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Background: Obstructive sleep apnea syndrome (OSAS) and chronic obstructive pulmonary disease (COPD) are two chronic diseases that afflict many individuals worldwide with negative effects on health that may overlap in Overlap Syndrome (OS). The aim of our study was to investigate the differences in mortality between OSAS alone and OS and the risk factors involved., Methods: The study was conducted on patients with OSAS or OS diagnosis that completed 15-year follow-up between 2005 and 2023. Of these, the clinical, functional, sleep and survival data were registered and analysed. Risk factors were found by regression analysis., Results: 501 patients (428 OSAS and 73 OS) were enrolled. Patients with OS had higher mortality than OSAS (p < 0,001). The morality risk factors for the overall population found were age >65 years (odds ratio (OR) = 10.69 (95%CI 3,85-29,69), p < 0,001) and low forced-expiratory volume in 1-s (FEV 1 ) (OR = 10.18 (95%CI 2,32-44,68), p = 0,002). In patients with OSAS, age and nocturnal hypoxemia (NH) (OR = 2.41 (95%CI 1,07-5,41), p = 0,03) were risk factors, while adherence to nighttime positive airway pressure (PAP) reduced mortality (OR = 0,36 (95%CI 0,15-0,83), p = 0,017). Multivariate analysis confirmed age and FEV 1 as risk factors in OS. Conversely, the risk factors for the overall population under 65 years were NH, which is confirmed in patients with OSAS alone (OR = 4,72 (95%CI 1,07-20,77), p = 0,04) in whom, on the other hand, PAP compliance reduced the mortality risk., Conclusions: The study suggests that NH is a risk factor for all-cause mortality in sleep disorders by excluding the age; conversely, nighttime PAP improves the survival., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Severe asthma affects about 10% of the population with asthma and is characterized by low lung function and a high count of blood leukocytes, mainly eosinophils. Various definitions are used in clinical practice and in the literature to identify asthma remission: clinical remission, inflammatory remission, and complete remission. This work highlights a consensus for asthma remission using a Delphi method. In the context of the Severe Asthma Network Italy, which accounts for 57 severe asthma centers and more than 2,200 patients, a board of six experts drafted a list of candidate statements in a questionnaire, which has been revised to minimize redundancies and ensure clear and consistent wording for the first round (R1) of the analysis. Thirty-two statements were included in the R1 questionnaire and then submitted to a panel of 80 experts, which used a 5-point Likert scale to measure agreement regarding each statement. Then, an interim analysis of R1 data was performed, and items were discussed and considered to produce a consistent questionnaire for round 2 (R2) of the analysis. Then, the board set the R2 questionnaire, which included only important topics. Panelists were asked to vote on the statements in the R2 questionnaire afterward. During R2, the criteria of complete clinical remission (the absence of the need for oral corticosteroids, symptoms, exacerbations or attacks, and pulmonary function stability) and those of partial clinical remission (the absence of the need for oral corticosteroids, and two of three criteria: the absence of symptoms, exacerbations or attacks, and pulmonary stability) were confirmed. This Severe Asthma Network Italy Delphi analysis defined a valuable and independent tool that is easy to use, to test the efficacy of different treatments in patients with severe asthma enrolled into the SANI registry., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The Controlling Nutritional Status (CONUT) score is a simple screening tool able to assess poor nutritional status as well as to predict clinical adverse outcomes in different clinical settings. No data are available in older patients with chronic obstructive pulmonary disease (COPD). This study aimed to investigate the CONUT score as a predictor of frequent exacerbations. We retrospectively enrolled 222 patients aged 65 years or older, classified in two groups according to the number of exacerbations (or hospitalizations because AECOPD) during the previous year. The two groups were further divided according to low (<5) or high (≥5) CONUT scores. A total of 67.2% of frequent exacerbators had a high CONUT score. These patients exhibited a significantly higher CAT score, lower FEV1 percentage value, and higher prevalence of severe GOLD stages compared to those with low CONUT. Multivariate analysis showed that a CONUT score ≥ 5 was the best independent predictor (OR 20.740, p < 0.001) of the occurrence of ≥2 exacerbations (or 1 hospitalization) during the previous year. The CONUT score seemed to have a high prognostic value for frequent exacerbations for COPD in older patients. The predictive role of different CONUT score cut-off values needs to be validated in larger COPD populations in future multi-center, prospective clinical studies.

Background: GAP (gender-age-physiology) and TORVAN are multi-parametric prognostication scores for idiopathic pulmonary fibrosis (IPF). We compared their prognostic value in patients treated with nintedanib or pirfenidone and explored their effect on patient survival in relation to disease staging., Study Design and Patients: Retrospective evaluation of 235 naïve IPF patients (M = 179; mean age 69.8 yrs±7.1; 102 treated with nintedanib and 133 with pirfenidone), referred to two Italian academic centers between February 2012 and December 2019., Results: During a median follow-up of 4.2 years, the incidence rate of death was 14.5 per 100 person-years (95% CI: 12 to 17.4), with no differences between nintedanib and pirfenidone (log-rank p = 0.771). According to time-ROC analysis, GAP and TORVAN showed a similar discrimination performance at 1, 2, and 5 years. Survival of GAP-2/GAP-3 IPF patients treated with nintedanib was worse than that of patients in GAP-1 (HR 4.8, 95% CI: 2.2 to 10.5 and HR 9.4, 95% CI: 3.8 to 23.2). TORVAN I patients treated with nintedanib exhibited better survival than those in stages III (HR 3.1, 95% CI: 1.4 to 6.6) and IV (HR 10.5, 95% CI: 3.5 to 31.6). A significant treatment x stage interaction was observed for both disease staging indexes (p = 0.042 for treatment by GAP interaction and p = 0.046 for treatment by TORVAN interaction). A better survival was associated with nintedanib in patients with mild disease (GAP-1 or TORVAN I stage) and with pirfenidone in GAP-3 or TORVAN IV cases, although these findings did not always reach statistical significance., Conclusions: GAP and TORVAN similarly perform in IPF patients on anti-fibrotic therapy. However, the survival of patients treated with nintedanib and pirfenidone appears to be differently affected by disease staging., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: The current definition of severe eosinophilic asthma (SEA) super-responders to biologic treatment does not include patients with other eosinophil-based comorbidities. Although eosinophilic granulomatosis with polyangiitis (EGPA) is frequently associated with SEA, we lack data on a possible super-response to biologic treatments in patients suffering from these two diseases. We aim to assess super-responder features in real-life patients with SEA and EGPA treated with mepolizumab and benralizumab., Methods: We enrolled 39 patients with SEA and EGPA eligible for treatment with mepolizumab or benralizumab. Super-responder assessment was performed considering oral corticosteroid (OCS) cessation, lack of exacerbations, forced expiratory volume in 1 s and Asthma Control Test (ACT) improvement., Results: Super-responders showed worse clinical baseline characteristics than non-super-responder patients, with a greater improvement in severe asthma exacerbations, OCS dose reduction and ACT score increase. Definition of super-responders was consistent only considering a 12-month course of monoclonal antibody, lacking sensitivity in earlier evaluations., Conclusion: Mepolizumab and benralizumab are safe and effective in patients with EGPA and SEA, since a consistent proportion of patients show a super-response after 12 months of treatment. Further studies will address specific criteria for super-responder assessment in these patients., Competing Interests: Conflict of interest: A. Portacci reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from AstraZeneca, GlaxoSmithKline, Chiesi and Sanofi. Conflict of interest: N. Crimi reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from AstraZeneca, GlaxoSmithKline and Sanofi. Conflict of interest: A. Benfante reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from AstraZeneca, GlaxoSmithKline and Sanofi. Conflict of interest: M. Triggiani reports consulting fees from AstraZeneca, GlaxoSmithKline and Novartis. Conflict of interest: G. Scioscia reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from AstraZeneca, GlaxoSmithKline and Sanofi. Conflict of interest: A. Detoraki reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from AstraZeneca, GlaxoSmithKline, Sanofi, Novartis and Lofarma. Conflict of interest: G. Valenti reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from GlaxoSmithKline and Sanofi. Conflict of interest: N. Scichilone reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from AstraZeneca, GlaxoSmithKline, Chiesi and Sanofi. Conflict of interest: G. Pelaia reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Chiesi, Sanofi, Guidotti, Menarini and Novartis. Conflict of interest: C. Crimi reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Astrazeneca, GlaxoSmithKline, Sanofi, Menarini, ResMed and Fisher&Paykel. Conflict of interest: G.E. Carlagnano reports grants or contracts from AstraZeneca, Chiesi, GlaxoSmithKline, Sanofi and Grifols; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from AstraZeneca, GlaxoSmithKline and Sanofi; and support for attending meetings and/or travel from Astrazeneca, Menarini and Chiesi., (Copyright ©The authors 2023.)

