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

Mariangela Rondanelli,1,2 Milena Anna Faliva,3 Gabriella Peroni,3 Vittoria Infantino,2 Clara Gasparri,3 Giancarlo Iannello,4 Simone Perna,5 Tariq AbdulKarim Alalwan,5 Salwa Al-Thawadi,5 Angelo Guido Corsico6,7 1IRCCS Mondino Foundation, Pavia 27100, Italy; 2Department of Public Health, Experimental and Forensic Medicine, Unit of Human and Clinical Nutrition, University of Pavia, Pavia 27100, Italy; 3Endocrinology and Nutrition Unit, Azienda di Servizi alla Persona “Istituto Santa Margherita”, University of Pavia, Pavia 27100, Italy; 4General Management, Azienda di Servizi alla Persona “Istituto Santa Margherita”, Pavia 27100, Italy; 5Department of Biology, College of Science, University of Bahrain, Sakhir 32038, Bahrain; 6Center for Diagnosis of Inherited Alpha 1-Antitrypsin Deficiency, Department of Internal Medicine and Therapeutics, University of Pavia, Pavia 27100, Italy; 7Division of Respiratory Diseases, IRCCS Policlinico San Matteo Foundation, Pavia 27100, ItalyCorrespondence: Gabriella PeroniEndocrinology and Nutrition Unit, Azienda di Servizi alla Persona “Istituto Santa Margherita”, University of Pavia, Pavia 27100, Italy, Tel +39 0382381739Fax +39 0382381218Email gabriella.peroni01@universitadipavia.itAbstract: Nutritional problems are an important part of rehabilitation for chronic obstructive pulmonary disease (COPD) patients. COPD patients often present with malnutrition, sarcopenia, and osteoporosis with possible onset of cachexia, with an inadequate dietary intake and a poor quality of life. Moreover, diet plays a pivotal role in patients with COPD through three mechanisms: regulation of carbon dioxide produced/oxygen consumed, inflammation, and oxidative stress. A narrative review based on 99 eligible studies was performed to evaluate current evidence regarding optimum diet therapy for the management of COPD, and then a food pyramid was built accordingly. The food pyramid proposal will serve to guide energy and dietary intake in order to prevent and treat nutritionally related COPD complications and to manage progression and COPD-related symptoms. The nutrition pyramid described in our narrative review is hypothetical, even in light of several limitations of the present review; the main limitation is the fact that to date there are no randomized controlled trials in the literature clearly showing that improved nutrition, via the regulation of carbon dioxide produced/oxygen consumed, inflammation and oxidative stress, improves symptoms and/or progression of COPD. Even if this nutritional pyramid is hypothetical, we hope that it can serve the valuable purpose of helping researchers focus on the often-ignored possible connections between body composition, nutrition, and COPD.Keywords: COPD, nutrients, inflammation, fat free mass, antioxidants, gas exchanges

Ilaria Baiardini,1 Paola Rogliani,2 Pierachille Santus,3 Angelo G Corsico,4 Marco Contoli,5 Nicola Scichilone,6 Fabiano Di Marco,7 Patrizia Lessi,8 Carla Scognamillo,8 Giorgia Molinengo,9 Fabio Ferri,10 Vincenzo Patella,11 Giuseppe Fiorentino,12 Mauro Carone,13 Fulvio Braido14 1Department of Biomedical Sciences, Humanitas University, Milan, Italy; 2Respiratory Unit, Department of Experimental Medicine, University of Rome “Tor Vergata”, Rome, Italy; 3Department of Biomedical and Clinical Sciences (DIBIC), University of Milan, Milan, Italy; 4Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy; 5Department of Medical Sciences, University of Ferrara, Ferrara, Italy; 6Department of Biomedicine and Internal and Specialistic Medicine (DIBIMIS), University of Palermo, Palermo, Italy; 7Department of Health Sciences, University of Milan, Milan, Italy; 8Boehringer Ingelheim, Milan, Italy; 9Department of Psychology, University of Turin, Turin, Italy; 10MediNeos Observational Research, Modena, Italy; 11U.O. di Allergologia e Immunologia Clinica del Dipartimento delle Discipline Mediche, Battipaglia, Italy; 12U.O.C. Malattie, Fisiopatologia e Riabilitazione Respiratoria A.O. dei Colli, Naples, Italy; 13UOC Pneumologia, ICS Maugeri, IRCCS Cassano Murge, Murge, Italy; 14Department of Internal Medicine, Respiratory Diseases and Allergy Clinic, University of Genova, Azienda Policlinico IRCCS San Martino, Genoa, Italy Background: Patient awareness of COPD refers to knowledge and acceptance of the disease and its treatment. Although it is relevant to management and outcomes, the disease awareness of patients is poorly investigated, and no validated questionnaires are currently available. We aimed to develop the novel Disease Awareness in COPD Questionnaire (DACQ), which was validated in relation to demographic and clinical features, in patients participating in the SATisfaction and Adherence to COPD Treatment (SAT) study.Methods: DACQ was developed according to a list of items regarding the patient’s knowledge, acceptance, and perception of COPD as well as of treatment needs. The questionnaire was validated by assessing internal structure and consistency, correlations with other patient-reported outcomes, and stability over time. Furthermore, the extent of disease awareness of patients enrolled in the SAT study was assessed by using DACQ, and correlations with demographic and clinical features were evaluated.Results: DACQ was composed of four domains. Overall reliability and stability over time were adequate; correlations between DACQ and other tools measuring different constructs (ie, treatment satisfaction, illness perception, impact of COPD symptoms on daily life, and dyspnea severity) were, as expected, more limited. In the enrolled patient sample, a suboptimal level of disease awareness (

