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Pierachille Santus,1 Fabiano Di Marco,2 Fulvio Braido,3 Marco Contoli,4 Angelo Guido Corsico,5 Claudio Micheletto,6 Girolamo Pelaia,7 Dejan Radovanovic,1 Paola Rogliani,8 Laura Saderi,9 Nicola Scichilone,10 Silvia Tanzi,11 Manlio Vella,11 Silvia Boarino,11 Giovanni Sotgiu,9 Paolo Solidoro12 1Department of Biomedical and Clinical Sciences (DIBIC), Università degli Studi di Milano, Division of Respiratory Diseases, Ospedale L. Sacco, ASST Fatebenefratelli-Sacco, Milano, Italy; 2Department of Health Sciences, Università degli Studi di Milano Pneumology, ASST Papa Giovanni XXIII, Bergamo, Italy; 3Department of Internal Medicine (DiMI), Respiratory Unit for Continuity of Care, IRCCS Ospedale Policlinico San Martino, University of Genova, Genova, Italy; 4Department of Translational Medicine, Respiratory Section, University of Ferrara, Ferrara, Italy; 5Department of Medical Sciences and Infective Diseases, Unit of Respiratory Diseases, IRCCS Policlinico San Matteo Foundation and University of Pavia Medical School, Pavia, Italy; 6Cardio-Thoracic Department, Respiratory Unit, University Integrated Hospital, Verona, Italy; 7Dipartimento di Scienze della Salute, Università Magna Graecia, Catanzaro, Italy; 8Department of Experimental Medicine, Unit of Respiratory Medicine, University of Rome ”Tor Vergata”, Division of Respiratory Medicine, University Hospital ”Tor Vergata”, Rome, Italy; 9Department of Medicine, Surgery and Pharmacy, University of Sassari, Sassari, Italy; 10Biomedical Department of Internal and Specialist Medicine, University of Palermo, Palermo, Italy; 11AstraZeneca Italia, Milan, Italy; 12Department of Medical Sciences, University of Turin, S.C. Pneumologia, Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Torino, ItalyCorrespondence: Pierachille Santus, Università degli Studi di Milano, Via G.B. Grassi 74, Milano, 20157, Italy, Tel +39 0239042801, Fax +39 0239042473, Email pierachille.santus@unimi.itObjective: To describe the burden of moderate to severe exacerbations and all-cause mortality; the secondary objectives were to analyze treatment patterns and changes over follow-up.Design: Observational, multicenter, retrospective, cohort study with a three year follow-up period.Setting: Ten Italian academic secondary- and tertiary-care centers.Participants: Patients with a confirmed diagnosis of COPD referring to the outpatient clinics of the participating centers were retrospectively recruited.Primary and Secondary Outcome Measures: Annualized frequency of moderate and severe exacerbations stratified by exacerbation history prior to study enrollment. Patients were classified according to airflow obstruction, GOLD risk categories, and divided in 4 groups: A = no exacerbations; B = 1 moderate exacerbation; C = 1 severe exacerbation; D = ≥ 2 moderate and/or severe exacerbations. Overall all-cause mortality stratified by age, COPD category, and COPD therapy. A logistic regression model assessed the association of clinical characteristics with mortality.Results: 1111 patients were included (73% males), of which 41.5% had a history of exacerbations. As expected, the proportion of patients experiencing ≥ 1 exacerbation during follow-up increased according to pre-defined study risk categories (B: 79%, C: 84%, D: 97.4%). Overall, by the end of follow-up, 45.5% of patients without a history of exacerbation experienced an exacerbation (31% of which severe), and 13% died. Deceased patients were significantly older, more obstructed and hyperinflated, and more frequently active smokers compared with survivors. Severe exacerbations were more frequent in patients that died (23.5%, vs 10.2%; p-value: 0.002). Chronic heart failure and ischemic heart disease were the only comorbidities associated with a higher odds ratio (OR) for death (OR: 2.2, p-value: 0.001; and OR: 1.9, p-value: 0.007). Treatment patterns were similar in patients that died and survivors.Conclusion: Patients with a low exacerbation risk are exposed to a significant future risk of moderate/severe exacerbations. Real life data confirm the strong association between mortality and cardiovascular comorbidities in COPD.Keywords: pulmonary disease chronic obstructive, heart failure, ischaemic heart disease, respiratory medicine, public health