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disorder with unknown etiology. To date, the identification of new diagnostic, prognostic and progression biomarkers of IPF turns out to be necessary. MicroRNA (miRNA) are small non-coding RNAs which negatively regulate gene expression at the post-transcriptional level in several biological and pathological processes. An aberrant regulation of gene expression by miRNA is often associated with various diseases, including IPF. As result, miRNAs have emerged as potential biomarkers with relevance to pulmonary fibrosis. Several reports suggested that miRNAs are secreted as microvesicles or exosome, and hance they are stable and can be readily detected in the circulation. In the contest of miRNAs as circulating biomarkers, different studies show their role in various types of interstitial lung diseases and suggest that these small molecules could be used as prognostic markers of the disease. Exosomes are small, lipid-bound vesicles able to carry various elements of the naïve cells such as proteins, lipids, mRNAs and miRNA to facilitate cell communication under normal and diseases condition. Exosomal miRNAs (exo-miRNA) have been studied in relation to many diseases. However, there is little or no knowledge regarding exo-miRNA in bronchoalveolar lavage (BAL) in IPF. Our study's aim is to evaluate the changes in the expression of two exo-miRNAs in BAL, respectively miR-21 and miR-92a, through highlighting the differences between IPF, progressive pulmonary fibrosis (PPF) and not-progressive pulmonary fibrosis (nPPF)., Methods: Exosomes were characterized by Western Blot and Multiplex Surface Marker Analysis. Exosomal miRNA expression was performed by qRT-PCR. ANOVA or Kruskal-Wallis test, based on data normality, was used to compare the differential expression between groups., Results: MiR-21 expression was significantly higher in the nPPF group than in both IPF and PPF. A result that could point above a possible role of miR-21, as a biomarker in the differential diagnosis between PPF and nPPF. MiR-92a, indeed, was down regulated in PPF compared to IPF and down regulated in PPF compared to nPPF., Conclusions: This study demonstrated the putative role of both miR-21 and miR-92a as possible biomarkers of pulmonary fibrosis progression. Moreover, the role of exo-miRNAs is examined as a possible future direction that could lead to new therapeutic strategies for the treatment of progressive and non-progressive pulmonary fibrosis., (© 2023. The Author(s).)

Severe asthma (SA) is a chronic inflammatory disease of the airways. Due to the extreme heterogeneity of symptoms, new biomarkers are currently needed. MiRNAs are non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. In biological fluids, miRNAs are contained within exosomes, vesicles capable of giving miRNAs considerable stability and resistance to degradation by RNAses. The main function attributed to the exosomes is intercellular communication. The goal of our study was to analyze intracellular and exosomal miRNAs in order to demonstrate their potential use as non-invasive biomarkers of asthma by showing, in particular, their role in SA. We detected miRNAs by qRT-PCR in both serum and serum-derived-exosomes of asthmatic patients and healthy controls. The levels of almost all analyzed intracellular miRNAs (miR-21, miR-223, and let-7a) were greater in asthmatic patients vs. healthy control, except for miR-223. In detail, miR-21 was greater in SA, while let-7a increased in mild-to-moderate asthma. On the other hand, in exosomes, all analyzed miRNAs were higher in SA. This study identified a series of miRNAs involved in SA, highlighting their potential role in asthma development and progression. These results need validation on a larger cohort.

Introduction: There is still a debate for the link between obstructive sleep apnoea (OSA) and cancer. The mechanisms underlying this causality are poorly understood. Several miRNAs are involved in cancer development and progression with expression being influenced by hypoxia. The aims of this work were (i) to compare miRNAs expression in controls versus patients affected by OSA without or with cancer (ONCO-OSA) and (ii) in colorectal cancer cells exposed to intermittent hypoxia (IH), to evaluate miRNAs impact on tumor progression in vitro., Methods: We detected miRNAs by qRT-PCR in patients' sera and in CaCo2 cells exposed to 2-32h of IH with or without acriflavine (ACF), a HIF-1 inhibitor. Viability and transwell invasion test were applied to investigate the proliferation and migration of CaCo2 exposed to IH and treated with miRNA inhibitors or acriflavine. HIF-1α activity was evaluated in CaCo2 cells after IH., Results: The levels of miR-21, miR-26a and miR-210 increased in OSA and ONCO-OSA patients compared to controls. MiR-23b increased in ONCO-OSA patients, and miR-27b and miR-145 increased in OSA but not ONCO-OSA patients. MiR-21, miR-26a, miR-23b and miR-210 increased in cells after IH. IH stimulated cell proliferation and migration. This effect was reduced after either miRNA inhibition or acriflavine treatment. MiRNA inhibition reduces HIF-1α gene expression. Conversely, acriflavine reduced the expression of these miRNAs., Conclusions: We identified a signature of miRNAs, induced by the IH environment. They could be implicated in cancer development and progression through a regulatory loop involving HIF-1., (Copyright © 2023 The Author(s). Published by Elsevier España, S.L.U. All rights reserved.)

Purpose: The diagnosis of obstructive sleep apnea (OSA) is instrument, operator, and time-dependent and therefore requires long waiting times. In recent decades, technological development has produced useful devices to monitor the health status of the population, including sleep. Therefore, the aim of this study was to evaluate a wearable device (WD) in a group of individuals at high risk of OSA., Methods: The study was conducted on consecutive subjects with high risk of OSA assessed by sleep questionnaires and clinical evaluation. All subjects performed cardio-respiratory monitoring (CRM) and WD simultaneously on a single night, after which the parameters of the two sleep investigations were compared., Results: Of 20 individuals enrolled, 60% were men and mean age was 57.3 ± 10.7 years. The apnea-hypopnea index (AHI) for the CRM was 23.1 ± 19.6 events·h -1 while it was 10.3 ± 8.3 events·h -1 for the WD. Correlation analysis between the results of the two investigations showed r = 0.19 (p = 0.40) for AHI and r = 0.4076 (p = 0.07) for sO2%. The accuracy for different stages of OSA severity was 70% in OSA cases and 60% in moderate to severe cases with sensitivity and specificity varying a great deal., Conclusion: Small and low-cost devices may prove to be a valuable resource to reduce costs and waiting times for a sleep investigation in suspected OSA. However, diagnosis of sleep apnea requires valid and reliable instruments, so validation tests are necessary before a device can be commercialized., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare vasculitis characterized by asthma, systemic manifestations, and blood and tissue eosinophilia., Objective: To assess the effectiveness and safety of mepolizumab (anti-IL-5) and benralizumab (anti-IL-5Rα) in EGPA for 24 months., Methods: We conducted a multicenter observational study, including patients with EGPA treated with anti-IL-5/Rα biologics in 9 Italian specialized facilities. Systemic disease activity, remission and relapse rate were evaluated from 3 to 24 months after treatment initiation. Respiratory outcomes, hematological parameters, corticosteroid (OCS) and immunosuppressants consumption were also assessed., Results: 49 patients with relapsing-refractory EGPA were included [26 (53.1%) benralizumab 30mg, 20 (40.8%) mepolizumab 100mg, 3 (6.1%) mepolizumab 300mg]. Overall, 38.8% and 57.1% achieved remission after 12 and 24 months, respectively (69.2% benralizumab and 43.5% mepolizumab). Lower OCS intake and higher blood eosinophil count at baseline were associated with remission at 24 months. Both biologics exerted beneficial effects on severe asthma outcomes. Indeed, 61.2% (61.5% benralizumab and 60.8% mepolizumab) remained exacerbation-free during treatment. Lung function parameters showed improvements in the overall cohort (all p< 0.05), but began to decline from month 12, especially with mepolizumab. Marked reduction in blood eosinophils was registered with mepolizumab ( p< 0.0001), while benralizumab depleted both eosinophils ( p< 0.0001) and basophils ( p <0.0001). In general, 69.6% (76% benralizumab and 61.9% mepolizumab) of OCS-dependent patients lowered their daily dose by 75%, while 28.3% discontinued these drugs. Immunosuppressants were suspended in 88.2% of cases. Adverse events were reported in 8.2% of patients., Conclusions: These real-world data suggest that anti-IL-5/Rα biologics are effective and safe in the long-term as add-on treatments for patients with EGPA., Competing Interests: AP has received speaker fees from AstraZeneca, GlaxoSmithKline, Chiesi and Sanofi. AB has received speaker fees from AstraZeneca, GlaxoSmithKline, and Sanofi. MT has received speaker and consultancy fees from Novartis, AstraZeneca and GlaxoSmithKline. GSc has received speaker fees from AstraZeneca, GlaxoSmithKline, and Sanofi. AD has received speaker fees from Sanofi, AstraZeneca, GlaxoSmithKline, Novartis, Lofarma. GV has received speaker fees from GlaxoSmithKline, and Sanofi. NC has received speaker and lecturer fees from AstraZeneca, GlaxoSmithKline and Sanofi. NS has received speaker fees from AstraZeneca, GlaxoSmithKline, Chiesi and Sanofi. GP has received speaker and lecturer fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Guidotti, Menarini, Novartis and Sanofi. GC has received grants from AstraZeneca, GlaxoSmithKline, Chiesi, Sanofi and Grifols; has received speaker and lecturer fees from AstraZeneca, GlaxoSmithKline, and Sanofi; has received supports for attending meetings from AstraZeneca, Menarini and Chiesi. CC has received speaker fees from ResMed, Fisher&Paykel, Sanofi, AstraZeneca, GlaxoSmithKline and Menarini. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor EH declared a past co-authorship with the authors SN, RC, CP, AB, MT, GS, MC, AD, NC, NS, GP, GC and CC., (Copyright © 2023 Nolasco, Portacci, Campisi, Buonamico, Pelaia, Benfante, Triggiani, Spadaro, Caiaffa, Scioscia, Detoraki, Valenti, Papia, Tomasello, Crimi, Scichilone, Pelaia, Carpagnano and Crimi.)