Fulvio Braido,1 Pierachille Santus,2 Angelo Guido Corsico,3 Fabiano Di Marco,4 Giovanni Melioli,5 Nicola Scichilone,6 Paolo Solidoro7 1Department of Internal Medicine, IRCCS San Martino di Genova University Hospital, Genoa, Italy; 2Department of Biomedical and Clinical Sciences, University of Milan, Division of Respiratory Diseases, “L. Sacco” University Hospital, ASST Fatebenefratelli-Sacco, Milan, Italy; 3Department of Internal Medicine and Therapeutics, Division of Respiratory Diseases, IRCCS Policlinico San Matteo Foundation, University of Pavia, Italy; 4Department of Health Sciences, University of Milan, San Paolo Hospital, Milan, Italy; 5Center for Precision Medicine, Asthma, and Allergy, Humanitas University, Milan, Italy; 6Department of Internal Medicine, University of Palermo, Palermo, Italy; 7Unit of Pulmonology, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Torino, Italy Purpose: The purposes of this study were development and validation of an expert system (ES) aimed at supporting the diagnosis of chronic obstructive lung disease (COLD). Methods: A questionnaire and a WebFlex code were developed and validated in silico. An expert panel pilot validation on 60 cases and a clinical validation on 241 cases were performed. Results: The developed questionnaire and code validated in silico resulted in a suitable tool to support the medical diagnosis. The clinical validation of the ES was performed in an academic setting that included six different reference centers for respiratory diseases. The results of the ES expressed as a score associated with the risk of suffering from COLD were matched and compared with the final clinical diagnoses. A set of 60 patients were evaluated by a pilot expert panel validation with the aim of calculating the sample size for the clinical validation study. The concordance analysis between these preliminary ES scores and diagnoses performed by the experts indicated that the accuracy was 94.7% when both experts and the system confirmed the COLD diagnosis and 86.3% when COLD was excluded. Based on these results, the sample size of the validation set was established in 240 patients. The clinical validation, performed on 241 patients, resulted in ES accuracy of 97.5%, with confirmed COLD diagnosis in 53.6% of the cases and excluded COLD diagnosis in 32% of the cases. In 11.2% of cases, a diagnosis of COLD was made by the experts, although the imaging results showed a potential concomitant disorder. Conclusion: The ES presented here (COLDES) is a safe and robust supporting tool for COLD diagnosis in primary care settings. Keywords: chronic obstructive lung diseases, expert systems, diagnosis

The lungs are most often a preferential target organ for malignant spreading and growth. It is well known that chronic parenchymal inflammation and prolonged injuries represents an independent risk factor for cancer onset. Growing evidence supports the implication of lung microbiota in the pathogenesis of lung cancer. However, the full interplay between chronic inflammation, bacterial colonization, pathologic condition as bronchiectasis and malignant growth deserves better clarification. We here aim at presenting and analyzing original data and discussing the state-of-the-art on the knowledge regarding how this complex milieu acts on the plasticity of the lung pre-metastatic niche to point out the rationale for early diagnosis and therapeutic targeting., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Pisanu, Mucaj, Conio, Bertuccio, Giana, Arlando, Russo, Montini, Bortolotto, Corsico and Stella.)

Background and rationale. Pleural mesothelioma (PM) is a rare and aggressive neoplasm that originates from the pleural mesothelium and whose onset is mainly linked to exposure to asbestos, which cannot be attacked with truly effective therapies with consequent poor prognosis. The rationale of this study is based on the use of mesenchymal stromal cells (MSCs) as a vehicle for chemotherapy drugs to be injected directly into the pathological site, such as the pleural cavity. Study design. The study involves the use of a conventional chemotherapeutic drug, Paclitaxel (PTX), which is widely used in the treatment of different types of solid tumors, including PM, although some limitations are related to pharmacokinetic aspects. The use of PTX-loaded MSCs to treat PM should provide several potential advantages over the systemically administered drug as reduced toxicity and increased concentration of active drug in the tumor-surrounding context. The PACLIMES trial explores the safety and toxicity of the local administration of Paclimes in chemonaive patients, candidates for pleurectomy. The secondary objective is to find the effective Paclimes dose for subsequent phase II studies and to observe and record the antitumor activity. Future direction . The experimental pre-clinical background and rationale are discussed as well.

