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Marika T Leving,1 Job FM van Boven,2– 4 Sinthia Z Bosnic-Anticevich,5,6 Joyce van Cooten,1 Jaime Correia de Sousa,7 Biljana Cvetkovski,5 Richard Dekhuijzen,8 Lars Dijk,1 Marina García Pardo,9 Asparuh Gardev,10 Rados&lstrok;aw Gawlik,11 Iris van der Ham,1 Elisabeth Sophia Hartgers-Gubbels,10 Ymke Janse,1 Federico Lavorini,12 Tiago Maricoto,13 Jiska Meijer,1 Boyd Metz,1 David B Price,14,15 Miguel Roman-Rodríguez,9 Kirsten Schuttel,1 Nilouq Stoker,1 Ioanna Tsiligianni,16 Omar S Usmani,17 Janwillem H Kocks1,2,15,18 1General Practitioners Research Institute, Groningen, the Netherlands; 2University Medical Centre Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, Groningen, the Netherlands; 3University Medical Centre Groningen, Department of Clinical Pharmacy & Pharmacology, University of Groningen, Groningen, the Netherlands; 4Medication Adherence Expertise Centre of the Northern Netherlands (MAECON), Groningen, the Netherlands; 5Woolcock Institute of Medical Research, University of Sydney, Sydney, Australia; 6Sydney Local Health District, Sydney, Australia; 7Life and Health Sciences Research Institute (ICVS), PT Government Associate Laboratory, School of Medicine, University of Minho, Braga, Portugal; 8Radboud University Medical Centre, Nijmegen, Netherlands; 9Primary Care Respiratory Research Unit, Instituto De Investigación Sanitaria De Baleares (IdISBa), Palma de Mallorca, Spain; 10Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany; 11Department of Internal Medicine, Allergology, Clinical Immunology, Medical University of Silesia, Katowice, Poland; 12Department of Experimental and Clinical Medicine, Careggi University Hospital, Florence, Italy; 13Faculty of Health Sciences, University of Beira Interior, Covilha, Portugal; 14Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UK; 15Observational and Pragmatic Research Institute, Singapore; 16Department of Social Medicine, Health Planning Unit, Faculty of Medicine, University of Crete, Rethymno, Greece; 17Airway Disease, National Heart and Lung Institute (NHLI), Imperial College London and Royal Brompton Hospital, London, UK; 18Department of Pulmonology, University of Groningen, University Medical Centre Groningen, Groningen, the NetherlandsCorrespondence: Janwillem H Kocks, General Practitioners Research Institute, Professor Enno Dirk Wiersmastraat 5, Groningen, 9713 GH, the Netherlands, Tel +31 50 211 3898, Email janwillem@gpri.nlPurpose: To assess the relationship between suboptimal Peak Inspiratory Flow (sPIF), inhalation technique errors, and non-adherence, with Healthcare Resource Utilisation (HCRU) in Chronic Obstructive Pulmonary Disease (COPD) patients receiving maintenance therapy via a Dry Powder Inhaler (DPI).Patients and methods: The cross-sectional, multi-country PIFotal study included 1434 COPD patients (≥ 40 years) using a DPI for maintenance therapy. PIF was measured with the In-Check DIAL G16, and sPIF was defined as a typical PIF lower than required for the device. Inhalation technique was assessed by standardised evaluation of video recordings and grouped into 10 steps. Patients completed the “Test of Adherence to Inhalers” questionnaire. HCRU was operationalised as COPD-related costs for primary healthcare, secondary healthcare, medication, and total COPD-related costs in a 1-year period.Results: Participants with sPIF had higher medication costs compared with those with optimal PIF (cost ratio [CR]: 1.07, 95% CI [1.01, 1.14]). Multiple inhalation technique errors were associated with increased HCRU. Specifically, “insufficient inspiratory effort” with higher secondary healthcare costs (CR: 2.20, 95% CI [1.37, 3.54]) and higher total COPD-related costs (CR: 1.16, 95% CI 1.03– 1.31). “no breath-hold following the inhalation manoeuvre (< 6 s)” with higher medication costs (CR: 1.08, 95% CI [1.02, 1.15]) and total COPD-related costs (CR 1.17, 95% CI [1.07, 1.28]), and “not breathing out calmly after inhalation” with higher medication costs (CR: 1.19, 95% CI [1.04, 1.37]). Non-adherence was not significantly associated with HCRU.Conclusion: sPIF and inhalation technique errors were associated with higher COPD-related healthcare utilisation and costs in COPD patients on DPI maintenance therapy.Keywords: chronic obstructive pulmonary disease, Dry Powder Inhaler, health economics, cost analysis, healthcare resource utilisation

Background: The surgical treatment of concomitant lung cancer in patients with idiopathic pulmonary fibrosis is challenging due to the risk of life-threatening complications such as acute exacerbation development in the perioperative period. Few studies have investigated the role of anti-fibrotic drugs in this setting. The aim of this multicenter retrospective study was to evaluate the incidence of acute exacerbation, according to Collard, after lung resection in patients affected by concomitant idiopathic pulmonary fibrosis and lung cancer who were or were not on antifibrotic treatment. Secondary outcomes included: 30 and 90-day mortality and an estimation of overall and disease-free survival., Material and Methods: The study population consisted of patients affected by idiopathic pulmonary fibrosis who received curative-intent lung surgery in three Italian academic centers between 2015 and 2022. Patients were divided into two groups based on whether they were on perioperative treatment with anti-fibrotic drugs (chronical or prophylactic use) or not. To define predictors of acute exacerbation, univariate and multivariable exact logistic regression analysis were performed. The Kaplan-Meier method with log-rank test was used to estimate survival., Results: During the study period, n = 55 patients underwent lung resection for lung cancer, including 29 patients who were treated with antifibrotic agents. Although the sample size was small and few events were studied, the incidence of acute exacerbation was significantly lower among patient on anti-fibrotic therapy (3.4% vs. 23.1%, p = 0.044); in addition, anti-fibrotic treatment was the strong factor preventing acute exacerbation at the multivariable analysis (OR 0.089, p = 0.038). Post-operative 30- and 90-day mortality rates were not significantly lower in the anti-fibrotic treatment group (0% and 0% vs. 7.7% and 11.5%, p = 0.21 and p = 0.099, respectively). Overall and disease-free survival rates were similar., Conclusions: Considering the limitations of this retrospective study with a small sample size, anti-fibrotic perioperative treatment was associated with reduced incidence of acute exacerbation. Based on these real-world data, this pathway could be proposed as a prophylactic treatment in patients with concomitant idiopathic pulmonary fibrosis and cancer undergoing lung resection.

Background: A few months after the COVID-19 pandemic onset, knowledge of SARS-CoV-2 infection and outcomes and treatments blew up. This paper aimed to evaluate the features of a Tuscany COVID-19 hospitalized cohort and to identify risk factors for COVID-19 severity. Methods: This retrospective observational COVID-19 cohort study (1 March 2020-1 March 2021) was conducted on patients ≥ 18 years old, admitted to Tuscany Hospital, and subjected to follow-up within 12 months after discharge. Patients were enrolled at Pisana, Senese and Careggi University Hospitals, and South East, North West, and Center Local Hospitals. Results : 2888 patients (M = 58.5%, mean age = 66.2 years) were enrolled, of whom 14.3% (N = 413) were admitted to an intensive care unit. Smokers were 25%, and overweight and obese 65%. The most used drugs were corticosteroids, antacids, antibiotics, and antithrombotics, all antiviral drugs, with slight differences between 2020 and 2021. A strong association was found between outcomes of evolution towards critical COVID-19 (non-invasive mechanical ventilation (NIV) and/or admission to intensive care) and smoking (RR = 4.91), ex-smoking (RR = 3.48), overweight (RR = 1.30), obese subjects (RR = 1.62), comorbidities (aRR = 1.38). The alteration of liver enzymes (aspartate aminotransferase, alanine aminotransferase, or gamma-glutamyl transpeptidase) was associated with NIV (aOR = 2.28). Conclusions: Our cohort, characterized by patients with a mean age of 66.2 years, showed 65% of patients were overweight and obese. Smoking/ex-smoking, overweight/obesity, and other comorbidities were associated with COVID-19 adverse outcomes. The findings also demonstrated that alterations in liver enzymes were associated with worse outcomes.