Background: Mepolizumab and benralizumab are monoclonal antibodies directed against anti-IL-5 and anti-IL5R, respectively, and their use reduces the exacerbation rate and maintains oral corticosteroid requirements in severe eosinophilic asthma. Previous studies have tested the therapeutic switch between two biologics with excellent results, further demonstrating the heterogeneity of asthmatic disease and the complexity of the therapeutic choice. It remains unclear if such patients may improve following a switch from mepolizumab to benralizumab., Aims: Within a multicentre real-life setting, we decided to evaluate the potential effectiveness of a therapeutic switch to benralizumab in patients with severe eosinophilic asthma initially treated with mepolizumab, who experienced sub-optimal responses. The secondary aim was to identify the clinical factors associated with a better response to benralizumab., Methods: We retrospectively assessed patients with severe eosinophilic asthma treated at six Italian specialist centres, who were switched from mepolizumab to benralizumab following a sub-optimal response, defined as a partial or total lack of clinical remission (i.e., frequent severe exacerbations and/or poorly controlled symptoms and/or higher OCS daily use in patients with a poor or moderate response in the global evaluation of treatment effectiveness scale), after at least 12 months of treatment., Results: Twenty-five patients were included in the analysis (mean age 56.76 ± 11.97 years, 65% female). At 6 months of treatment with benralizumab, the ACT score was significantly higher than the ACT score with mepolizumab (20.24 ± 3.38 vs. 16.77 ± 3.48, p < 0.0001); the mean number of daily SABA inhalations was significantly lower after 6 months and 12 months of treatment with benralizumab than that after treatment with mepolizumab; OCS intake and the prednisone median dosage at 6 months of treatment with benralizumab were significantly lower than those with mepolizumab. Benralizumab treatment resulted in a marked improvement in asthma control, suppressed blood eosinophil levels and reduction in the number of exacerbations in the subgroup of patients with severe eosinophilic asthma and nasal polyposis., Conclusions: Patients diagnosed with severe eosinophilic asthma who experience a partial response to mepolizumab could benefit from switching to benralizumab, and even more those who have nasal polyposis.

Introduction : The co-presence of bronchiectasis (BE) in severe eosinophilic asthma (SEA) is common. Data about the effectiveness of benralizumab in patients with SEA and BE (SEA + BE) are lacking. Aim : The aim of this study was to evaluate the effectiveness of benralizumab and remission rates in patients with SEA compared to SEA + BE, also according to BE severity. Methods : We conducted a multicentre observational study, including patients with SEA who underwent chest high-resolution computed tomography at baseline. The Bronchiectasis Severity Index (BSI) was used to assess BE severity. Clinical and functional characteristics were collected at baseline and after 6 and 12 months of treatment. Results : We included 74 patients with SEA treated with benralizumab, of which 35 (47.2%) showed the co-presence of bronchiectasis (SEA + BE) with a median BSI of 9 (7-11). Overall, benralizumab significantly improved the annual exacerbation rate ( p < 0.0001), oral corticosteroids (OCS) consumption ( p < 0.0001) and lung function ( p < 0.01). After 12 months, significant differences were found between SEA and SEA + BE cohorts in the number of exacerbation-free patients [64.1% vs. 20%, OR 0.14 (95% CI 0.05-0.40), p < 0.0001], the proportion of OCS withdrawal [-92.6% vs. -48.6, p = 0.0003], and the daily dose of OCS [-5 mg (0 to -12.5) vs. -12.5 mg (-7.5 to -20), p = 0.0112]. Remission (zero exacerbations + zero OCS) was achieved more frequently in the SEA cohort [66.7% vs. 14.3%, OR 0.08 (95% CI 0.03-0.27), p < 0.0001]. Changes in FEV 1 % and FEF 25-75% were inversely correlated with BSI ( r = -0.36, p = 0.0448 and r = -0.41, p = 0.0191, respectively). Conclusions : These data suggest that benralizumab exerts beneficial effects in SEA with or without BE, although the former achieved less OCS sparing and fewer respiratory-function improvements.

Currently, three classes of monoclonal antibodies targeting type 2 inflammation pathways are available in Italy for the treatment of severe asthma: anti-IgE (Omalizumab), anti-IL-5/anti-IL-5Rα (Mepolizumab and Benralizumab), and anti-IL-4Rα (Dupilumab). Numerous randomized controlled trials (RCTs) and real-life studies have been conducted to define their efficacy and identify baseline patients' characteristics potentially predictive of favorable outcomes. Switching to another monoclonal antibody is recommended in case of a lack of benefits. The aim of this work is to review the current knowledge on the impact of switching biological therapies in severe asthma as well as on predictors of treatment response or failure. Almost all of the information about switching from a previous monoclonal antibody to another comes from a real-life setting. In the available studies, the most frequent initial biologic was Omalizumab and patients who were switched because of suboptimal control with a previous biologic therapy were more likely to have a higher baseline blood eosinophil count and exacerbation rate despite OCS dependence. The choice of the most suitable treatment may be guided by the patient's clinical history, biomarkers of endotype (mainly blood eosinophils and FeNO), and comorbidities (especially nasal polyposis). Due to overlapping eligibility, larger investigations characterizing the clinical profile of patients benefiting from switching to different monoclonal antibodies are needed.

Objectives: We validated a screening protocol in which thoracic ultrasound (TUS) acts as a first-line complementary imaging technique in selecting patients which may deserve a second-line low-dose high resolution computed tomography (HRCT) scan among a population of asymptomatic high-risk subjects for interstitial lung abnormalities (ILA) and lung cancer. Due to heavy environmental pollution burden, the district Tamburi of Taranto has been chosen as "case study" for this purpose., Methods: From July 2018 to October 2020, 677 patients aged between 45 and 65 year and who had been living in the Tamburi district of Taranto for at least 10 years were included in the study. After demographic, clinical and risk factor exposition data were collected, each participant underwent a complete TUS examination. These subjects were then asked to know if they agreed to perform a second-level examination by low-dose HRCT scan., Results: On a total of 167 subjects (24.7%) who agreed to undergo a second-level HRCT, 85 patients (50.9%) actually showed pleuro-pulmonary abnormalities. Interstitial abnormalities were detected in a total of 36 patients on HRCT scan. In particular, 34 participants presented subpleural ILAs, that were classified in the fibrotic subtype in 7 cases. The remaining 2 patients showed non-subpleural interstitial abnormalities. Subpleural nodules were observed in 46 patients. TUS showed an overall diagnostic accuracy of 88.6% in detecting pleuro-pulmonary abnormalities in comparison with HRCT scan, with a sensitivity of 95.3%, a specificity of 81.7%, a positive predictive value of 84.4% and a negative predictive value of 94.4%. The matched evaluation of specific pulmonary abnormalities on HRTC scan (i.e., interstitial abnormalities or pulmonary nodules) with determinate sonographic findings revealed a reduction in both TUS sensibility and specificity. Focusing TUS evaluation on the assessment of interstitial abnormalities, a thickened pleural line showed a sensitivity of 63.9% and a specificity of 69.5%, hypoechoic striae showed a sensitivity of 38.9% and a specificity of 90.1% and subpleural nodules showed a sensitivity of 58.3% and a specificity of 77.1%. Regarding to the assessment of subpleural nodules, TUS showed a sensitivity of 60.9% and a specificity of 81.0%. However, the combined employment of TUS examination and HRCT scans allowed to identify 34 patients with early subpleural ILA and to detect three suspicious pulmonary nodules (of which two were intraparenchymal and one was a large subpleural mass), which revealed to be lung cancers on further investigations., Conclusion: A first-line TUS examination might aid the identification of subjects highly exposed to environmental pollution, who could benefit of a second-line low-dose HRCT scan to find early interstitial lung diseases as well as lung cancer., Protocol Registration Code: PLEURO-SCREENING-V1.0&#95;15 Feb, 17., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Quarato, Dama, Maggi, Feragalli, Borelli, Del Colle, Taurchini, Maiello, De Cosmo, Lacedonia, Barbaro, Carpagnano, Scioscia, Graziano, Termine, Frongillo, Santamaria, Venuti, Grimaldi, Notarangelo, Saponara, Copetti, Colangelo, Cuttano, Macrodimitris, Mazzarelli, Talia, Mirijello, Pazienza, Perna, Simeone, Vergara, Varriale, Carella, Bianchi and Sperandeo.)

