly gaining recognition. In this review, after recalling the essential steps of COPD pathogenesis, we summarize the current evidence on the roles of EVs collected in different biological mediums as biomarkers in COPD and as potential players in the specific mechanisms leading to disease development. We will also briefly review the data on EV as potential therapeutic targets and potential therapeutic agents