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Background: The effects of elexacaftor/tezacaftor/ivacaftor (ETI) on respiratory outcomes for people with cystic fibrosis (CF) were demonstrated by several clinical trials, mainly based on simple spirometry. However, gains in lung function may vary greatly between patients, and predictors of FEV 1 change after treatment have yet to be defined., Research Question: Which ventilatory parameters are involved in the heterogeneity of FEV 1 change after 12-month ETI treatment in people with CF and advanced lung disease?, Study Design and Methods: This was a multicenter, observational, prospective cohort study at two major CF centers in Italy. We enrolled 47 adults with CF and advanced lung disease (FEV 1  < 40% or actively listed for lung transplant) who started ETI treatment between December 2019 and December 2021. At treatment initiation and after 12 months, patients underwent body plethysmography. Values were compared at the two time points. To assess the relationship between baseline plethysmography measurements and treatment-induced changes in FEV 1 , we used the Spearman rank correlation coefficient (r s ) and median quantile regressions., Results: After 12 months of ETI treatment, there was a significant increase in FEV 1 % predicted from a median value of 36.0 (25th-75th percentile, 33-39) to 52 (25th-75th percentile, 43-61) (P < .001). Inspiratory capacity/total lung capacity (TLC) ratio also increased from 32.0 (25th-75th percentile, 28.6-36.9) to 36.3 (25th-75th percentile, 33.4-41.3) (P < .001). Specific airway resistance decreased from 263 (25th-75th percentile, 182-405) to 207 (25th-75th percentile, 120-258) (P < .001). Functional residual capacity/TLC ratio decreased from 68.2 (25th-75th percentile, 63.3-71.9) to 63.9 (25th-75th percentile, 58.8-67.1) (P < .001), and residual volume/TLC ratio decreased from 53.1 (25th-75th percentile, 48.3-59.4) to 45.6 (25th-75th percentile, 39.4-49.8) (P < .001). Changes in FEV 1 % predicted negatively correlated with baseline functional residual capacity/TLC ratio (r s  = -0.38, P = .009) and residual volume/TLC ratio (r s = -0.42, P = .004). After adjustment for age at treatment initiation and cystic fibrosis transmembrane conductance regulator genotype, we estimated that for each 10-unit increase in baseline residual volume/TLC ratio, the expected median change in FEV 1 decreased by 2.3 (95% CI, -5.8 to -0.8)., Interpretation: ETI was associated with improvements in both static and dynamic volumes in people with CF and advanced lung disease. Heterogeneity in FEV 1 % predicted change after 12 months of treatment may be predicted by the severity of hyperinflation at baseline., Competing Interests: Financial/Nonfinancial Disclosures None declared., (Copyright © 2024 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: People with cystic fibrosis (pwCF) are considered at risk of developing severe forms of respiratory viral infections. We studied the consequences of COVID-19 and virus-host cell interactions in CF vs. non-CF individuals., Methods: We enrolled CF and non-CF individuals, with /without COVID-like symptoms, who underwent nasopharyngeal swab for detection of SARS-CoV-2. Gene expression was evaluated by RNA sequencing on the same nasopharyngeal swabs. Criteria for COVID-19 severity were hospitalization and requirement or increased need of oxygen therapy., Results: The study included 171 patients (65 pwCF and 106 non-CF individuals). Among them, 10 pwCF (15.4 %) and 43 people without CF (40.6 %) tested positive at RT-PCR. Symptomatic infections were observed in 8 pwCF (with 2 requiring hospitalization) and in 11 individuals without CF (6 requiring hospitalization). Host transcriptomic analysis revealed that genes involved in protein translation, particularly ribosomal components, were downregulated in CF samples irrespective of SARS-CoV-2 status. In SARS-CoV-2 negative individuals, we found a significant difference in genes involved with motile cilia expression and function, which were upregulated in CF samples. Pathway enrichment analysis indicated that interferon signaling in response to SARS-CoV-2 infection was upregulated in both pwCF and non-CF subjects., Conclusions: COVID-19 does not seem to be more severe in CF, possibly due to factors intrinsic to this population: the lower expression of ribosomal genes may downregulate the protein translation machinery, thus creating an unfavorable environment for viral replication., Competing Interests: Declaration of competing interest Davide Cacchiarelli is the founder, shareholder, and consultant of NEGEDIA (Next Generation Diagnostic srl). Patrizia Annunziata is an employee of NEGEDIA. All other authors have no conflicts of interest. Luis J.V. Galietta on behalf of all authors, (Copyright © 2024. Published by Elsevier B.V.)