Background & Aims: Homozygous ZZ alpha-1 antitrypsin (AAT) deficiency produces mutant AAT (Z-AAT) proteins in hepatocytes, leading to progressive liver fibrosis. We evaluated the safety and efficacy of an investigational RNA interference therapeutic, fazirsiran, that degrades Z-AAT messenger RNA, reducing deleterious protein synthesis., Methods: This ongoing, phase 2 study randomized 40 patients to subcutaneous placebo or fazirsiran 25, 100, or 200 mg. The primary endpoint was percent change in serum Z-AAT concentration from baseline to week 16. Patients with fibrosis on baseline liver biopsy received treatment on day 1, at week 4, and then every 12 weeks and had a second liver biopsy at or after weeks 48, 72, or 96. Patients without fibrosis received 2 doses on day 1 and at week 4., Results: At week 16, least-squares mean percent declines in serum Z-AAT concentration were -61%, -83%, and -94% with fazirsiran 25, 100, and 200 mg, respectively, vs placebo (all P < .0001). Efficacy was sustained through week 52. At postdose liver biopsy, fazirsiran reduced median liver Z-AAT concentration by 93% compared with an increase of 26% with placebo. All fazirsiran-treated patients had histologic reduction from baseline in hepatic globule burden. Portal inflammation improved in 5 of 12 and 0 of 8 patients with a baseline score of >0 in the fazirsiran and placebo groups, respectively. Histologic meta-analysis of histologic data in viral hepatitis score improved by >1 point in 7 of 14 and 3 of 8 patients with fibrosis of >F0 at baseline in the fazirsiran and placebo groups, respectively. No adverse events led to discontinuation, and pulmonary function tests remained stable., Conclusions: Fazirsiran reduced serum and liver concentrations of Z-AAT in a dose-dependent manner and reduced hepatic globule burden. (ClinicalTrials.gov, Number NCT03945292)., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Pulmonary alveolar proteinosis (PAP) is a syndrome that results from the accumulation of lipoproteinaceous material in the alveolar space. According to the underlying pathogenetic mechanisms, three different forms have been identified, namely primary, secondary and congenital. Primary PAP is caused by disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) signalling due to the presence of neutralising autoantibodies (autoimmune PAP) or GM-CSF receptor genetic defects (hereditary PAP), which results in dysfunctional alveolar macrophages with reduced phagocytic clearance of particles, cholesterol and surfactant. The serum level of GM-CSF autoantibody is the only disease-specific biomarker of autoimmune PAP, although it does not correlate with disease severity. In PAP patients with normal serum GM-CSF autoantibody levels, elevated serum GM-CSF levels is highly suspicious for hereditary PAP. Several biomarkers have been correlated with disease severity, although they are not specific for PAP. These include lactate dehydrogenase, cytokeratin 19 fragment 21.1, carcinoembryonic antigen, neuron-specific enolase, surfactant proteins, Krebs von Lungen 6, chitinase-3-like protein 1 and monocyte chemotactic proteins. Finally, increased awareness of the disease mechanisms has led to the development of pathogenesis-based treatments, such as GM-CSF augmentation and cholesterol-targeting therapies., Competing Interests: Conflict of interest: F. Bonella reports consultancy fees from Boehringer Ingelheim, Sanofi, BMS and CSL-Behring, payment or honoraria for lectures, presentations, manuscript writing or educational events from Boehringer Ingelheim and Sanofi, support for attending meetings from Boehringer Ingelheim, Astra Zeneca and Atyr, and participation on a data safety monitoring board or advisory board with Boehringer Ingelheim, Sanofi and BMS. I. Campo reports consultancy fees from Partner Therapeutics, and participation on a data safety monitoring board or advisory board with Savara. All other authors have nothing to disclose., (Copyright ©The authors 2024.)