Background: The efficacy of dupilumab as biological treatment of severe asthma and chronic rhinosinusitis with nasal polyps (CRSwNP) depends on its ability to inhibit the pathophysiologic mechanisms involved in type 2 inflammation., Objective: To assess in a large sample of subjects with severe asthma, the therapeutic impact of dupilumab in real-life, with regard to positive or negative skin prick test (SPT) and CRSwNP presence or absence., Methods: Clinical, functional, and laboratory parameters were measured at baseline and 24 weeks after the first dupilumab administration. Moreover, a comparative evaluation was carried out in relation to the presence or absence of SPT positivity and CRSwNP., Results: Among the 127 recruited patients with severe asthma, 90 had positive SPT, while 78 reported CRSwNP. Compared with the 6 months preceding the first dupilumab injection, asthma exacerbations decreased from 4.0 (2.0-5.0) to 0.0 (0.0-0.0) (p < 0.0001), as well as the daily prednisone intake fell from 12.50 mg (0.00-25.00) to 0.00 mg (0.00-0.00) (p < 0.0001). In the same period, asthma control test (ACT) score increased from 14 (10-18) to 22 (20-24) (p < 0.0001), and sino-nasal outcome test (SNOT-22) score dropped from 55.84 ± 20.32 to 19.76 ± 12.76 (p < 0.0001). Moreover, we observed relevant increases in forced expiratory volume in one second (FEV1) from the baseline value of 2.13 L (1.62-2.81) to 2.39 L (1.89-3.06) (p < 0.0001). Fractional exhaled nitric oxide (FeNO) values decreased from 27.0 ppb (18.0-37.5) to 13.0 ppb (5.0-20.0) (p < 0.0001). These improvements were quite similar in subgroups of patients characterized by SPT negativity or positivity, and CRSwNP absence or presence. No statistically significant correlations were detected between serum IgE levels, baseline blood eosinophils or FeNO levels and dupilumab-induced changes, with the exception of FEV1 increase, which was shown to be positively correlated with FeNO values (r = 0.3147; p < 0.01)., Conclusion: Our results consolidate the strategic position of dupilumab in its role as an excellent therapeutic option currently available within the context of modern biological treatments of severe asthma and CRSwNP, frequently driven by type 2 airway inflammation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Pelaia, Benfante, Busceti, Caiaffa, Campisi, Carpagnano, Crimi, D’Amato, Foschino Barbaro, Maglio, Minenna, Nolasco, Paglino, Papia, Pelaia, Portacci, Ricciardi, Scichilone, Scioscia, Triggiani, Valenti, Vatrella and Crimi.)

Background: Chronic respiratory diseases (CRDs) are common diseases with a heterogeneous distribution worldwide. Due to their impact on disability, weight assistance and pharmaceutical spending, they represent an important global burden for national health systems. However, few studies have investigated the use and consumption of inhaled drugs in real life in patients with CRDs., Objective: This study aimed to investigate the real-life consumption of health care resources of main CRDs through an analysis of the administrative databases of the local health authority (ASL) in the Puglia region (Italy)., Methods: The present study is an observational study that longitudinally reviewed the administrative and health databases associated with patients' consumption of health resources between 2017 and 2018., Results: The first important finding is a marked underestimation of the true incidence of CRDs despite the search for disease-specific exemption codes. Another important result is that the real-life consumption of inhaled drugs among these patients is well below the minimum acceptable values for adherence. The most commonly used inhaled drugs, for which at least one pack was withdrawn, were inhaled steroids (61.6%), followed by the ICS/LABA combination (43.7%) and LABAs (32.4%). However, less than one-third of patients (31%) withdrew at least three packages of ICS or ICS/LABA during the year, while the percentage was reduced to less than 15% for other combinations. Another alarming finding is that only 8.4% of patients taking CRDs drugs reported at least one spirometry during the study period., Conclusions: The wide availability of computerized systems may be an important tool for increasing therapeutic adherence and optimizing the resources of health systems in the diagnosis, treatment and management of patients with CRDs.

Ultrasound (US) is acoustic energy that interacts with human tissues, thus, producing bioeffects that may be hazardous, especially in sensitive organs (i.e., brain, eye, heart, lung, and digestive tract) and embryos/fetuses. Two basic mechanisms of US interaction with biological systems have been identified: thermal and non-thermal. As a result, thermal and mechanical indexes have been developed to provide a means of assessing the potential for biological effects from exposure to diagnostic US. The main aims of this paper were to describe the models and assumptions used to estimate the "safety" of acoustic outputs and indices and to summarize the current state of knowledge about US-induced effects on living systems deriving from in vitro models and in vivo experiments on animals. This review work has made it possible to highlight the limits associated with the use of the estimated safety values of thermal and mechanical indices relating above all to the use of new US technologies, such as contrast-enhanced ultrasound (CEUS) and acoustic radiation force impulse (ARFI) shear wave elastography (SWE). US for diagnostic and research purposes has been officially declared safe, and no harmful biological effects in humans have yet been demonstrated with new imaging modalities; however, physicians should be adequately informed on the potential risks of biological effects. US exposure, according to the ALARA (As Low As Reasonably Achievable) principle, should be as low as reasonably possible.

Diagnosis of interstitial lung diseases (ILD) is difficult to perform. Extracellular vesicles (EVs) facilitate cell-to-cell communication, and they are released by a variety of cells. Our goal aimed to investigate EV markers in bronchoalveolar lavage (BAL) from idiopathic pulmonary fibrosis (IPF), sarcoidosis and hypersensitivity pneumonitis (HP) cohorts. ILD patients followed at Siena, Barcelona and Foggia University Hospitals were enrolled. BAL supernatants were used to isolate the EVs. They were characterized by flow cytometry assay through MACSPlex Exsome KIT. The majority of alveolar EV markers were related to the fibrotic damage. CD56, CD105, CD142, CD31 and CD49e were exclusively expressed by alveolar samples from IPF patients, while HP showed only CD86 and CD24. Some EV markers were common between HP and sarcoidosis (CD11c, CD1c, CD209, CD4, CD40, CD44, CD8). Principal component analysis distinguished the three groups based on EV markers with total variance of 60.08%. This study has demonstrated the validity of the flow cytometric method to phenotype and characterize EV surface markers in BAL samples. The two granulomatous diseases, sarcoidosis and HP, cohorts shared alveolar EV markers not revealed in IPF patients. Our findings demonstrated the viability of the alveolar compartment allowing identification of lung-specific markers for IPF and HP.

Patients affected by idiopathic pulmonary fibrosis (IPF) have a high mortality rate in the first 2-5 years from diagnosis. It is therefore necessary to identify a prognostic indicator that can guide the care process. The Gender-Age-Physiology (GAP) index and staging system is an easy-to-calculate prediction tool, widely validated, and largely used in clinical practice to estimate the risk of mortality of IPF patients at 1-3 years. In our study, we analyzed the GAP index through machine learning to assess any improvement in its predictive power in a large cohort of IPF patients treated either with pirfenidone or nintedanib. In addition, we evaluated this event through the integration of additional parameters. As previously reported by Y. Suzuki et al., our data show that inclusion of body mass index (BMI) is the best strategy to reinforce the GAP performance in IPF patients under treatment with currently available anti-fibrotic drugs.