Background: Quality of life and survival in Cystic Fibrosis (CF) have improved dramatically, making family planning a feasible option. Maternal and perinatal outcomes in women with CF (wwCF) are similar to those seen in the general population. However, the effect of undergoing multiple pregnancies is unknown., Methods: A multinational-multicenter retrospective cohort study. Data was obtained from 18 centers worldwide, anonymously, on wwCF 18-45 years old, including disease severity and outcome, as well as obstetric and newborn complications. Data were analyzed, within each individual patient to compare the outcomes of an initial pregnancy (1st or 2nd) with a multigravid pregnancy (≥3) as well as secondary analysis of grouped data to identify risk factors for disease progression or adverse neonatal outcomes. Three time periods were assessed - before, during, and after pregnancy., Results: The study population included 141 wwCF of whom 41 (29%) had ≥3 pregnancies, "multiparous". Data were collected on 246 pregnancies, between 1973 and 2020, 69 (28%) were multiparous. A greater decline in ppFEV 1 was seen in multiparous women, primarily in pancreatic insufficient (PI) wwCF and those with two severe (class I-III) mutations. Multigravid pregnancies were shorter, especially in wwCF over 30 years old, who had high rates of prematurity and newborn complications. There was no effect on pulmonary exacerbations or disease-related complications., Conclusions: Multiple pregnancies in wwCF are associated with accelerated respiratory deterioration and higher rates of preterm births. Therefore, strict follow-up by a multidisciplinary CF and obstetric team is needed in women who desire to carry multiple pregnancies., Competing Interests: Declaration of competing interest MCC received honoraria for lectures from Vertex. EP received a grant from Grifols; consulting fees from Moderna, Pfizer, Insmed and Chiesi; honoraria for lectures from Moderna, Pfizer, Vertex, GSK, TEVA, Chiesi and Insmed; payment for expert testimony from Chiesi; and support for attending meetings from Moderna, Pfizer, Vertex, GSK and Insmed. AG received consuting fees (personal) from Vertex, Menarini and Zambon; honoraria for lectures (personal) from Insmed and Vertex; support for attending meetings from Neupharma and Zambon; and payment (personal) for participation on a Data Safety Monitoring (DSM) Board or Advisory Board from Vertex. She is also an Associate Editor for Respiratory Research, Managment board member at IRENE NTM network and ERS chair Adult CF group-assembly 10. DP received consulting fees from Vertex. MMZ received support from the ECFS to attend the European CF meeting 2023. MS received grants from GSK and Trudell pharma; consulting fees (personal) from AstraZeneca, Boehringer Ingelheim, Dexel, Kamada, Synchrony medical, Trumed and Zambon; honoraria for lectures (personal) from AstraZeneca, Boehringer Ingelheim, Kamada and Sanofi; support for attending meetings from Boehringer Ingelheim, AstraZeneca and Kamada; payment (personal) for participating on DSM Board or Advisory Board from Bonus Biotherapeutics, Boehringer Ingelheim and AstraZeneca; and received oPEP devices for clinical trial from Trudell Medical International. She is also an Associate Editor at AJRCCM; Management board member at the Israeli Pulmonology society, Israeli society for Tuberculosis and mycobacterial diseases; and Editorial board member: Chest ERJ taskforce-bronchiectasis guidelines. DGD received grants from Chiesi; consulting fees from Vertex, Proteostasis and Insmed; honoraria for lectures from Chiesi and Gilead. He is also the current Director of the European CF Society Clinical Trials Network. PML received grant (institution) and payment for testimony (personal) from Vertex; consulting fees and honoraria for lectures (personal) from Vertex and Chiesi; support for attending meetings (personal) from Chiesi, Pari and AstraZeneca; and participation on a DSM Board or Advisory Board for Vertex and AstraZeneca. PJ received consulting fees from Centrum hydraulického výzkumu spol. s.r.o.; honoraria for lectures from MSD and Vertex; support for attending meetings, and participation on a DSM Board or Advisory Board from Chiesi: and leadership or fiduciary role in Vertex. TMK received a grant from the Cystic Fibrosis Foundation and the National Institutes of Health; consulting fees from the Cystic Fibrosis Foundation; and honoraria for lectures from the Johns Hopkins Institute. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

This is the final of four papers updating standards for the care of people with CF. That this paper "Planning a longer life" was considered necessary, highlights how much CF care has progressed over the past decade. Several factors underpin this progress, notably increased numbers of people with CF with access to CFTR modulator therapy. As the landscape for CF changes, so do the hopes and aspirations of people with CF and their families. This paper reflects the need to consider people with CF not as a "problem" to be solved, but as a success, a potential and a voice to be heard. People with CF and the wider CF community have driven this approach, reflecting many of the topics in this paper. This exercise involved wide stakeholder engagement. People with CF are keen to contribute to research priorities and be involved in all stages of research. People with CF want healthcare professionals to respect them as individuals and consider the impact of our actions on the world around us. Navigating life presents challenges to all, but for people with CF these challenges are heightened and complex. In this paper we highlight the concerns and life moments that impact people with CF, and events that the CF team should aim to support, including the challenges around having a family. People with CF and their care teams must embrace the updated standards outlined in these four papers to enjoy the full potential for a healthier life., Competing Interests: Declaration of competing interest The authors had no declarations of interest in relation to the current work. Declarations of interest for each author outside the current work are summarised in Supplementary Table 4., (Copyright © 2024. Published by Elsevier B.V.)