Case Presentation: A 41-year-old man who currently smokes with previous sporadic use of cocaine and cannabinoids was admitted at the hospital suffering from hemoptysis which had developed 4 days before. The patient was on anticoagulant therapy with rivaroxaban due to paroxysmal atrial fibrillation diagnosed in 2018, for which he had undergone pulmonary vein electrical isolation by radiofrequency and ablation of cavotricuspid isthmus in January 2019. The procedure was completed in July 2019. Treatment with flecainide was introduced due to recurrences of atrial fibrillation. In February 2021, a new attempt at ablation was performed by electrical isolation of the left atrial posterior wall. The latest cardiologic checkup documented an echocardiographic framework of mild left atrial dilatation and normal-sized right ventricle with longitudinal shortening index at the lower limits, and a recurrence of asymptomatic atrial fibrillation at Holter ECG (March 2022)., Competing Interests: Financial/Nonfinancial Disclosures None declared., (Copyright © 2024 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

A 64-year-old woman presented to Our Department with 2 weeks history of fever and cough. Through a series of radiological and invasive diagnostic studies we finally reach an unexpected diagnosis of Tsukamurella pneumonia ; Diagnosing an ILD is a dynamic process, and that is the reason why complex cases discussed in a multidisciplinary team may need to be reconsidered in light of evolution of the disease and the results of the performed exams with a flexible approach. Tsukamurella spp. is an obligate aerobic, Gram-positive, weakly acid-fast, non-motile bacillus that belongs to the order Actinomycetales. Pneumonia caused by Tsukamurella is exceedingly rare, and only few cases are reported in the literature. Our aim is to evidence the paramount importance of Multidisciplinary team discussion in deciding the most appropriate diagnostic is of and therapeutical strategy., Competing Interests: All authors declare that they have no conflicts of interest., (© 2024 The Authors.)

Background: Sex and gender influence many aspects of chronic obstructive pulmonary disease (COPD). Limited data are available on this topic in alpha-1 antitrypsin deficiency (AATD). We therefore aimed to investigate sex issues in the EARCO registry, a prospective, international, observational cohort study., Methods: Baseline data from PiZZ individuals, enrolled in the registry with complete data on sex and smoking history were analysed by group comparisons and binary logistic regression analyses., Results: 1283 patients with AATD, 49.3% women were analysed. Females reported less tobacco consumption (16.8±12.2 vs. 19.6±14.5 PY, p=0.006), occupational exposures towards gases, dusts or asbestos (p<0.005 each) and consumed less alcohol (5.5±7.6 vs. 8.4±10.3u/week, p<0.001). Females reported COPD (41% vs. 57%, p<0.001) and liver disease (11% vs. 20%, p<0.001) less often. However, they had a higher prevalence of bronchiectasis (24% vs. 13%, p<0.001). Despite better lung function (FEV 1 %pred. 73.6±29.9 vs. 62.7±29.5, p<0.001) females reported a similar symptom burden (CAT 13.4±9.5 vs. 12.5±8.9, p=ns) and exacerbation frequency (at least one in the previous year 30% vs. 26%, p=ns) compared to males. In multivariate analyses, female sex was an independent risk factor for exacerbations in the previous year OR 1.6 p=0.001 in addition to smoking history, COPD, asthma and bronchiectasis and was also identified as risk factors for symptom burden (CAT≥10) OR 1.4 p=0.014 besides age, BMI, COPD and smoking history., Conclusion: Men had higher rates of COPD and liver disease, women were more likely to have bronchiectasis. Women's higher symptom burden and exacerbation frequency suggest they may need tailored treatment approaches., (Copyright © 2024 The Author(s). Published by Elsevier España, S.L.U. All rights reserved.)

Pulmonary hypertension (PH) is not considered a known risk factor for non-tuberculous mycobacterial lung disease (NTM-LD), despite that many studies state that incidence is almost equal to other chronic lung diseases. Current standard of care for NTM-LD consists in multidrug antibiotic regimen for several months. However, it results in negative culture conversion in a minority of cases. Therefore, when feasible an adjuvant surgical approach is indicated. In this case report we highlight the importance of multidisciplinary team discussion in providing the best therapeutic strategy in presence of significant comorbidities like chronic thromboembolic pulmonary hypertension., 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.)

Specific molecular and inflammatory endotypes have been identified for chronic respiratory disorders, including asthma and COPD (chronic obstructive pulmonary disease). These endotypes correspond with clinical aspects of disease, enabling targeted medicines to address certain pathophysiologic pathways, often referred to as "precision medicine". With respect to bronchiectasis, many comorbidities and underlying causes have been identified. Inflammatory endotypes have also been widely studied and reported. Additionally, several genes have been shown to affect disease progression. However, the lack of a clear classification has also hampered our understanding of the disease's natural course. The aim of this review is, thus, to summarize the current knowledge on biomarkers and actionable targets of this complex pathologic condition and to point out unmet needs, which are required in the design of effective diagnostic and therapeutic trials.

