Heterogeneity in response to Elexacaftor/Tezacaftor/Ivacaftor in people with cystic fibrosis.

BACKGROUND: Highly effective modulators of the CFTR channel have been demonstrated to dramatically impact disease progression and outcome. However, real-world data indicates that the magnitude of the clinical benefit is not equal among all patients receiving the treatment. We aimed to assess the variability in treatment response (as defined by the 6-month change in sweat chloride concentration, forced expiratory volume in one second [ppFEV1], body mass index [BMI], and CF Questionnaire-Revised [CFQ-R] respiratory domain score) and identify potential predictors in a group of patients receiving Elexacaftor-Tezacaftor-Ivacaftor (ETI) triple combination therapy. METHODS: This was a single-center, prospective cohort study enrolling adults with CF at a major center in Italy. We used linear regression models to identify a set of potential predictors (including CFTR genotype, sex, age, and baseline clinical characteristics) and estimate the variability in treatment response. RESULTS: The study included 211 patients (median age: 29 years, range: 12-58). Median changes (10-90th percentile) from baseline were: - 56 mEq/L (-76; -27) for sweat chloride concentration, +14.5 points (2.5; 32.0) for ppFEV1, +0.33 standard deviation scores (-0.13; 1.05) for BMI and +17 points (0; 39) for the CFQ-R respiratory domain score. The selected predictors explained 23 % of the variability in sweat chloride concentration changes, 18 % of the variability in ppFEV1 changes, 39 % of the variability in BMI changes, and 65 % of the variability in CFQ-R changes. CONCLUSIONS: This study highlights a high level of heterogeneity in treatment response to ETI, which can only be partially explained by the baseline characteristics of the disease.

Standards of care and educational gaps in adult cystic fibrosis units: a European Respiratory Society survey.

Background: Significant progress in the field of cystic fibrosis (CF) has substantially extended the life expectancy of patients with CF (pwCF). Consequently, the population of adult pwCF has outnumbered paediatric patients in most developed countries. Ageing is a new factor that can contribute to disease complexity and can require adaptation of CF units. Therefore, the necessity for standardised, specialised and multidisciplinary care is imperative. Concerns arise regarding the adequacy of current healthcare, therapeutic and educational offerings. Methods: To address these concerns, a multinational survey was conducted to assess the current state of care in specialised multidisciplinary adult and paediatric CF units and identify areas for improvement. Responses were collected from 44 centres providing regular care to CF patients. Results: The survey unveiled considerable disparities in the availability of critical resources, including diagnostic access, supplementary testing, treatment modalities, transplant and transition programmes, and healthcare professionals' training. Conclusion: This study underscores the urgent need to standardise care across these centres in order to minimise disparities in terms of available resources and training with a particular emphasis on adult pwCF who are becoming more numerous and showing different needs with ageing. The changing landscape of CF in adulthood will require constant monitoring to ensure proper adaptation of the current model of care.

Endotypes of Exacerbation in Bronchiectasis: An Observational Cohort Study.

RATIONALE: Bronchiectasis is characterised by acute exacerbations but the biological mechanisms underlying these events is poorly characterised. Objectives To investigate the inflammatory and microbial characteristics of exacerbations of bronchiectasis. METHODS: 120 patients with bronchiectasis were enrolled and presented with acute exacerbations within 12 months. Spontaneous sputum samples were obtained during a period of clinical stability and again at exacerbation prior to receipt of antibiotic treatment. A validated rapid PCR assay for bacteria and viruses was used to classify exacerbations as bacterial, viral or both. Sputum inflammatory assessments included label free Liquid chromography/mass spectrometry and measurement of sputum cytokines and neutrophil elastase activity. 16s rRNA sequencing was used to characterise the microbiome. MEASUREMENTS AND MAIN RESULTS: Bronchiectasis exacerbations showed profound molecular heterogeneity. At least one bacteria was identified in 103 samples (86%) and a high bacterial load (total bacterial load >10(7) copies/g) was observed in 81 patients (68%). Respiratory viruses were identified in 55 (46%) patients with rhinovirus being the most common virus (31%). PCR was more sensitive than culture. No consistent change in the microbiome was observed at exacerbation. Exacerbations were associated with increased neutrophil elastase, proteinase-3, Il-1beta and CXCL8. There markers were particularly associated with bacterial and bacterial+viral exacerbations. Distinct inflammatory and microbiome profiles were seen between different exacerbation subtypes, including bacterial, viral and eosinophilic events in both hypothesis led, and hypothesis-free analysis using integrated microbiome and proteomics, demonstrating 4 subtypes of exacerbation. CONCLUSION: Bronchiectasis exacerbations are heterogeneous events with contributions from bacteria, viruses and inflammatory dysregulation.