Background: Although cystic fibrosis (CF) standards of care have been produced and regularly updated, they are not specifically targeting at the adult population. The ECFS Standards of Care Project established an international task force of experts to identify quality standards for adults with CF and assess their adherence., Methods: This study was composed of two phases. In the first one, a task force of international experts derived from published guidelines and graded ten quality standards for adult CF care using a modified Delphi methodology. In the second phase, an international audit was conducted among adult CF centers to retrospectively validate the quality statements and monitor adherence., Results: The task force identified 10 quality standards specific to the care of adults with CF, mainly based on the 2018 ECFS standards of care. 14 adult CF centers participated in the audit, which showed that most quality standards for the management of CF in adults are met across Europe. Heterogeneity in adherence to standards was found across centers according to geographical setting and centers' characteristics., Conclusions: The identification of quality standards is a valuable resource for the standardization and monitoring of care delivery across centers taking care of adults with CF., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest related to this work., (Copyright © 2023 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

This is the third in a series of four papers updating the European Cystic Fibrosis Society (ECFS) standards for the care of people with CF. This paper focuses on recognising and addressing CF health issues. The guidance was produced with wide stakeholder engagement, including people from the CF community, using an evidence-based framework. Authors contributed sections, and summary statements which were reviewed by a Delphi consultation. Monitoring and treating airway infection, inflammation and pulmonary exacerbations remains important, despite the widespread availability of CFTR modulators and their accompanying health improvements. Extrapulmonary CF-specific health issues persist, such as diabetes, liver disease, bone disease, stones and other renal issues, and intestinal obstruction. These health issues require multidisciplinary care with input from the relevant specialists. Cancer is more common in people with CF compared to the general population, and requires regular screening. The CF life journey requires mental and emotional adaptation to psychosocial and physical challenges, with support from the CF team and the CF psychologist. This is particularly important when life gets challenging, with disease progression requiring increased treatments, breathing support and potentially transplantation. Planning for end of life remains a necessary aspect of care and should be discussed openly, honestly, with sensitivity and compassion for the person with CF and their family. CF teams should proactively recognise and address CF-specific health issues, and support mental and emotional wellbeing while accompanying people with CF and their families on their life journey., Competing Interests: Declaration of competing interest The authors had no declarations of interest in relation to the current work. Declarations of interest for each author outside the current work are summarised in Supplementary Table 4., (Copyright © 2024. Published by Elsevier B.V.)

This is the second in a series of four papers updating the European Cystic Fibrosis Society (ECFS) standards for the care of people with CF. This paper focuses on establishing and maintaining health. The guidance is produced using an evidence-based framework and with wide stakeholder engagement, including people from the CF community. Authors provided a narrative description of their topic and statements, which were more directive. These statements were reviewed by a Delphi exercise, achieving good levels of agreement from a wide group for all statements. This guidance reinforces the importance of a multi-disciplinary CF team, but also describes developing models of care including virtual consultations. The framework for health is reinforced, including the need for a physically active lifestyle and the strict avoidance of all recreational inhalations, including e-cigarettes. Progress with cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy is reviewed, including emerging adverse events and advice for dose reduction and interruption. This paper contains guidance that is pertinent to all people with CF regardless of age and eligibility for and access to modulator therapy., Competing Interests: Declaration of competing interest KWS has no competing interests. See supplementary materials for full CoI statements for all authors., (Copyright © 2023. Published by Elsevier B.V.)

Background: To limit the progression of disease, people with cystic fibrosis (pwCF) perform daily respiratory physiotherapy, which is perceived as the most burdensome routine in managing their condition. The elexacaftor-tezacaftor-ivacaftor (ETI) combination has changed respiratory management., Objective: To investigate how the perceived treatment burden changed in 1 year of treatment with ETI., Design: Prospective observational study., Methods: Ad hoc questionnaires for the pwCF and for the caregivers of pwCF < 18 years were administered before the initiation of ETI therapy and then at 6-12 months. The Cystic Fibrosis Questionnaire-Revised (CFQ-R) and the Sinonasal Outcome Test (SNOT-22) were administered to explore disease-related symptoms and social limitations. The International Physical Activity Questionnaire was used to determine levels of physical activity. Mixed-effect models were fitted to explore whether the time engaged in respiratory physiotherapy changed during 1 year., Results: The study included 47/184 pwCF aged 21.4 (5.7) years, who completed 1 year of ETI therapy. At 6 months, time on aerosol therapy was decreased by 2.5 (95% CI -32.9 to 27.8) min/day, time on airway clearance therapies (ACTs) was decreased by 8.8 (95% CI -25.9 to 8.3) min/day, and time for cleaning and disinfecting respiratory equipment was decreased by 10.6 (95% CI -26.5 to 5.3) min/day. At 1 year, gains in time saved were nearly 15 min/day on average. At 1 year, 5/47 (10.6%) pwCF reported that they had discontinued positive expiratory pressure mask., Conclusion: PwCF on ETI may note less time engaged in their daily respiratory physiotherapy routine. Nonetheless, aerosol therapy, ACTs and maintaining respiratory equipment were still perceived as time-consuming daily activities.