Background. Limited studies and observations conducted on a too small number of patients prevent determining the actual clinical utility of pulmonary contrast-enhanced ultrasound (CEUS). The aim of the present study was to examine the efficacy of contrast enhancement (CE) arrival time (AT) and other dynamic CEUS findings for differentiating between malignant and benign peripheral lung lesions. Methods. 317 inpatients and outpatients (215 men, 102 women; mean age: 52 years) with peripheral pulmonary lesions were included in the study and underwent pulmonary CEUS. Patients were examined in a sitting position after receiving an intravenous injection of 4.8 mL of sulfur hexafluoride microbubbles stabilized by a phospholipid shell as ultrasound contrast agent (SonoVue-Bracco; Milan, Italy). Each lesion was observed for at least 5 min in real-time and the following temporal characteristics of enhancement were detected: the arrival time (AT) of microbubbles in the target lesion; the enhancement pattern; the wash-out time (WOT) of microbubbles. Results were then compared in light of the definitive diagnosis of community acquired pneumonia (CAP) or malignancies, which was not known at the time of CEUS examination. All malignant cases were diagnosed by histological results, while pneumonia was diagnosed on the basis of clinical and radiological follow-up, laboratory findings and, in some cases, histology. Results. CE AT has not been shown to differ between benign and malignant peripheral pulmonary lesions. The overall diagnostic accuracy and sensibility of a CE AT cut-off value < 10 s in discriminating benign lesions were low (diagnostic accuracy: 47.6%; sensibility: 5.3%). Poor results were also obtained in the sub-analysis of small (mean diameter < 3 cm) and large (mean diameter > 3 cm) lesions. No differences were recorded in the type of CE pattern showed between benign and malignant peripheral pulmonary lesions. In benign lesions we observed a higher frequency of delayed CE wash-out time (WOT) > 300 s. Anyhow, a CE WOT cut-off value > 300 s showed low diagnostic accuracy (53.6%) and sensibility (16.5%) in discriminating between pneumonias and malignancies. Similar results were also obtained in the sub-analysis by lesion size. Squamous cell carcinomas showed a more delayed CE AT compared to other histopathology subtypes. However, such a difference was statistically significant with undifferentiated lung carcinomas. Conclusions. Due to an overlap of CEUS timings and patterns, dynamic CEUS parameters cannot effectively differentiate between benign and malignant peripheral pulmonary lesions. Chest CT remains the gold standard for lesion characterization and the eventual identification of other pneumonic non-subpleural localizations. Furthermore, in the case of malignancy, a chest CT is always needed for staging purposes.

Obstructive sleep apnoea-hypopnoea syndrome (OSAHS) is an extremely common sleep-related breathing disorder (SRBD) characterised by complete or partial collapse of the upper airways. These nocturnal phenomena cause high-frequency hypoxemic desaturations (or intermittent hypoxia, IH) during sleep and alterations in gas exchange. The result of IH is the development or worsening of cerebro-cardio-vascular, metabolic and other diseases, which cause a high risk of death. Hence, OSAHS is a multifactorial disease affecting several organs and systems and presenting with various clinical manifestations involving different medical branches. Although it has been estimated that about one billion individuals worldwide are affected by OSAHS, this SRBD remains underestimated also due to misinformation regarding both patients and physicians. Therefore, this review aims to provide information on the main symptoms and risk factors for the detection of individuals at risk of OSAHS, as well as to present the diagnostic investigations to be performed and the different therapeutic approaches. The scientific evidence reported suggest that OSAHS is an extremely common and complex disorder that has a large impact on the health and quality of life of individuals, as well as on healthcare expenditure. Moreover, given its multifactorial nature, the design and implementation of diagnostic and therapeutic programmes through a multidisciplinary approach are necessary for a tailor-made therapy for each patient.

Background. Severe asthma and bronchiectasis are heterogeneous diseases that frequently coexist. The location of bronchiectasis is generally determined by specific underlying pathophysiological mechanisms. The aim of this study was to determine whether in a population suffering from both severe asthma and bronchiectasis there was a correlation between eosinophilic inflammation and localization of bronchiectasis. Methods. We enrolled 41 patients with coexisting bronchiectasis from eight different severe asthma center outpatient clinics and collected the following data: baseline characteristics, Asthma Control Test, Asthma Control Questionnaire, IgE level, blood count, high-resolution computed tomography and bronchiectasis-related parameters, skin prick test, FeNO50 and flow-volume spirometry. The study was retrospectively registered. Results. The presence of eosinophils > 1000 cells/μL was related to distribution of lower pulmonary bronchiectasis (9.1% upper lobes vs. 53.3% lower lobes, p = 0.014). Indeed, the presence of eosinophilic counts > 1000 increased the probability of lower localization of bronchiectasis compared to upper lobes (ODD 0.088 (0.010−0.772), p = 0.028). Conclusions. An increase in blood eosinophils > 1000 cells/μL seems to be associated with lower preferential localization of bronchiectasis with sparing of the upper lung lobes. This could represent a new potential radiological phenotype that could have a dedicated therapeutic strategy in the future.

Sleep-disordered breathing (SDB) includes a broad spectrum of diseases, of which obstructive sleep apnea syndrome (OSA) is the most clinically significant manifestation. OSA is a respiratory disorder characterized by episodes of complete or partial obstruction of the upper airways that disturb ventilation and sleep architecture. In recent years, interest in the clinical implications of OSA seems to have increased, probably due to the numerous studies that have shown the existence of an important correlation between OSA and cardiovascular, dysmetabolic, and neoplastic changes. The guidelines currently available highlight the importance of diagnosis and effective treatment for OSA, underlining the need for new biomarkers that are useful in clinical practice, feasible, and reproducible to guide medical decision making. In this review, we intend to provide an overview of the potential role of microRNAs as new indicators for OSA management. MicroRNAs (miRNAs) are small non-coding RNA molecules that play an important role in RNA silencing and regulation of gene expression at the post-transcriptional level. These can bind specifically to their target genes by forming silencing complexes, thus inducing degradation or altered gene expression. A wide range of miRNAs have been extensively studied in a variety of diseases including cancer, and recently, miRNAs have been shown to have enormous potential to function as diagnostic and clinical biomarkers of disease. This review includes recent studies that establish the inevitable role of miRNAs in the pathogenesis of OSA.

Background and Aim: Sleep-disordered breathing (SDB) is an extremely common disorder with a high impact on morbidity and mortality. The purpose of this study was to compare overlap syndrome (OS) and obesity hypoventilation syndrome (OHS) and to highlight and understand the differences between them. Material and Methods: The study was conducted retrospectively on 132 subjects selected by consecutive sampling from those attending our unit for suspected SDB. After clinical evaluation as well as functional and sleep investigations, the population was divided according to diagnosis in OS and OHS; then, the clinical parameters of two groups were compared with different statistical analysis. Results: The subjects with OHS were younger and reported higher rated daytime sleepiness (p = 0.005). In addition, they presented more nocturnal respiratory events (apnea-hypopnea index (AHI) 63.61 ± 22.79 events·h−1 vs. AHIOS 42.21 ± 22.91 events·h−1, p < 0.0001) at the sleep investigation as worse gas exchange during sleep leading to a higher percentage of nocturnal hypoxemia (p < 0.0001). In contrast, subjects with OS had more an impaired respiratory function. With regard to night-time ventilatory therapy, more subjects with OS were effectively treated with continuous positive airway pressure (CPAP) (p = 0.011), while more OHS were treated with auto-adjusting PAP (APAP) (14% vs. 1%, p = 0.008). Conclusions: The present study tried to establish a framework for OS and OHS because proper management of the two disorders would reduce their burden on healthcare.