Lung donor bronchoalveolar lavage positivity: Incidence, risk factors, and lung transplant recipients' outcome.

BACKGROUND: Inconsistent data exists regarding the risk factors for bronchoalveolar lavage (BAL) positivity in lung donors, the incidence of donor-derived infections (DDI), and the effect of BAL positivity on lung transplant (LuTx) recipients' outcome. METHODS: A retrospective analysis was conducted on consecutive LuTx at a single center from January 2016 to December 2022. Donors' data, including characteristics, graft function and BAL samples were collected pre-procurement. Recipients underwent BAL before LuTx and about the 3rd, 7th and 14th day after LuTx. A DDI was defined as BAL positivity (bacterial growth ≥104 colony forming units) for identical bacterial species between donor and recipient. Recipients' pre-operative characteristics, intra-operative management, and post-operative outcomes were assessed. Two recipient cohorts were identified based on lung colonization status before undergoing LuTx. RESULTS: Out of 188 LuTx procedures performed, 169 were analyzed. Thirty-six percent of donors' BAL tested positive. Donors' characteristics and graft function at procurement were not associated with BAL positivity. Fourteen DDI were detected accounting for 23% of recipients receiving a graft with a positive BAL. Only among uncolonized recipients, receiving a graft with positive BAL is associated with higher likelihood of requiring invasive ventilation at 72 hours after LuTx on higher positive end-expiratory pressure levels having lower PaO2/FiO2, prolonged duration of mechanical ventilation and longer ICU stay. No difference in hospital length of stay was observed. CONCLUSIONS: Receiving a graft with a positive BAL, which is poorly predicted by donors' characteristics, carries the risk of developing a DDI and is associated to a worse early graft function among uncolonized recipients.

Objective sputum colour assessment and clinical outcomes in bronchiectasis: data from the European Bronchiectasis Registry (EMBARC).

BACKGROUND: A validated 4-point sputum colour chart can be used to objectively evaluate the levels of airway inflammation in bronchiectasis patients. In the European Bronchiectasis Registry (EMBARC), we tested whether sputum colour would be associated with disease severity and clinical outcomes. METHODS: We used a prospective, observational registry of adults with bronchiectasis conducted in 31 countries. Patients who did not produce spontaneous sputum were excluded from the analysis. The Murray sputum colour chart was used at baseline and at follow-up visits. Key outcomes were frequency of exacerbations, hospitalisations for severe exacerbations and mortality during up to 5-year follow-up. RESULTS: 13 484 patients were included in the analysis. More purulent sputum was associated with lower forced expiratory volume in 1 s (FEV1), worse quality of life, greater bacterial infection and a higher bronchiectasis severity index. Sputum colour was strongly associated with the risk of future exacerbations during follow-up. Compared to patients with mucoid sputum (reference group), patients with mucopurulent sputum experienced significantly more exacerbations (incident rate ratio (IRR) 1.29, 95% CI 1.22-1.38; p<0.0001), while the rates were even higher for patients with purulent (IRR 1.55, 95% CI 1.44-1.67; p<0.0001) and severely purulent sputum (IRR 1.91, 95% CI 1.52-2.39; p<0.0001). Hospitalisations for severe exacerbations were also associated with increasing sputum colour with rate ratios, compared to patients with mucoid sputum, of 1.41 (95% CI 1.29-1.56; p<0.0001), 1.98 (95% CI 1.77-2.21; p<0.0001) and 3.05 (95% CI 2.25-4.14; p<0.0001) for mucopurulent, purulent and severely purulent sputum, respectively. Mortality was significantly increased with increasing sputum purulence, hazard ratio 1.12 (95% CI 1.01-1.24; p=0.027), for each increment in sputum purulence. CONCLUSION: Sputum colour is a simple marker of disease severity and future risk of exacerbations, severe exacerbations and mortality in patients with bronchiectasis.