Introduction: Over the last ten years an increasing prevalence and incidence of non-tuberculous mycobacteria (NTM) has been reported among patients with cystic fibrosis (CF) Viviani (J Cyst Fibros, 15(5):619-623, 2016). NTM pulmonary disease has been associated with negative clinical outcomes and often requires pharmacological treatment. Although specific guidelines help clinicians in the process of diagnosis and clinical management, the focus on the multidimensional assessment of concomitant problems is still scarce., Main Body: This review aims to identify the treatable traits of NTM pulmonary disease in people with CF and discuss the importance of a multidisciplinary approach in order to detect and manage all the clinical and behavioral aspects of the disease. The multidisciplinary complexity of NTM pulmonary disease in CF requires careful management of respiratory and extra-respiratory, including control of comorbidities, drug interactions and behavioral factors as adherence to therapies., Conclusions: The treatable trait strategy can help to optimize clinical management through systematic assessment of all the aspects of the disease, providing a holistic treatment for such a multi-systemic and complex condition., (© 2023. The Author(s).)

Background: The advent of elexacaftor/tezacaftor/ivacaftor (ETI) resulted in unprecedented clinical benefits for eligible adults with CF. As a result, the question of whether chronic treatments can be safely stopped or adapted to this new situation has become a matter of great interest. Our objective was to derive a consensus among Italian experts on the impact of ETI on the current clinical management of CF lung disease., Methods: From December 2021 to April 2022 a panel of Italian experts endorsed by the national CF scientific society derived and graded a set of statements on the pulmonary management of adults with cystic fibrosis through a modified Delphi methodology., Results: The panel produced 13 statements exploring possible modifications in the fields of inhaled antibiotics and mucoactives; airway clearance and physical activity; chronic macrolides and bronchodilators; and lung transplant referral. The areas that the experts considered most urgent to explore were the impact of ETI on the role of inhaled antibiotics and lung transplant., Conclusions: The list of priorities that emerged from this study could be useful to guide and inform clinical research on the most urgent area of impact of ETI on CF lung disease and its clinical management., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This study was supported by an unrestricted grant supplied by Chiesi Italia., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

There is considerable activity with respect to diagnosis in the field of cystic fibrosis (CF). This relates primarily to developments in newborn bloodspot screening (NBS), more extensive gene analysis and improved characterisation of CFTR-related disorder (CFTR-RD). This is particularly pertinent with respect to accessibility to variant-specific therapy (VST), a transformational intervention for people with CF with eligible CFTR gene variants. This advance reinforces the need for a timely and accurate diagnosis. In the future, there is potential for trials to assess effectiveness of variant-specific therapy for CFTR-RD. The guidance in this paper reaffirms previous standards, clarifies a number of issues, and integrates emerging evidence. Timely and accurate diagnosis has never been more important for people with CF., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier B.V.)

Cystic fibrosis (CF) causes infertility and subfertility due to various factors, including altered cervical mucus, delayed puberty, and hormonal imbalances. With the introduction of the CFTR modulator therapy elexacaftor-tezacaftor-ivacaftor, we have observed an increase in unplanned pregnancies among women undergoing ETI treatment in our CF center, despite repeated recommendations for strict fertility monitoring. It appears that these pregnancies are more likely attributed to reduced attention to the possibility of conception rather than contraceptive failure. The perception of subfertility developed by women with CF over time, before the era of modulators, can influence their long-term habits and lead to the underuse of contraceptive methods. While further research is needed to fully understand the effects of ETI on fertility, healthcare providers should be attentive to the fertility concerns of women with CF, particularly those treated with modulators in adulthood., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are a group of new drugs for the treatment of cystic fibrosis (CF) and elexacaftor + tezacaftor + ivacaftor (ETI) triple combination therapy has been approved as first choice therapy in the treatment of patients with at least 1 copy of F508del variation. Data on the effects of CFTR modulators on glucose metabolism are limited to small studies with conflicting results. We conducted a prospective observational study on 24 CF patients with CF-related diabetes requiring insulin therapy, with the aim to evaluate the effectiveness of ETI on glucose metabolism, glucose variability and body composition. After six months of treatment, HbA1c and coefficient of variation, measured through flash or continuous glucose monitoring, significantly decreased (median changes: -0.5, P = 0.029 and -6.3, P = 0.008, respectively), despite unchanged insulin requirements. Over the treatment period, percent of fat mass increased by a median value of 3% (p = 0.029)., 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 Elsevier Masson SAS. All rights reserved.)