Background: The most impacting direct costs associated to COPD for the National Health Systems (NHS) are those related to accesses to the emergency room and hospital admissions, due to the onset of one or more COPD exacerbations. At the same time, severe COPD treatment, that often require a combination of medicaments, represents a substantial economic burden for the National Health Systems (NHS). This study aimed to evaluate the potential saving deriving from the implementation in the prescription of the two currently available single-inhaler triple therapies (SITTs) versus the currently used multiple-inhaler triple therapies (MITTs) in an eligible COPD population residing in the Apulia Region., Methods: A budget impact model was developed hypothesizing the progressive replacement of the different MITTs on the reference market (Scenario A) with the pre-established SITTs, assuming a degree of penetration of 30%, 50% and 100% (Scenario B). Drug costs were based on prices published on the Official Gazette and therapy durations were based on prescribing information over the year 2019 (IQVIA™ prescription dataset)., Results: Our analysis showed that the extemporaneous MITT with the highest prevalence on the reference market was the inhaled corticosteroids/long-acting β 2 -agonists (ICS/LABA) combination plus a long-acting muscarinic antagonists (LAMA). This association of medicaments was paradoxically also the one associated to the highest expense value. The expanded use of a pre-established ICS/LAMA/LABA SITT was associated to a significant economic saving, ranging from a minimum of -€ 1,108,814 (SITT use: 30%) to a maximum of -€ 3,658,950 (SITT use: 100%). The cheapest pre-established SITT contained the fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) combination., Conclusion: A pre-fixed ICS/LAMA/LABA SITT is cost-saving, compared to the different currently used extemporaneous MITTs. Clinicians should consider the potential benefits of finding less expensive regimens while maintaining adequate efficacy in the prescriptive decision making process of COPD patients., (© 2022. The Author(s).)

Background: Obstructive sleep apnoea (OSA) has an important impact on the risk of morbidity and mortality, so we have designed the present study to understand which factor is most involved in the risk of developing a comorbidity between OSA severity and nocturnal hypoxemia., Methods: A retrospective study was conducted on 617 adult subjects who were referred to our unit for a suspicion of OSA between January 2018 and January 2020., Results: Sleep investigations performed by participants (72% male and obese in 70% of cases) reported an overall mean apnoea-hypopnoea index (AHI) of 44.0 ± 24.8 events·h -1 . Overall, 66% were classified as severe OSA and 76% experienced nocturnal hypoxemia. By analysing the burden of OSA severity and nocturnal hypoxemia on the comorbidities risk, multivariate analysis highlighted the predominant role of age and obesity. Accordingly, after the exclusion of the older and obese participants from the analyses, we noticed that severe OSA was related to the risk of hypertension (odds ratio (OR) = 3.0 [95% confidence interval [CI] 1.4-6.2], p = 0.004) as well as nocturnal hypoxemia (OR = 2.6 [95% CI 1.2-5.4], p = 0.01)., Conclusions: The study seems to suggest that in young, non-obese subjects, OSA is a predisposing factor for the risk of developing hypertension.

Idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), asthma and sleep disorders are chronic respiratory diseases that affect the airways, compromising lung function over time. These diseases affect hundreds of millions of people around the world and their frequency seems to be increasing every year. Extracellular vesicles (EVs) are small-sized vesicles released by every cell in the body. They are present in most body fluids and contain various biomolecules including proteins, lipids, mRNA and non-coding RNA (micro-RNA). The EVs can release their cargo, specifically micro-RNAs (miRNAs), to both neighboring and/or distal cells, playing a fundamental role in cell-cell communication. Recent studies have shown their possible role in the pathogenesis of various chronic respiratory diseases. The expression of miRNAs and, in particular, of miRNAs contained within the extracellular vesicles seems to be a good starting point in order to identify new potential biomarkers of disease, allowing a non-invasive clinical diagnosis. In this review we summarize some studies, present in the literature, about the functions of extracellular vesicles and miRNAs contained in extracellular vesicles in chronic respiratory diseases and we discuss the potential clinical applications of EVs and EVs-miRNAs for their possible use such as future biomarkers.

Background: Transthoracic ultrasound (TUS) is an accepted complementary tool in the diagnostic process of several pleuro-pulmonary diseases. However, to the best of our knowledge, TUS findings in patients with severe asthma have never been systematically described., Objective: To explore if TUS examination is a useful imaging method in suggesting the presence of a "small airways disease" in patients with severe uncontrolled asthma., Methods: Seventy-two consecutive subjects with a diagnosis of severe uncontrolled asthma were enrolled. The presence of a "small airways disease" was assessed through the execution of pulmonary function tests. All the patients underwent a complete TUS examination and a chest high resolution computed tomography (HRCT), which was regarded as the reference standard for comparison with TUS findings., Results: Pulmonary function tests results have confirmed a reduction in expiratory flows relative to the small airways and a condition of hyperinflation in 78% and 82% of our patients, respectively. The main signs observed in the TUS examination were a thickened and/or irregular pleural line and the lack or reduction of the "gliding sign." TUS showed high sensitivity and specificity in suggesting the presence of hyperinflation and distal airways inflammation according to the HRCT scan. K Cohen's coefficients showed substantial agreement between the 2 diagnostic tests., Conclusion: TUS in patients with severe uncontrolled asthma can provide useful information on the state of the peripheral lung, suggesting the execution of a second-line HRCT scan for better assessment of eventual alterations that may represent the underlying causes of nonresponse to treatment., (Copyright © 2022 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: It is still unclear if low lymphocyte levels are directly related to immunological modifications induced by the TB infection or if they depend on the general pre-existing health impairment of affected patients. Our aim was to detect eventual differences in the immunological status of patients with pulmonary TB compared to an age and sex-matched group of hospitalized patients with other bacterial community-acquired pneumonia (CAP). In addition, we tried to assess an association between alterations in the peripheral lymphocyte subsets and the development of different CT patterns of active TB and to discover differences in the immunological status and in the radiological patterns of TB presentation between patients of different geographic proveniences., Methods: This observational study included 48 patients with TB and 48 sex- and age-matched patients affected by other bacterial CAP. The presence of HIV/AIDS, other immunocompromising conditions, and confounding chronic pulmonary comorbidities was excluded. Flow cytometry was performed on all the enrolled subjects at admission, before starting the appropriate antibiotic therapy. Patients with TB also underwent a computed tomography (CT) scan., Results: Patients with TB showed a decrease in the absolute count of all the lymphocyte subsets compared to the CAP group. Only the reduction in the percentage of CD4+ T-lymphocytes was significant, while the percentage of CD8+ T-lymphocytes was significantly increased. Patients presenting exudative forms with atypical locations of TB showed a significant reduction in the absolute count and percentage of CD19+ B-lymphocytes compared to those affected by productive TB forms with the typical location. Despite being younger, our black Sub-Saharan Africans showed a significant reduction in the CD4+ T-lymphocytes compartment and a higher prevalence of atypical and exudative forms of TB compared with white Europeans., Conclusion: Tuberculosis itself may alter peripheral blood lymphocyte subsets compared to other CAP. An impaired CD19+ B-lymphocyte compartment may result in an abnormal exudative response in atypical locations and a suboptimal bacterial control. Other constitutive or environmental causes may influence immunological differences found in patients with TB, particularly in case of different geographic origins. Anyhow, flow cytometry may be of great value in evaluating the immune function of these patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Scioscia, Lacedonia, Giuffreda, Caccavo, Quarato, Soccio, Tondo, Sassani, Pescatore and Foschino Barbaro.)

Introduction: Asthma and bronchiectasis appear to be two related diseases and in their complex inflammatory interaction, the cysteinyl leukotriene/cysteinyl leukotriene receptor 1 (cysLT/cysLTR1) axis appears to play an important role given its involvement also in the neutrophilic pathway. To our knowledge, few studies have been conducted so far to evaluate the role of the leukotriene cysLT/cysLTr1 axis in the management of clinical and inflammatory outcomes within a population of patients with severe asthma and bronchiectasis. The aim of our study was to verify in this population the effect of leukotriene receptor antagonist (LTRA) therapy in clinical and inflammatory control before and after 6 months of introduction of biologic therapy., Methods: We retrospectively enrolled, from eight different severe asthma centers' outpatients, 36 atopic patients with the simultaneous presence of non-cystic fibrosis (non-CF) and non-allergic bronchopulmonary aspergillosis (non-ABPA) bronchiectasis and severe asthma. The first biological injection was performed at baseline (T0 time). Patients who were already taking LTRA therapy at time T0 were recorded, and no new prescriptions were made. We observed our population over a 6-month period (T1 time). At the baseline we collected the following data: baseline characteristics, clinical history, high resolution computed tomography and bronchiectasis-related parameters and skin prick test. At both times T0 and T1 we collected the following data: asthma control test (ACT), asthma control questionnaire (ACQ), immunoglobulin E (IgE) level, blood count, fractional exhaled nitric oxide 50 (FeNO 50) and flow-volume spirometry. The study was retrospectively registered., Results: Our population had a mean age of 59.08 ± 11.09 and 50% were female. At T1, patients on LTRA therapy had a significantly lower FeNO value (33.03 ± 23.61 vs. 88.92 ± 77.96; p = 0.012). We assessed that the value of ΔFeNO (FeNO 50 T1 - FeNO 50 T0) and the number of unplanned specialist visits allowed a discrimination of 66.7% in the presence of LTRA therapy. We also verified how low FeNO values at time T1 were statistically significant predictors of LTRA therapy (ODD = 9.96 (0.94-0.99); p = 0.032)., Conclusion: The presence of LTRA in therapy in a population of severe asthmatics with coexisting non-ASBPA bronchiectasis and non-cystic fibrosis, acting simultaneously on the T helper type 2 (TH2) pathway and probably on the neutrophilic component of bronchiectasis, would allow a further amplification of the beneficial effects of biological therapy, leading to a reduction in the number of unplanned visits to specialists.