Introduction: The deposition of inhaled medications is the first step in the pulmonary pharmacokinetic process to produce a therapeutic response. Not only lung dose but more importantly the distribution of deposited drug in the different regions of the lung determines local bioavailability, efficacy, and clinical safety. Assessing aerosol deposition patterns has been the focus of intense research that combines the fields of physics, radiology, physiology, and biology., Areas Covered: The review covers the physics of aerosol transport in the lung, experimental, and in-silico modeling approaches to determine lung dose and aerosol deposition patterns, the effect of asthma, chronic obstructive pulmonary disease, and cystic fibrosis on aerosol deposition, and the clinical translation potential of determining aerosol deposition dose., Expert Opinion: Recent advances in in-silico modeling and lung imaging have enabled the development of realistic subject-specific aerosol deposition models, albeit mainly in health. Accurate modeling of lung disease still requires additional refinements in existing imaging and modeling approaches to better characterize disease heterogeneity in peripheral airways. Nevertheless, recent patient-centric innovation in inhaler device engineering and the incorporation of digital technology have led to more consistent lung deposition and improved targeting of the distal airways, which better serve the clinical needs of patients.

Objective: To implement subjective methods for measuring the impact of chronic cough on patients' daily life, including an Italian version of the symptom-specific, health status measure for patients with chronic cough, i.e. the Leicester Cough Questionnaire (LCQ)., Methods: Sixty-five chronic cough patients attended a tertiary cough clinic on two separate occasions 8 weeks apart. The visual analogue scale for cough severity (VAS), the LCQ and the cough disturbance score (CDS) were administered on both occasions. The LCQ was adapted for Italian conditions following a forward-backward translation procedure. Concurrent validation, internal consistency, repeatability and responsiveness were determined., Results: The CDS, VAS and LCQ were correlated (r coefficients ranging from 0.69 to 0.94, p < 0.01). The internal consistency for each LCQ domain was high (alpha coefficient range 0.87-0.93), as was the 8-week repeatability of the LCQ in the patients (n = 36, 60 %) who displayed no change in CDS and VAS (intra-class correlation coefficient = 0.86, p < 001) over the same period. Patients who reported an improvement in CDS and VAS after 8 weeks (n = 29) also demonstrated significant improvements in each LCQ domain. The mean difference in LCQ total score before and after improvements was 2.26 (95 % CI: 1.58-4.47)., Conclusions: The Italian version of the LCQ appears to be just as valid as the other language versions of the questionnaire. In addition, the CDS appears to be a clinically useful, symptom-specific measure of the overall disturbance provoked by cough., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Poor adherence to asthma and chronic obstructive pulmonary disease maintenance therapies impairs health outcomes. Proven and cost-effective programs to promote adherence and persistence are not yet in regular widespread use. Implementation costs are a potential barrier to uptake of such programs., Objective: We undertook a systematic literature review and narrative synthesis of studies investigating the cost-effectiveness of treatment adherence-promoting programs or that determined their impact on health care budget directly or via health care resource use (HCRU)., Methods: We identified relevant publications using Medline and PreMEDLINE (PubMed), Embase (Embase.com, Elsevier), and EconLit for publications between January 2000 and July 2021. We also searched clinical trial databases and selected conference proceedings., Results: Of 1,910 potentially relevant articles, 26 met prespecified inclusion criteria and underwent data extraction. Eleven reported a direct assessment of adherence, 15 included economic evaluations, and 17 described HCRU. None included an analysis of biologic medication use. When they were studied, interventions were often found to be highly cost-effective, with dominant incremental cost-effectiveness ratios in some cases. Reductions in direct costs and HCRU (health care visits, hospital admissions, and/or the use of medications, including add-on/reliever treatment and antibiotics) were frequently reported. Reported use of maintenance treatments improved in some studies. Counseling and/or digitally informed programs were used in all cases in which favorable outcomes were observed., Conclusions: Adherence-promoting interventions are mostly cost-effective and often result in reduced HCRU and associated costs. Multidisciplinary care involving one-to-one advice and digitally enhanced communications appear to offer the greatest benefit., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Cough represents a natural mechanism that plays an important defensive role in the respiratory tract, but in some conditions, it may become persistent, nonproductive, and harmful. In general, refractory chronic cough (RCC) occurs in about 20% of individuals; hence, we aimed to assess the presence of altered gut-lung communication in RCC patients through a compositional and functional characterization of both gut (GM) and oral microbiota (OM)., Methods: 16S rRNA sequencing was used to characterize both GM and OM composition of RCC patients and healthy controls (HC). PICRUST2 assessed functional changes in microbial communities while gas chromatography was used to evaluate fecal short-chain fatty acid levels and serum-free fatty acid (FFA) abundances., Results: In comparison with HC, RCC patients reported increased saliva alpha-diversity and statistically significant beta-diversity in both GM and OM. Also, a, respectively, significant increased or reduced Firmicutes/Bacteroidota ratio in stool and saliva samples of RCC patients has been shown, in addition to a modification of the abundances of several taxa in both GM and OM. Moreover, a potential fecal over-expression of lipopolysaccharide biosynthesis and lipoic acid metabolism pathways and several differences in serum FFA levels have been reported in RCC patients than in HC., Conclusion: Since differences in both GM and OM of RCC patients have been documented, these findings could provide new information about RCC pathogenesis and also pave the way for the development of novel nutritional or pharmacological interventions for the management of RCC through the restoration of eubiotic gut-lung communication., (© 2024. The Author(s).)

Introduction: There is increasing pressure to use environmentally friendly dry powder inhalers (DPI) instead of pressurized metered-dose inhalers (pMDI). However, correct inhalation technique is needed for effective inhaler therapy, and there is persistent concern whether patients with chronic obstructive pulmonary disease (COPD) can generate sufficient inspiratory effort to use DPIs successfully. The aims of this study were to find clinical predictors for peak inspiratory flow rate (PIF) and to assess whether patients with COPD had difficulties in generating sufficient PIF with a high resistance DPI., Methods: Pooled data of 246 patients with COPD from previous clinical trials was analyzed to find possible predictors of PIF via the DPI Easyhaler (PIFEH) and to assess the proportion of patients able to achieve an inhalation flow rate of 30 l/min, which is needed to use the Easyhaler successfully., Results: The mean PIF was 56.9 l/min and 99% (243/246) of the study patients achieved a PIF ≥ 30 l/min. A low PIF was associated with female gender and lower forced expiratory volume in 1 s (FEV1), but the association was weak and a statistical model including both only accounted for 18% of the variation seen in PIFEH., Conclusions: Based on our results, impaired expiratory lung function or patient characteristics do not predict patients' ability to use DPIs in COPD; 99% of the patients generated sufficient PIFEH for successful dose delivery. Considering the targets for sustainability in health care, this should be addressed as DPIs are a potential option for most patients when choosing the right inhaler for the patient., Trial Registration: Two of three included trials were registered under numbers NCT04147572 and NCT01424137. Third trial preceded registration platforms and therefore, was not registered., (© 2023. The Author(s).)