Background: The introduction of the novel therapy, Elexacaftor/Tezacaftor/Ivacaftor (ETI) has been effective in improving weight gain in both clinical trials and real-world studies. However, the magnitude of this effect appears to be heterogeneous across patient subgroups. This study aims to identify potential determinants of heterogeneity in weight gain following 6-month ETI therapy., Methods: We conducted a multicenter, prospective cohort study enrolling 92 adults with CF at two major CF centers in Italy with follow-up visit at one month and six months from ETI initiation. The treatment's effect on weight changes was evaluated using mixed effect regression models that included subject-specific random intercepts and fixed effects for potential predictors of treatment response, time and a predictor-by-time interaction term., Results: The mean weight gain at six months from the start of treatment was 4.6 kg (95% CI: 2.3-6.9) for the 10 patients with underweight, 3.2 kg (95% CI: 2.3-4.0) for the 72 patients with normal weight, and 0.7 kg (95% CI: -1.6-3.0) for the 10 patients with overweight. After six months of ETI treatment, 8 (80%) of the patients with underweight transitioned to the normal weight category, while 11 (15.3%) of the normal-weight patients became overweight. The major determinants of heterogeneity in weight gain were the baseline BMI and the presence of at least one CFTR residual function mutation, explaining 13% and 8% of the variability, respectively., Conclusions: Our results indicate that ETI is highly effective in improving weight gain in underweight subjects with CF. However, our data also suggests the need for close monitoring of excess weight gain to prevent potential cardiometabolic complications., (© 2023. The Author(s).)

Cystic fibrosis (CF) has entered the era of variant-specific therapy, tailored to the genetic variants in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. CFTR modulators, the first variant-specific therapy available, have transformed the management of CF. The latest standards of care from the European CF Society (2018) did not include guidance on variant-specific therapy, as CFTR modulators were becoming established as a novel therapy. We have produced interim standards to guide healthcare professionals in the provision of variant-specific therapy for people with CF. Here we provide evidence-based guidance covering the spectrum of care, established using evidence from systematic reviews and expert opinion. Statements were reviewed by key stakeholders using Delphi methodology, with agreement (≥80%) achieved for all statements after one round of consultation. Issues around accessibility are discussed and there is clear consensus that all eligible people with CF should have access to variant-specific therapy., (Copyright © 2022. Published by Elsevier B.V.)

Elexacaftor/tezacaftor/ivacaftor (ETI) is associated with major improvements in respiratory outcomes of individuals with cystic fibrosis (CF) and at least one Phe508del mutation. Although ETI was well tolerated in registration studies, the attention on adverse events not previously described is very high in the post-marketing phase. In this case series we report the onset of systemic arterial hypertension in 4 individuals with CF within the first weeks of starting therapy. All patients needed cardiac evaluation and started chronic anti-hypertensive therapy. Until more data is available, this report could foster the attention of CF physicians towards careful monitoring of cardiovascular parameters in patients starting ETI., Competing Interests: Declaration of Competing Interest The authors have no specific funding to report for this work., (Copyright © 2022. Published by Elsevier B.V.)

Objective: Imaging represents an important noninvasive means to assess cystic fibrosis (CF) lung disease, which remains the main cause of morbidity and mortality in CF patients. While the development of new imaging techniques has revolutionised clinical practice, advances have posed diagnostic and monitoring challenges. The authors aim to summarise these challenges and make evidence-based recommendations regarding imaging assessment for both clinicians and radiologists., Study Design: A committee of 21 experts in CF from the 10 largest specialist centres in Italy was convened, including a radiologist and a pulmonologist from each centre, with the overall aim of developing clear and actionable recommendations for lung imaging in CF. An a priori threshold of at least 80% of the votes was required for acceptance of each statement of recommendation., Results: After a systematic review of the relevant literature, the committee convened to evaluate 167 articles. Following five RAND conferences, consensus statements were developed by an executive subcommittee. The entire consensus committee voted and approved 28 main statements., Conclusions: There is a need for international guidelines regarding the appropriate timing and selection of imaging modality for patients with CF lung disease; timing and selection depends upon the clinical scenario, the patient's age, lung function and type of treatment. Despite its ubiquity, the use of the chest radiograph remains controversial. Both computed tomography and magnetic resonance imaging should be routinely used to monitor CF lung disease. Future studies should focus on imaging protocol harmonisation both for computed tomography and for magnetic resonance imaging. The introduction of artificial intelligence imaging analysis may further revolutionise clinical practice by providing fast and reliable quantitative outcomes to assess disease status. To date, there is no evidence supporting the use of lung ultrasound to monitor CF lung disease., Competing Interests: Conflict of interest: P. Ciet reports personal fees from Editamed, during the conduct of the study. S. Bertolo reports personal fees from Vertex pharmaceuticals, outside the submitted work. M. Ros reports personal fees from Vertex Pharmaceuticals, personal fees from Chiesi Farmaceutici, outside the submitted work. R. Casciaro has nothing to disclose. M. Cipolli has nothing to disclose. S. Colagrande reports that during the last 5 years, he has had and has various projects in place that have involved remuneration, which has always been devolved to the SBSC department for which Prof. Colagrande works. This refers to experimental/conventional activities for which it has received compensation. Nothing has ever been personally perceived by Prof. Colagrande and all the part destined to the university was conferred to the department. The companies involved were Novartis, Sanofi, Lilly, Celther, Pfizer, Janssen, etc. All the fees have been paid following the signing of a contract among the company, the university and the Hospital. S. Costa has nothing to disclose. V. Galici has nothing to disclose. A. Gramegna has nothing to disclose. C. Lanza has nothing to disclose. F. Lucca has nothing to disclose. L. Macconi has nothing to disclose. F. Majo has nothing to disclose. A. Paciaroni has nothing to disclose. G.F. Parisi has nothing to disclose. F. Rizzo has nothing to disclose. I. Salamone has nothing to disclose. T. Santangelo has nothing to disclose. L. Scudeller has nothing to disclose. L. Saba has nothing to disclose. P. Tomà has nothing to disclose. G. Morana has nothing to disclose., (Copyright ©The authors 2022.)