Continuous positive airway pressure (CPAP) is the "gold-standard" therapy for obstructive sleep apnea (OSA), but the main problem is the poor adherence. Therefore, we have searched for the causes of poor adherence to CPAP therapy by applying predictive machine learning (ML) methods. The study was conducted on OSAs in nighttime therapy with CPAP. An outpatient follow-up was planned at 3, 6, 12 months. We collected several parameters at the baseline visit and after dividing all patients into two groups (Adherent and Non-adherent) according to therapy adherence, we compared them. Statistical differences between the two groups were not found according to baseline characteristics, except gender ( P < .01). Therefore, we applied ML to predict CPAP adherence, and these predictive models showed an accuracy and sensitivity of 68.6% and an AUC (area under the curve) of 72.9% through the SVM (support vector machine) classification method. The identification of factors predictive of long-term CPAP adherence is complex, but our proof of concept seems to demonstrate the utility of ML to identify subjects poorly adherent to therapy. Therefore, application of these models to larger samples could aid in the careful identification of these subjects and result in important savings in healthcare spending.

Chronic rhinosinusitis (CRS) is one of the most frequent comorbidities associated with asthma and it contributes to an amplified global disease burden in asthmatics. CRS prevalence is much higher in asthmatic patients compared to the general population and it is more frequently related to severe asthma, especially in presence of nasal polyps (chronic rhinosinusitis with nasal polyps, CRSwNP). Moreover, asthma exacerbation has a higher occurrence in CRSwNP. From a pathologic point of view, CRS and asthma share similar and connected mechanisms (e.g., type-2 inflammation). A multidisciplinary approach represents a crucial aspect for the optimal management of patients with concomitant asthma and CRSwNP and improvement of patient quality of life. An Italian panel of clinicians with different clinical expertise (pulmonologists, ear, nose and throat specialists, immunologists and allergy physicians) identified three different profiles of patients with coexisting asthma and nasal symptoms and discussed the specific tracks to guide a comprehensive approach to their diagnostic and therapeutic management. Currently available biological agents for the treatment of severe asthma act either on eosinophil-centered signaling network or type-2 inflammation, resulting to be effective also in CRSwNP and representing a valid option for patients with concomitant conditions.

MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. An aberrant regulation of gene expression by miRNAs is associated with numerous diseases, including cancer. MiRNAs expression can be influenced by various stimuli, among which hypoxia; however, the effects of different types of continuous hypoxia (moderate or marked) on miRNAs are still poorly studied. Lately, some hypoxia-inducible miRNAs (HRMs, hypoxia-regulated miRNAs) have been identified. These HRMs are often activated in different types of cancers, suggesting their role in tumorigenesis. The aim of this study was to evaluate changes in miRNAs expression both in moderate continuous hypoxia and marked continuous hypoxia to better understand the possible relationship between hypoxia, miRNAs, and colorectal cancer. We used RT-PCR to detect the miRNAs expression in colorectal cancer cell lines in conditions of moderate and marked continuous hypoxia. The expression of miRNAs was analyzed using a two-way ANOVA test to compare the differential expression of miRNAs among groups. The levels of almost all analyzed miRNAs (miR-21, miR-23b, miR-26a, miR-27b, and miR-145) were greater in moderate hypoxia versus marked hypoxia, except for miR-23b and miR-21. This study identified a series of miRNAs involved in the response to different types of continuous hypoxia (moderate and marked), highlighting that they play a role in the development of cancer. To date, there are no other studies that demonstrate how these two types of continuous hypoxia could be able to activate different molecular pathways that lead to a different expression of specific miRNAs involved in tumorigenesis.

Competing Interests: The authors reported no potential conflicts of interest with respect to the research, authorship, and/ or publication of this article.

Obesity is a pathology characterized by an excessive accumulation of adipose tissue and it is a condition associated with complex alterations affecting different organs and systems. Obesity has great influences on cardiovascular and respiratory morbidity and mortality, and impairs the multiple aspects of metabolism. Since micro-RNAs (miRNAs) are thought to play a role in the regulation of various pathological processes, in this complex framework, the investigation of these classes of noncoding regulatory RNA seems to be promising. Selected group of obese subjects was recruited. We analyzed the expression of seven miRNAs from obese adipose tissue supposed to have a role in the pathogenesis of cardiovascular and respiratory disease related to obesity and we compared it with the expression of the same miRNAs in a group of nonobese controls. In this study what emerged is miR-27b and miR-483 significant downregulation in subcutaneous adipose tissue from obese group compared with nonobese ones. For visceral adipose tissue, a significant decrease in miR-27b and miR-223 expression was observed in obese group. Moreover, a different expression of miR-26a and miR-338 in the obese group was found. Those findings could help the individuation of previously unknown key players in the development of different diseases usually associated with obesity, such as cardiovascular and pulmonary diseases. Clinical Trials.gov ID: Ref 17/CE/2014.

Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive, fibrosing interstitial pneumonia of unknown cause that leads to respiratory failure and death within few years of diagnosis. Pulmonary hypertension (PH) is a common complication in IPF, where it is strongly associated with increased morbidity and mortality. Patients with IPF and PH have particularly poor prognosis, despite current best medical therapies and the anti-fibrotic therapy with pirfenidone or nintedanib. The aim of our study was to assess the clinical and prognostic impact of PH in patients affected by IPF, already treated with pirfenidone or nintedanib. Seventy-four consecutive outpatients with a diagnosis of IPF, in therapy with pirfenidone or nintedanib, were prospectively enrolled in the study. All patients underwent pulmonary and cardiology assessment by clinical exam, spirometry, DLCO test, chest CT, 6MWT and echocardiography performed by a cardiologist experienced in PH in an ambulatory setting under resting conditions. GAP index has been determinate for all patients. During follow-up, all patients were evaluated every 6 months, or less if necessary. Data about mortality were then collected in a 3-year follow-up. Of the seventy-four patients enrolled, 38 were treated with pirfenidone and 36 with nintedanib. The two groups were comparable for age, gender, FVC, DLCO and PAPS. The patients were also divided in four groups, based on presence of mild/moderate/severe PH by echocardiography at baseline. Significant differences were found for DLCO and the GAP index. Severity of PH was significantly associated with a reduction of DLCO and with an increased GAP index. Survival was directly correlated with 6MWT (R = 0.48), DLCO (R = 0.29, p < 0.01), and reversely with tGAP index (- 0.31, p < 0.01 in all cases), while no significant correlation was found with PAsP. 36-month survival analysis showed an HR of 4.05 (95% CI 1.07-7.34, p = 0.02) for DLCO < 50% and of 1.56 (95% CI 1.02-2.39, p = 0.03) for GAP index. The development and progression of PH in patients affected by IPF reduce the survival and the severity of PH is associated with a reduction of DLCO value and an increase of the GAP index. Echocardiographic stratification based on PAsP values may be useful in stratifying prognosis in IPF patients and deciding specific PAH drugs., (© 2021. Società Italiana di Medicina Interna (SIMI).)

Background: Exhaled breath temperature (EBT) has been shown to reflect airway inflammation as well as increased vascularization, both involved in the pathogenesis of lung cancer. The aim of this study was to look for evidence that continuous EBT monitoring by such a device may help the early detection of relapse of lung cancer in patients with NSCLC who have been subjected to surgery with radical intent. Case Series . We included 11 subjects, who had been subjected to lung resection with radical intent for NSCLC in a prospective observational study. All patients received individual devices for EBT measurement and used them daily for 24 months after surgery. Subjects were also followed up by means of regular standard-of-care clinical and radiologic monitoring for lung cancer at four intervals separated by 6 months (T0, T1, T2, T3, and T4). In 5 patients, relapse of lung cancer was documented by means of lung biopsies. All of them recorded an elevation of their EBT at least one-time interval (T1), corresponding to 6 months, before the relapse was diagnosed at T4. The individual EBT graphs over time differed among these patients, and their mean EBT variability increased by +4% towards the end of 24 months of monitoring. By contrast, patients without a relapse did not document an elevation of their EBT and their variability decreased by -1.4%., Conclusions: Our pilot study provided evidence that continuous EBT monitoring can help in the early detection of lung cancer relapse., Competing Interests: The authors declare that they have no conflict of interest., (Copyright © 2022 Giovanna Elisiana Carpagnano et al.)

