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.

Maternal and Fetal Outcomes in Multiparous Women with Cystic Fibrosis.

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 isease severity and outcome, as well as obstetric and newborn complications. Data was 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 was collected on 246 pregnancies, between 1973 and 2020, 69 (28%) were multiparous. A greater decline in ppFEV1 was seen with 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.

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.

Immediate Unilateral Subpectoral Implant-Based Breast Reconstruction does not Impair Pulmonary Functions: A Preliminary Prospective Study.

BACKGROUND: Implant-based breast reconstruction is one of the most common procedures among women with breast cancer undergoing mastectomy. Prosthetic devices may be positioned either beneath or above the pectoralis major muscle, which is considered an accessory muscle of ventilation. This preliminary prospective study aimed to investigate whether subpectoral unilateral implant-based breast reconstruction has any effect on patients' pulmonary functions. METHODS: A prospective study of fourteen women who underwent immediate unilateral implant-based subpectoral breast reconstruction by a single surgeon over 10 months was conducted. Spirometry and maximal voluntary ventilation tests were conducted 1 day prior to surgery, and 1- and 3 months following breast reconstruction. ANOVA or Friedman test were used to compare pulmonary function tests before and after surgery. RESULTS: Fourteen patients completed the study protocol. No statistically significant differences were found when comparing spirometry parameters in the three time points. CONCLUSIONS: Pectoralis muscle release does not impair pulmonary function among patients undergoing immediate unilateral implant-based breast reconstruction following mastectomy. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

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.

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.

Asymptomatic Dysphagia and Aspiration in Patients with Idiopathic Bronchiectasis.

PURPOSE: Although considered contributors to idiopathic bronchiectasis (IB), neither dysphagia nor silent aspiration have been systematically evaluated in IB patients. We aimed to explore the prevalence of asymptomatic dysphagia and silent aspiration in IB patients and to identify parameters predictive of their presence. METHODS: This prospective cohort study included IB patients from our Pulmonary Institute without prior history of dysphagia and without prior dysphagia workup. Swallowing function was assessed by the Eating Assessment Tool (EAT-10) questionnaire and by the Fiberoptic Endoscopic Evaluation of Swallowing (FEES) test. RESULTS: Forty-seven patients (31 females, mean age 67 ± 16 years) were recruited. An EAT-10 score ≥ 3 (risk for swallowing problems) was present in 21 patients (44.6%). Forty-two patients (89.3%) had at least one abnormal swallowing parameter in the FEES test. Six patients (12.7%) had a penetration aspiration score (PAS) in the FEES of at least 6, indicating aspiration. An EAT-10 score of 3 was found to be the ideal cutoff to predict aspiration in the FEES, with a good level of accuracy (area under the curve = 0.78, 95% CI 0.629-0.932, p = 0.03) and sensitivity of 83%. This cutoff also showed a trend towards a more severe disease using the FACED (forced expiratory volume, age, colonization with pseudomonas, extension of lung involvement, dyspnea) score (p = 0.05). CONCLUSION: Dysphagia is prevalent in IB and may be undiagnosed if not specifically sought. We recommend screening all patients with IB for dysphagia by the EAT-10 questionnaire and referring all those with a score of ≥ 3 to formal swallowing assessment.

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.

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.

Bronchiectasis with Chronic Rhinosinusitis Is Associated with Eosinophilic Airway Inflammation and Is Distinct from Asthma.