Silvia Tognella,1 Claudio Micheletto,2 Alessandro Roggeri,3 Guido Polese,4 Denise Artioli,1 Gianenrico Senna,5 Marco Caminati,5,6 Daniela Paola Roggeri3 1Pulmonology Unit, Mater Salutis Hospital, Legnago (Verona), Italy; 2Pulmonology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy; 3ProCure Solutions, Nembro, Bergamo, Italy; 4Pulmonology Unit, Magalini Hospital, Villafranca (Verona), Italy; 5Asthma Center and Allergy Unit, Verona University Hospital, Verona, Italy; 6Department of Medicine, Allergy and Clinical Immunology Section, University of Verona and Verona University Hospital, Verona, 37134, ItalyCorrespondence: Alessandro RoggeriProCure Solutions, Via Camozzi 1/C, Nembro, 24027, BG, ItalyTel +39 035 521121Email alessandro.roggeri@procuresolutions.itPurpose: A Regional Technical Commission was set in 2017 by Veneto region (Italy) to provide opinions and recommendations on drug prescriptions and to implement treatment-pathway guidelines for severe asthma. In this observational study, we describe the first structured, integrated, multidisciplinary, patient-centered outpatient clinic for the care of severe-asthma patients in Italy, and characterize patients referring to the center for specialist visits.Patients and Methods: To characterize patients that accessed the outpatient clinic in 2018, data on demographic characteristics, treatments, severity of asthma, phenotypes, and relevant comorbidities by phenotype were collected. Use of biologic agents and indicators of the performance of the outpatient clinic were described.Results: A structured multidisciplinary outpatient pathway for taking charge of patients and for administration and monitoring of biological agents was developed. A total of 146 patients accessed the outpatient clinic in 2018: 62.3% had uncontrolled asthma upon admission and 27.4% were already being treated with biologic agents. Among patients with uncontrolled asthma, 66% had severe uncontrolled asthma, 22% had moderate–severe uncontrolled asthma, and 12% had mild–moderate uncontrolled asthma. Main asthma phenotypes in uncontrolled-asthma patients were allergic (58% of patients), eosinophilic (22%), allergic plus eosinophilic (10%) and non-atopic asthma (10%). Among patients affected by severe asthma, 47% had allergic asthma, 28% had eosinophilic asthma, 13% had allergic plus eosinophilic asthma, and 12% had non-atopic asthma. Nasal polyps were more frequent in eosinophilic and allergic plus eosinophilic asthma, while gastro-esophageal reflux disease was more frequent in non-atopic asthma.Conclusion: This structure of an outpatient clinic for the treatment of severe asthma, with its dedicated pathway and multidisciplinary approach, may allow a stricter control of asthma and optimization of therapies, as well as minimization of drug misuse.Keywords: asthma, severe, multidisciplinary, outpatient

Pierluigi Paggiaro,1 Simona Barbaglia,2 Stefano Centanni,3,4 Davide Croce,5 Enrico Desideri,6 Saffi Giustini,7,8 Claudio Micheletto,9 Antonino Musarra,10 Nicola Scichilone,11 Ugo Trama,12 Maria Teresa Zedda,7,13 Giorgio Walter Canonica14 1Department of Surgery, Medicine, Molecular Biology, and Critical Care, University of Pisa, Pisa, Italy; 2Associazione Nazionale Pazienti “Respiriamo Insieme”, Padova, Italy; 3Department of Health Sciences, Università degli Studi di Milano, Milan, Italy; 4Respiratory Unit, ASST Santi Paolo e Carlo, Milan, Italy; 5Center for Health Economics, Social and Health Care Management, LIUC-Università Cattaneo, Castellanza, Italy; 6Fondazione Innovazione e Sicurezza in Sanità, Rome, Italy; 7Italian General Practitioners’ Association “SIMG”, Florence, Italy; 8Local Health Unit of Montale, Pistoia, Italy; 9Cardio-Thoracic Department, Respiratory Unit, Integrated University Hospital, Verona, Italy; 10Allergy Unit, National Healthcare System, Reggio Calabria, Italy; 11Biomedical Department of Internal and Specialist Medicine, University of Palermo, Palermo, Italy; 12Dirigente UOD 06 Politica del Farmaco e Dispositivi, Naples, Italy; 13General