Prognostic Significance of NLR and PLR in COVID-19: A Multi-Cohort Validation Study.

INTRODUCTION: Recent studies have highlighted the prognostic value of easily accessible inflammatory markers, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) for predicting severe outcomes in patients affected by Coronavirus disease 2019 (COVID-19). Our study validates NLR and PLR cut-off values from a prior cohort at IRCCS Policlinico San Matteo (OSM) of Pavia, Italy, across two new cohorts from different hospitals. This aims to enhance the generalizability of these prognostic indicators. METHODS: In this retrospective cohort study, conducted at Milan's Ospedale Luigi Sacco (OLS) and IRCCS Ospedale Maggiore Policlinico (OMP) hospitals, we assess the predictive capacity of NLR and PLR for three main outcomes-non-invasive ventilation (NIV) or continuous positive airway pressure (CPAP) usage, invasive ventilation (IV), and death-in patients with COVID-19 at admission. For each outcome, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were computed separately for male and female cohorts. Distinct NLR and PLR cut-off values were used for men (7.00, 7.29, 7.00 for NLR; 239.22, 248.00, 250.39 for PLR) and women (6.36, 7.00, 6.28 for NLR; 233.00, 246.45, 241.54 for PLR), retrieved from the first cohort at OSM. RESULTS: A total of 3599 patients were included in our study, 1842 from OLS and 1757 from OMP. OLS and OMP sensitivity values for both NLR and PLR (NLR: 24-67%, PLR: 40-64%) were inferior to specificity values (NLR: 64-76%, PLR: 55-72%). Additionally, PPVs generally remained lower (< 63%), while NPVs consistently surpassed 68% for PLR and 72% for NLR. Finally, both PLR and NLR exhibited consistently higher NPVs for more severe outcomes (> 82%) compared to NPVs for CPAP/NIV. CONCLUSIONS: Consistent findings across diverse patient populations validate the reliability and applicability of NLR and PLR cut-off values. High NPVs emphasize their role in identifying individuals less likely to experience severe outcomes. These markers not only aid in risk stratification but also guide resource allocation in emergencies or limited-resource situations.

Structural Lung Disease and Clinical Phenotype in Bronchiectasis Patients: The EMBARC CT Study.

RATIONALE: Chest computed tomography -scans (CTs) are essential to diagnose and monitor bronchiectasis (BE). To date, little quantitative data is available about the nature and extent of structural lung abnormalities (SLA) on CTs of BE patients. OBJECTIVES: to investigate SLA on CTs of patients with bronchiectasis and the relationship of SLAs to clinical features using the European Bronchiectasis Registry (EMBARC) Methods: CTs from BE patients included in the EMBARC registry were analyzed using the validated Bronchiectasis Scoring Technique for CT (BEST-CT). BEST-CT subscores are expressed as % of total lung volume. Scored items are: atelectasis/consolidation (%ATCON), bronchiectasis with and without mucus plugging (%BEMP, %BEwMP), airway wall thickening (%AWT), mucus plugging (%MP), ground-glass opacities (%GGO), bullae (%BUL), airways and parenchyma (%A,%P). Four composite scores were calculated: Total BE (%TBE=%BEMP+%BEwMP), total MP (%TMP=%BEMP+%MP), total inflammatory changes (%TinF=%ATCON+%BEMP+%MP+%GGO) and total disease (%DIS= all but %A & %P).¬ Measurments and Main Results: CTs of 524 BE patients were analyzed. Mean (range) of subscores were: %TBE 4.6 (2.3-7.7), %TMP 4.2 (1.2-8.1), %TinF 8.3 (3.5-16.7) and %DIS 14.9 (9.1-25.9). BE associated with primary ciliary dyskinesia was associated with more SLA, while COPD was associated with less SLA. Lower FEV1, longer disease duration, Pseudomonas aeruginosa and NTM infection, and severe exacerbations were all independently associated with worse SLA. CONCLUSION: Patients with bronchiectasis have highly heterogeneous type and extent of structural lung abnormalities. Strong relationships between radiological disease and clinical features suggest CT analysis may be a useful tool for clinical phenotyping.