The prevalence of anti-SARS-CoV-2 antibodies in people with cystic fibrosis (CF) is largely unknown. We carried out a cross-sectional study between March and June 2021 with the aim of estimating the seroprevalence of anti-SARS-CoV-2 antibodies in two CF centres in Northern Italy. Total serum anti-SARS-CoV-2 (spike) antibodies levels were measured and values ≥0.8 U/mL were considered positive. Among 434 patients aged >12 years, 64 patients had a positive result (14.7%, 95% CI: 11.5-18.4), 36 (56.3%) without experiencing any COVID-19-related symptoms. Three out of 49 transplanted patients tested positive with an odds ratio for a positive result among transplanted as compared to non-transplanted patients of 0.35 (95% CI: 0.07-1.14). No significant differences were observed between sexes, age groups, socioeconomic status and lung disease severity. In conclusion, SARS-CoV-2 has infected a relatively high proportion of our patients but in most cases the infection was asymptomatic., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021. Published by Elsevier B.V.)

Background: Over the last decades aggressive interventions have been successful to improve nutritional outcomes in people with cystic fibrosis (CF). As a result, with improvement of life expectancy and new CFTR modulators, overweight and obesity are progressively becoming a source of concern for adult population and in developed countries., Methods: This was a multicenter, observational, cross-sectional study of 321 adults with CF at three large CF centers in Italy. Patients were divided into three groups according to BMI classes, overweight and obesity (OW) group including patients with BMI ≥25 kg/m 2 , normal weight (NW) group with BMI 18.6-24.9 kg/m 2 and underweight (UW) group with BMI ≤18.5 kg/m 2 ., Results: We demonstrated that prevalence of OW in adults with CF in Italy is 22%. OW status is independently associated with male sex (OR 3.520, P = 0.001), pancreatic sufficiency (OR 2.873, P = 0.014) and older age at diagnosis (1.015, P = 0.042). BMI correlated with ppFEV1 (r = 0.337; P<0.0001) with median ppFEV1 significantly higher in patients with OW than comparisons. We also reported preliminary data on unfavorable cardiovascular risk factors in a subgroup of patients, where median blood levels [IQR] of cholesterol and systemic hypertension [%] were significantly higher in the OW group than in the NW and UW., Conclusions: People with CF and OW is a relevant patient group that might deserve better definition and proper clinical management., Competing Interests: Declaration of competing of interest The authors declare no conflict of interest., (Copyright © 2021. Published by Elsevier B.V.)

We conducted a prospective, observational study at the Adult CF Center, Ospedale Policlinico, Milano, Italy, from March 2017 to September 2019 to assess the prevalence and serotypes of Streptococcus pneumoniae (SP) in adults with CF naive to pneumococcal vaccination. Spontaneous sputum samples from 129 patients were analyzed for SP DNA and serotyped. SP was found in 24 subjects (19%) and the most common serotypes were 19F (16%), 4 (6%), and 9VA (3%). Higher FEV1 and non-pseudomonas infection significantly associate with SP on sputum. These results define a subgroup of patients that might deserve implementation of microbiological techniques directed to pneumococcal detection., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Cystic fibrosis is the most common life-limiting genetic disease in the Caucasian population, with median predicted survival progressively improving up to 50 years, thanks to highly standardized multidisciplinary approach. Patients with p.Phe508del homozygosity usually have poorer lung function and higher mortality rates per year than other groups. By reason of that, this population has been among the most eligible target of the cystic fibrosis transmembrane conductance regulator (CFTR) modulators, a new class of drugs that can partially restore CFTR function by the correction of CFTR misfolding and trafficking to the cell surface. This narrative review summarizes the current preclinical and clinical evidence of the triple combination of elexacaftor-tezacaftor-ivacaftor, the new benchmark among highly effective CFTR modulators. It provides details on the efficacy and safety that led to drug regulation and approval and discusses future developments in clinical and translational research., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Competing Interests: DECLARATION OF INTERESTS: The authors have no interests to declare.