Practice, Cagliari, Italy; 14Personalized Medicine Asthma & Allergy Clinic, Humanitas University and Research Hospital-IRCCS, Milan, ItalyCorrespondence: Pierluigi PaggiaroDepartment of Surgery, Medicine, Molecular Biology and Critical Care, University of Pisa, Via Paradisa No. 2, Pisa, 56124, ItalyTel +39 050 995365Fax +39 050 580124Email pierluigi.paggiaro@unipi.itIntroduction: People with severe asthma (SA) often have poor disease control and quality of life, and are at high risk of exacerbations, lung function decline and asthma-related death. The present expert opinion article aimed to identify unmet needs in the management of SA in Italy, and propose possible solutions to address these needs.Methods: At five multidisciplinary events in Italy, attendees identified factors that interfered with the effective management of SA and suggested how these barriers could be overcome. A core group of 12 Italian experts (pulmonologists, general practitioners, allergists, payers and patients) identified the main issues and proposed possible solutions based on the results from the meetings and relevant articles from the literature.Results and Conclusions: We reviewed the gap between real-world practice and guidelines, oral corticosteroid overuse, SA-related mortality, and barriers to effective SA treatment. Common themes were lack of awareness about SA among both patients and clinicians, and lack of networking/information exchange between those involved in the treatment of SA. Participants agreed on the need to implement patient education and create multidisciplinary groups of specialists to improve SA management through multidisciplinary educational initiatives, meetings with local experts, development of a flow chart for referral/connection with local experts and specialized centers. Clinical instruments that might help specialists improve SA management included referral networks, integrated care pathways, phenotyping and treatment algorithms, exacerbation tracking, and examination of electronic medical records for patients with uncontrolled asthma. The following actions need to be implemented in Italy: i) maximize the use of advanced therapies, eg, biologics; ii) increase/improve education for physicians and patients; iii) improve multidisciplinary communication and care coordination; iv) introduce regional and local protocols for SA diagnosis and treatment; and v) change the structure of healthcare services to reduce specialist waiting times and facilitate access to biologic therapies.Keywords: biologic therapy, expert opinion, oral corticosteroids, severe asthma, unmet needs

Claudio Micheletto,1 Fulvio Braido,2 Marco Contoli,3 Fabiano Di Marco,4 Pierachille Santus5 1Respiratory Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy; 2Department of Internal Medicine, Respiratory Diseases and Allergy Clinic, University of Genova, Azienda Policlinico IRCCS San Martino, Genoa, Italy; 3Department of Medical Sciences, University of Ferrara, Ferrara, Italy; 4Department of Health Sciences, Università degli Studi di Milano, Respiratory Unit, Papa Giovanni XXIII Hospital, Bergamo, Italy; 5Department of Health Sciences, Università degli Studi di Milano,Pulmonary Unit, Luigi Sacco University Hospital, ASST Fatebenefratelli, Milan, ItalyCorrespondence: Claudio MichelettoRespiratory Unit, Azienda Ospedaliera Universitaria Integrata, Piazzale Stefani 1, Verona 37122, ItalyTel +39 045 8122248Email claudio.micheletto@univr.itAbstract: While chronic obstructive pulmonary disease (COPD) continues to be a major cause of morbidity and mortality, pharmacological therapy has a definite benefit on symptoms as well as the frequency and severity of exacerbations, and general health. The most recent Global Initiative for Obstructive Lung Disease (GOLD) guidelines recommend triple therapy (long-acting beta2 agonists [LABA] + long-acting muscarinic antagonists [LAMA] + inhaled corticosteroids [ICS]) only for patients with exacerbations, elevated eosinophils, and without control using a LABA/LAMA or ICS/LABA combination. Long-term monotherapy with ICS is not currently recommended, but may be considered in association with LABAs in patients with a history of