Asthma management, focused on the use of oral corticosteroids: the opinions of Italian asthmatic patients.

OBJECTIVE: Patients' perceptions of asthma symptoms, and attitudes regarding diagnosis and management, can affect their ability to reach good asthma control. The aim of the study was to explore patients' perceptions of asthma management, with focus on treatment with oral corticosteroids (OCS). METHODS: A DOXAPHARMA survey was conducted. A questionnaire with 46 multiple choice questions was completed by 50 patients with severe uncontrolled asthma, and 258 with mild-moderate controlled or partly controlled asthma. Participants were representative of Italian asthmatic patients-with medium age, long asthma duration, delayed diagnosis, poor asthma control, and frequent exacerbations. RESULTS: Many asthmatics reported inadequate pharmacologic treatment. The majority but not all patients regularly used ICS/LABA. Oral treatment was common, mainly with OCS, particularly in severe asthmatics. One-fourth of patients did not regularly use inhaled therapy, and adherence was poor, resulting in frequent OCS use to treat exacerbations, which were common in mild-moderate cases. Patients were fairly satisfied with asthma therapies, but many had concerns about long-term corticosteroid use. Patients complained about poor management of comorbidities associated with asthma and OCS use, but were generally satisfied with their patient/doctor relationships. Many patients failed to achieve optimal health-related quality of life (HRQoL), mainly those with severe asthma who used OCS treatment and emphasized how OCS therapy impacted QoL. CONCLUSIONS: The survey results confirmed many problems related to mild-moderate and severe asthma management in Italy and highlighted the overuse of OCS rather than more effective and safe treatments, which had strong negative effects on HRQoL.

Airway clearance management in people with bronchiectasis: data from the European Bronchiectasis Registry (EMBARC).

BACKGROUND: International guidelines recommend airway clearance management as one of the important pillars of bronchiectasis treatment. However, the extent to which airway clearance is used for people with bronchiectasis in Europe is unclear. The aim of the study was to identify the use of airway clearance management in patients with bronchiectasis across different countries and factors influencing airway clearance use. METHODS: Prospective observational study using data from the EMBARC Registry between January 2015 and April 2022. Pre-specified options for airway clearance management were recorded, including airway clearance techniques, devices and use of mucoactive drugs. RESULTS: 16 723 people with bronchiectasis from 28 countries were included in the study. Mean age was 67 years (interquartile range 57-74 years, range 18-100 years) and 61% were females. Seventy-two percent of the participants reported daily sputum expectoration and 52% (95% CI 51-53%) of all participants reported using regular airway clearance management. Active cycle of breathing technique was used by 28% of the patients and airway clearance devices by 16% of participants. The frequency of airway clearance management and techniques used varied significantly between different countries. Patients who used airway clearance management had greater disease severity and worse symptoms, including a higher daily sputum volume compared to those who did not use it regularly. Mucoactive drugs were also more likely to be used in patients with more severe disease. Access to specialist respiratory physiotherapy was low throughout Europe, but particularly low in Eastern Europe. CONCLUSIONS: Only half of the people with bronchiectasis in Europe use airway clearance management. Use and access to devices, mucoactive drugs and specialist chest physiotherapy appears to be limited in many European countries.

Vasoactive drugs for the treatment of pulmonary hypertension associated with interstitial lung diseases: a systematic review.

OBJECTIVES: Vasoactive drugs have exhibited clinical efficacy in addressing pulmonary arterial hypertension, manifesting a significant reduction in morbidity and mortality. Pulmonary hypertension may complicate advanced interstitial lung disease (PH-ILD) and is associated with high rates of disability, hospitalisation due to cardiac and respiratory illnesses, and mortality. Prior management hinged on treating the underlying lung disease and comorbidities. However, the INCREASE trial of inhaled treprostinil in PH-ILD has demonstrated that PH-ILD can be effectively treated with vasoactive drugs. METHODS: This comprehensive systematic review examines the evidence for vasoactive drugs in the management of PH-ILD. RESULTS: A total of 1442 pubblications were screened, 11 RCTs were considered for quantitative synthesis. Unfortunately, the salient studies are limited by population heterogeneity, short-term follow-up and the selection of outcomes with uncertain clinical significance. CONCLUSIONS: This systematic review underscores the necessity of establishing a precision medicine-oriented strategy, directed at uncovering and addressing the intricate cellular and molecular mechanisms that underlie the pathophysiology of PH-ILD. PROSPERO REGISTRATION NUMBER: CRD42023457482.

