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Peter MA Calverley,1 Alberto Papi,2 Clive Page,3 Paola Rogliani,4 Roberto W Dal Negro,5 Mario Cazzola,4 Arrigo F Cicero,6 Jadwiga A Wedzicha7 1Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK; 2Respiratory Medicine, University of Ferrara, Ferrara, Italy; 3Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, Faculty of Life Sciences and Medicine, King’s College, London, UK; 4Respiratory Medicine Unit, Department of Experimental Medicine, University of Rome “Tor Vergata”, Rome, Italy; 5National Centre for Respiratory Pharmacoeconomics and Pharmacoepidemiology, Verona, Italy; 6Medical and Surgical Department, University of Bologna, Bologna, Italy; 7Respiratory Division, National Heart and Lung Institute, Imperial College London, London, UKCorrespondence: Peter MA Calverley, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK, Tel +44 1515295886, Fax +44 1515295888, Email pmacal@liverpool.ac.ukPurpose: To explore the effect of erdosteine on COPD exacerbations, health-related quality of life (HRQoL), and subjectively assessed COPD severity.Patients and methods: This post-hoc analysis of the RESTORE study included participants with COPD and spirometrically moderate (GOLD 2; post-bronchodilator forced expiratory volume in 1 second [FEV1] 50‒79% predicted; n = 254), or severe airflow limitation (GOLD 3; post-bronchodilator FEV1 30‒49% predicted; n = 191) who received erdosteine 300 mg twice daily or placebo added to usual maintenance therapy for 12 months. Antibiotic and oral corticosteroid use was determined together with patient-reported HRQoL (St George’s Respiratory Questionnaire, SGRQ). Patient and physician subjective COPD severity scores (scale 0‒4) were rated at baseline, 6 and 12 months. Data were analyzed using descriptive statistics for exacerbation severity, COPD severity, and treatment group. Comparisons between treatment groups used Student’s t-tests or ANCOVA as appropriate.Results: Among GOLD 2 patients, 43 of 126 erdosteine-treated patients exacerbated (7 moderate-to-severe exacerbations), compared to 62 of 128 placebo-treated patients (14 moderate-to-severe exacerbations). Among those with moderate-to-severe exacerbations, erdosteine-treated patients had a shorter mean duration of corticosteroid treatment (11.4 days vs 13.3 days for placebo, P = 0.043), and fewer patients required antibiotic treatment with/without oral corticosteroids (71.4% vs 85.8% for placebo, P < 0.001). Erdosteine-treated GOLD 2 patients who exacerbated showed significant improvements from baseline in SGRQ total scores and subjective disease severity scores (patient- and physician-rated), compared with placebo-treated patients regardless of exacerbation severity. Among GOLD 3 patients, there were no significant differences between treatment groups on any of these measures.Conclusion: Adding erdosteine to the usual maintenance therapy of COPD patients with moderate airflow limitation reduced the number of exacerbations, the duration of treatment with corticosteroids and the episodes requiring treatment with antibiotics. Additionally, treatment with erdosteine improved HRQoL and patient-reported disease severity.Keywords: antibiotic, chronic obstructive pulmonary disease, erdosteine, COPD exacerbation, health-related quality of life, systemic corticosteroid

Roberto W Dal Negro,1 Paola Turco,2 Massimiliano Povero3 1National Centre for Respiratory Pharmacoeconomics and Pharmacoepidemiology, Verona, Italy; 2Research & Clinical Governance, Verona, Italy; 3AdRes Health Economics and Outcome Research, Torino, ItalyCorrespondence: Massimiliano PoveroAdRes Health Economics and Outcome Research, Torino, ItalyEmail m.povero@adreshe.comBackground: The MiniBox+™ is an innovative technique for assessing lung volumes (LVs) and the diffusing capacity of the lung for carbon monoxide (DLco). Differently from the equipment needed for whole body plethysmography (WBP), the MiniBox+ is a small, transportable instrument, which derives total lung capacity (TLC) during tidal breathing by analyzing gas pressures and airflows immediately preceding and immediately following airway occlusions.Aim: To compare the consistency and the feasibility of LV and DLco measurements between the two instruments in different lung function disorders, and their cost of execution.Methods: Consecutive patients of both genders with obstructive and restrictive respiratory disorders were randomly recruited. LVs and DLco were measured by a randomized sequence. The failure risk, number of attempts to achieve the first reliable measurement, corresponding time spent, and costs per patient were compared.Results: A total of 134 patients were enrolled: 42 asthmatics (32.1%), and 47 patients with obstructive (35.1%) and 44 with restrictive respiratory disorders (32.8%). The overall failure risk was 19.4% for WBP and 8.2% for the MiniBox+ (risk ratio=0.417, 95% CI 0.242 to 0.72). LVs and DLco values proved equal with both techniques, regardless of the patients’ age, sex, schooling level, and initial lung disorder. Number of attempts and total time spent in achieving the first reliable measurement were significantly lower with the MiniBox+. Mean cost per patient was € 87.58 with WBP and € 75.11 with the MiniBox+, with a mean saving of € 12.33 (95% CI 5.93 to 18.73), mainly due to the saving in productivity loss.Conclusion: LV and DLco measurements with the MiniBox+ were highly consistent with those obtained with WBP. The MiniBox+ proved easier to use (lower failure risk) and more convenient (lower execution costs) than WBP.Keywords: economic impact, lung volumes, CO diffusing capacity, failure risk, whole body plethysmography, MiniBox+&#x2122

