Endotypes of Exacerbation in Bronchiectasis: An Observational Cohort Study.

Rationale: Bronchiectasis is characterized by acute exacerbations, but the biological mechanisms underlying these events are poorly characterized. Objectives: To investigate the inflammatory and microbial characteristics of exacerbations of bronchiectasis. Methods: A total of 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 before 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 chromatography-tandem mass spectrometry and measurement of sputum cytokines and neutrophil elastase activity. 16 s rRNA sequencing was used to characterize the microbiome. Measurements and Main Results: Bronchiectasis exacerbations showed profound molecular heterogeneity. At least one bacterium was identified in 103 samples (86%), and a high bacterial load (total bacterial load > 107 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 testing 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-1ß, and CXCL8. These markers were particularly associated with bacterial and bacterial plus 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 four subtypes of exacerbation. Conclusions: Bronchiectasis exacerbations are heterogeneous events with contributions from bacteria, viruses, and inflammatory dysregulation.

Pseudomonas aeruginosa isolation is an important predictor for recurrent hemoptysis after bronchial artery embolization in patients with idiopathic bronchiectasis: a multicenter cohort study.

BACKGROUND: Nearly half of bronchiectasis patients receiving bronchial artery embolization (BAE) still have recurrent hemoptysis, which may be life-threatening. Worse still, the underlying risk factors of recurrence remain unknown. METHODS: A retrospective cohort was conducted of patients with idiopathic bronchiectasis who received BAE from 2015 to 2019 at eight centers. Patients were followed up for at least 24 months post BAE. Based on the outcomes of recurrent hemoptysis and recurrent severe hemoptysis, a Cox regression model was used to identify risk factors for recurrence. RESULTS: A total of 588 individuals were included. The median follow-up period was 34.0 months (interquartile range: 24.3-53.3 months). The 1-month, 1-year, 2-year, and 5-year cumulative recurrent hemoptysis-free rates were 87.2%, 67.5%, 57.6%, and 49.4%, respectively. The following factors were relative to recurrent hemoptysis: 24-h sputum volume (hazard ratio [HR] = 1.99 [95% confidence interval [95% CI]: 1.25-3.15, p = 0.015]), isolation of Pseudomonas aeruginosa (HR = 1.50 [95% CI: 1.13-2.00, p = 0.003]), extensive bronchiectasis (HR = 2.00 [95% CI: 1.29-3.09, p = 0.002]), and aberrant bronchial arteries (AbBAs) (HR = 1.45 [95% CI: 1.09-1.93, p = 0.014]). The area under the receiver operating characteristic curve of the nomogram was 0.728 [95% CI: 0.688-0.769]. CONCLUSIONS: Isolation of Pseudomonas aeruginosa is an important independent predictor of recurrent hemoptysis. The clearance of Pseudomonas aeruginosa might effectively reduce the hemoptysis recurrence rate.

Characterization of Eosinophilic Bronchiectasis: A European Multicohort Study.

Rationale: Bronchiectasis is classically considered a neutrophilic disorder, but eosinophilic subtypes have recently been described. Objectives: To use multiple datasets available through the European Multicentre Bronchiectasis Audit and Research Collaboration to characterize eosinophilic bronchiectasis as a clinical entity focusing on the impact of eosinophils on bronchiectasis exacerbations. Methods: Patients were included from five countries to examine the relationships between blood eosinophil counts and clinical phenotypes after excluding coexisting asthma. 16S rRNA sequencing was used to examine relationships between eosinophil counts and the sputum microbiome. A post hoc analysis of the PROMIS (Inhaled Promixin in the Treatment of Non-Cystic Fibrosis Bronchiectasis) phase 2 trial was used to examine the impact of blood eosinophil counts on exacerbations in patients with Pseudomonas aeruginosa infection. Measurements and Main Results: A relationship between sputum and blood eosinophil counts was demonstrated in two cohorts. In analysis of 1,007 patients from five countries, 22.6% of patients had blood eosinophil counts of ⩾300 cells/µl. Counts of <100 cells/µl were associated with higher bronchiectasis severity and increased mortality. There was no clear relationship with exacerbations. Blood eosinophil counts of ⩾300 cells/µl were associated with both Streptococcus- and Pseudomonas-dominated microbiome profiles. To investigate the relationship of eosinophil counts with exacerbations after controlling for the confounding effects of infection, 144 patients were studied in a clinical trial after treatment with antipseudomonal antibiotics. Compared with patients with blood eosinophil counts of <100 cells/µl (reference), elevated eosinophil counts of 100-299 cells/µl (hazard ratio, 2.38; 95% confidence interval, 1.33-4.25; P = 0.003) and ⩾300 cells/µl (hazard ratio, 3.99; 95% confidence interval, 2.20-7.85; P < 0.0001) were associated with shorter time to exacerbation. Conclusions: Eosinophilic bronchiectasis affects approximately 20% of patients. After accounting for infection status, raised blood eosinophil counts are associated with shortened time to exacerbation.