Rationale: Bronchiectasis is an airway inflammatory disease that is frequently associated with chronic rhinosinusitis (CRS). An eosinophilic endotype of bronchiectasis has recently been described, but detailed testing to differentiate eosinophilic bronchiectasis from asthma has not been performed. Objectives: This prospective observational study aimed to test the hypotheses that bronchiectasis with CRS is enriched for the eosinophilic phenotype in comparison with bronchiectasis alone and that the eosinophilic bronchiectasis phenotype exists as a separate entity from bronchiectasis associated with asthma. Methods: People with idiopathic or postinfectious bronchiectasis were assessed for concomitant CRS. We excluded people with asthma or primary ciliary dyskinesia and smokers. We assessed sputum and blood cell counts, nasal NO and fractional excreted NO, methacholine reactivity, skin allergy testing and total and specific immunoglobulin (Ig) E, cytokines in the sputum and serum, and the microbiome in the sputum and nasopharynx. Results: A total of 22 people with CRS (BE + CRS) and 17 without CRS (BE - CRS) were included. Sex, age, Reiff score, and bronchiectasis severity were similar. Median sputum eosinophil percentages were 0% (IQR, 0-1.5%) in BE - CRS and 3% (1-12%) in BE + CRS (P = 0.012). Blood eosinophil counts were predictive of sputum eosinophilia (counts ⩾3%; area under the receiver operating characteristic curve, 0.68; 95% confidence interval, 0.50-0.85). Inclusion of CRS improved the prediction of sputum eosinophilia by blood eosinophil counts (area under the receiver operating characteristic curve, 0.79; 95% confidence interval, 0.65-0.94). Methacholine tests were negative in 85.7% of patients in the BE - CRS group and 85.2% of patients in the BE + CRS group (P > 0.99). Specific IgE and skin testing were similar between the groups, but total IgE levels were increased in people with increased sputum eosinophils. Microbiome analysis demonstrated distinct microbiota in nasopharyngeal and airway samples in the BE + CRS and BE - CRS groups, without significant differences between groups. However, interactome analysis revealed altered interactomes in individuals with high sputum eosinophil counts and CRS. Conclusions: Bronchiectasis with CRS is associated with an eosinophilic airway inflammation that is distinct from asthma.

A BEAT-PCD consensus statement: a core outcome set for pulmonary disease interventions in primary ciliary dyskinesia.

Background: Consistent use of reliable and clinically appropriate outcome measures is a priority for clinical trials, with clear definitions to allow comparability. We aimed to develop a core outcome set (COS) for pulmonary disease interventions in primary ciliary dyskinesia (PCD). Methods: A multidisciplinary international PCD expert panel was set up. A list of outcomes was created based on published literature. Using a modified three-round e-Delphi technique, the panel was asked to decide on relevant end-points related to pulmonary disease interventions and how they should be reported. First, inclusion of an outcome in the COS was determined. Second, the minimum information that should be reported per outcome. The third round finalised statements. Consensus was defined as ≥80% agreement among experts. Results: During the first round, experts reached consensus on four out of 24 outcomes to be included in the COS. Five additional outcomes were discussed in subsequent rounds for their use in different subsettings. Consensus on standardised methods of reporting for the COS was reached. Spirometry, health-related quality-of-life scores, microbiology and exacerbations were included in the final COS. Conclusion: This expert consensus resulted in a COS for clinical trials on pulmonary health among people with PCD.

Prescribing preferences and availability of nebulisers and inhalers for inhaled medications in bronchiectasis: results of a specialist survey.

Specialists caring for people with bronchiectasis recommend specialised nebulisers for inhaled antibiotics, but are often limited by availability and cost of nebulisation devices https://bit.ly/40FvFdZ.

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.

Eradication treatment for Pseudomonas aeruginosa infection in adults with bronchiectasis: a systematic review and meta-analysis.

INTRODUCTION: Pseudomonas aeruginosa is the most commonly isolated pathogen in bronchiectasis and is associated with worse outcomes. Eradication treatment is recommended by guidelines, but the evidence base is limited. The expected success rate of eradication in clinical practice is not known. METHODS: We conducted a systematic review and meta-analysis according to Meta-Analysis of Observational Studies in Epidemiology guidelines. PubMed, Embase, the Cochrane Database of Systematic Reviews and Clinicaltrials.gov were searched for studies investigating P. aeruginosa eradication treatment using antibiotics (systemic or inhaled) in patients with bronchiectasis. The primary outcome was the percentage of patients negative for P. aeruginosa at 12 months after eradication treatment. Cystic fibrosis was excluded. RESULTS: Six observational studies including 289 patients were included in the meta-analysis. Our meta-analysis found a 12-month P. aeruginosa eradication rate of 40% (95% CI 34-45%; p<0.00001), with no significant heterogeneity (I2=0%). Combined systemic and inhaled antibiotic treatment was associated with a higher eradication rate (48%, 95% CI 41-55%) than systemic antibiotics alone (27%, 13-45%). CONCLUSION: Eradication treatment in bronchiectasis results in eradication of P. aeruginosa from sputum in ∼40% of cases at 12 months. Combined systemic and inhaled antibiotics achieve higher eradication rates than systemic antibiotics alone.