The Impact of Antimicrobial Resistance in Cystic Fibrosis.

The phenomenon of antimicrobial resistance (AMR) is a critical global health challenge, with prospects indicating its potential to become the leading cause of death worldwide in the coming years. Individuals with pre-existing conditions, such as neoplastic disease undergoing chemotherapy, those on immunosuppressive therapy, and individuals with rare diseases like cystic fibrosis (CF), face heightened challenges due to AMR. CF is a rare disease caused by a deficiency in the synthesis of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) channel protein, resulting in multi-organ clinical symptoms, particularly in the respiratory system. PwCF experience recurrent pulmonary exacerbations triggered by bacterial or viral infections, making them particularly vulnerable to the impact of AMR. This review delves into the complex relationship between AMR and climate dynamics, focusing on the unique challenges faced by individuals with CF. It discusses the methods employed to measure AMR, its global impact on antibiotic resistance, and the specific microbial communities present in the CF airway. The review also explores the intricacies of antimicrobial resistance within the context of cystic fibrosis, emphasizing the urgent need for research in this field.

Diagnostic delay in bronchiectasis: an Italian perspective.

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.

Perceived burden of respiratory physiotherapy in people with cystic fibrosis taking elexacaftor-tezacaftor-ivacaftor combination: a 1-year observational study.

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.

Understanding the challenges of respiratory physiotherapy in individuals with cystic fibrosis using triple therapy: a one-year study.In order to slow down the progression of their disease, people with cystic fibrosis typically do daily respiratory physiotherapy, which they find to be the most challenging part of managing their condition. The elexacaftor-tezacaftor-ivacaftor combination has changed how they manage their respiratory health. We wanted to see how the perceived difficulty of the treatment changed over one year of using elexacaftor-tezacaftor-ivacaftor. We gave questionnaires to people with cystic fibrosis and to their caregivers before they started the triple therapy and again at 6-12 months. We also used two international questionnaires to learn about symptoms and social limitations related to the disease. The International Physical Activity Questionnaire helped us understand their physical activity levels. We used statistical models to see if the time spent on respiratory physiotherapy changed over the year. Our study involved 47 individuals with cystic fibrosis, with an average age of 21 years, who completed one year of elexacaftor-tezacaftor-ivacaftor therapy. After 6 months, time spent on aerosol therapy decreased by 2.5 minutes per day, time on airway clearance therapies decreased by 8.8 minutes per day, and time for cleaning respiratory equipment decreased by 10.6 minutes per day. By the end of the year, they were saving almost 15 minutes per day on average. At one year, 5 out of 47 said they had stopped using the positive expiratory pressure mask. People with cystic fibrosis using elexacaftor-tezacaftor-ivacaftor may find that they spend less time on their daily respiratory physiotherapy routine. However, activities like aerosol therapy, airway clearance therapies, and maintaining respiratory equipment were still seen as time-consuming.

Relationship Between Lung Volumes and Heterogeneity in the Response to Elexacaftor/Tezacaftor/Ivacaftor in Patients With Cystic Fibrosis and Advanced Lung Disease.

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 FEV1 change after treatment are still missing. RESEARCH QUESTION: Which ventilatory parameters are involved in the heterogeneity of FEV1 change after 12-month ETI treatment in people with CF with 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 (FEV1 < 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 FEV1, we used the Spearman rank correlation coefficient (r) and median quantile regressions. RESULTS: After 12 months of ETI treatment, there was a significant increase in FEV1 % 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 (RV)/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 FEV1 % predicted negatively correlated with baseline functional residual capacity/TLC ratio (r = -0.38, P = .009) and RV/TLC ratio (r= -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 RV/TLC ratio, the expected median change in FEV1 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 FEV1 % predicted change after 12 months of treatment may be predicted by the severity of hyperinflation at baseline.