The Establishment of China Bronchiectasis Registry and Research Collaboration (BE-China): Protocol of a prospective multicenter observational study.

BACKGROUND: Bronchiectasis is a highly heterogeneous chronic airway disease with marked geographic and ethnic variations. Most influential cohort studies to date have been performed in Europe and USA, which serve as the examples for developing a cohort study in China where there is a high burden of bronchiectasis. The Establishment of China Bronchiectasis Registry and Research Collaboration (BE-China) is designed to: (1) describe the clinical characteristics and natural history of bronchiectasis in China and identify the differences of bronchiectasis between the western countries and China; (2) identify the risk factors associated with disease progression in Chinese population; (3) elucidate the phenotype and endotype of bronchiectasis by integrating the genome, microbiome, proteome, and transcriptome with detailed clinical data; (4) facilitate large randomized controlled trials in China. METHODS: The BE-China is an ongoing prospective, longitudinal, multi-center, observational cohort study aiming to recruit a minimum of 10,000 patients, which was initiated in January 2020 in China. Comprehensive data, including medical history, aetiological testing, lung function, microbiological profiles, radiological scores, comorbidities, mental status, and quality of life (QoL), will be collected at baseline. Patients will be followed up annually for up to 10 years to record longitudinal data on outcomes, treatment patterns and QoL. Biospecimens, if possible, will be collected and stored at - 80 °C for further research. Up to October 2021, the BE-China has enrolled 3758 patients, and collected 666 blood samples and 196 sputum samples from 91 medical centers. The study protocol has been approved by the Shanghai Pulmonary Hospital ethics committee, and all collaborating centers have received approvals from their local ethics committee. All patients will be required to provide written informed consent to their participation. CONCLUSIONS: Findings of the BE-China will be crucial to reveal the clinical characteristics and natural history of bronchiectasis and facilitate evidence-based clinical practice in China. Trial registration Registration Number in ClinicalTrials.gov: NCT03643653.

FUS-induced circular RNA ZNF609 promotes tumorigenesis and progression via sponging miR-142-3p in lung cancer.

Circular RNAs (circRNAs) have been associated with lung cancer (LC), one of the most common cancers, but the underlying molecular mechanisms of the specific correlation with LC carcinogenesis remain unveiled. Quantitative real-time polymerase chain reaction was applied to examine the level of circZNF609. LC cells were transfected with silenced circZNF609 by siRNAs, and cell proliferation, migration, and apoptosis were evaluated to reflect the influences of circZNF609 knockdown in LC. Biotin-coupled circRNA capture, FISH and luciferase reporter assays were performed to study the relationship between circZNF609 and miR-142-3p. In current work, it was discovered that circZNF609 functioned as an onco-circRNA, which exhibited high expression as well as facilitated the proliferation and migration in LC cells. Next, we discovered that FUS RNA-binding protein, which could bind to the ZNF609 pre-mRNA, induced circZNF609 formation, and increased circZNF609 expression in LC. Furthermore, circZNF609 was verified to sponge and sequester miR-142-3p; circZNF609 enhanced LC cell proliferative and migrative ability via targeting miR-142-3p. Finally, G protein subunit beta 2 (GNB2) was figured out to involve in circZNF609/miR-142-3p axis-induced LC development. Conclusively, the results indicated that FUS-induced circZNF609 exerts promotional effects on LC cell proliferation and migration through modulation of the miR-142-3p/GNB2 axis, which could offer new insight for understanding LC.