Peter MA Calverley,1 Clive Page,2 Roberto W Dal Negro,3 Giovanni Fontana,4 Mario Cazzola,5 Arrigo F Cicero,6 Edoardo Pozzi7,†, Jadwiga A Wedzicha8 1Department of Medicine, Clinical Sciences Centre, University Hospital Aintree, Liverpool, UK; 2Faculty of Life Sciences and Medicine, King’s College, London, UK; 3Lung Unit, National Centre for Respiratory Pharmacoeconomics and Pharmacoepidemiology, Verona, Italy; 4Pulmonology Department, Cough Centre, Careggi University Hospital, Firenze, Italy; 5Department of Systems Medicine, Chair of Respiratory Medicine, University of Rome ‘Tor Vergata’, Rome, Italy; 6Medical and Surgical Department, University of Bologna, Bologna, Italy; 7Medical Affairs Department, Edmond Pharma, Paderno, Italy; 8Respiratory Division, National Heart And Lung Institute, Imperial College London, London, UK†Dr Pozzii passed away on 9th July, 2019Correspondence: Peter MA CalverleyDepartment of Medicine, University Hospital Aintree, Lower Lane, Liverpool, Merseyside, UKTel +44 1515295886Fax +44 1515295888Email pmacal@liverpool.ac.ukBackground: The RESTORE study, a multi-national randomized, placebo-controlled study, showed that erdosteine – a muco-active antioxidant that modulates bacterial adhesiveness – reduced the rate and duration of exacerbations in moderate and severe COPD with a history of exacerbations. How much benefit patients with less severe disease experience when taking this drug remains unclear.Methods: This post hoc analysis of the 254 RESTORE participants with spirometrically-defined moderate COPD (post-bronchodilator forced expiratory volume in 1 second [FEV1] 50‒79% predicted) examined exacerbation rate and duration, time to first exacerbation, and exacerbation-free time. Data were analyzed using descriptive statistics and comparisons between treatment groups used Wilcoxon rank-sum tests, Mann–Whitney U-tests, or log rank tests.Results: Patients with moderate COPD received erdosteine 300 mg twice daily (n=126) or placebo (n=128) added to usual COPD therapy for 12 months. During this time, there were 53 exacerbations in the erdosteine group and 74 in the placebo group, with 42.1% and 57.8% of patients, respectively, experiencing an exacerbation. There was a 47% reduction in the mean exacerbation rate with erdosteine compared to placebo (0.27 vs 0.51 exacerbations per-patient per-year, respectively, P=0.003), and a 58.3% reduction in the mild exacerbation rate (0.23 vs 0.53 mild exacerbations per-patient per-year, P=0.001). Mean duration of exacerbations was 26% shorter in erdosteine-treated patients (9.1 vs 12.3 days for placebo, P=0.022), with significant reductions in the duration of mild and moderate-to-severe exacerbations. Mean time to first exacerbation was prolonged by 7.7% (182 days for erdosteine vs 169 days for placebo, P

Jean Bourbeau,1 Denis Granados,2 Stéphane Roze,3 Isabelle Durand-Zaleski,4 Pere Casan,5 Dieter Köhler,6 Silvia Tognella,7 Jose Luis Viejo,8 Roberto W Dal Negro,9 Romain Kessler10 1Department of Medicine, Division of Experimental Medicine, Respiratory Epidemiology and Clinical Research Unit, Research Institute of the McGill University Health Centre, Montreal, QC, Canada; 2Medical R&D – Real World & Clinical Evidence, Air Liquide Santé International, Gentilly, France; 3Department of Health Economics, HEVA HEOR, Lyon, France; 4URCEco Ile de France Hôpital de l’Hotel Dieu, Paris, France; 5Department of Pneumology, Asturias University Hospital, Oviedo, Spain; 6Department of Internal Medicine, Kloster Grafschaft Specialised Hospital, Schmallenberg, Germany; 7Department of Pneumology, Bussolengo General Hospital, Bussolengo, Italy; 8Department of Pneumology, Burgos University Hospital, Burgos, Spain; 9Department of Pneumology, Bussolengo Hospital, Bussolengo, Italy; 10Department of Pneumology, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France Purpose: Efficient management of COPD represents an international challenge. Effective management strategies within the means of limited health care budgets are urgently required. This analysis aimed to evaluate the cost-effectiveness of a home-based disease management (DM) intervention vs usual management (UM) in patients from the COPD Patient Management European Trial (COMET). Methods: Cost-effectiveness was evaluated in 319 intention-to-treat patients over 12 months in COMET. The analysis captured unplanned all-cause hospitalization days, mortality, and quality-adjusted life expectancy. Costs were evaluated from a National Health Service perspective for France, Germany, and Spain, and in a pooled analysis, and were expressed in 2015 Euros (EUR). Quality of life was assessed using the 15D health-related quality-of-life instrument and mapped to utility scores. Results: Home-based DM was associated with improved mortality and quality-adjusted life expectancy. DM and UM were associated with equivalent direct costs (DM reduced costs by EUR -37 per patient per year) in the pooled analysis. DM was associated with lower costs in France (EUR -806 per patient per year) and Spain (EUR -51 per patient per year), but higher costs in Germany (EUR 391 per patient per year). Evaluation of cost per death avoided and cost per quality-adjusted life year (QALY) gained showed that DM was dominant (more QALYs and cost saving) in France and Spain, and cost-effective in Germany vs UM. Nonparametric bootstrapping analysis, assuming a willingness-to-pay threshold of EUR 20,000 per QALY gained, indicated that the probability of home-based DM being cost-effective vs UM was 87.7% in France, 81.5% in Spain, and 75.9% in Germany. Conclusion: Home-based DM improved clinical outcomes at equivalent cost vs UM in France and Spain, and in the pooled analysis. DM was cost-effective in Germany with an incremental cost-effectiveness ratio of EUR 2,541 per QALY gained. The COMET home-based DM intervention could represent an attractive alternative to UM for European health care payers. Keywords: cost-effectiveness, France, Spain, Germany, home-based disease management, COPD

Roberto W Dal Negro,1 Paola Turco,2 Massimiliano Povero3 1National Centre for Respiratory Pharmacoeconomics and Pharmacoepidemiology, Verona, Italy; 2Research & Clinical Governance, Verona, Italy; 3AdRes Health Economics and Outcome Research, Torino, Italy Objectives: Acute cough is the most common symptom among children in primary care, but the economic impact of cough episodes has never been investigated in Italian families.Materials and methods: A cross-sectional telephone survey was conducted on a representative sample of Italian families, randomly selected from general population. Collected data were analyzed to evaluate the economic impact of cough episodes according to, first, Italian Family Perspective and, second, National Health System Perspective (NHS-P). The costs considered in the analysis were the cost of drugs used (antibiotics, corticosteroids, antitussive drugs, and aerosol therapy) and the cost of child care during nursery/school absenteeism.Results: Six hundred four valid questionnaires were analyzed: mean age of children is 7 years (SD=3.3) and that of parents is 40 years (SD=6.2). Mean rate of cough episodes was 3.15/year, and in general, they were short lasting (94.6%, €30 in 19.7% of cases). The overall economic impact on Italian families was estimated as €1,204 (SD=€88); it resulted in a cost per cough episode equal to €337, mainly due to nursery/school absenteeism (94.6%), whereas pharmaceutical expenditure was marginal (5.4%).Conclusion: Cough episodes are acute (lasting