The association between MPO-ANCA-associated vasculitis (AAV) and interstitial lung disease (ILD) has been well established. Pulmonary fibrosis may coexist with, follow, or even precede the diagnosis of AAV, and its presence adversely affects the prognosis. The optimal approach to investigating ANCA in patients with ILD remains a subject of ongoing debate. Here we aim to describe presentation and progression of MPO-ANCA ILD. We conducted a retrospective evaluation of a cohort of individuals diagnosed with MPO-ANCA ILD, with or without accompanying renal impairment, at the Immunology and Cell Therapy Unit, Careggi University Hospital, Florence, Italy, between June 2016 and June 2022. Clinical records, imaging studies, pathologic examinations, and laboratory test results were collected. Among the 14 patients identified with MPO-ANCA ILD, we observed a significant association between MPO-ANCA titers assessed at the time of ILD diagnosis and renal involvement. Renal impairment in these cases often manifested as subclinical or slowly progressive kidney damage. Interestingly, complement C3 deposits were consistently found in all renal biopsy specimens, thereby suggesting the potential for novel therapeutic targets in managing renal complications associated with MPO-ANCA ILD. The presentation of MPO-ANCA vasculitis as ILD can be the first and only clinical manifestation. MPO-ANCA levels at ILD diagnosis could warn on the progression to renal involvement in patients with MPO-ANCA ILD, hence caution is needed because renal disease can be subclinical or smoldering., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Diagnosing COVID-19 and treating its complications remains a challenge. This review reflects the perspective of some of the Dragon (IMI 2-call 21, #101005122) research consortium collaborators on the utility of bronchoalveolar lavage (BAL) in COVID-19. BAL has been proposed as a potentially useful diagnostic tool to increase COVID-19 diagnosis sensitivity. In both critically ill and non-critically ill COVID-19 patients, BAL has a relevant role in detecting other infections or supporting alternative diagnoses and can change management decisions in up to two-thirds of patients. BAL is used to guide steroid and immunosuppressive treatment and to narrow or discontinue antibiotic treatment, reducing the use of unnecessary broad antibiotics. Moreover, cellular analysis and novel multi-omics techniques on BAL are of critical importance for understanding the microenvironment and interaction between epithelial cells and immunity, revealing novel potential prognostic and therapeutic targets. The BAL technique has been described as safe for both patients and healthcare workers in more than a thousand procedures reported to date in the literature. Based on these preliminary studies, we recognize that BAL is a feasible procedure in COVID-19 known or suspected cases, useful to properly guide patient management, and has great potential for research., Competing Interests: ST declares consultancy and speaker’s fees from Roche and Boehringer Ingelheim. 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., (Copyright © 2024 Tomassetti, Ciani, Luzzi, Gori, Trigiani, Giuntoli, Lavorini, Poletti, Ravaglia, Torrego, Maldonado, Lentz, Annunziato, Maggi, Rossolini, Pollini, Para, Ciurleo, Casini, Rasero, Bartoloni, Spinicci, Munavvar, Gasparini, Comin, Cerinic, Peired, Henket, Ernst, Louis, Corhay, Nardi and Guiot.)

Background: To assess the clinical effectiveness of Tocilizumab (TCZ) in moderate-to-severe hospitalized COVID-19 patients and factors associated with clinical response., Methods: Five hundred eight inpatients with moderate-to-severe SARS-CoV-2 infection were enrolled. TCZ effect in addition to standard medical therapy was evaluated in terms of death during hospital stay. Unadjusted and adjusted risk of mortality for TCZ treated patients versus TCZ untreated ones was estimated using robust Cox regression model. We considered the combination of TCZ and ICU as time-dependent exposure and created a model using duplication method to assess the TCZ effect in very severe COVID-19 patients., Results: TCZ reduced death during hospital stay in the unadjusted model (HR 0.54, 95%CI 0.33-0.88) and also in the adjusted model, although with loss of statistical significance (HR 0.72, 0.43-1.20). Better effectiveness was observed in patients with low SpO2/FiO2 ratio (HR 0.35, 0.21-0.61 vs. 1.61, 0.54-4.82, P<0.05), and, without statistical significance, in patients with high CRP (HR 0.51, 0.30-0.87 vs. 0.41, 0.12-1.37, P=NS) and high IL-6 (HR 0.49, 0.29-0.82 vs. 1.00, 0.28-3.55, P=NS). TCZ was effective in patients not admitted to ICU, both in the unadjusted (HR 0.33, 0.14-0.74) and in the adjusted (HR 0.39, 0.17-0.91) model but no benefit was observed in critical ICU-admitted patients both in the unadjusted (HR 0.66, 0.37-1.15) and in the adjusted model (HR 0.95, 0.54-1.68)., Conclusions: Our real-life study suggests clinical efficacy of TCZ in moderate-to-severe COVID-19 patients but not in end-stage disease. Thus, to enhance TCZ effectiveness, patients should be selected before grave compromise of clinical conditions.

Background: COVID-19 is a pandemic disease affecting predominantly the respiratory apparatus with clinical manifestations ranging from asymptomatic to respiratory failure. Chest CT is a crucial tool in diagnosing and evaluating the severity of pulmonary involvement through dedicated scoring systems. Nonetheless, many questions regarding the relationship of radiologic and clinical features of the disease have emerged in multidisciplinary meetings. The aim of this retrospective study was to explore such relationship throughout an innovative and alternative approach., Materials and Methods: This study included 550 patients (range 25-98 years; 354 males, mean age 66.1; 196 females, mean age 70.9) hospitalized for COVID-19 with available radiological and clinical data between 1 March 2021 and 30 April 2022. Radiological data included CO-RADS, chest CT score, dominant pattern, and typical/atypical findings detected on CT examinations. Clinical data included clinical score and outcome. The relationship between such features was investigated through the development of the main four frequently asked questions summarizing the many issues arisen in multidisciplinary meetings, as follows 1) CO-RADS, chest CT score, clinical score, and outcomes; 2) the involvement of a specific lung lobe and outcomes; 3) dominant pattern/distribution and severity score for the same chest CT score; 4) additional factors and outcomes., Results: 1) If CT was suggestive for COVID, a strong correlation between CT/clinical score and prognosis was found; 2) Middle lobe CT involvement was an unfavorable prognostic criterion; 3) If CT score < 50%, the pattern was not influential, whereas if CT score > 50%, crazy paving as dominant pattern leaded to a 15% increased death rate, stacked up against other patterns, thus almost doubling it; 4) Additional factors usually did not matter, but lymph-nodes and pleural effusion worsened prognosis., Conclusions: This study outlined those radiological features of COVID-19 most relevant towards disease severity and outcome with an innovative approach., (© 2023. The Author(s).)