Prevalence and Clinical Characteristics of Nontuberculous Mycobacteria in Patients with Bronchiectasis: A Systematic Review and Meta-Analysis.

BACKGROUND: Although international bronchiectasis guidelines recommended screening of nontuberculous mycobacteria (NTM) both at initial evaluation and prior to administration of macrolide treatment, data regarding NTM in bronchiectasis remain elusive. OBJECTIVE: To establish the prevalence, species, and clinical features of NTM in adults with bronchiectasis. METHODS: We searched PubMed, Embase, and Web of Science for studies published before April 2020 reporting the prevalence of NTM in adults with bronchiectasis. We only included studies with bronchiectasis confirmed by computed tomography and NTM identified by mycobacteria culture or molecular methods. Random-effects meta-analysis was employed. RESULTS: Of the 2,229 citations identified, 21 studies, including 12,454 bronchiectasis patients were included in the final meta-analysis. The overall pooled prevalence of NTM isolation and pulmonary NTM disease were 7.7% (5.0%-11.7%) (n/N = 2,677/12,454) and 4.1% (1.4%-11.4%) (n/N = 30/559), respectively, with significant heterogeneity (I2 = 97.7%, p < 0.001 and I2 = 79.9%, p = 0.007; respectively). The prevalence of NTM isolation varied significantly among different geographical regions with the highest isolation at 50.0% (47.3%-52.7%) reported in the United States. Mycobacterium avium complex and Mycobacterium abscessus complex accounted for 66 and 16.6% of all species, respectively. Some clinical and radiological differences were noted between patients with and without the presence of NTM isolation although the results are inconsistent. CONCLUSIONS: Heterogeneity in prevalence estimates of NTM isolation indicated that both local surveys to inform development of clinical services tailored to patients with bronchiectasis and population-based studies are needed. The clinical features associated with NTM in bronchiectasis and their incremental utility in studying the association is unknown and merits further investigation.

Relationship between Symptoms, Exacerbations, and Treatment Response in Bronchiectasis.

Rationale: Bronchiectasis guidelines regard treatment to prevent exacerbation and treatment of daily symptoms as separate objectives.Objectives: We hypothesized that patients with greater symptoms would be at higher risk of exacerbations and therefore that a treatment aimed at reducing daily symptoms would also reduce exacerbations in highly symptomatic patients.Methods: Our study comprised an observational cohort of 333 patients from the East of Scotland (2012-2016). Either symptoms were modeled as a continuous variable or patients were classified as having high, moderate, or low symptom burden (>70, 40-70, and <40 using the St. George's Respiratory Questionnaire symptom score). The hypothesis that exacerbation reductions would only be evident in highly symptomatic patients was tested in a post hoc analysis of a randomized trial of inhaled dry powder mannitol (N = 461 patients).Measurements and Main Results: In the observational cohort, daily symptoms were a significant predictor of future exacerbations (rate ratio [RR], 1.10; 95% confidence interval [CI], 1.03-1.17; P = 0.005). Patients with higher symptom scores had higher exacerbation rates (RR, 1.74; 95% CI, 1.12-2.72; P = 0.01) over 12-month follow-up than those with lower symptoms. Inhaled mannitol treatment improved the time to first exacerbation (hazard ratio, 0.56; 95% CI, 0.40-0.77; P < 0.001), and the proportion of patients remaining exacerbation free for 12 months of treatment was higher in the mannitol group (32.7% vs. 14.6%; RR, 2.84; 95% CI, 1.40-5.76; P = 0.003), but only in highly symptomatic patients. In contrast, no benefit was evident in patients with lower symptom burden.Conclusions: Highly symptomatic patients have increased risk of exacerbations, and exacerbation benefit with inhaled mannitol was only evident in patients with high symptom burden.

lncRNA SNHG11 promotes lung cancer cell proliferation and migration via activation of Wnt/ß-catenin signaling pathway.