Bronchiectasis and asthma: Data from the European Bronchiectasis Registry (EMBARC).

BACKGROUND: Asthma is commonly reported in patients with a diagnosis of bronchiectasis. OBJECTIVE: The aim of this study was to evaluate whether patients with bronchiectasis and asthma (BE+A) had a different clinical phenotype and different outcomes compared with patients with bronchiectasis without concomitant asthma. METHODS: A prospective observational pan-European registry (European Multicentre Bronchiectasis Audit and Research Collaboration) enrolled patients across 28 countries. Adult patients with computed tomography-confirmed bronchiectasis were reviewed at baseline and annual follow-up visits using an electronic case report form. Asthma was diagnosed by the local investigator. Follow-up data were used to explore differences in exacerbation frequency between groups using a negative binomial regression model. Survival analysis used Cox proportional hazards regression. RESULTS: Of 16,963 patients with bronchiectasis included for analysis, 5,267 (31.0%) had investigator-reported asthma. Patients with BE+A were younger, were more likely to be female and never smokers, and had a higher body mass index than patients with bronchiectasis without asthma. BE+A was associated with a higher prevalence of rhinosinusitis and nasal polyps as well as eosinophilia and Aspergillus sensitization. BE+A had similar microbiology but significantly lower severity of disease using the bronchiectasis severity index. Patients with BE+A were at increased risk of exacerbation after adjustment for disease severity and multiple confounders. Inhaled corticosteroid (ICS) use was associated with reduced mortality in patients with BE+A (adjusted hazard ratio 0.78, 95% CI 0.63-0.95) and reduced risk of hospitalization (rate ratio 0.67, 95% CI 0.67-0.86) compared with control subjects without asthma and not receiving ICSs. CONCLUSIONS: BE+A was common and was associated with an increased risk of exacerbations and improved outcomes with ICS use. Unexpectedly we identified significantly lower mortality in patients with BE+A.

Long-Term Outcomes in Severe Community-Acquired Pneumonia.

Community-acquired pneumonia (CAP) is globally one of the major causes of hospitalization and mortality. Severe CAP (sCAP) presents great challenges and need a comprehensive understanding of its long-term outcomes. Cardiovascular events and neurological impairment, due to persistent inflammation and hypoxemia, contribute to long-term outcomes in CAP, including mortality. Very few data are available in the specific population of sCAP. Multiple studies have reported variable 1-year mortality rates for patients with CAP up to 40.7%, with a clear influence by age, comorbidities, and disease severity. In terms of treatment, the potential protective role of macrolides in reducing mortality emphasizes the importance of appropriate empiric antibiotic therapy. This narrative review explores the growing interest in the literature focusing on the long-term implications of sCAP. Improved understanding of long-term outcomes in sCAP can facilitate targeted interventions and enhance posthospitalization care protocols.

The Association Between Bronchiectasis and Chronic Obstructive Pulmonary Disease: Data from the European Bronchiectasis Registry (EMBARC).

RATIONALE AND OBJECTIVE: Bronchiectasis and COPD are associated conditions but misdiagnosis is believed to be common. A recently published international consensus definition of bronchiectasis (BE) and COPD association: The ROSE criteria (radiological bronchiectasis(R), obstruction: FEV1/FVC ratio<0.7 (O), symptoms (S) and exposure:≥10 pack year smoking (E) allows objective diagnosis of the BE-COPD association. METHODS: Analysis of the EMBARC registry, a prospective observational study of patients with CT confirmed bronchiectasis from 28 countries. The ROSE criteria were used to objectively defined BE-COPD association. Key outcomes during up to 5-years follow-up were exacerbations, hospitalization and mortality. MEASUREMENT AND MAIN RESULTS: 16730 patients with bronchiectasis were included. 4336 had a co-diagnosis of COPD and these patients had more exacerbations, worse quality of life and higher severity scores. We observed marked overdiagnosis of COPD using the ROSE criteria: 22.2% of patients with a diagnosis of COPD did not have airflow obstruction and 31.9% did not have a history of ≥10 pack years smoking. Therefore the proportion meeting the ROSE criteria for COPD was 2157 (55.4%). Compared to patients without COPD, patients meeting ROSE criteria had increased risk of exacerbations and exacerbations resulting in hospitalisation during follow-up (IRR 1.25 95%CI 1.15-1.35 and 1.69 95%CI 1.51-1.90 respectively) but patients with a diagnosis of COPD who did not meet ROSE criteria also had increased risk of exacerbations. CONCLUSIONS: The label of COPD is often applied to bronchiectasis patients without objective evidence of airflow obstruction and smoking history. Patients with a clinical label of COPD have worse clinical outcomes.