exacerbations and elevated eosinophils in spite of appropriate treatment with long-acting bronchodilators. However, long-term use of ICS in combination therapy has been associated with adverse effects, even if widely used in routine management for decades. The available evidence suggests that ICS can be rationally discontinued in patients with stable disease and is not likely to have unfavorable effects on lung function, overall health, or be associated with a greater risk of exacerbations. Indeed, it is widely accepted that ICS therapy should be limited to a small proportion of patients after careful assessment of the individual risk-benefit profile. Unfortunately, however, there are no international recommendations that provide specific guidance or a protocol for withdrawal of ICS. Herein, the available evidence on the use of ICS is reviewed and an easy to use tool is proposed that can provide clinicians with a simple management scheme to guide the most appropriate therapy for management of COPD and use of ICS. In management of COPD, a highly personalized approach is advocated so that the most appropriate therapy for each individual patient can be selected.Keywords: COPD, exacerbation, inhaled corticosteroids, LABA, LAMA, deprescribing

Alessandro Roggeri,1 Claudio Micheletto,2 Daniela Paola Roggeri1 1ProCure Solutions, Nembro, Bergamo, Italy, 2Respiratory Unit, Mater Salutis Hospital, Legnago, Verona, Italy Background: Different inhalation devices are characterized by different techniques of use. The untrained switching of device in chronic obstructive pulmonary disease (COPD) and asthma patients may be associated with inadequate inhalation technique and, consequently, could lead to a reduction in adherence to treatment and limit control of the disease. The aim of this analysis was to estimate the potential economic impact related to errors in inhalation in patients switching device without adequate training. Methods: An Italian real-practice study conducted in patients affected by COPD and asthma has shown an increase in health care resource consumption associated with misuse of inhalers. Particularly, significantly higher rates of hospitalizations, emergency room visits (ER), and pharmacological treatments (steroids and antimicrobials) were observed. In this analysis, those differences in resource consumption were monetized considering the Italian National Health Service (INHS) perspective. Results: Comparing a hypothetical cohort of 100 COPD patients with at least a critical error in inhalation vs 100 COPD patients without errors in inhalation, a yearly excess of 11.5 hospitalizations, 13 ER visits, 19.5 antimicrobial courses, and 47 corticosteroid courses for the first population were revealed. In the same way, considering 100 asthma patients with at least a critical error in inhalation vs 100 asthma patients without errors in inhalation, the first population is associated with a yearly excess of 19 hospitalizations, 26.5 ER visits, 4.5 antimicrobial courses, and 21.5 corticosteroid courses. These differences in resource consumption could be associated with an increase in health care expenditure for INHS, due to inhalation errors, of €23,444/yr in COPD and €44,104/yr in asthma for the considered cohorts of 100 patients. Conclusion: This evaluation highlights that misuse of inhaler devices, due to inadequate training or nonconsented switch of inhaled medications, is associated with a decrease in disease control and an increase in health care resource consumption and costs. Keywords: inhalers, devices, switch, training, errors, costs, asthma, COPD