Lung cancer ranks topmost among the most frequently diagnosed cancers. Despite increasing research, there are still unresolved mysteries in the molecular mechanism of lung cancer. Long noncoding RNA small nucleolar RNA host gene 11 (SNHG11) was found to be upregulated in lung cancer and facilitated lung cancer cell proliferation, migration, invasion, and epithelial-mesenchymal transition progression while suppressed cell apoptosis. Moreover, the high expression of SNHG11 was correlated with poor prognosis of lung cancer patients, TNM stage, and tumor size. Further assays demonstrated that SNHG11 functioned in lung cancer cells via Wnt/ß-catenin signaling pathway. Subsequently, Wnt/ß-catenin pathway was found to be activated through SNHG11/miR-4436a/CTNNB1 ceRNA axis. As inhibiting miR-4436 could only partly rescue the suppression of cell function induced by silencing SNHG11, it was suspected that ß-catenin might enter cell nucleus through other pathways. Mechanism investigation proved that SNHG11 would directly bind with ß-catenin to activate classic Wnt pathway. Subsequently, in vivo tumorigenesis was also demonstrated to be enhanced by SNHG11. Hence, SNHG11 was found to promote lung cancer progression by activating Wnt/ß-catenin pathway in two different patterns, implying that SNHG11 might contribute to lung cancer treatment by acting as a therapeutic target.

Factors associated with prolonged viral shedding and impact of lopinavir/ritonavir treatment in hospitalised non-critically ill patients with SARS-CoV-2 infection.

BACKGROUND: The duration of viral shedding is central to the guidance of decisions about isolation precautions and antiviral treatment. However, studies regarding the risk factors associated with prolonged shedding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the impact of lopinavir/ritonavir (LPV/r) treatment on viral shedding remain scarce. METHODS: Data were collected from all SARS-CoV-2 infected patients who were admitted to isolation wards and had reverse transcription PCR conversion at the No. 3 People's Hospital of Hubei province, China, between 31 January and 9 March 2020. We compared clinical characteristics and SARS-CoV-2 RNA shedding between patients initiated with LPV/r treatment and those without. Logistic regression analysis was employed to evaluate the risk factors associated with prolonged viral shedding. RESULTS: Of 120 patients, the median age was 52 years, 54 (45%) were male and 78 (65%) received LPV/r treatment. The median duration of SARS-CoV-2 RNA detection from symptom onset was 23 days (interquartile range 18-32 days). Older age (OR 1.03, 95% CI 1.00-1.05; p=0.03) and the lack of LPV/r treatment (OR 2.42, 95% CI 1.10-5.36; p=0.029) were independent risk factors for prolonged SARS-CoV-2 RNA shedding. Patients who initiated LPV/r treatment within 10 days from symptom onset, but not initiated from day 11 onwards, had significantly shorter viral shedding duration compared with those without LPV/r treatment (median 19 days versus 28.5 days; log-rank p<0.001). CONCLUSION: Older age and the lack of LPV/r treatment were independently associated with prolonged SARS-CoV-2 RNA shedding in patients with coronavirus disease 2019 (COVID-19). Earlier administration of LPV/r treatment could shorten viral shedding duration.

Arterial stiffness in adults with steady-state bronchiectasis: association with clinical indices and disease severity.