Over the last years CFTR (cystic fibrosis transmembrane conductance regulator) modulators have shown the ability to improve relevant clinical outcomes in patients with cystic fibrosis (CF). This review aims at a systematic research of the current evidence on efficacy and tolerability of CFTR modulators for different genetic subsets of patients with CF. Two investigators independently performed the search on PubMed and included phase 2 and 3 clinical trials published in the study period 1 January 2005-31 January 2020. A final pool of 23 papers was included in the systematic review for a total of 4219 patients. For each paper data of interest were extracted and reported in table. In terms of lung function, patients who had the most beneficial effects from CFTR modulation were those patients with one gating mutation receiving IVA (ivacaftor) and patients with p.Phe508del mutation, both homozygous and heterozygous, receiving ELX/TEZ/IVA (elexacaftor/tezacaftor/ivacaftor) had the most relevant beneficial effects in term of lung function, pulmonary exacerbation decrease, and symptom improvement. CFTR modulators showed an overall favorable safety profile. Next steps should aim to systematize our comprehension of scientific data of efficacy and safety coming from real life observational studies.

Neutrophil elastase (NE) is a crucial marker of neutrophilic inflammation. We aimed to compare different techniques to detect active NE in sputum samples of 50 Bronchiectasis (BE) and 50 Cystic Fibrosis (CF) patients. Three methods including a ProteaseTag® Active NE Immunoassay (ELISA) and two enzymatic digestion assays (chromogenic -CS- and fluorogenic -FS- substrate) were compared. Results of active NE were also correlated with clinical data. The three methods provided statistically different values for NE activity in the same sputum samples in both cohorts. In the BE cohort, the highest correlations between NE activity and Bronchiectasis Severity Index (rho = 0.40, P < 0.0001), sputum purulence (AUC = 0.79), and chronic infections due to any pathogen (AUC = 0.76) and P. aeruginosa (AUC = 0.80) were found when NE was measured through the activity-based immunoassay. In the CF cohort, the highest correlations between NE activity and sputum quantity (rho = 0.71) and FEV1% (rho = 0.42, P = 0.03) were observed when the FS method was used, while similar correlations with chronic P. aeruginosa infection were identified with the FS and ELISA methods. NE activity in sputum correlates with clinical variables in both diseases. However, different methods to evaluate active NE in sputum lead to significantly different results, also in terms of correlation with clinical data., (Copyright © 2019. Published by Elsevier Ltd.)

Background: Immunodeficiencies (IDs) are conditions caused by immune system dysfunctions which predispose to chronic infections. Cystic fibrosis (CF) patients are characterized by the presence of bronchiectasis filled with hyper-viscous secretions that constitute the ideal environment for infections. Although CF and IDs might share similarities in the pathophysiological mechanism of bronchiectasis development, they each offer different treatment options. We hypothesize that the introduction of a bundle of tests would increase the number of ID diagnoses among adults with Cystic Fibrosis Transmembrane conductance Regulator (CFTR) dysfunction. Objectives: The primary objectives of this study were (1) assessing the prevalence of IDs in CF and (2) defining clinical characteristics of adults with both CF and IDs. The secondary objectives were: (1) assessing the prevalence of IDs in CFTR-Related Disorder (CFTR-RD) patients; (2) comparing the prevalence of IDs in CF and CFTR-RD; (3) comparing the prevalence of treatable IDs in CF and CFTR-RD. Design: We conducted an observational, prospective, consecutive study on a cohort of 190 adult patients affected by CF or CFTR-RD. Methods: Blood samples underwent a standardized immunological screening, including complete white blood count, IgG, IgA, IgM, IgG subclasses, total IgE, lymphocyte subsets, and HIV test. Comprehensive clinical history was assessed to identify risk factors for secondary IDs. Results: We identify a high prevalence of immunodeficiencies among the entire cohort: 34 (20.1%) CF patients and 10 (47.6%) CFTR-RD patients are diagnosed with IDs via a blood screening. No statistically significant difference in terms of clinical characteristics was found between immunocompromised and immunocompetent CF patients. Conclusion: We identify a high prevalence of immunodeficiencies in both CF and CFTR-RD. [ABSTRACT FROM AUTHOR]