Alessandro Zanasi,1 Luigi Morcaldi,2 Salvatore Cazzato,3 Massimiliano Mazzolini,4 Marzia Lecchi,5 Antonio Maria Morselli-Labate,6 Marianna Mastroroberto,6 Roberto W Dal Negro7 1Italian Association for Cough Study, Bologna, 2National Observatory of Health in Childhood and Adolescence (PAIDOSS: Osservatorio Nazionale sulla Salute dell’Infanzia e dell’Adolescenza), Rome, 3Department of Pediatrics, Salesi Children’s Hospital, Ancona, 4Department of Specialist, Diagnostic and Experimental Medicine, Respiratory and Critical Care Unit, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, 5Department of Biotechnology and Biosciences, University of Milan Bicocca, Milan, 6Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, 7National Centre for Respiratory Pharmacoeconomics and Pharmacoepidemiology, Verona, Italy Context: Children’s cough is a daily concern for most pediatricians. The management of both acute and chronic cough requires a systematic and comprehensive approach. Despite the approved protocols for management, the pediatric assessment of cough and the corresponding prescribing attitude frequently do not fit these protocols, which can be affected by parental suggestions – sometimes substantially. Objective: The objective of this study was to investigate both the perception and the behavior of a representative sample of Italian pediatricians toward cough in real life. Methods: A specific questionnaire consisting of 18 questions was prepared. The questionnaire was completed by 300 pediatricians (all members of PAIDOSS: Italian National Observatory on Health of Childhood and Adolescence) who represented ~300,000 children. Results: A vast majority of children have cough throughout the year (99.3% of respondents have cough during autumn/winter and 64.7% in spring/summer). Allergic disease is the most frequent suspected cause of chronic cough in children (53%), and this is supported by the high demand for consultations: 73% seek the opinion of allergologists, 62% of otorhinolaryngologists and only 33% of pulmonologists. The majority of pediatricians (92%) reported that they prescribe therapy in acute cough regardless of cough guidelines. Moreover, the survey pointed out the abuse of aerosol therapy (26% in acute cough and 38% in chronic cough) and of antibiotics prescription (22% in acute cough and 42% in chronic cough). Conclusion: Our survey suggests that some Italian pediatricians’ therapeutic attitudes should be substantially improved in order to achieve better management of cough in children and to minimize the burden of cough. Keywords: acute cough, chronic cough, cough in children, pediatricians’ prescriptions, cough impact

Roberto W Dal Negro1, Massimiliano Povero2 1National Centre for Respiratory Phamacoeconomics and Pharmacoepidemiology – CESFAR, Verona, 2AdRes Health Economics and Outcome Research, Torino, Italy Background: The usability of inhalation devices depends on several factors, eg, the drug to inhale, device handling, and patients’ training. Usability is then presumed to have economic consequences. Aim: To assess and compare the cost of patients’ training for proper usability of Breezhaler and Genuair (both dry powder inhalers) and Respimat (a soft mist inhaler) in asthma and chronic obstructive pulmonary disease (COPD) outpatients. Methods: The acceptance and handling of the three devices were investigated by means of the Handling Questionnaire. The time spent in specific training for ensuring a proper actuation and the corresponding costs were also calculated. Linear and logistic regressions were used in order to investigate the factors influencing proper handling of the devices. A significance level of P

Roberto W Dal Negro,1,2 Luca Bonadiman,1 Paola Turco,2 Silvia Tognella,3 Sergio Iannazzo41National Center for Respiratory Pharmacoeconomics and Pharmacoepidemiology, Verona, Italy; 2Research and Clinical Governance, Verona, Italy; 3General Hospital, ULSS 22 Regione Veneto, Bussolengo, Italy; 4SIHS Health Economics Consulting, Torino, ItalyBackground: Chronic obstructive pulmonary disease (COPD) is a major cause of chronic morbidity and mortality worldwide, and its epidemiological, clinical, and socioeconomic impact is progressively increasing. A first estimate of the economic burden of COPD in Italy was conducted in 2008 (the SIRIO [Social Impact of Respiratory Integrated Outcomes] study). The aim of the present study is to provide an updated picture of the COPD economic burden in Italy.Methods: Sequential patients presenting at the specialist center for the first time during the period 2008–2012 and with record file complete (demographic, clinical, lung function, and therapeutic data; health care resources consumed in the 12 months before the enrollment and for the 3 subsequent years) were selected from the institutional database.Results: Two hundred and seventy-five COPD patients fitting the inclusion criteria were selected (226 males; mean age: 70.9 years [standard deviation: ±8.4 years]; 45.8% were from the north, 25.1% from central Italy, and 29.1% from south Italy). COPD-related average costs per patient in the 12 months before enrollment were as follows: hospitalization: €1,970; outpatient care: €463; pharmaceutical: €499; and indirect costs: €358. Average direct costs and total societal costs were €2,932 and €3,291, respectively. Direct cost was €2,461 (hospitalization: €1,570; outpatient: €344; and pharmaceutical: €547) in the first year of follow-up, while total societal cost was €2,707. No significant difference was reported in any cost category between sexes.Conclusion: The therapeutic approach followed in a specialist center, based on the application of clinical guidelines, has been shown to be a highly effective investment for the long-term management of COPD. A small increase of pharmaceutical costs per year allowed a substantial saving in terms of hospitalizations, costs related to outpatient services, and indirect costs.Keywords: COPD, health costs, pharmacoeconomic, sex dependency

Roberto W Dal Negro,1 Luca Bonadiman,1 Silvia Tognella,2 Fernanda P Bricolo,3 Paola Turco31National Center for Respiratory Pharmacoeconomics and Pharmacoepidemiology (CESFAR), Verona, Italy; 2Lung Division, Bussolengo General Hospital, Bussolengo, Italy; 3Research and Clinical Governance, Verona, Italy Background: Chronic obstructive pulmonary disease (COPD) can affect cognition. The effects of other less severe chronic airway disorders on cognition remain to be clarified. This study aimed to measure and compare cognitive deterioration in subjects with COPD, subjects with chronic non-obstructive bronchitis (CNOB), and asymptomatic smokers (AS), and to relate the corresponding prevalence to several demographic and clinical variables and to normal reference values. Methods: Four hundred and two subjects (COPD n=229, CNOB n=127, and AS n=46) of comparable age were included in the study. Cognitive impairment was assessed using the Mini Mental Status test, the Clock Drawing test, and the Trail Making test A and B. Results: The extent and prevalence of cognitive deterioration was greater in COPD subjects, followed by CNOB subjects and AS (P

Introduction: The reduction of lung capillary blood volume (Vc) had been identified as the microvascular injury mostly underlying the respiratory Long-COVID syndrome following post-COVID-19 pneumonia. The same kind of injury have been recently also found in several individuals after milder paucisymptomatic SARS-CoV-2 infections. Though current guidelines strongly recommend vac-cination, studies aimed to investigate the in vivo protection of anti-SARS-CoV-2 vaccines on lung microvascular targets still are missing to our best knowledge., Aim: to assess the protection of mRNA vaccines from the reduction of lung capillary blood volume (Vc) caused by pauci-symptomatic SARS.CoV-2 infections in vaccinated compared to unvaccinated individuals., Methods: Non-smoking individuals with recent paucisymptomatic SARS-CoV-2 infection were divided into vaccinated and unvaccinated groups. Lung function parameters, including single-breath diffusing capacity and microvascular blood volume, were compared between groups., Results: fifty vaccinated and twenty-five unvaccinated well-matched individuals were studied. Differently than usual lung function parameters, only the single-breath simultaneous assessment of sDLCO, sDLNO/sDLCO ratio and Vc allowed to identify the occurrence of the lung microvascular injury with high sensitivity and specificity (p<0.001)., Conclusion: mRNA vaccines proved to exert a high protection from the loss of lung capillary blood volume (Vc) induced by SARS.CoV-2 paucisymptomatic infections (p<0.001). The availability of this non-invasive investigational model should be regarded as a very helpful tool for assessing and comparing in vivo the protective effect of mRNA vaccines on the human microvascular structures of the deep lung.