Background: Current guidelines on the management of chronic cough do not provide recommendations for the operation of specialist cough clinics. The objective of the present study was to develop expert consensus on goals and standard procedures for specialist cough clinics., Methods: We undertook a modified Delphi process, whereby initial statements proposed by experts were categorised and presented back to panellists over two ranking rounds using an 11-point Likert scale to identify consensus., Results: An international panel of 57 experts from 19 countries participated, with consensus reached on 15 out of 16 statements, covering the aims, roles and standard procedures of specialist cough clinics. Panellists agreed that specialist cough clinics offer optimal care for patients with chronic cough. They also agreed that history taking should enquire as to cough triggers, cough severity rating scales should be routinely used, and a minimum of chest radiography, spirometry and measurements of type 2 inflammatory markers should be undertaken in newly referred patients. The importance of specialist cough clinics in promoting clinical research and cough specialty training was acknowledged. Variability in healthcare resources and clinical needs between geographical regions was noted., Conclusions: The Delphi exercise provides a platform and guidance for both established cough clinics and those in planning stages., Competing Interests: Conflict of interest: W-J. Song declares grants from Merck Sharp & Dohme Corp. and AstraZeneca, consulting fees from Merck, Bellus, AstraZeneca, Shionogi and GSK, and lecture fees from Merck, AstraZeneca, GSK, Sanofi and Novartis, outside the submitted work; and is Deputy Chief Editor of this journal. K.F. Chung has received honoraria for participating on advisory board meetings of GSK, AstraZeneca, Novartis, Merck, Nocion, Shionogi and Reckitt Benckiser, and on the scientific advisory board of the Clean Breathing Institute supported by GSK Health Care Consumer Products; he has also been remunerated for speaking engagements by AstraZeneca, Novartis and Merck. M. Dąbrowska reports fees from MSD for consultations on chronic cough and fees from Chiesi Poland for lectures on chronic cough. P. Dicpinigaitis reports consultant fees from Algernon, Boehringer Ingelheim, Bellus, Chiesi, Merck and Trevi, outside the submitted work. P.G. Gibson reports grant funding to his institution from GSK, MRFF and NHMRC; and funding to present educational lectures from AstraZeneca, GSK and Novartis, outside the submitted work. C.D. Ribas has acted as consultant for GSK, AstraZeneca and Sanofi; and has received funding for travel or speaker fees from ALK, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Menarini, Novartis, Stallergenes and Pfizer. J.H. Hull has received advisory fees from MSD Pharmaceuticals and is a medical advisor to Bellus Health; he is an Associate Editor of this journal. P. Kardos received personal consultation fees from Bayer, Klosterfrau, Merck Sharp & Dohme and Shionogi; honoraria for presentations from Bionorica, Engelhard, Klosterfrau, Merck Sharp & Dohme and Schwabe; and clinical trial participation fees from Bellus and Merck Sharp & Dohme. F. Lavorini received grants for research from Chiesi Farmaceutici, GSK and MSD Italy; and honoraria for talks or participation in advisory boards from AstraZeneca, Chiesi Farmaceutici, GSK, Menarini International, MSD Italy, HIKMA, Cipla and Trudell International. A.H. Morice has received consulting fees from Bayer, Bellus, Merck, NeRRi and Shionogi; lecture fees from Boehringer Ingelheim, Merck and Chiesi; and grant support from Bayer, Bellus, Merck, Nocion, Philips, NeRRi and Shionogi, outside the submitted work; and is an Associate Editor of this journal. A. Niimi reports grants from KYORIN Pharmaceutical Co., Ltd; payment or honoraria for speaker's fees from AstraZeneca K.K., KYORIN Pharmaceutical Co. Ltd, GSK K.K., Sanofi K.K. and Novartis Pharma K.K.; and participation on a data safety monitoring or advisory board of KYORIN Pharmaceutical Co., Ltd and MSD K.K. S.M. Parker reports advisory fees from Merck and Trevi. I. Satia reports grants and personal fees from Merck Canada, Bellus Health and GSK; clinical trial participation from Bayer; and personal fees from Respiplus, Genentech and AstraZeneca, outside the submitted work; and is an Associate Editor of this journal. The other authors declare that they have no competing interests., (Copyright ©The authors 2023.)

Pressurised metered-dose inhalers (pMDIs) and dry powder inhalers (DPIs), are widely used to deliver drugs for the treatment of asthma and chronic obstructive pulmonary disease (COPD). Incorrect use of inhalers is one of the main obstacles to achieving better clinical control. Indeed, with pMDIs, patients fail to synchronise actuation with inhalation due to a lack of coordination and with DPIs insufficient inspiratory effort compromises drug deposition in lungs. More than 50% of patients desire to switch their pMDIs and DPIs for a better device. This led to the development of pressurised breath-actuated inhalers (BAIs) with the aim of combining the beneficial features of pMDIs and DPIs and mitigating their problems. BAIs, e.g., Synchrobreathe™, are designed such that they are activated by a low inhalation effort and mechanically actuate the dose in synchrony to inspiration, thereby resolving the need to coordinate actuation with inspiration. BAIs have advantages, including ease of use, high lung deposition of medication, and greater patient preference. We discussed the design features, operating procedure, and clinical evidence of the Synchrobreathe™ device (Cipla Ltd, India), a BAI available with a wide range of drug combinations. Studies have shown that a higher number of patients (68.19%) used the Synchrobreathe™ without any error than the pMDI (56.21%), and that the vast majority of them (92%) found it easy to understand and use. The Synchrobreathe™ is an innovative, easy-to-use inhaler that may overcome many limitations associated with pMDIs and DPIs, thus potentially improving management of obstructive airway diseases and patients' quality of life., Competing Interests: Declaration of competing interest There is no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Correct inhaler use depends on a complex interplay of factors, including device preparation and generating sufficient inspiratory flow. It is currently unknown which inhalation technique errors can be considered critical in Chronic Obstructive Pulmonary Disease (COPD) patients on Dry Powder Inhaler (DPI) maintenance therapy., Objective: To investigate the association between inhalation technique errors and health status or exacerbations in patients with COPD. Additionally, the association between the number of errors and COPD outcomes was determined., Methods: The PIFotal study is a cross-sectional multi-country observational study in a primary care setting, including 1434 COPD patients aged ≥ 40 years (50.1% female; mean age 69.2 yrs) using a DPI for their maintenance therapy. Inhalation technique was video recorded and scored by two independent researchers using inhaler-specific checklists. Health status was assessed with two questionnaires; the Clinical COPD Questionnaire (CCQ) and the COPD Assessment Test (CAT). The number of moderate and severe exacerbations in the past 12 months was recorded. Critical errors were identified based on their association with health status or exacerbations through multi-level prediction models adjusted for identified confounding., Results: Errors in inhalation technique steps 'Breathe in', 'Hold breath', and 'Breathe out calmly after inhalation' were significantly associated with poorer CCQ and CAT outcomes and thus deemed critical. None of the errors were significantly associated with moderate exacerbations. Patients with errors 'Preparation', 'Hold inhaler in correct position during inhalation', and 'Breathe in' had significantly more severe exacerbations, and therefore these errors were also deemed critical. 81.3% of patients with COPD made at least one critical error. Specific combinations of errors were associated with worse outcomes. The more inhalation technique errors identified, the poorer the health status and the higher the exacerbation rate., Conclusion: In this study, we identified multiple critical inhalation technique errors in COPD patients using DPIs each associated with poorer outcomes. Explorative analysis revealed that specific combinations of errors may be of clinical relevance, especially those related to the inhalation manoeuvre. COPD outcomes worsened with increasing error count. These results warrant further prospective longitudinal studies to establish the effect of correcting these errors on COPD control., Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04532853 (31/08/2020)., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Rationale: Therapies that slow idiopathic pulmonary fibrosis (IPF) progression are now available and recent studies suggest that the use of antifibrotic therapy may reduce IPF mortality., Objectives: The aim of the study was to evaluate whether, to what extent, and for which factors the survival of IPF in a real-life setting has changed in the last 15 years., Methods: Historical eye is an observational study of a large cohort of consecutive IPF patients diagnosed and treated in a referral center for ILDs with prospective intention. We recruited all consecutive IPF patients seen at GB Morgagni Hospital, Forlì, Italy between January 2002 and December 2016 (15 years). We used survival analysis methods to describe and model the time to death or lung transplant and Cox regression to model prevalent and incident patient characteristics (time-dependent Cox models were fitted)., Measurements and Main Results: The study comprised 634 patients. The year 2012 identifies the time point of mortality shift (HR 0.58, CI 0.46-0.63, p < 0.001). In the more recent cohort, more patients had better preserved lung function, underwent cryobiopsy instead of surgery, and were treated with antifibrotics. Highly significant negative prognostic factors were lung cancer (HR 4.46, 95% CI 3.3-6, p < 0.001), hospitalizations (HR 8.37, 95% CI 6.5-10.7, p < 0.001), and acute exacerbations (HR 8.37, 95% CI 6.52-10.7, p < 0.001). The average antifibrotic treatment effect estimated using propensity score matching showed a significant effect in the reduction of all-cause mortality (ATE coeff -0.23, SE 0.04, p < 0.001), acute exacerbations (ATE coeff -0.15, SE 0.04, p < 0.001), and hospitalizations (ATE coeff -0.15, SE 0.04, p < 0.001) but no effect on lung cancer risk (ATE coeff -0.03, SE 0.03, p = 0.4)., Conclusion: Antifibrotic drugs significantly impact hospitalizations, acute exacerbations, and IPF survival. After the introduction of cryobiopsy and antifibrotic drugs, the prognosis of IPF patients has significantly improved together with our ability to detect IPF at an earlier stage., Competing Interests: ST declares speaker's fee from Boehringer-Ingelheim, Roche, Erbe, PulmoniX. VP declares speaker's fees from Boehringer-inghelhem, Erbe, Ambu, and Roche. 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., (Copyright © 2023 Tomassetti, Ravaglia, Piciucchi, Ryu, Wells, Donati, Dubini, Klersy, Luzzi, Gori, Rosi, Lavorini and Poletti.)