Aromatic L-Amino Acid Decarboxylase Deficiency: A Genetic Screening in Sicilian Patients with Neurological Disorders.

Aromatic L-amino acid decarboxylase deficiency (AADCd) is a rare autosomal recessive neurometabolic disorder caused by AADC deficiency, an enzyme encoded by the DDC gene. Since the enzyme is involved in the biosynthesis of serotonin and dopamine, its deficiency determines the lack of these neurotransmitters, but also of norepinephrine and epinephrine. Onset is early and the key signs are hypotonia, movement disorders (oculogyric crises, dystonia and hypokinesia), developmental delay and autonomic dysfunction. Taiwan is the site of a potential founder variant (IVS6+4A>T) with a predicted incidence of 1/32,000 births, while only 261 patients with this deficit have been described worldwide. Actually, the number of affected persons could be greater, given that the spectrum of clinical manifestations is broad and still little known. In our study we selected 350 unrelated patients presenting with different neurological disorders including heterogeneous neuromuscular disorders, cognitive deficit, behavioral disorders and autism spectrum disorder, for which the underlying etiology had not yet been identified. Molecular investigation of the DDC gene was carried out with the aim of identifying affected patients and/or carriers. Our study shows a high frequency of carriers (2.57%) in Sicilian subjects with neurological deficits, with a higher concentration in northern and eastern Sicily. Assuming these data as representative of the general Sicilian population, the risk may be comparable to some rare diseases included in the newborn screening programs such as spinal muscular atrophy, cystic fibrosis and phenylketonuria.

Airway 'Resistotypes' and Clinical Outcomes in Bronchiectasis.

INTRODUCTION: Application of whole-genome shotgun metagenomics to the airway microbiome in bronchiectasis highlights a diverse pool of antimicrobial resistance genes: the 'resistome', the clinical significance of which remains unclear. METHODS: Individuals with bronchiectasis were prospectively recruited into cross-sectional and longitudinal cohorts (n=280) including the international multicentre cross-sectional Cohort of Asian and Matched European Bronchiectasis 2 study (CAMEB 2; n=251) and two independent cohorts, one describing patients experiencing acute exacerbation and a further cohort of patients undergoing P. aeruginosa eradication treatment. Sputum was subjected to metagenomic sequencing and the bronchiectasis resistome evaluated in association with clinical outcomes and underlying host microbiomes. RESULTS: The bronchiectasis resistome features a unique resistance gene profile and elevated counts of aminoglycoside, bicyclomycin, phenicol, triclosan and multi-drug resistance genes. Longitudinally, it exhibits within-patient stability over time and during exacerbations despite between-patient heterogeneity. Proportional differences in baseline resistome profiles including increased macrolide and multi-drug resistance genes associate with shorter intervals to next exacerbation, while distinct resistome archetypes associate with frequent exacerbations, poorer lung function, geographic origin, and the host microbiome. Unsupervised analysis of resistome profiles identified two clinically relevant 'resistotypes' RT1 and RT2, the latter characterized by poor clinical outcomes, increased multi-drug resistance and P. aeruginosa. Successful targeted eradication in P. aeruginosa-colonized individuals mediated reversion from RT2 to RT1, a more clinically favourable resistome profile demonstrating reduced resistance gene diversity. CONCLUSION: The bronchiectasis resistome associates with clinical outcomes, geographic origin, and the underlying host microbiome. Bronchiectasis 'resistotypes' link to clinical disease and are modifiable through targeted antimicrobial therapy. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Mycobacterium avium complex pulmonary disease patients with limited treatment options.

How to identify MAC-PD patients with limited treatment options: an expert consensus https://bit.ly/3QwLQ8T.