A provider survey assessing fetal impact of CFTR modulator use in males with CF during assisted and unassisted reproduction and partner pregnancy.

BACKGROUND: Most males with cystic fibrosis (mwCF) are infertile but with CF transmembrane conductance regulator (CFTR) modulator-conferred benefits, more are utilizing assisted reproductive technologies (ART). Administration of normal human doses of modulators in animal reproductive models caused no genotoxicity; no human data exists. Potential health decline following modulator discontinuation makes the decision to withhold therapy during reproduction challenging. METHODS: From August-October 2021, international CF clinicians completed an anonymous questionnaire regarding mwCF who used modulators during reproduction. RESULTS: We received 42 surveys for mwCF with partner pregnancies. Forty of 42 mwCF utilized ART; 35 continued modulators during sperm retrieval and 40/42 during partner pregnancy. One of four males who discontinued modulators experienced clinical deterioration. First trimester miscarriages occurred in 11.9 % of partner pregnancies. No congenital anomalies were reported. CONCLUSIONS: Use of CFTR modulators during reproduction and partner pregnancy in mwCF did not result in a higher-than-expected miscarriage rate nor congenital anomalies.

Inflammatory Molecular Endotypes in Bronchiectasis: A European Multicenter Cohort Study.

Rationale: Although inflammation and infection are key disease drivers in bronchiectasis, few studies have integrated host inflammatory and microbiome data to guide precision medicine. Objectives: To identify clusters among patients with bronchiectasis on the basis of inflammatory markers and to assess the association between inflammatory endotypes, microbiome characteristics, and exacerbation risk. Methods: Patients with stable bronchiectasis were enrolled at three European centers, and cluster analysis was used to stratify the patients according to the levels of 33 sputum and serum inflammatory markers. Clusters were compared in terms of microbiome composition (16S ribosomal RNA sequencing) and exacerbation risk over a 12-month follow-up. Measurements and Main Results: A total of 199 patients were enrolled (109 [54.8%] female; median age, 69 yr). Four clusters of patients were defined according to their inflammatory profiles: cluster 1, milder neutrophilic inflammation; cluster 2, mixed-neutrophilic and type 2; cluster 3, most severe neutrophilic; and cluster 4, mixed-epithelial and type 2. Lower microbiome diversity was associated with more severe inflammatory clusters (P < 0.001), and ß-diversity analysis demonstrated distinct microbiome profiles associated with each inflammatory cluster (P = 0.001). Proteobacteria and Pseudomonas at phylum and genus levels, respectively, were more enriched in clusters 2 and 3 than in clusters 1 and 4. Furthermore, patients in cluster 2 (rate ratio [RR], 1.49; 95% confidence interval [CI], 1.16-1.92) and cluster 3 (RR, 1.61; 95% CI, 1.12-2.32) were at higher risk of exacerbation over a 12-month follow-up compared with cluster 1, even after adjustment for prior exacerbation history. Conclusions: Bronchiectasis inflammatory endotypes are associated with distinct microbiome profiles and future exacerbation risk.

CFTR modulator therapy: transforming the landscape of clinical care in cystic fibrosis.

Following discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in 1989 and subsequent elucidation of the varied CFTR protein abnormalities that result, a new era of cystic fibrosis management has emerged-one in which scientific principles translated from the bench to the bedside have enabled us to potentially treat the basic defect in the majority of children and adults with cystic fibrosis, with a resultant burgeoning adult cystic fibrosis population. However, the long-term effects of these therapies on the multiple manifestations of cystic fibrosis are still under investigation. Understanding the effects of modulators in populations excluded from clinical trials is also crucial. Furthermore, establishing appropriate disease measures to assess efficacy in the youngest potential trial participants and in those whose post-modulator lung function is in the typical range for people without chronic lung disease is essential for continued drug development. Finally, recognising that a health outcome gap has been created for some people and widened for others who are not eligible for, cannot tolerate, or do not have access to modulators is important.