Alpha-1 antitrypsin (AAT) deficiency, an autosomal co-dominant condition, decreases protein concentration and activity at both serum and tissue levels. Few studies investigated whether the type of SERPINA1 gene phenotype in patients with severe asthma can influence symptoms and disease control during follow-up.To assess whether the presence of a non-MM genotype of SERPINA1 in patients with severe asthma is associated with disease control, systemic and airway inflammation, lung function and comorbidities prevalence compared to severe asthma patients with a homozygous genotype (MM).Asthmatic patients belonging to Global Initiative for Asthma (GINA) step 5 were retrospectively analysed in an Italian reference asthma clinic. We collected clinical, biological and functional variables at baseline and for the three following years.Out of 73 patients enrolled, 14 (19.18%) were non-MM and 59 (80.8%) were MM. Asthmatics with non-MM genotype had lower serum AAT concentration ( P = 0.004) and higher emphysema prevalence than the MM group ( P = 0.003) at baseline. During follow up, only MM patients showed a significant improvement of both ACQ-6 score ( P < 0.0001) and eosinophilic systemic inflammation ( P < 0.0001).Our findings emphasise the importance of a screening for AAT deficiency in severe asthma, as alleles mutation may influence patient's follow-up..

Sarcoidosis is a multisystem disease, which is diagnosed on a compatible clinical presentation, non-necrotizing granulomatous inflammation in one or more tissue samples, and exclusion of alternative causes of granulomatous disease. Considering its heterogeneity, numerous aspects of the disease remain to be elucidated. In this context, the identification and integration of biomarkers may hold significance in clinical practice, aiding in appropriate selection of patients for targeted clinical trials. This work aims to discuss and analyze how validated biomarkers are currently integrated in disease category definitions. Future studies are mandatory to unravel the diverse contributions of genetics, socioeconomic status, environmental exposures, and other sociodemographic variables to disease severity and phenotypic presentation. Furthermore, the implementation of transcriptomics, multidisciplinary approaches, and consideration of patients' perspectives, reporting innovative insights, could be pivotal for a better understanding of disease pathogenesis and the optimization of clinical assistance.

It takes ∼3.5 years to reach a diagnosis of bronchiectasis from onset of symptoms: the long patient's journey in Italy https://bit.ly/46XMWAz., Competing Interests: Conflict of interest: G. Sotgiu is an associate editor of this journal. Conflict of interest: A. Gramegna reports consulting fees from Vertex and Zambon, outside the submitted work; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Vertex, Chiesi and Insmed, outside the submitted work; support for attending meetings and/or travel from Neupharma, Chiesi and Insmed, outside the submitted work; participation on a Data Safety Monitoring Board or Advisory Board for Vertex, outside the submitted work. Conflict of interest: F. Blasi reports grants or contracts from AstraZeneca, Chiesi, GlaxoSmithKline and Insmed, outside the submitted work; consulting fees from GlaxoSmithKline, Menarini and OM Pharma, outside the submitted work; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing or educational events from AstraZeneca, Chiesi, GlaxoSmithKline, Grifols, Insmed, Menarini, Om Pharma, Pfizer, Sanofi, Vertex, Viatris and Zambon, outside the submitted work. Conflict of interest: C. Crimi reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from GSK, Sanofi, AstraZeneca, F&P, ResMed and Novartis, outside the submitted work; and patent pending number 102023000013077 not related to the submitted work. Conflict of interest: S. Aliberti reports grants or contracts from Insmed Incorporated, Chiesi, Fisher & Paykel and GSK, outside the submitted work; royalties or licenses from McGraw Hill, outside the submitted work; consulting fees from Insmed Incorporated, Insmed Italy, Insmed Ireland Ltd, Zambon Spa, AstraZeneca UK Limited, AstraZeneca Pharmaceutical LP, CSL Behring GmbH, Grifols, Fondazione Internazionale Menarini, Moderna, Chiesi, MSD Italia S.r.l., BRAHMS, Physioassist SAS and GlaxoSmithKline Spa, outside the submitted work; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing or educational events from GlaxoSmithKline Spa, Thermofisher Scientific, Insmed Italy, Insmed Ireland Ltd, Zambon and Fondazione Internazionale Menarini, outside the submitted work; and participation on a Data Safety Monitoring Board or Advisory Board for Insmed Incorporated, Insmed Italy, AstraZeneca UK Limited and MSD Italia S.r.l, outside the submitted work. Conflict of interest: The remaining authors have nothing to disclose., (Copyright ©The authors 2024.)