Background: Dupilumab is a humanized monoclonal antibody targeting the IL4/IL13 signaling pathway, already used for atopic dermatitis and chronic rhinitis with nasal polyps, recently approved for severe type-2 asthma. Its efficacy has been demonstrated in randomized control trials. The aim of our study is to evaluate possible early clinical improvement and type 2 biomarkers modifications in severe asthmatic patients treated with dupilumab in a real-life setting., Methods: We included 12 patients with severe, uncontrolled asthma and dupilumab was chosen if there was at least one evidence of blood eosinophils> 150 cells/ml and/or FeNO>25 ppb during last year. Recent blood eosinophil count report, assessment through ACT, FeNO test and spirometry were performed at baseline and after 3 months of treatment. We calculated also the number of patients achieving a minimal, yet clinically relevant difference in FEV 1 and ACT., Results: After three months of treatment with dupilumab, ACT had a significant improvement (mean ACT pre 13.25±4.65 vs mean ACT post 19.17±4.45; p<0.01), so as FEV 1 % (mean FEV 1 % pre 62.58±15.73 vs mean FEV 1 % post 71.00±13.11; p<0.01). FeNO had a significant reduction (median FeNO 32 pre, IQR 19-48.5 vs median FeNO19 post, IQR 16.5-26), differently from eosinophils blood count (median eosinophils pre 280, IQR 193.8-647.3 vs median eosinophils post 349.5, IQR 103-836.8; p=0.52). Four patients (33%) had a positive MCID for FEV 1 , and eight patients (67%) had a positive MCID for ACT., Conclusions: In RCTs performed during clinical development program dupilumab showed an early efficacy in increasing FEV 1 , reducing FeNO and improving asthma control. Our study demonstrates early improvement in asthmatic symptoms, lung function and FeNO in severe type-2 asthma patients after only 3 months of dupilumab biologic therapy. The introduction of FeNO levels evaluation in the selection criteria for dupilumab, further helps the identification of eligible patients among type-2 severe asthma patients and allows a complete outpatient assessment. Further real-life studies with a longer follow up time will be useful to confirm dupilumab efficacy and to promote its use in clinical practice., (©Copyright: the Author(s).)

Background: Benralizumab is effective in severe eosinophilic asthma (SEA), but suboptimal responses are observed in some patients. Although several factors have been associated with benralizumab response, no cluster analysis has yet been undertaken to identify different responsiveness sub-phenotypes., Objective: To identify SEA sub-phenotypes with differential responsiveness to benralizumab., Methods: One hundred and five patients diagnosed with SEA who had completed 6 months of benralizumab treatment were included in a hierarchical cluster analysis based on a set of clinical variables that can be easily collected in routine practice (age, age at disease onset, disease length, allergen sensitization status, blood eosinophil count, IgE levels, FEV 1 % predicted, nasal polyposis, bronchiectasis)., Results: Four clusters were identified: Clusters 2 and 3 included patients with high levels of both IgE and eosinophils (type-2 biomarkers high), whereas Clusters 1 and 4 included patients with only one type-2 biomarker at a high level: IgE in Cluster 1 and eosinophils in Cluster 4. Clusters 2 and 3 (both type-2 biomarkers high) showed the highest response rate to benralizumab in terms of elimination of exacerbations (79% and 80% respectively) compared to Clusters 1 and 4 (52% and 60% respectively). When super-response (the absence of exacerbation without oral corticosteroid use) was assessed, Cluster 2, including patients with more preserved lung function than the other clusters, but comparable exacerbation rate, oral corticosteroid use and symptom severity, was the most responsive cluster (87.5% of patients)., Conclusions: Our cluster analysis identified benralizumab differential response sub-phenotypes in SEA, with the potential of improving disease treatment and precision management., (© 2021 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

Purpose: The aim of this study was to assess whether new-generation shear wave elastography (SWE) is suitable for the characterization of lung subpleural lesions., Methods: In total, 190 consecutive patients with subpleural lung lesions received ultrasonography and SWE. Patients with suspected malignancy underwent ultrasound-guided transthoracic needle biopsy. Final diagnoses were made on the basis of patients' clinical course, microbiological studies, and histological results. SWE was also performed in 25 healthy volunteers., Results: We found no statistically significant differences in stiffness between lung carcinomas, lung metastases, and pneumonia (P=0.296) or between different histological types of lung cancer (P=0.393). Necrosis was associated with reduced stiffness in pneumonia. Excluding necrotic lesions, pneumonia showed higher stiffness than lung carcinomas (2.95±0.68 m/s vs. 2.60±0.54 m/s, P=0.006). Chronic pneumonia showed increased stiffness (3.03±0.63 m/s), probably due to the presence of fibrotic tissue on histology. Pleural effusion was associated with a statistically significant reduction in stiffness, both in lung carcinomas (P=0.004) and lung metastases (P=0.002). The presence of air in healthy lung tissue may lead to incorrect speed estimates due to shear wave reflection (very high values, 14.64±2.19 m/s)., Conclusion: Transthoracic SWE could not distinguish lung malignancy from pneumonia, or between different histological types of lung carcinomas. In particular, SWE seems unable to resolve the clinical dilemma of chronic subpleural consolidations.

Tuberculosis (TB) is a severe infectious disease that still represents a major cause of mortality and morbidity worldwide. For these reasons, clinicians and radiologists should use all the available diagnostic tools in the assessment of the disease in order to provide precise indications about starting an anti-tubercular treatment and reduce risk of TB transmission and complications especially in developing countries where the disease is still endemic. As TB mycobacteria are mainly transmitted through respiratory droplets, the pulmonary parenchyma is usually the first site of infection. As a result, chest imaging plays a central role in the diagnostic process. Thoracic ultrasound (TUS) is a portable, non-invasive, radiation-free, and cost-contained technology which could be easily available in resource-limited settings. This perspective article focuses on the potential role of TUS in the diagnosis and management of patients with pulmonary TB. Unfortunately, there are still insufficient evidence and too contrasting data to judge TUS as an appropriate diagnostic method for the screening of the disease. Despite this, TUS may have a useful role in identifying pleural and anterior pericardial effusions or in the identification of abscesses of the anterior chest wall and paraspinal collections in low- and middle-income settings. In addition, TUS seems to have a milestone role in guiding minimally invasive interventional procedures, such as placement of chest tubes, drainage of loculated collections, thoracentesis and pericardiocentesis, and percutaneous biopsy of subpleural pulmonary consolidations or pleural plaques., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Rea, Sperandeo, Lieto, Bocchino, Quarato, Feragalli, Valente, Scioscia, Giuffreda, Foschino Barbaro and Lacedonia.)

Due to the high prevalence of obstructive sleep apnea (OSA), it is recommended to use in-laboratory polysomnography (PSG) or a home sleep apnea test (HSAT) in uncomplicated adult subjects at high risk of OSA. The aims of the present study were to compare a HSAT device, a wrist worn peripheral arterial tone signal device (WatchPAT™-200 [WP]) with PSG and respiratory polygraphy (RP) in a low-risk population of OSA. A total of 47 adult subjects at low risk of OSA were simultaneously examined with the three different approaches in a single night. The sleep studies were scored independently and in a blinded fashion, then the results and the parameters (Respiratory Disturbance Index, apnea-hypopnea index [AHI] and oxygen desaturation index of 3%) were compared with several statistical analyses. The agreement between the sleep tools and correlation for the assessed parameters were analysed and compared with Bland and Altman plots and Pearson's coefficient (WP versus PSG, r = 0.86). For the severity of OSA ranked according to PSG, the Cohen's k was 0.60 and 0.82 for WP and RP, respectively. Specificity was higher for RP compared to WP for identifying the presence of OSA (AHIPSG cut-off ≥5 events/hr: 0.85 versus 0.73), while was quite similar in identifying patients who were more likely to be treated (AHIPSG cut-off ≥15 events/hr: 0.94 versus 0.96). Assessing the costs and the simplicity of the examination, the results of our present study demonstrate the usefulness of WP compared to PSG, especially in screening and follow-up for the ability to exclude subjects from treatment with continuous positive airway pressure (AHI <15 events/hr) in a population with a low pre-test risk of moderate-to-severe OSA., (© 2021 European Sleep Research Society.)