Inhalation represents the most convenient route for delivering respiratory drugs. Delivery systems showed a huge technological progress and several pocket inhalers had been engineered over the last decades for clinical use. Despite the growing technological efforts aimed to simplify the inhalation procedures and optimize the therapeutic outcomes, the effectiveness of drug inhalation through inhalers still represents a major challenge in respiratory medicine. Patients may actually incur in different types of critical errors when using all inhalers and are not capable to inhale throughout all devices equally well. Therefore, the choice of the most suitable and convenient device to prescribe still is a critical issue in real life. Usability is the only comprehensive parameter consenting the effective and objective assessment of pocket inhalers' performance, and allowing their objective comparison and ranking. Unpredictable discrepancies are in fact easily detectable between inhalers (even belonging to the same class) in terms of Usability, independently of the patient's awareness. The reasons were described and discussed for each class of inhalers presently available. Usability is a multidimensional parameter that is much more multifaceted and complex than usually presumed. Usability takes origin from the integrated, balanced and objective assessment of the role played by several factors from different domains, such as: factors related to patient's beliefs, to patients' behavioural components, to device engineering and to the overall cost. Usability is the key parameter for assessing and optimizing the appropriateness of any inhalation treatment through whatever device. Usability would also represent a key investigational instrument for supporting the future development of -innovative and more performing inhaler devices objectively.

Bronchial asthma is characterized by variable airflow obstruction, airway inflammation, and bronchial hyperresponsiveness (BHR) to non-specific stimuli. The role of underlying airway inflammation and of related long-lasting BHR has been suboptimally investigated in teenagers with mild-to-moderate asthma, as has the corresponding economic impact over time. The aim of the present study was to calculate the cost of mild-to-moderate atopic asthma in teenagers arising from their degree of persisting BHR over a twelve-month period., Methods: Patients aged 12-18 years with mild-to-moderate symptoms treated with fluticasone fumarate/vilanterol 92/22 mcg daily were retrospectively followed for 12 months. Usual spirometric parameters, BHR to methacholine (MCh), and resource consumption (visits, hospitalizations, systemic steroids and/or antibiotics courses, school days off) were assessed at recruitment (the index date) and after 6 and 12 months. Adherence to treatment was also calculated. The cost of asthma was calculated based on Italian tariffs and published papers. The trend over time in BHR and the association between response to MCh and total cost were investigated by using regression models adjusted for repeated measures., Results: 106 teenagers (53 males, age 15.9 ± 1.6 years) were investigated. The annual cost of asthma proved significantly related to the BHR trend: every increment of a factor 10 in the response to MCh was associated with a saving of EUR 184.90 (95% CI -305.89 to -63.90). BHR was progressively optimized after 6 and 12 months in relation to the patients' compliance to treatment (≥70% of prescribed inhalation doses)., Conclusions: the usual spirometric parameters are largely insufficient to reflect the effects of underlying persistent inflammation in milder forms of asthma in teenagers. In terms of clinical governance, the periodic assessment of non-specific BHR is the appropriate procedure from this point of view. Non-specific BHR proves a reliable procedure for predicting and monitoring the economic impact of mild-to-moderate asthma in teenagers over time.

Bronchial asthma has a high socio-economic impact in Western countries. Low adherence to prescribed inhalation treatments contributes to poor asthma control and the higher utilization of healthcare resources. Although adolescents usually do not comply with long-term inhaled treatments prescribed on a regular basis, the related economic consequences still are poorly investigated in Italy., Aim: A 12-month estimation of the economic impact of non-adherence to inhalation treatments in adolescents with mild-to-moderate atopic asthma., Methods: Non-smoking adolescents aged 12-19 years, without any significant comorbidity, prescribed with inhaled cortico-steroids (ICS) or ICS/long-acting beta(2)-adrenergics (LABA) via dry powder inhalers (DPIs) on a regular basis were automatically selected from the institutional database. Spirometric lung function, clinical outcomes, and pharmacological information were collected. The adolescents' adherence to their prescribed regimen was calculated monthly. Adolescents were divided in two sub-groups based on their adherence to prescriptions: ≤70% (not adherent) or >70% (adherent), and statistically compared (Wilcoxon test, assuming p < 0.05)., Results: Overall, 155 adolescents fulfilled the inclusion criteria (males, 49.0%; mean age, 15.6 years ± 2.9 SD; mean BMI, 19.1 ± 1.3 SD). Mean values of lung function were: FEV1 = 84.9% pred. ± 14.8 SD, FEV1/FVC = 87.9 ± 12.5 SD; MMEF = 74.8% pred. ± 15.1 SD and V25 = 68.4% pred. ± 14.9 SD. ICS had been prescribed in 57.4% of subjects and ICS/LABA in 42.6%. Mean adherence to original prescriptions was 46.6% ± 9.2 SD in non-adherent and 80.3% ± 6.6 SD in adherent adolescents, respectively ( p < 0.001). The mean rates of hospitalizations, exacerbations, and GP visits; the average duration of absenteeism; the frequency of systemic steroids and antibiotics courses needed over the study period were significantly and substantially lower in adolescents adherent to prescriptions (all p < 0.001). The mean total annual extra cost calculated in the two sub-groups was EUR 705.8 ± 420.9 SD in non-adherent adolescents and EUR 192.1 ± 68.1 SD in adherent adolescents, respectively ( p < 0.001), which was 3.7 times higher than in non-adherent adolescents., Conclusions: In adolescents, the clinical control of mild-to-moderate atopic asthma is directly and strictly related to the degree of adherence to prescribed inhalation therapies. All clinical and economic outcomes prove dramatically poor when adherence is low, and treatable asthma can be frequently mistaken for refractory asthma in these cases. Adolescents' non-adherence impacts the burden of the disease quite substantially. Much more effective strategies centered specifically on adolescents' asthma are needed.