Cystic fibrosis (CF) and alpha-1 antitrypsin (AAT) deficiency are two of the commonest genetic diseases affecting the Caucasian population. Neutrophil-mediated inflammation due to protease–antiprotease imbalance leads to progressive pulmonary involvement in both diseases. The aim of this study was to investigate the prevalence of AAT deficiency in CF adults. A prospective study enrolling CF adults was conducted at the Adult CF Center based in Milan from January 2018 to March 2019. Patients were tested for AAT serum protein quantification and expanded genotyping characterization of SERPINA1 during clinical stability. Genotyping characterization of SERPIN1 was compared to a control population of 2848 Caucasian individuals with the same geographical origin and similar demographic characteristics. Among 173 patients included in the study, the prevalence of AAT deficiency was 0. Genotype analysis was piMM in 166 (94.9%) patients and piMS in 9 patients (5.1%), respectively. No differences in terms of genotype characterization were found between the CF population and the control population. These data show that AAT deficiency is not common among adults with CF. [ABSTRACT FROM AUTHOR]

Background: The impact of COVID-19 on respiratory outcomes in people with cystic fibrosis (pwCF) has not been clearly characterized. We evaluated changes in respiratory function indicators derived from spirometry and pulmonary exacerbation rates 6 months after SARS-CoV-2 infection. Methods: This multicentre prospective study was based on pwCF enrolled between October, 2020 and June, 2021 in the DECO COVID-19 project. PwCF complaining of COVID-like symptoms were tested with real-time polymerase chain reaction (RT-PCR) for SARS-CoV-2 on nasopharyngeal swab. Mean changes in respiratory function indicators and time to first episode of pulmonary exacerbation were compared in RT-PCR-positive and RT-PCR-negative patients. Regression models were used to adjust for baseline percent predicted forced expiratory volume in one second (ppFEV1) values, number of comorbidities, and initiation of CFTR modulator therapy during the follow-up. Results: We enrolled 26 pwCF with RT-PCR-confirmed infection and 42 with a RT-PCR-negative test. After 6 months of follow-up, mean ppFEV1 changes were not significantly different between groups (+0.3% in positive vs. +0.2% in negative patients, p = 0.19). The 6-month cumulative probabilities of a first episode of pulmonary exacerbation were: 0.425 among RT-PCR-negative patients and 0.465 among those with a positive test (adjusted hazard ratio: 0.88, 95% CI: 0.44–1.75). Conclusions: COVID-19 did not appear to negatively influence respiratory outcomes of pwCF at 6 months from infection. [ABSTRACT FROM AUTHOR]

It is estimated that about 60-70% of Cystic Fibrosis patients develop Pseudomonas aeruginosa chronic infection, with progressive loss of lung function, as well as increased antibiotic resistance and mortality. The current strategy is to maintain lung function by chronic suppressive antipseudomonas antibiotic therapy. Tobramycin inhalation solution was the first approved aerosolised antibiotic to be used against P. aeruginosa; inhalatory tobramycin frequency of administration is twice daily and inhalation time is estimated to be 15 to 20 min. From the pharmacokinetic point of view, aminoglycosides are dose-dependent antibiotics and therefore once-daily dosing intravenous regimens have shown to be superior to the conventional multiple daily dosing. Therefore, there is no pharmacological reason to prefer the b.i.d administration as it is usually performed in current clinical practice. Should this be confirmed also for inhalatory route, the use of once-daily dosed aerosolized tobramycin could be an important step in making treatment burden easier in CF patients. The aim of this proof of concept study was to explore the effectiveness of treatment with once daily inhaled tobramycin in reducing P. aeruginos a density in sputum of chronically infected patients. [ABSTRACT FROM AUTHOR]

Cystic Fibrosis (CF) is a multisystemic disease, with pulmonary disease being the major cause of morbidity and mortality. Pulmonary Rehabilitation (PR) is mandatory and should be started at diagnosis. The main goal is to maintain adequate clearance of bronchial secretions, prevent infections and exacerbations, and improve adherence. Airway clearance, exercise training, and self-management education are the cornerstones of PR interventions in CF patients. [ABSTRACT FROM AUTHOR]

Background: Bronchiectasis is the final result of different processes and most of the guidelines advocate for a careful evaluation of those etiologies which might be treated or might change patients’ management, including cystic fibrosis (CF). Main body: CFTR mutations have been reported with higher frequency in bronchiectasis population. Although ruling out CF is considered as a main step for etiological screening in bronchiectasis, CF testing lacks of a standardized approach both from a research and clinical point of view. In this review a list of most widely used tests in CF is provided. Conclusions: Exclusion of CF is imperative for patients with bronchiectasis and CFTR testing should be implemented in usual screening for investigating bronchiectasis etiology. Physicians taking care of bronchiectasis patients should be aware of CFTR testing and its limitations in the adult population. Further studies on CFTR expression in human lung and translational research might elucidate the possible role of CFTR in the pathogenesis of bronchiectasis. [ABSTRACT FROM AUTHOR]