Objectives: Alpha-1-antitrypsin deficiency is a genetic disorder caused by mutations in the SERPINA1 gene encoding alpha-1-antitrypsin (AAT), the major serine protease inhibitor in plasma. Reduced AAT levels are associated with elevated risk of developing emphysema mainly due to uncontrolled activity of neutrophil elastase in the lungs. The prevalent Z-AAT mutant and many rare pathogenic AAT variants also predispose to liver disease due to their accumulation as polymeric chains in hepatocytes. Part of these polymers are secreted into the bloodstream and could represent biomarkers of intra-hepatic accumulation. Moreover, being inactive, they further lower lung protection against proteases. Aim of our study is to accurately quantify the percentage of circulating polymers (CP) in a cohort of subjects with different SERPINA1 genotypes., Methods: CP concentration was measured in plasma or Dried Blood Spot (DBS) by a sensitive sandwich ELISA based on capture by the polymer-specific 2C1 monoclonal antibody., Results: CP were significantly elevated in patients with the prevalent PI*SZ and PI*ZZ genotypes, with considerable intra-genotype variability. Notably, higher percentage of polymers was observed in association with elevated C-reactive protein. CP levels were also increased in carriers of the M malton variant, and of M procida , I, P lowell and M herleen in heterozygosity with Z-AAT., Conclusions: These findings highlight the importance of implementing CP quantification in a clinical laboratory. Indeed, the variable amount of CP in patients with the same genotype may correlate with the variable severity of the associated lung and liver diseases. Moreover, CP can reveal the polymerogenic potential of newly discovered ultrarare AAT variants., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Background: Severe alpha1-antitrypsin (AAT) deficiency (AATD) is associated with a high risk of airflow obstruction and emphysema. The risk of lung disease in those with intermediate AAT deficiency is unclear. Our aims were to compare pulmonary function, time of onset of symptoms, and indicators of quality of life among patients with severe AATD (PI*ZZ), patients with intermediate AATD (PI*MZ) from the Italian Registry of AATD with a chronic obstructive pulmonary disease (COPD) cohort of patients without AATD (PI*MM)., Methods: We considered a total of 613 patients: 330 with the PI*ZZ genotype, 183 with the PI*MZ genotype and 100 with the PI*MM genotype. Radiological exams, pulmonary function test, and measurement of quality of life have been performed on all cohorts of patients., Results: The three populations differ significantly in terms of age at COPD/AATD diagnosis (P=0.00001), respiratory function (FEV1, FVC, DLCO P<0.001), quality of life (P=0.0001) and smoking history (P<0.0001). PI*ZZ genotype had 24.9 times a higher likelihood of developing airflow obstruction. The MZ genotype is not associated with a significant early risk of airflow obstruction., Conclusions: The comparison of populations with PI*ZZ, MZ and MM genotypes allows to delineate the role of alpha1-antitrypsin deficiency on respiratory function and on the impact on quality of life, in relation to other risk factors. These results highlight the crucial role of primary and secondary prevention on smoking habits in PI*MZ subjects and the importance of an early diagnosis.

Air pollution is a leading risk factor for global mortality and morbidity. Oxidative stress is a key mechanism underlying air-pollution-mediated health effects, especially in the pathogenesis/exacerbation of airway impairments. However, evidence lacks on subgroups at higher risk of developing more severe outcomes in response to air pollution. This multi-centre study aims to evaluate the association between air pollution and oxidative stress in healthy adults and in patients affected by airway diseases from the Italian GEIRD (Gene Environment Interactions in Respiratory Diseases) multi-case control study. Overall, 1841 adults (49 % females, 20-83 years) were included from four Italian centres: Pavia, Sassari, Turin, and Verona. Following a 2-stage screening process, we identified 1273 cases of asthma, chronic bronchitis, rhinitis, or COPD and 568 controls. Systemic oxidative stress was quantified by urinary 8-isoprostane and 8-OH-dG. Individual residential exposures to NO 2 , PM 10 , PM 2.5 , and O 3 were derived using an innovative five-stage machine-learning-based approach. Linear mixed regression models tested the association between oxidative stress biomarkers and air pollution tertiles, adjusting by age, sex, BMI, smoking, education and season, with recruiting centres as random intercept. Only cases exhibited higher levels of log-transformed 8-isoprostane and 8-OH-dG in association with NO 2 (β: 0.30 95 % CI: 0.08-0.52 and 0.20 95 % CI: 0.03-0.37), PM 10 (0.34 95 % CI: 0.12-0.55 and 0.21 95 % CI: 0.05-0.37) and PM 2.5 (0.27 95 % CI: 0.09-0.49 and 0.18 95 % CI: 0.02-0.34) as compared to the first tertile of exposure. No significant associations were observed for summer O 3 . Our findings suggest that exposure to air pollution may increase systemic oxidative stress levels in people suffering from airway diseases. This introduces a potential novel approach available for future epidemiological studies and Public Health for effective prevention strategies oriented at the quantification of early biological effects in susceptible people, whose additional risk level might be currently underrated. Air-pollution-mediated exacerbations, driven by oxidative stress, still deserve our attention., Competing Interests: Declaration of competing interest 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., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Understanding the natural history of abnormal spirometric patterns at different stages of life is critical to identify and optimise preventive strategies. We aimed to describe characteristics and risk factors of restrictive and obstructive spirometric patterns occurring before 40 years (young onset) and between 40 and 61 years (mid-adult onset)., Methods: We used data from the population-based cohort of the European Community Respiratory Health Survey (ECRHS). Prebronchodilator forced expiratory volume in one second (FEV 1 ) and forced vital capacity (FVC) were assessed longitudinally at baseline (ECRHS1, 1993-1994) and again 20 years later (ECRHS3, 2010-2013). Spirometry patterns were defined as: restrictive if FEV 1 /FVC≥LLN and FVC<10th percentile, obstructive if FEV 1 /FVC