It has been shown that muscarinic acetylcholine receptors (mAChRs) located within the caudal nucleus tractus solitarii (cNTS) mediate a cholinergic inhibitory control mechanism of the cough reflex. Thus, identification of the involved mAChR subtypes could be of considerable interest for novel therapeutic strategies. In pentobarbital sodium-anesthetized, spontaneously breathing rabbits we investigated the contribution of different mAChR subtypes in the modulation of mechanically and chemically induced cough reflex. Bilateral microinjections of 1 mM muscarine into the cNTS increased respiratory frequency and decreased expiratory activity even to complete suppression. Interestingly, muscarine induced strong cough-suppressant effects up to the complete abolition of the reflex. Microinjections of specific mAChR subtype antagonists (M 1 -M 5 ) into the cNTS were performed. Only microinjections of the M 4 antagonist tropicamide (1 mM) prevented muscarine-induced changes in both respiratory activity and cough reflex. The results are discussed in light of the notion that cough involves the activation of the nociceptive system. They also suggest that M 4 receptor agonists may have an important role in cough downregulation within the cNTS.

Introduction: There has been an active discussion on the sustainability of inhaler therapy in respiratory diseases, and it has cast a shadow on pMDIs which rely on propellant with high global warming potential (GWP). DPIs offer a lower GWP and effective alternative, but there has been concern whether all patients can generate sufficient inspiratory effort to disperse the drug. This review focuses on airflow resistance of DPIs and its clinical relevance., Areas Covered: For this narrative review, we searched the literature for studies comparing flow patterns with different devices. We also included a section on clinical trials comparing reliever administration with DPI, pMDI with spacer, and nebulizer during exacerbation., Expert Opinion: The evidence supports the efficacy of DPIs irrespective of respiratory condition or age of the patient even during acute exacerbations. Air flow resistance does not limit the use of DPIs and the patients were able to generate sufficient inspiratory flow rate with almost any device studied. None of 16 identified clinical trials comparing reliever administration via DPIs to other types of devices during exacerbation or bronchial challenge showed statistically significant difference between the device types in FEV1 recovery. DPIs performed as well as other types of inhaler devices even during asthma or COPD exacerbation.

Background: Recently we identified in patients with chronic cough a sensory dysregulation via which the urge-to-cough (UTC) or coughing are evoked mechanically from "somatic points for cough" (SPCs) in the neck and upper trunk. We investigated the prevalence and the clinical relevance of SPCs in an unselected population of patients with chronic cough., Methods: From 2018 to 2021, symptoms of 317 consecutive patients with chronic cough (233 females) were collected on four visits (V1-V4) 2 months apart at the Cough Clinic of the University Hospital in Florence (I). Participants rated the disturbance caused by the cough (0-9 modified Borg Scale). We attempted to evoke coughing and/or UTC using mechanical actions in all participants who were subsequently categorised as responsive (somatic point for cough positive, SPC+) or unresponsive (SPC-) to these actions. An association was established between chronic cough and its commonest causes; treatments were administered accordingly., Findings: 169 patients were SPC+ and had a higher baseline cough score (p < 0.01). In most of the patients, the treatments reduced (p < 0.01) cough-associated symptoms. All patients reported a decrease (p < 0.01) in cough score at V2 (from 5.70 ± 1.4 to 3.43 ± 1.9 and from 5.01 ± 1.5 to 2.74 ± 1.7 for SPC+ and SPC- patients respectively). However, whilst in SPC- patients the cough score continued to decrease indicating virtually complete cough disappearance at V4 (0.97 ± 0.8), in SPC+ patients this variable remained close to V2 values during the entire follow-up., Interpretation: Our study suggests that the assessment of SPCs may identify patients whose cough is unresponsive and are eligible for specific treatments., Funding: This work was funded by an unrestricted grant from Merck (Italy)., Competing Interests: F.L. and G.A.F. received grant for research and fees for speaking by MSD Italy. S.M. received grant for research by MSD Italy. G.B., C.F., D.M. and E.C. have no conflict to declare., (© 2023 The Authors.)

Background: A subgroup of IPF patients can meet IPAF criteria (features suggesting an underlying autoimmune process without fulfilling established criteria for a CTD). This study was aimed to evaluate whether IPAF/IPF patients compared to IPF patients differ in clinical profile, prognosis and disease course., Methods: This is a retrospective, single center, case-control study. We evaluated 360 consecutive IPF patients (Forlì Hospital, between 1/1/2002 and 28/12/2016) and compared characteristics and outcome of IPAF/IPF to IPF., Results: Twenty-two (6%) patients met IPAF criteria. IPAF/IPF patients compared to IPF were more frequently females ( N = 9/22, 40.9% vs. N = 68/338, 20.1%, p = 0.02), suffered more frequently from gastroesophageal reflux (54.5% vs. 28.4%, p = 0.01), and showed a higher prevalence of arthralgias (86.4% vs. 4.8%, p < 0.0001), myalgias (14.3% vs. 0.3%, p = 0.001) and fever (18.2% vs. 1.9%, p = 0.002). The serologic domain was detected in all cases (the most frequent were ANA in 17 and RF in nine cases) and morphologic domain (histology features) was positive in 6 out of 10 lung biopsies (lymphoid aggregates). Only patients with IPAF/IPF evolved to CTD at follow-up (10/22, 45.5%; six rheumatoid arthritis, one Sjögren's and three scleroderma). The presence of IPAF was a positive prognostic determinant (HR 0.22, 95% CI 0.08-0.61, p = 0.003), whereas the isolated presence of circulating autoantibody did not impact prognosis (HR 1.00, 95% CI 0.67-1.49, p = 0.99)., Conclusion: The presence of IPAF criteria in IPF has a major clinical impact correlating with the risk of evolution to full blown-CTD during follow-up and identifying a subgroup of patients with a better prognosis., Competing Interests: ST declares speaker’s fee from Boehringer-Ingelheim, Roche, Erbe, PulmoniX; and VP declares speaker’s fees from Boehringer-inghelhem, Erbe, Ambu, and Roche. 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., (Copyright © 2023 Tomassetti, Ravaglia, Puglisi, Wells, Ryu, Bosi, Dubini, Piciucchi, Girelli, Parronchi, Lavorini, Rosi, Luzzi, Cerinic and Poletti.)