Background: Pulmonary microvascular occlusions can aggravate SARS-CoV-2 pneumonia and result in a variable decrease in capillary blood volume (Vc). Dyspnoea may persist for several weeks after hospital discharge in many patients who have "radiologically recovered" from COVID-19 pneumonia. Dyspnoea is frequently "unexplained" in these cases because abnormalities in lung vasculature are understudied. Furthermore, even when they are identified, therapeutic options are still lacking in clinical practice, with nitric oxide (NO) supplementation being used only for severe respiratory failure in the hospital setting. Nebivolol is the only selective β 1 adrenoceptor antagonist capable of inducing nitric oxide-mediated vasodilation by stimulating endothelial NO synthase via β 3 agonism. The purpose of this study was to compare the effect of nebivolol versus placebo in patients who had low Vc and complained of dyspnoea for several weeks after COVID-19 pneumonia., Methods: Patients of both genders, aged ≥18 years, non-smokers, who had a CT scan that revealed no COVID-related parenchymal lesions but still complaining of dyspnoea 12-16 weeks after hospital discharge, were recruited. Spirometrical volumes, blood haemoglobin, SpO 2 , simultaneous diffusing capacity for carbon monoxide (CO) and NO (DL CO and DL NO , respectively), DL NO /DL CO ratio, Vc and exhaled NO (eNO) were measured together with their dyspnoea score (DS), heart frequency (HF), and blood arterial pressure (BAP). Data were collected before and one week after both placebo (P) and nebivolol (N) (2.5 mg od) double-blind cross-over administered at a two-week interval. Data were statistically compared, and p<0.05 assumed as statistically significant., Results: Eight patients (3 males) were investigated. In baseline, their mean DS was 2.5±0.6 SD, despite the normality of lung volumes. DL CO and DL NO mean values were lower than predicted, while mean DL NO /DL CO ratio was higher. Mean Vc proved substantially reduced. Placebo did not modify any variable (all p=ns) while N improved DLco and Vc significantly (+8.5%, p<0.04 and +17.7%, p<0.003, respectively). eNO also was significantly increased (+17.6%, p<0.002). Only N lowered the dyspnoea score (-76%, p<0.001). Systolic and diastolic BAP were slightly lowered (-7.5%, p<0.02 and -5.1%, p<0.04, respectively), together with HF (-16.8%, p<0.03)., Conclusions: The simultaneous assessment of DL NO , DL CO , DL NO /DL CO ratio, and Vc confirmed that long-lasting dyspnoea is related to hidden abnormalities in the lung capillary vasculature. These abnormalities can persist even after the complete resolution of parenchymal lesions regardless of the normality of lung volumes. Nebivolol, but not placebo, improves DS and Vc significantly. The mechanism suggested is the NO-mediated vasodilation via the β3 adrenoceptor stimulation of endothelial NO synthase. This hypothesis is supported by the substantial increase of eNO only assessed after nebivolol. As the nebivolol tolerability in these post-COVID normotensive patients was very good, the therapeutic use of nebivolol against residual and symptomatic signs of long-COVID can be suggested in out-patients., (©Copyright: the Author(s).)

Adolescents with asthma are usually insufficiently adherent to regular inhalation treatments, thus limiting their effectiveness. The aim of this study is to investigate the role of adherence to single-inhaler long-acting LABA/ICS dry-powder combination o.d. in affecting lung function, bronchial hyperreactivity, and health outcomes over a twelve-month survey of a group of non-smoking adolescents with mild to moderate asthma. Methods: Age, gender, BMI and atopy, forced expiratory volume in 1 s (FEV1), maximum mid-expiratory flow (MMEF), and maximum expiratory flow at 25% of lung filling (MEF25) were assessed via a Boolean selection process from the institutional database at recruitment, as well as after 6 and 12 months, together with the incidence of exacerbation, school days that were taken off, GP and specialist visits, and systemic steroid and/or antibiotic courses. Adherence was checked monthly via a direct telephone call. Statistics were calculated with an ANOVA trend analysis, assuming p < 0.05. Results: Two well-matched sample groups of 54 subjects each were obtained. The mean annual adherence to treatment ranged from 48.2% doses ± 10.9 sd to 79.3% doses ± 8.8 sd (p < 0.001), regardless of age and gender. Only adolescents that adhered to the o.d. ICS/LABA inhalation regimen progressively achieved complete control of all lung function parameters (FEV1: 0.001; MMEF: p < 0.002; MEF25 < 0.001; <0.001), minimized their bronchial hyperreactivity (p < 0.001), and optimized all health outcomes (p < 0.001—p < 0.002) over the survey duration. Discussion: A good adherence to treatment is essential for asthma management, particularly in young patients. Factors that are totally independent of the complexity of the therapeutic regimen adopted (namely, only a once-daily inhalation in the present survey) probably represent the major reasons limiting the adolescents’ adherence. Cultural, educational, behavioral, and psychological factors are frequently involved, are difficult to control, and can present barriers to adolescents’ asthma management. Further studies aiming to deeply understand and possibly remove the reasons for such adolescents’ attitudes are needed, in cooperation with actions oriented in this direction by families, educators, and health professionals.

Background: During SARS-CoV-2 infection, diffuse alveolar damage and pulmonary microvascular abnormalities are critical events that result in gas exchange disorders of varying severity and duration. The only measure of carbon monoxide (CO) diffusing capacity (DL CO ) is unable to distinguish the alveolar from the vascular side of present and residual diffusive abnormalities, and measure of nitric oxide (NO) diffusing capacity (DL NO ) is also recommended. Dyspnoea, despite being understudied, persists in a significant proportion of patients for several weeks after hospital discharge. The goal of this study was to look into the underlying cause of long-term dyspnoea in patients who were "clinically and radiologically recovered" from COVID pneumonia by assessing DL CO and DL NO at the same time., Methods: Patients of both genders, aged ≥18 years, who had a CT scan showing complete resolution of COVID-related parenchymal lesions were recruited consecutively. Spirometrical volumes, blood haemoglobin, SpO 2 , DL CO , DL NO and capillary blood volume (Vc) were measured. Data from patients without dyspnoea (group A) and from patients still claiming dyspnoea after 12-16 weeks from their hospital discharge (group B) were statistically compared., Results: Forty patients were recruited: 19 in group A and 21 in group B. Groups were comparable for their general characteristics and spirometrical volumes, that were in the normal range. Mean values for DL CO , DL NO and Vc were significantly and substantially lower than predicted only in patients of group B (p<0.011; p<0.0036; p<0.02; p<0.001, respectively). The DL NO / DL CO ratio was higher in group B (p<0.001) and inversely correlated to Vc values (-0.3636)., Conclusions: The single-breath, simultaneous measurement of DL CO , DL NO , and Vc demonstrated that problems with blood gas exchange can persist even after parenchymal lesions have healed completely. Regardless of the normality of spirometric volumes, there was a significant reduction in lung capillary blood volume. In these patients, the cause of long-term dyspnoea may be related to hidden abnormalities in the vascular side of diffusive function. In the near future, novel therapeutic approaches against residual and symptomatic signs of long-COVID are possible., (©Copyright: the Author(s).)