Rationale: Whole lung lavage (WLL) is a widely accepted palliative treatment for autoimmune pulmonary alveolar proteinosis (aPAP) but does not correct myeloid cell dysfunction or reverse the pathological accumulation of surfactant. In contrast, inhaled recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) is a promising pharmacological approach that restores alveolar macrophage functions including surfactant clearance. Here, we evaluate WLL followed by inhaled rGM-CSF (sargramostim) as therapy of aPAP., Methods: 18 patients with moderate-to-severe aPAP were enrolled, received baseline WLL, were randomised into either the rGM-CSF group (receiving inhaled sargramostim) or control group (no scheduled therapy) and followed for 30 months after the baseline WLL. Outcome measures included additional unscheduled "rescue" WLL for disease progression, assessment of arterial blood gases, pulmonary function, computed tomography, health status, biomarkers and adverse events. Patients requiring rescue WLL were considered to have failed their assigned intervention group., Results: The primary end-point of time to first rescue WLL was longer in rGM-CSF-treated patients than controls (30 versus 18 months, n=9 per group, p=0.0078). Seven control patients (78%) and only one rGM-CSF-treated patient (11%) required rescue WLL, demonstrating a 7-fold increase in relative risk (p=0.015). Compared to controls, rGM-CSF-treated patients also had greater improvement in peripheral arterial oxygen tension, alveolar-arterial oxygen tension difference, diffusing capacity of the lungs for carbon monoxide and aPAP biomarkers. One patient from each group withdrew for personal reasons. No serious adverse events were reported., Conclusions: This long-term, prospective, randomised trial demonstrated inhaled sargramostim following WLL reduced the requirement for WLL, improved lung function and was safe in aPAP patients. WLL plus inhaled sargramostim may be useful as combined therapy for aPAP., Competing Interests: Conflict of interest: I. Campo, B.C. Trapnell and B.C. Carey serve as investigators on another clinical trial of inhaled rGM-CSF therapy of autoimmune PAP. B.C. Trapnell and B.C. Carey have served as consultants regarding the development of inhaled rGM-CSF as therapy of aPAP. No other authors have no financial or other conflicts of interest to declare related to this work., (Copyright ©The authors 2024.)

Interstitial lung diseases (ILDs) are a heterogeneous group of pulmonary disorders characterized by variable degrees of inflammation, interstitial thickening, and fibrosis leading to distortion of the pulmonary architecture and gas exchange impairment. Among them, idiopathic pulmonary fibrosis (IPF) displays the worst prognosis. The only therapeutic options consist of the two antifibrotic drugs, pirfenidone and nintedanib, which limit fibrosis progression but do not reverse the lung damage. The shift of the pathogenetic paradigm from inflammatory disease to epithelium-derived disease has definitively established the primary role of type II alveolar cells, which lose their epithelial phenotype and acquire a mesenchymal phenotype with production of collagen and extracellular matrix (EMC) deposition. Some predisposing environmental and genetic factors (e.g., smoke, pollution, gastroesophageal reflux, variants of telomere and surfactant genes) leading to accelerated senescence set a pro-fibrogentic microenvironment and contribute to the loss of regenerative properties of type II epithelial cells in response to pathogenic noxae. This review provides a complete overview of the different pathogenetic mechanisms leading to the development of IPF. Then, we summarize the currently approved therapies and the main clinical trials ongoing. Finally, we explore the potentialities offered by agents not only interfering with the processes of fibrosis but also restoring the physiological properties of alveolar regeneration, with a particular focus on potentialities and concerns about cell therapies based on mesenchymal stem cells (MSCs), whose anti-inflammatory and immunomodulant properties have been exploited in other fibrotic diseases, such as graft versus host disease (GVHD) and COVID-19-related ARDS.