Objectives: The functional impact of thoracoscopic basal segmentectomy in comparison with lower lobectomy has not been investigated in-depth and the aim of this study was to clarify this topic., Methods: We retrospectively analysed a cohort of patients who underwent surgery between 2015 and 2019 for non-small-cell lung cancer, peripherally located lung nodules, far enough from both the apical segment and the lobar hilum to allow an oncologically safe thoracoscopic lower lobectomy or basal segmentectomy. Pulmonary function tests (PFTs) including spirometry and plethysmography were performed 1 month after surgery and forced expiratory volume in 1 s, forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO) were collected; the difference, the loss and the recovery rate of pulmonary function were calculated and compared with the Wilcoxon-Mann-Whitney test., Results: During the study period, n = 45 and n = 16 patients for video-assisted thoracoscopic surgery (VATS) lower lobectomy and for VATS basal segmentectomy, respectively, completed the study protocol: the 2 groups were homogeneous as to preoperative variables and PFT values. Postoperative outcomes were similar and PFTs revealed significant differences between postoperative forced expiratory volume in 1 s %, FVC%, ΔFVC and ΔFVC%. The loss percentage of FVC%, DLCO% and the recovery rate was better for FVC and DLCO in the VATS basal segmentectomy group., Conclusions: Thoracoscopic basal segmentectomy seems to be associated with a more preserved lung function, maintaining more FVC and DLCO levels than lower lobectomy, and could be performed in selected cases ensuring also adequate oncological margins., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Objectives: It has recently become possible to assess lung vascular and parenchymal changes quantitatively in thoracic CT images using automated software tools. We investigated the vessel parameters of patients with SSc, quantified by CT imaging, and correlated them with interstitial lung disease (ILD) features., Methods: SSc patients undergoing standard of care pulmonary function testing and CT evaluation were retrospectively evaluated. CT images were analysed for ILD patterns and total pulmonary vascular volume (PVV) extents with Imbio lung texture analysis. Vascular analysis (volumes, numbers and densities of vessels, separating arteries and veins) was performed with an in-house developed software. A threshold of 5% ILD extent was chosen to define the presence of ILD, and commonly used cut-offs of lung function were adopted., Results: A total of 79 patients [52 women, 40 ILD, mean age 56.2 (s.d. 14.2) years, total ILD extent 9.5 (10.7)%, PVV/lung volume % 2.8%] were enrolled. Vascular parameters for total and separated PVV significantly correlated with functional parameters and ILD pattern extents. SSc-associated ILD (SSc-ILD) patients presented with an increased number and volume of arterial vessels, in particular those between 2 and 4 mm of diameter, and with a higher density of arteries and veins of <6 mm in diameter. Considering radiological and functional criteria concomitantly, as well as the descriptive trends from the longitudinal evaluations, the normalized PVVs, vessel numbers and densities increased progressively with the increase/worsening of ILD extent and functional impairment., Conclusion: In SSc patients CT vessel parameters increase in parallel with ILD extent and functional impairment, and may represent a biomarker of SSc-ILD severity., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Over 1400 patients using dry powder inhalers (DPIs) to deliver COPD maintenance therapies were recruited across Europe and Australia. Their peak inspiratory flow (PIF) was measured, inhaler technique was observed, and adherence to treatment assessed. From relating the findings with patient health status, and thereby identifying critical errors, key clinical recommendations for primary care clinicians were determined, namely - measure PIF before prescribing a DPI to ensure inhalation manoeuvre ability is well-matched with the device. Some patients could benefit from inhalation training whereas others should have their DPI changed for one better suited to their inspiratory ability or alternatively be prescribed an active device (such as a soft mist inhaler or pressurized metered dose inhaler). Observing the inhalation technique was valuable however this misses suboptimal PIF (approaching one fourth of patients with a satisfactory observed manoeuvre had a suboptimal PIF for their DPI). Assess adherence as deliberate non-adherence can point to a mismatch between a patient and their inhaler (deliberate non-adherence was significantly associated with PIFs below the minimum for the DPI). In-person observation of inhalation technique was found to be inferior to video rating based on device-specific checklists. Where video assessments are not possible, observation training for healthcare professionals would therefore be valuable particularly to improve the ability to identify the critical errors associated with health status namely 'teeth and lips sealed around mouthpiece', 'breathe in' and 'breathing out calmly after inhalation'. However, it is recommended that observation alone should not replace PIF measurement in the DPI selection process.Trial registration: https://clinicaltrials.gov/ct2/show/NCT04532853 ., (© 2022. The Author(s).)

We tested the prognostic performance of different scores for the identification of subjects with acute respiratory failure by COVID-19, at risk of in-hospital mortality and NIV failure. We conducted a retrospective study, in the Medical High-Dependency Unit of the University-Hospital Careggi. We included all subjects with COVID-19 and ARF requiring non-invasive ventilation (NIV) between March 2020 and January 2021. Clinical parameters, the HACOR score (Heart rate, Acidosis, Consciousness, Oxygenation, Respiratory Rate) and ROX index ((SpO2/FiO2)/respiratory rate) were collected 3 (-3) and 1 day (-1) before the NIV initiation, the first day of treatment (Day0) and after 1 (+1), 2 (+2), 5 (+5), 8 (+8) and 11 (+11) of treatment. The primary outcomes were in-hospital mortality and NIV failure. We included 135 subjects, mean age 69±13 years, 69% male. Patients, who needed mechanical ventilation, showed a higher HACOR score (Day0: 6 [5-7] vs 6 [6-7], p=.057; Day+2: 6 [6-6] vs 6 [4-6], p=.013) and a lower ROX index (Day0: 4.2±2.3 vs 5.1±2.3, p=.055; Day+2: 4.4±1.2.vs 5.5±1.3, p=.001) than those with successful NIV. An HACOR score >5 was more frequent among nonsurvivors (Day0: 82% vs 58%; Day2: 82% vs 48%, all p<0.01) and it was associated with in-hospital mortality (Day0: RR 5.88, 95%CI 2.01-17.22; Day2: RR 4.33, 95%CI 1.64-11.41) independent to age and Charlson index. In conclusion, in subjects treated with NIV for ARF caused by COVID19, respiratory parameters collected after the beginning of NIV allowed to identify those at risk of an adverse outcome. An HACOR score >5 was independently associated with increased mortality rate., (© 2022. The Author(s).)

COVID-19 has been associated with a broad range of long-term sequelae, commonly referred to as "long-COVID" or "post-COVID-19" syndrome. Despite an increasing body of literature, long COVID remains poorly characterized. We retrospectively analysed data from electronic medical records of patients admitted to the post-COVID-19 outpatient service of the Infectious and Tropical Diseases Unit, Careggi University Hospital, Florence, Italy, between June 2020 and June 2021, 4-12 weeks after hospital discharge. A total of 428 patients, 41% women, median age 64 years, underwent a follow-up visit a median 53 days after hospital discharge. Overall, 76% patients reported at least one persistent symptom, including dyspnoea (37%), chronic fatigue (36%), insomnia (16%), visual disorders (13%) and brain fog (13%). Increasing oxygen support (OR 1.4, 95% CI 1.1-1.8), use of immunosuppressants (OR 6.4, 95% CI 1.5-28) and female sex (OR 1.8, 95% CI 1.1-2.9) were associated with a higher risk of long COVID symptoms. Comparison between symptomatic patients infected in the period March-December 2020 (prevalent circulation of wild-type SARS-CoV-2) with those infected in the period January-April 2021 (prevalent circulation of B.1.1.7 Alpha variant) showed a significant modification in the pattern of symptoms belonging to the neurological and cognitive/emotional categories. Our findings confirmed shortness of breath and chronic fatigue as the most frequent long COVID manifestations, while female sex and severe COVID-19 course were the main risk factors for developing lingering symptoms. SARS-CoV-2 variants may induce different long COVID phenotypes, possibly due to changes in cell tropism and differences in viral-host interaction.