Alessandro Roggeri,1 Claudio Micheletto,2 Daniela Paola Roggeri11ProCure Solutions, Bergamo, Italy; 2Respiratory Unit, Mater Salutis Hospital, Legnago, Verona, ItalyPurpose: Fixed-dose combinations of inhaled corticosteroids and long-acting ß2-agonists have proven to prevent and reduce chronic obstructive pulmonary disease (COPD) exacerbations. The aim of this analysis was to explore the clinical consequences and direct health care costs of applying the findings of the PATHOS (An Investigation of the Past 10 Years Health Care for Primary Care Patients with Chronic Obstructive Pulmonary Disease) study to the Italian context.Patients and methods: Effectiveness data from the PATHOS study, a population-based, retrospective, observational registry study conducted in Sweden, in terms of reduction in COPD and pneumonia-related hospitalizations, were considered, in order to estimate the differences in resource consumption between patients treated with budesonide/formoterol and fluticasone/salmeterol. The base case considers the average dosages of the two drugs reported in the PATHOS study and the actual public price in charges to the Italian National Health Service, while the difference in hospitalization rates reported in the PATHOS study was costed based on Italian real-world data.Results: The PATHOS study demonstrated a significant reduction in COPD hospitalizations and pneumonia-related hospitalizations in patients treated with budesonide/formoterol versus fluticasone/salmeterol (-29.1% and -42%, respectively). In the base case, the treatment of a patient for 1 year with budesonide/formoterol led to a saving of €499.90 (€195.10 for drugs, €193.10 for COPD hospitalizations, and €111.70 for pneumonia hospitalizations) corresponding to a -27.6% difference compared with fluticasone/salmeterol treatment.Conclusion: Treatment of COPD with budesonide/formoterol compared with fluticasone/salmeterol could lead to a reduction in direct health care costs, with relevant improvement in clinical outcomes.Keywords: disease management, pharmacoeconomics, direct health care costs, hospitalizations

OBJECTIVE: Growing interest is directed to the outcomes of COVID-19 in survivors, both in the convalescent period and in the long-term, which are responsible for morbidity and quality of life deterioration. This article aims to describe the mechanisms supporting the possible use of NAC as an adjuvant treatment for post-COVID-19 pulmonary fibrosis. MATERIALS AND METHODS: A search was performed in PubMed/MEDLINE. RESULTS: Interstitial changes have been observed in the CT scan of COVID-19 pneumonia. In patients with respiratory outcomes in the post-COVID-19 stage, glutathione (GSH) deficiency was found and interpreted as a reaction to the inflammatory cascade caused by the viral infection, while the pathophysiological process of pulmonary fibrosis involves numerous cytokines, such as TGF-β, TNF-α, IL-1, PDGF and VEGF. NAC has a good tolerability profile, is easily administered orally and inexpensively, and has antioxidant and anti-inflammatory effects that may target the pathophysiologic mechanisms involved in pulmonary fibrosis. It may revert GSH deficiency, exerts direct and indirect antioxidant activity, anti-inflammatory activity and improves immune T-cell response. CONCLUSIONS: The mechanism of action of NAC suggests a role in the treatment of pulmonary fibrosis induced by COVID-19. [ABSTRACT FROM AUTHOR]

Sleep is a significant dimension of daily life. However, only a few studies have examined the sleep quality of asthmatics in a real-world clinical settings. This study is aimed to estimate the prevalence of sleep impairments among asthmatic patients and examine the relationship between sleep quality, asthma control, rhinitis symptoms, and sociodemographic characteristics. The present study adopted the observational cross-sectional research design that has been designed by the Italian Respiratory Society and used valid assessments to measure the study variables. Data from 1150 asthmatic patients (mean age 51.01 years ± 16.03) were subjected to analysis. 58.3% of the patients had impaired sleep quality (Pittsburgh Sleep Quality Index [PSQI] total scores > 5), and their mean PSQI score was 5.68 (SD = 3.4). A significant correlation emerged between sleep quality and asthma control (p = 0.0001) and a significant albeit weak correlation emerged between PSQI total scores and Total 5 Symptoms Score (r = 0.24, p = 0.0001). Sleep quality was significantly associated health-related quality of life [HRQoL]. (r = 0.50, p < 0.001). After exclusion of patients at risk for Obstructive Sleep Apnea Syndrome (OSAS) and Gastro Esophageal Reflux Disease (GERD), the most important determinants of PSQI score were HRQoL, In the entire sample asthma control is the strongest predictor of both sleep quality and HRQoL. The results of this real-world study highlight the prevalence, impact and predictors of sleep disturbances in asthmatic patients and suggest the need for physicians to detect poor sleep quality [ABSTRACT FROM AUTHOR]