Background: Tracheal stenosis represents a fearsome complication that substantially impairs quality of life. The recent SARS-CoV-2 pandemic increased the number of patients requiring invasive ventilation through prolonged intubation or tracheostomy, increasing the risk of tracheal stenosis. Study design and methods: In this prospective, observational, multicenter study performed in Lombardy (Italy), we have exanimated 281 patients who underwent prolonged intubation (more than 7 days) or tracheostomy for severe COVID-19. Patients underwent CT scan and spirometry 2 months after hospital discharge and a subsequent clinical follow-up after an additional 6 months (overall 8 months of follow-up duration) to detect any tracheal lumen reduction above 1%. The last follow-up evaluation was completed on 31 August 2022. Results: In the study period, 24 patients (8.5%, CI 5.6-12.4) developed tracheal stenosis in a median time of 112 days and within a period of 200 days from intubation. Compared to patients without tracheal stenosis, tracheostomy was performed more frequently in patients that developed stenosis (75% vs 54%, p = 0.034). Tracheostomy and alcohol consumption (1 unit of alcohol per day) increased risk of developing tracheal stenosis of 2.6-fold ( p = 0.047; IC 0.99-6.8) and 5.4-fold ( p = 0.002; CI 1.9-16), respectively. Conclusions : In a large cohort of patients, the incidence of tracheal stenosis increased during pandemic, probably related to the increased use of prolonged intubation. Patients with histories of prolonged intubation should be monitored for at least 200 days from invasive ventilation in order to detect tracheal stenosis at early stage. Alcohol use and tracheostomy are risk factors for developing tracheal stenosis.

Background: We aimed to assess whether exposure to risk factors in early life from conception to puberty continue to contribute to lung function decline later in life by using a pooled cohort comprising approx. 11,000 adults followed for more than 20 years and with up to three lung function measurements., Methods: Participants (20-68 years) in the ECRHS and NFBC1966 cohort studies followed in the periods 1991-2013 and 1997-2013, respectively, were included. Mean annual decline in maximum forced expired volume in 1 s (FEV 1 ) and forced vital capacity (FVC) were main outcomes. Associations between early life risk factors and change in lung function were estimated using mixed effects linear models adjusted for sex, age, FEV 1 , FVC and height at baseline, accounting for personal smoking., Findings: Decline in lung function was accelerated in participants with mothers that smoked during pregnancy (FEV 1 2.3 ml/year; 95% CI: 0.7, 3.8) (FVC 2.2 ml/year; 0.2, 4.2), with asthmatic mothers (FEV 1 2.6 ml/year; 0.9, 4.4) (FEV 1 /FVC 0.04 per year; 0.04, 0.7) and asthmatic fathers (FVC 2.7 ml/year; 0.5, 5.0), and in women with early menarche (FVC 2.4 ml/year; 0.4, 4.4). Personal smoking of 10 pack-years contributed to a decline of 2.1 ml/year for FEV 1 (1.8, 2.4) and 1.7 ml/year for FVC (1.3, 2.1). Severe respiratory infections in early childhood were associated with accelerated decline among ever-smokers. No effect-modification by personal smoking, asthma symptoms, sex or cohort was found., Interpretation: Mothers' smoking during pregnancy, parental asthma and early menarche may contribute to a decline of FEV 1 and FVC later in life comparable to smoking 10 pack-years., Funding: European Union's Horizon 2020; Research Council of Norway; Academy of Finland; University Hospital Oulu; European Regional Development Fund; Spanish Ministry of Science and Innovation; Generalitat de Catalunya., Competing Interests: SCD and CJL have received an investigator-initiated grant from GSK and a partnership grant from AZ for unrelated work. All other authors declare no conflict of interest., (© 2023 The Authors.)

Pleural mesothelioma is an aggressive disease with diffuse nature, low median survival, and prolonged latency presenting difficulty in prognosis, diagnosis, and treatment. Here, we review all these aspects to underline the progress being made in its investigation and to emphasize how much work remains to be carried out to improve prognosis and treatment.

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

Alpha-1 antitrypsin deficiency (AATD) is an underdiagnosed disorder associated with mutations in the SERPINA1 gene encoding alpha-1 antitrypsin (AAT). Severe AATD can manifest as pulmonary emphysema and progressive liver disease. Besides the most common pathogenic variants S (E264V) and Z (E342K), many rarer genetic variants of AAT have been found in patients and in the general population. Here we report a panel of new SERPINA1 variants, including 4 null and 16 missense alleles, identified among a cohort of individuals with suspected AATD whose phenotypic follow-up showed inconclusive or atypical results. Because the pathogenic significance of the missense variants was unclear purely on the basis of clinical data, the integration of computational, biochemical, and cellular studies was used to define the associated risk of disease. Established pathogenicity predictors and structural analysis identified a panel of candidate damaging mutations that were characterized by expression in mammalian cell models. Polymer formation, intracellular accumulation, and secretory efficiency were evaluated experimentally. Our results identified two AAT mutants with a Z-like polymerogenic severe deficiency profile (S milano and M campolongo ) and three milder variants (X sarezzo , P dublin , and C tiberias ). Overall, the experimentally determined behavior of the variants was in agreement with the pathogenicity scores of the REVEL (an ensemble method for predicting the pathogenicity of rare missense variants) predictor, supporting the utility of this bioinformatic tool in the initial assessment of newly identified amino acid substitutions of AAT. Our study, in addition to describing 20 new SERPINA1 variants, provides a model for a multidisciplinary approach to classification of rare AAT variants and their clinical impact on individuals with rare AATD genotypes.