A lower thirst sensitivity frequently characterizes children and adolescents. The daily water intake can be frequently insufficient for the homeostasis and the integrity of their airway epithelium. Little is known about the real-life relationship between dehydration and coughing in young students with asthma. The aim was to investigate the effect of dehydration on coughing in asthmatic students aged ≤16 years. A validated questionnaire aimed to investigate their respiratory history and cough incidence was used. Urine samples were also collected for assessing osmolality. Wilcoxon test, the Pearson Chi Square and the Fisher Exact Test were used; p < 0.05 was assumed as significant. Valid data were obtained from 305 healthy and 56 asthmatic students. Mean urine osmolality was significantly higher in asthmatic than in healthy students (1012 ± 197.7 vs. 863.0 ± 223.0 mOsm/kg, respectively; p < 0.001), particularly in symptomatic asthmatic students (1025 ± 191.6 mOsm/kg, p < 0.01). Both the incidence and duration of coughing episodes were directly related to the degree of urine osmolality (both p < 0.001). Dehydration affects the prevalence and the duration of a cough in asthmatic students aged ≤16 years. Adequate daily water intake should be stimulated in these subjects in order to contain their basic cough attitude.

Several factors affect drug delivery from dry powder inhalers (DPIs). Some are related to patient's physiological characteristics, while others depend on DPIs' technical aspects. The patient's inspiratory airflow rate (IAR) affects the pressure drop and the turbulence needed to disaggregate the powder inside a DPI. The present study investigated whether lung function limitations occurring in asthmatic adolescents affect their IAR when inhaling through a DPI simulator. Eighteen consecutive adolescents with asthma were recruited, and IAR was randomly assessed at low-, mid-, and high-resistance regimens. A multiple logistic model was developed to evaluate the association of patients' lung function characteristics and devices' resistance with the probability to achieve the expected IAR (E-IAR). The mean value of E-IAR achieved seemed to be sex- and age-independent. Low- and high-resistance regimens were less likely to consent the E-IAR level (odds ratio [OR] = 0.035 and OR = 0.004, respectively). Only the basal residual volume and the inspiratory resistance, but not the Forced Expiratory Volume in 1 s (FEV1), seemed to affect the extent of IAR in asthmatic adolescents (OR = 1.131 and OR = 0.290, respectively). The results suggest that the assessment of current lung function is crucial for choosing the proper DPI for asthmatic adolescents.

The COVID-19 outbreak variably affected people's mental reactions worldwide but was only episodically investigated in healthy Italian teenagers. Our aim was to investigate the emotional responses of Italian middle and high school students to the pandemic. An anonymous 10-item questionnaire was distributed in pre-selected school samples. Responders had to score their perceived extent for each reaction from 0 (lowest perception) to 10 (highest perception). A group of adults was selected as control. Generalized linear models were used to estimate differences among adults and students, high school (HS) and middle school (MS) students, and urban (U) and rural (R) MS students. Comparisons were presented as mean difference (Δ) with a 95% confidence interval (CI). A total of 1512 questionnaires (635 adults, 744 HS, 67 UMS, and 66 RMS) were analyzed. Students appeared more indifferent (Δ = 1.97, 1.52-2.41), anxious (Δ = 0.56, 0.07-1.04), aggressive (Δ = 2.21, 1.72-2.70), and depressed (Δ = 1.87, 1.40-2.34) than adults did, and claimed a higher loss of interest in their activities (Δ = 1.21, 0.72-1.70). Students were less disbelieving (Δ = -0.93, -1.50-0.35) and feared for their loved ones (Δ = -0.89, -1.40-0.39). MS students were less affected by the outbreak than HS students were. Furthermore, R-MS students were significantly less aggressive and depressed, but more indifferent and disbelieving than U-MS. Female sex was an independent factor associated to almost all the questionnaire domains. The pattern of the psychological responses to the pandemic in Italian students proved multifaceted. In addition to anxiety, loss of interest in activities, and depression, aggressiveness emerged as the most characterizing mental attitude in response to the pandemic.

The useability of DPIs (dry powder inhalers) depends on several factors that are influenced by the patients' subjectivity and objectivity. The short-form global usability score (S-GUS), a specific tool for the quick ranking and comparison in real life of an inhaler's usability, was used to investigate six of the most prescribed DPIs (Breezhaler, Diskus, Ellipta, Nexthaler, Spiromax, and Turbohaler) in consecutive asthma patients aged <18 years. A Bayesian indirect comparison (IC) was carried out to merge all pairwise comparisons between the six DPIs. Thirty-three subjects participated: eighteen tested Breezhaler, Spiromax, Nexthaler, and Ellipta simultaneously, while fifteen tested Breezhaler, Spiromax, Diskus, and Turbohaler. The estimates of the S-GUS, by the IC model, allowed us to rank the DPIs by their degree of usability: Ellipta, Diskus, and Spiromax were classified as "good to pretty good" (S-GUS > 15), while Spiromax, Turbohaler, and Breezhaler were classified as "insufficient" (S-GUS < 15). The multidomain assessment is recommended in asthma adolescents in order to approximate the effective usability of different DPIs as best as possible. The S-GUS proves particularly suitable in current clinical practice because of the short time required for its use in adolescents.

Background: Chronic obstructive pulmonary disease (COPD) is a generic term identifying a condition characterized by variable changes in peripheral airways and lung parenchyma. Standard spirometry cannot discriminate the relative role of conductive airways inflammatory changes from destructive parenchymal emphysema changes. The aim of this study was to quantify the emphysema component in COPD by a simple parameter (the Emphysema Severity Index - ESI), previously proved to reflect CT-assessed emphysema., Methods: ESI was obtained by fitting the descending limb of MEFV curves by a fully automated procedure providing a 0 to 10 score of emphysema severity. ESI was computed in COPD patients enrolled in the CLIMA Study., Results: The vast majority of ESI values ranged from 0 to 4, compatible with no-to-mild/moderate emphysema component. A limited proportion of patients showed ESI values >4, compatible with severe-to-very severe emphysema. ESI values were greatly dispersed within each GOLD class indicating that GOLD classification cannot discriminate emphysema and conductive airways changes in patients with similar airflow limitation. ESI and diffusing capacity (DL CO ) were significantly correlated (p<0.001). However, the great dispersion in their correlation suggests that ESI and DL CO reflect partially different anatomo-functional determinants in COPD., Conclusions: Airflow limitation has heterogenous determinants in COPD. Inflammatory and destructive changes may combine in CT densitometric alterations that cannot be detected by standard spirometry. ESI computation from spirometric data helps to define the prevailing pathogenetic mechanism underlying the measured airflow limitation. ESI could be a reliable advancement to select large samples of patients in clinical or epidemiological trials, and to compare different pharmacological treatments., (©Copyright: the Author(s).)