Background: Switching inhaler regimens can be driven by poor disease control but also by nonclinical factors, such as cost and environmental impact. The consequences of switching for nonclinical reasons are largely unclear., Objective: To systematically review the real-world consequences of switching inhaler regimens for nonclinical reasons in asthma and/or chronic obstructive pulmonary disease patients., Methods: Embase, MEDLINE, EBM Reviews, and EconLit were searched to November 21, 2020. Conference searches and reference checking were also performed. Real-world studies of asthma and/or chronic obstructive pulmonary disease patients undergoing a switch in inhaler regimen for any reason apart from clinical need were included. Two reviewers screened and extracted data. Key outcomes included symptom control, exacerbations, and patient-doctor relationships., Results: A total of 8,958 records were screened and 21 studies included. Higher-quality (matched comparative) studies were prioritized. Five matched studies (6 datasets) reported on symptom control: 5 datasets (n = 7,530) with unclear patient consent reported improved disease control following switching, and 1 dataset (n = 1,648) with non-consented patients reported significantly worsened disease control. Three matched studies (5 datasets, n = 10,084) reported on exacerbation rate ratios; results were heterogeneous depending on the definition used. Two studies (n = 137) reported that switching inhaler regimens could have a negative impact on the doctor-patient relationship, especially when the switches were non-consented. Study quality was generally low., Conclusions: Switching inhaler regimens is a complex issue that can have variable clinical consequences and can harm the patient-doctor relationship. Limited high-quality evidence was identified, and study designs were heterogeneous. A robust framework is needed to guide the personalized switching of inhalers., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The prevalence of asthma in Italy is estimated to be around 4%; it affects approximately 2,000,000 citizens, and up to 80-90% of patients have mild-to-moderate asthma. Despite the clinical relevance of mild-to-moderate asthma, longitudinal observational data are very limited, including data on disease progression (worsening vs. improvement), the response to treatment, and prognosis. Studies are needed to develop long-term, observational, real-life research in large cohorts. The primary outcomes of this study will be based on prospective observation and the epidemiological evolution of mild and moderate asthma. Secondary outcomes will include patient-reported outcomes, treatments over time, disease-related functional and inflammatory patterns, and environmental and life-style influences., Methods: This study, called the Mild/Moderate Asthma Network of Italy (MANI), is a research initiative launched by the Italian Respiratory Society and the Italian Society of Allergology, Asthma and Clinical Immunology. MANI is a cluster-based, real world, cross-sectional, prospective, observational cohort study that includes 20,000 patients with mild-to-moderate asthma. (ClinicalTrials.gov Identifier: NCT04796844)., Results and Conclusion: Despite advances in asthma care, several research gaps remain to be addressed through clinical research. This study will add important new knowledge about long-term disease history, the transferability of clinical research results to daily practice, the efficacy of currently recommended strategies, and their impact on the burden and evolution of the disease., Abbreviations: MANI:Mild/Moderate Asthma Network of ItalySANI:Severe Asthma Network ItalyGINA:Global Initiative for AsthmaSABA:short acting β2-agonistsICS:inhaled corticosteroidsCRF:Case Report Form.

In patients with chronic cough and age-matched control subjects, we attempted to evoke coughing and/or an urge to cough (UTC) by finger pressure along the sternocleidomastoid and sternum, on the lower cervical or first dorsal vertebrae, the jugular notch as well as with maximum neck extension and flexion These mechanical actions were ineffective in controls but reproducibly evoked coughing or UTC in about 50% of chronic coughers; sternal and spinal responses were abolished temporarily by local cooling. The results may disclose a novel paradigm of cough sensitisation possibly involving central convergence of somatic and visceral neural stimuli., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Inhaled medications are central to treating asthma and chronic obstructive pulmonary disease (COPD), yet critical inhaler technique errors are made by up to 90% of patients. In the clinical research setting, recruitment of subjects with poor inhaler technique may give a false impression of both the benefits and the necessity of add-on treatments such as biologic therapies., Objective: To assess the frequency with which inhaler technique is assessed and reliably optimized before and during patient enrollment into randomized controlled trials (RCTs) addressing the efficacy of topical therapy, and the escalation of therapy for asthma and COPD., Methods: Systematic searches were conducted of PubMed and Embase for RCTs published in the past 10 years involving patients with a diagnosis of asthma or COPD undergoing escalation of baseline inhaled therapy (stepping up, changing, adding, switching, increasing, etc) or the introduction of biologic agents., Results: Searches highlighted 1,014 studies, 118 of which were eligible after the removal of duplicates as well as screening and full text review. Of these, only 14 (11.9%) included accessible information in the methods section or referred to such information in online supplements or protocols concerning assessment of participants' inhaler technique. We therefore developed the proposed Best Practice Inhaler Technique Assessment and Reporting Checklist., Conclusions: Our study identifies a concerning lack of checking and correcting inhaler technique, or at least reporting that this was undertaken, before enrollment in asthma and COPD RCTs, which may affect the conclusions drawn. Mandating the use of a standardized checklist in RCT protocols and ensuring all published RCTs report checking and correcting inhaler technique before enrollment are important next steps., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The study aimed to determine the associations of Peak Inspiratory Flow (PIF), inhalation technique and adherence with health status and exacerbations in participants with COPD using DPI maintenance therapy. This cross-sectional multi-country observational real-world study included COPD participants aged ≥40 years using a DPI for maintenance therapy. PIF was measured three times with the In-Check DIAL G16: (1) typical PIF at resistance of participant's inhaler, (2) maximal PIF at resistance of participant's inhaler, (3) maximal PIF at low resistance. Suboptimal PIF (sPIF) was defined as PIF lower than required for the device. Participants completed questionnaires on health status (Clinical COPD Questionnaire (CCQ)), adherence (Test of Adherence to Inhalers (TAI)) and exacerbations. Inhalation technique was assessed by standardised evaluation of video recordings. Complete data were available from 1434 participants (50.1% female, mean age 69.2 years). GOLD stage was available for 801 participants: GOLD stage I (23.6%), II (54.9%), III (17.4%) and IV (4.1%)). Of all participants, 29% had a sPIF, and 16% were shown able to generate an optimal PIF but failed to do so. sPIF was significantly associated with worse health status (0.226 (95% CI 0.107-0.346), worse units on CCQ; p = 0.001). The errors 'teeth and lips sealed around mouthpiece', 'breathe in', and 'breathe out calmly after inhalation' were related to health status. Adherence was not associated with health status. After correcting for multiple testing, no significant association was found with moderate or severe exacerbations in the last 12 months. To conclude, sPIF is associated with poorer health status. This study demonstrates the importance of PIF assessment in DPI inhalation therapy. Healthcare professionals should consider selecting appropriate inhalers in cases of sPIF., (© 2022. The Author(s).)