Background: In patients with asthma, particularly severe asthma, poor adherence to inhaled drugs negatively affects the achievement of disease control. A better adherence rate is expected in the case of injected drugs, such as omalizumab, as they are administered only in a hospital setting. However, adherence to omalizumab has never been systematically investigated. The aim of this study was to review the omalizumab drop-out rate in randomized controlled trials (RCTs) and real-life studies. A comparative analysis was performed between published data and the Italian North East Omalizumab Network (NEONet) database.Results: In RCTs the drop-out rate ranged from 7.1 to 19.4 %. Although the reasons for withdrawal were only occasionally reported, patient decision and adverse events were the most frequently reported causes. In real-life studies the drop-out rate ranged from 0 to 45.5 %. In most cases lack of efficacy was responsible for treatment discontinuation. According to NEONet data, 32 % of treated patients dropped out, with an increasing number of drop outs observed over time. Patient decision and lack of efficacy accounted for most treatment withdrawals.Conclusions: Treatment adherence is particularly crucial in patients with severe asthma considering the clinical impact of the disease and the cost of non-adherence. The risk of treatment discontinuation has to be carefully considered both in the experimental and real-life settings. Increased knowledge regarding the main reasons for patient withdrawal is important to improve adherence in clinical practice. [ABSTRACT FROM AUTHOR]

Aspirin-induced asthma (AIA) is a clinical syndrome characterized by acute airway reaction to aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDS). The most recent etiological hypothesises is that an overexpression of the enzyme LTC4 synthase occurs in AIA, with the consequent production of sulfidopeptide leukotrienes (LTs). Aim of the present study was to assess the effect of Montelukast, a selective cys-LT receptor antagonist, on nasal function, nasal reactivity to ASA and blood markers of eosinophilic inflammation in mild-to-moderate AIA. Thirty-six nonsmoker subjects with AIA (17 males, 22–52 years) performed a nasal provocation test (NPT) with lysine-aspirin (L-ASA) in baseline and after a 4-week Montelukast 10 mg or placebo treatment. Nasal function was assessed by the acoustic rhinomanometry, and they also performed a lung function test (forced expiratory volume in 1 s), and a blood sample for the eosinophil count and the eosinophil cationic protein (ECP) plasma measurements. After both treatments, all subjects repeated the NPT, the lung function, and the ECP and the eosinophil blood count. t-Test was used to compare mean values ± SD between groups, and P < 0.05 was assumed as the level for statistical significance. Airway patency was never affected by the NPT with L-ASA. In baseline, NPT with L-ASA precipitated a nasal reaction in all subjects, with a substantial increase in nasal resistance ( calculated resistance [REQ]; from 0.89 ± 0.18 to 2.2 ± 0.17 cmH2O/l/min in group M, P < 0.001; and from 0.91 ± 0.48 to 2.3 ± 0.21 cmH2O/l/min in group P, P < 0.001); and a significant reduction in total nasal volume in at least one nostril ( volume [VOL]; from 11.1 ± 3.2 to 8.1 ± 4.1 cm3 in the group M, P < 0.001 , and from 12.3 ± 4.1 to 7.9 ± 4.5 cm3 in the group P, P < 0.001). The nasal reaction to L-ASA remained unchanged following placebo, but it was completely minimized following a 4-week treatment with Montelukast. Also nasal function, the nasal symptom score, and the markers of eosinophilic inflammation proved significantly affected and improved by the active drug only. Montelukast 10 mg daily for 4 weeks, but not placebo, improves nasal function and nasal response to Aspirin substantially in ASA-sensitive asthmatics. [ABSTRACT FROM AUTHOR]