Background: Chronic obstructive pulmonary disease (COPD) is a complex, progressive respiratory condition characterized by heterogeneous clinical presentations (phenotypes). The aim of this study was to assess the prevalence of the main COPD phenotypes and match of each phenotype to the most fitting clinical and lung function profile., Methods: the CLIMA (Clinical Phenotypes in Actual Clinical Practice) study was an observational, cross-sectional investigation involving twenty-four sites evenly distributed throughout Italy. Patients were tentatively grouped based on their history and claimed prevailing symptoms at recruitment: chronic cough (CB, suggesting chronic bronchitis); dyspnoea (possible emphysema components, E); recurrent wheezing (presuming asthma components, A). Variables collected were: anagraphics; smoking habit; history of asthma; claim of >1 exacerbations in the previous year; blood eosinophil count; total blood IgE and alpha 1 anti-trypsin (α 1 -AT) levels; complete lung function, and the chest X-ray report. mMRC, CAT, BCS, EQ5d-5L were also used. The association between variables and phenotypes were checked by Chi-square test and multinomial logistic regression., Results: The CB phenotype was prevalent (48.3%), followed by the E and the A phenotypes (38.8% and 12.8%, respectively). When dyspnoea was the prevailing symptom, the probability of belonging to the COPD-E phenotype was 3.40 times higher. Recurrent wheezing was mostly related to the COPD-A phenotype. Lung function proved more preserved in the COPD-CB phenotype. Smoke; n. exacerbations/year; VR, and BODE index were positively correlated with the COPD-E phenotype, while SpO 2 , FEV 1 /FVC, FEV 1 /VC, and FEV 1 reversibility were negatively correlated. Lower DLco values were highly probative for the COPD-E phenotype (p<0.001). Conversely, smoke, wheezing, plasma eosinophils, FEV 1 reversibility, and DLco were positively correlated with the COPD-A phenotype. The probability of belonging to the COPD-A phenotype raised by 2.71 times for any increase of one unit in % plasma eosinophils (p<0.001). Also multiparametrical scores contributed to discriminate the three phenotypes., Conclusion: The recognition of the main phenotypes of COPD can be effectively pursued by means of a few clinical and instrumental parameters, easy to obtain also in current daily practice. The phenotypical approach is crucial in the management of COPD as it allows to individualize the therapeutic strategy and to obtain more effective clinical outcomes., (©Copyright: the Author(s).)

Background: Current techniques for measuring absolute lung volumes rely on bulky and expensive equipment and are complicated to use for the operator and the patient. A novel method for measurement of absolute lung volumes, the MiniBox method, is presented., Research Question: Across a population of patients and healthy participants, do values for total lung capacity (TLC) determined by the novel compact device (MiniBox, PulmOne Advanced Medical Devices, Ltd.) compare favorably with measurements determined by traditional whole body plethysmography?, Study Design and Methods: A total of 266 participants (130 men) and respiratory patients were recruited from five global centers (three in Europe and two in the United States). The study population comprised individuals with obstructive (n = 197) and restrictive (n = 33) disorders as well as healthy participants (n = 36). TLC measured by conventional plethysmography (TLC Pleth ) was compared with TLC measured by the MiniBox (TLC MB )., Results: TLC values ranged between 2.7 and 10.9 L. The normalized root mean square difference (NSD) between TLC Pleth and TLC MB was 7.0% in healthy participants. In obstructed patients, the NSD was 7.9% in mild obstruction and 9.1% in severe obstruction. In restricted patients, the NSD was 7.8% in mild restriction and 13.9% in moderate and severe restriction. No significant differences were found between TLC values obtained by the two measurement techniques. Also no significant differences were found in results obtained among the five centers., Interpretation: TLC as measured by the novel MiniBox system is not significantly different from TLC measured by conventional whole body plethysmography, thus validating the MiniBox method as a reliable method to measure absolute lung volumes., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: The performance of DPIs depends on several physiological (patient-dependent) and technological (device-dependent) factors. The inspiratory airflow rate is the only active force generated and operating in the system for inducing the required pressure drop and eliciting the resistance-induced turbulence needed to disaggregate the powder through the device. The present study aimed to investigate in the most prevalent respiratory disorders whether and at what extent the inspiratory airflow rate achievable when inhaling through a DPIs' simulator reproducing different intrinsic resistance regimens (low, mid, and high resistance) is affected by peculiar changes in lung function and/or can be predicted by any specific lung function parameter., Methods: The inspiratory airflow rate was assessed in randomized order by the In-Check DIAL G16 at low, mid, and high resistance regimens in a sample of consecutive subjects at recruitment. Independent predictors of the probability to achieve the expected inhalation airflow rate were investigated by means of a multivariate logistic regression model, specific to the disease., Results: A total of 114 subjects were recruited (asthmatics n=30; COPD n=50, restrictive patients n=16, and normal subjects n=18). The mean values of the expected inspiratory airflow rate achieved proved significantly different within the groups (p<0.0001), independently of sex and age. In asthmatics and in COPD patients, the mid-resistance regimen proved highly associated with the highest mean values of airflow rates obtained. Low- and high-resistance regimens were significantly less likely to consent to achieve the expected level of inspiratory airflow rate (OR<1 in all comparisons). Restrictive patients performed the lowest airflow rates at the low-resistance regimen (p<0.01). Unlike FEV 1 , RV in asthmatics (OR=1.008); RV and I Raw in COPD (OR=0.587 and OR=0.901, respectively), and FIF and TLC in restrictive patients (OR=1.041, and OR=0.962, respectively) proved the only sensitive predictors of the inspiratory airflow rate achievable at the different resistive regimens., Conclusions: The intrinsic resistive regimen of DPIs can play a critical role. The patients' lung function profile also affects the extent of their inhalation airflow rate. Some specific lung function parameters (such as: FIF; RV; I Raw ; TLC, but not FEV 1 ) may be regarded as specific predictors in real-life. In order to optimize the DPI choice, further to the device's technology, also the current patients' lung function should be properly investigated and carefully assessed., (©Copyright: the Author(s).)