Rationale: Lung biopsy (LBx) has a relevant role in the prediction of prognosis of interstitial lung diseases (ILDs), but its impact on the clinical management of patients remains unexplored. Objectives: This study evaluates whether LBx may change the therapeutic strategy and assesses the effect of diagnostic reclassification after LBx on long-term prognosis. Methods: We evaluated the LBx of 426 consecutive patients with ILDs, without a definite usual interstitial pneumonia pattern on high-resolution computed tomographic imaging. A total of 266 patients underwent transbronchial lung cryobiopsy (TBLC), and 160 patients underwent surgical lung biopsy (SLB). The multidisciplinary team (MDT) determined a diagnosis with high or low confidence, and a management strategy, both before and after the LBx data. Results: Final MDT diagnoses were 189 idiopathic pulmonary fibrosis (IPF), 143 non-IPF fibrotic ILDs, and 94 nonfibrotic ILDs. LBx data changed the management strategy in 145 cases (34%), with similar results for TBLC and SLB (the treatment strategy changed in 31.5% of TBLC cases, 84/266, P  < 0.001, and in 38% of SLB, 61/160, P  < 0.001). After LBx, the MDT was less inclined to "wait and see" (from 15% to 4% of cases, P  < 0.001) or to prescribe steroids only (from 54% to 37%, P  < 0.001) and was more confident to treat with antifibrotics (from 23% to 44%, P  < 0.001) or immunosuppressive drugs (from 7% to 14%, P  < 0.001). The therapeutic strategy changed in 70% of reclassified cases (60/85) and in 59% of cases in which LBx increased the MDT confidence (84/142). Reclassification significantly impacted the outcome. The cases classified as non-IPF by clinician and radiologist and then reclassified to be IPF after LBx showed a significantly worse survival compared with non-IPF confirmed cases (adjusted hazard ratio [HR], 3.8; 95% confidence interval [CI], 1.75-8.3); P  = 0.001. Cases initially classified as IPF and then reclassified as non-IPF after LBx showed a better prognosis compared with IPF confirmed cases (HR, 0.41; 95% CI, 0.18-0.94; P  = 0.03). Conclusions: Reclassification of cases with LBx data increased diagnostic confidence and changed the therapeutic strategy in one-third of cases. Pathologic reclassification of cases refined prognosis prediction. Patients classified as non-IPF by clinician and radiologist and then reclassified IPF after LBx had worse prognosis compared with the non-IPF confirmed cases.

Objective: The aim of this study was to identify the main CT features that may help in distinguishing a progression of interstitial lung disease (ILD) secondary to SSc from COVID-19 pneumonia., Methods: This multicentric study included 22 international readers grouped into a radiologist group (RADs) and a non-radiologist group (nRADs). A total of 99 patients, 52 with COVID-19 and 47 with SSc-ILD, were included in the study., Results: Fibrosis inside focal ground-glass opacities (GGOs) in the upper lobes; fibrosis in the lower lobe GGOs; reticulations in lower lobes (especially if bilateral and symmetrical or associated with signs of fibrosis) were the CT features most frequently associated with SSc-ILD. The CT features most frequently associated with COVID- 19 pneumonia were: consolidation (CONS) in the lower lobes, CONS with peripheral (both central/peripheral or patchy distributions), anterior and posterior CONS and rounded-shaped GGOs in the lower lobes. After multivariate analysis, the presence of CONs in the lower lobes (P < 0.0001) and signs of fibrosis in GGOs in the lower lobes (P < 0.0001) remained independently associated with COVID-19 pneumonia and SSc-ILD, respectively. A predictive score was created that was positively associated with COVID-19 diagnosis (96.1% sensitivity and 83.3% specificity)., Conclusion: CT diagnosis differentiating between COVID-19 pneumonia and SSc-ILD is possible through a combination of the proposed score and radiologic expertise. The presence of consolidation in the lower lobes may suggest COVID-19 pneumonia, while the presence of fibrosis inside GGOs may indicate SSc-ILD., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To investigate the persistence of symptoms compatible with COVID-19 in a real-file prospective cohort of patients at 12 months from hospital discharge., Methods: Longitudinal, prospective, single-center, cohort telephone follow-up (FU) study in a Tertiary Care Hospital. All consecutive patients >18 years admitted for COVID-19 were prospectively enrolled in a telephone FU program aimed at monitoring symptoms after 1,3,6,9 and 12 months from hospital discharge. The survey screened for somatic (fatigue, dyspnea, dyspnea, palpitations, cough, chest pain, abdominal pain, ageusia, anosmia, bowel symptoms) and emotional symptoms (insomnia, confusion, altered sense of reality, loss of appetite, fear, and depression) and frailty. Only patients with 12 months FU data were analyzed (N=254). Prevalence and factors associated with symptoms were the main outcomes. Frailty was defined by the presence of ≥3 indicators: weakness, slowness/impaired mobility, weight-loss, low physical activity, and exhaustion., Results: At 12 months, 40.5% of patients reported at least one symptom. The most common somatic ones were fatigue, exertional dyspnea, cough, bowel complaints while the most common psycho-emotional were insomnia, confusion, fear, and depression. Age, gender, gender, frailty, multiple symptoms at baseline and chronic obstructive pulmonary disease (COPD) were associated with symptoms persistence. Furthermore, frailty, COPD and multiple symptoms at baseline were associated with increased risk of somatic symptoms at 12 months, while age and gender were associated with emotional ones., Conclusions: Burden of the long COVID-19 symptoms decreased over time but remained as high as 40% at 12 months with important gender and functional differences, highlighting potential patient categories who may benefit from specific follow up strategies., (Copyright © 2021 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Asthma and chronic obstructive pulmonary disease (COPD) are major causes of morbidity and mortality worldwide. Optimal control of these conditions is a constant challenge for both physicians and patients. Poor inhaler practice is widespread and is a substantial contributing factor to the suboptimal clinical control of both conditions. The practicality, dependability, and acceptability of different inhalers influence the overall effectiveness and success of inhalation therapy. In this paper, experts from various European countries (Finland, Germany, Hungary, Italy, Poland, Spain, and Sweden) address inhaler selection with special focus on the Easyhaler ® device, a high- or medium-high resistance dry-powder inhaler (DPI). The evidence examined indicates that use of the Easyhaler is associated with effective control of asthma or COPD, as shown by the generally accepted indicators of treatment success. Moreover, the Easyhaler is widely accepted by patients, is reported to be easy to learn and teach, and is associated with patient adherence. These advantages help patient education regarding correct inhaler use and the rational selection of drugs and devices. We conclude that switching inhaler device to the Easyhaler may improve asthma and COPD control without causing any additional risks. In an era of climate change, switching from pressurized metered-dose inhalers to DPIs is also a cost-effective way to reduce emissions of greenhouse gases. Enhanced feature (slides, video, animation) (MP4 43768 kb)., (© 2021. The Author(s).)

Introduction: Dry powder inhalers (DPIs), a commonly prescribed inhaler type for respiratory diseases, require patients to generate sufficient peak inspiratory flow (PIF) to ensure optimal drug delivery to the airways. Effectiveness of therapy also requires a good inhalation technique and adequate medication adherence. For patients with chronic obstructive pulmonary disease (COPD), recent studies conducted in tertiary care suggest that DPI users with suboptimal PIF have poorer COPD-related health status and increased exacerbation risk versus those with optimal PIF. The PIFotal study will investigate the impact of PIF, inhalation technique and medication adherence on patient-reported outcomes in patients with COPD in primary care using a DPI for their maintenance therapy., Methods and Analysis: This cross-sectional observational study will assess 1200 patients (aged ≥ 40 years, diagnosed with COPD and using a DPI for COPD maintenance therapy for ≥ 3 months) from the Netherlands, Spain, Portugal, Poland, Greece and Australia. Assessments will consist of (1) PIF measurements (usual patient inhalation manoeuvre, maximal PIF against resistance of own inhaler, and maximal PIF against low resistance); (2) Clinical COPD Questionnaire (CCQ), COPD Assessment Test and Test of Adherence to Inhalers scores; and (3) video recordings of patient inhalation technique. Dependent variables include health status (CCQ score), number of self-reported exacerbations in previous 12 months, and healthcare resource utilisation in previous 6 months. Independent variables include PIF values, inhalation technique errors, medication adherence, and demographic and clinical characteristics. In the primary analysis, the mean difference in CCQ score between patients (1) with optimal/suboptimal PIF, (2) exhibiting/not exhibiting inhalation technique errors, and (3) adhering/not adhering to medication will be examined in a multivariable linear mixed model., Ethics: The study protocol was approved by ethics committees/institutional review boards of all participating sites prior to enrolment; written informed consent was obtained from all study participants., Trial Registration Number: ClinicalTrials.gov: NCT04532853., (© 2021. The Author(s).)