Background: The choice of the Dry Powder Inhaler (DPI) to prescribe is a critical issue. The estimation of DPIs usability depends on the objective assessment of several indices related to both subjective and objective determinants. The Global Usability Score (GUS) Questionnaire is a comprehensive tool usable for checking, comparing, and ranking inhalers' usability objectively in real life, but it takes some time to fill., Aim: The aim of this study was to favour the quicker check of DPIs usability in clinical practice by means of a simplified short-form GUS (S-GUS) Questionnaire, while maintaining the high specificity and sensitivity of the original, extended version of the Questionnaire (O-GUS questionnaire)., Methods: The usability of the six most prescribed DPIs was assessed in 222 patients with persistent airway obstruction and needing long-term inhalation treatments. LASSO regression and multicollinearity test were used to select the subset of questions of the O-GUS questionnaire, with the highest information power. Each item was then scored using the corresponding coefficient in the linear regression (normalized at 50 as the O-GUS score). Agreement between the original and the short-form questionnaire was evaluated using the Cohen's kappa statistic (κ). The overall S-GUS values obtained for each DPI were then compared to those from the O-GUS, in the same patients, using a Bayesian indirect comparison (IC) model., Results: After the statistical selection of the items mostly contributing to the overall score, the novel S-GUS questionnaire consists of twelve items only. Nine items are related to patients' opinion before DPIs handling, and three to the nurse's assessment after DPIs practicality. O-GUS and S-GUS score were strongly correlated (R 2 =0.9843, p <0.0001) and the usability score calculated for each DPI by means of the O- and of S- GUS overlapped almost completely (κ=84.5%, 95% CI 81.3% to 89.2%). Furthermore, S-GUS was much faster to complete than O-GUS (mean time 6.1 vs 23.4 minutes, p <0.001). Estimates of S-GUS, obtained from the IC model, allowed to propose a simple classification of usability: "good" by GUS values >25; "pretty good" by values ≤25≥15, and "insufficient" by values <15., Conclusions: The S-GUS proves as much specific and suitable as the extended O-GUS questionnaire in measuring DPIs usability, while maintaining the same high sensitivity. As the time required for its use is quite shorter, S-GUS is also particularly suitable and helpful in current clinical practice., Competing Interests: Conflict of interest: The authors declare that they have no competing interests. RWD is Associate Editor of Multidisciplinary Respiratory Medicine., (©Copyright: the Author(s).)

The natural history of COVID-19 caused by SARS-CoV-2 is extremely variable, ranging from asymptomatic or mild infection, mainly in children, to multi-organ failure, eventually fatal, mainly in the eldest. We propose here the first model explaining how the outcome of first, crucial 10-15 days after infection, depends on the balance between the cumulative dose of viral exposure and the efficacy of the local innate immune response (natural IgA and IgM antibodies, mannose-binding lectin). If SARS-CoV-2 runs the blockade of this innate immunity and spreads from the upper airways to the alveoli in the early phases of the infections, it can replicate with no local resistance, causing pneumonia and releasing high amounts of antigens. The delayed and strong adaptive immune response (high-affinity IgM and IgG antibodies) that follows, causes severe inflammation and triggers mediator cascades (complement, coagulation, and cytokine storm), leading to complications often requiring intensive therapy and being, in some patients, fatal. Low-moderate physical activity can still be recommended. However, extreme physical activity and oral breathing with hyperventilation during the incubation days and early stages of COVID-19 facilitates re-inhalation and early direct penetration of high numbers of own virus particles in the lower airways and the alveoli, without impacting on the airway's mucosae covered by neutralizing antibodies ("viral auto-inhalation" phenomenon). This allows the virus to bypass the efficient immune barrier of the upper airway mucosa in already infected, young, and otherwise healthy athletes. In conclusion, whether the virus or the adaptive immune response reaches the lungs first is a crucial factor deciding the fate of the patient. This "quantitative and time-/sequence-dependent" model has several implications for prevention, diagnosis, and therapy of COVID-19 at all ages., (© 2020 The Authors. Pediatric Allergy and Immunology published by John Wiley & Sons Ltd.)

Introduction: Inhalation devices affect both the effectiveness and the therapeutic outcomes in persistent airway obstruction, and the effects are largely independent of the drug(s) assumed. Usability is a complex and comprehensive indicator of inhalation devices' performance. The Global Usability Score (GUS) Questionnaire is an investigational tool designed to assess objectively the patients'-related and unrelated domains of devices' usability., Methods: The GUS questionnaire was administered to all consecutive COPD patients referring for three months to the Lung Unit of CEMS Specialist Centre (Verona, Italy). The usability of seven Dry Powder Inhalers (DPIs) indicated as appropriate in COPD was tested and compared: Breezhaler, Diskus, Ellipta, Genuair, Nexthaler, Spiromax, and Turbohaler. Patients were divided in two groups, checked separately, according to their DPIs previous experience. A Bayesian Indirect Comparison (IC) model was built to assess "global usability" ranking., Results: A total of 103 patients were investigated: 74 patients already instructed in DPI use and 29 naive to DPIs. IC analysis proved Ellipta as the device characterized by the highest usability, while Breezhaler the device with the lowest usability in both groups of COPD patients (both with probability > 90%). Moreover, Turbohaler ranked second according to the Bayesian pooling, followed by Diskus, Spiromax, Nexthaler, and Genuair in patients already instructed in DPI use, while the ranking order was not as much well defined in naïve patients, likely due to their too small sample., Conclusions: Usability is a multifaceted indicator that contributes to assess the factual DPIs' convenience in real life. DPIs are characterized by different levels of real-life usability, which can be checked, compared and ranked by means of the GUS score., Competing Interests: Competing interestsThe authors declare no conflict of interest. RWD is Associate Editor of Multidisciplinary Respiratory Medicine.

Background: Acute cough is the most common symptom among children in primary care, but the impact of cough episodes was never investigated in Italian families., Methods: A cross-sectional telephone survey was conducted on a representative sample of Italian families, randomly selected from general population; a specific and validated questionnaire was used., Results: The sample (604 calls) was uniform by geographical distribution, and by children age and gender. Mean cough episode was 3.1/year, they were short lasting (only 4.7% > 2 weeks). Independent predictors of children cough episodes were parents' active smoking habit and work ( p  < 0.05). The mean nursery/school absenteeism was mostly < 7 days, but of a 7-15-day duration in near 30% of cases. The pediatrician was contacted immediately only by 25% of parents and a second consultation (mostly a lung physician) usually occurred after 2-3 weeks of cough. Meanwhile, home/pharmacist suggested remedies were adopted in 50-70% of cases. Usual prescriptions were mucolytics (85.8%), antitussive agents (55.6%), non-steroideal anti-inflammatory drugs (33.8%), antibiotics (regularly or episodically 80%), and corticosteroids (systemic steroids in less than 50%, but via aerosol in more than 80% of cases). Moreover, pediatricians claimed to use homeopathic drugs regularly or episodically in almost 50%. The respondents' willingness to spend out-of-pocket for an "effective remedy" against cough was of € 20 (>€ 30 in 18.4% of cases)., Conclusions: Parents' actions against cough episodes were variable, depending on their beliefs, smoking habit, and occupational status. The parents' perceived efficacy of usual prescriptions is poor, and their willingness to pay out-of-pocket for an "effective remedy" against cough is high. The interest for alternative treatments is not negligible in these circumstances., Competing Interests: The study was approved by the CESFAR Ethical Committee on October 26th, 2016 (n. A/002/16).; all participants have given their consent.Not applicable.Roberto Dal Negro is an Associate Editor of Multidisciplinary Respiratory Medicine. Alessandro Zanasi participated as speaker at Boiron’s internal meeting in the past. Paola Turco and Massimiliano Povero declare no conflict of interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.