BACKGROUND: Cardiovascular disease are common co-morbidities in bronchiectasis and contribute substantially to disease burden and mortality. Brachial-ankle pulse wave velocity (baPWV), a measure of arterial stiffness, has a strong predictive value for cardiovascular event. We hypothesized that baPWV would be increased in steady-state bronchiectasis patients, and correlates with the degree of systemic inflammation and disease severity assessed with Bronchiectasis Severity Index and FACED scores. METHODS: Eighty patients with steady-state bronchiectasis and 80 age- and sex-matched controls were enrolled. BaPWV was measured as an indicator of arterial stiffness. Demographic, clinical indices, radiology, spirometry, sputum bacteriology and systemic inflammatory mediators were also assessed. RESULTS: Bronchiectasis patients had significantly increased baPWV [median 1514 cm/s vs. 1352 cm/s, P = 0.0003] compared with control subjects. BaPWV significantly correlated with Bronchiectasis Severity Index (rho = 0.65, P < 0.001) and FACED (rho = 0.49, P < 0.001) scores. In multivariate regression analysis, age, Pseudomonas aeruginosa colonization, systolic blood pressure, body-mass index and exacerbation frequency in the last 12 months, but not systemic inflammatory markers, were independent factors influencing on baPWV in bronchiectasis patient after adjustment for other clinical variables. Reproducibility of baPWV measurement was good. CONCLUSION: Bronchiectasis patients have increased arterial stiffness compared with control subjects, which correlates with disease severity, but not systemic inflammatory markers. Age, Pseudomonas aeruginosa colonization, systolic blood pressure, body-mass index and exacerbation frequency in last 12 months might independently predict the severity of arterial stiffness in bronchiectasis. Therefore, arterial stiffness might have contributed to the increased risks of developing cardiovascular diseases in bronchiectasis.

Noninvasive ventilation with helmet versus control strategy in patients with acute respiratory failure: a systematic review and meta-analysis of controlled studies.

BACKGROUND: Noninvasive ventilation (NIV) has proved to be a useful technique for breathing support. However, complications, discomfort, and failure of NIV were commonly caused by the mask. Therefore, the helmet was developed to improve performance and reduce complications; however, there has been no conclusive results on its effect until now. Thus, we performed a systematic review and meta-analysis to investigate the effect of NIV with a helmet versus the control strategy in patients with acute respiratory failure (ARF). METHODS: We searched Cochrane Library, PubMed, Ovid, and Embase databases and bibliographies of relevant articles published before June 2016. Randomized and case-control studies that adopted the helmet as an NIV interface and compared it with another interface were included. The primary outcomes were hospital mortality, intubation rate, and complications. The secondary outcomes included the length of intensive care unit (ICU) stay, gas exchange, and respiratory rate. Pooled odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated by the Mantel-Haenszel method and mean difference by the inverse variance method in a fixed effect model or random effects model according to the heterogeneity. RESULTS: A total of 11 studies involving 621 patients were included. The overall hospital mortality was 17.53 % in the helmet NIV group versus 30.67 % in the control group. Use of the helmet was associated with lower hospital mortality (OR 0.43, 95 % CI 0.26 to 0.69, p = 0.0005), intubation rate (OR 0.32, 95 % CI 0.21 to 0.47, P < 0.00001), and complications (OR 0.6, 95 % CI 0.4 to 0.92, P = 0.02). In contrast, there was no significant difference in gas exchange and ICU stay (P >0.05). Subgroup analysis found the helmet reduced mortality mainly in hypoxemic ARF patients (P < 0.05) and a lower intubation rate was shown in randomized trials; fewer complications caused by the helmet might be restricted to case-control trials. Additionally, the effect of the helmet on PaCO2 was influenced by type of ARF and ventilation mode (P <0.00001). CONCLUSION: NIV with a helmet was associated with reduced hospital mortality and intubation requirement. The helmet was as effective as the mask in gas exchange with no additional advantage. Large randomized controlled trials are needed to provide more robust evidence.

Impact of COPD and emphysema on survival of patients with lung cancer: A meta-analysis of observational studies.

Both COPD and emphysema are associated with an increased incidence of lung cancer, but the impacts of these comorbidities on lung cancer prognosis are still unclear. Herein, we conducted a meta-analysis to clarify whether the presence of these comorbidities indicates poor survival in patients with lung cancer. A comprehensive search was conducted using PubMed, Embase, Web of Science, ASCO Abstracts and Cochrane library for articles published before 1 June 2015. Papers referenced by the obtained articles were also reviewed. Main outcomes were overall survival (OS) and disease-free survival (DFS) in patients with lung cancer. Pooled hazard ratio (HR) and 95% confidence intervals (CIs) were calculated using random-effects models. Subgroup and sensitivity analyses were also conducted. Of 58 full texts reviewed, 26 met our inclusion criteria that were derived from 21 and seven studies examining the impacts of COPD and emphysema on survival of lung cancer, respectively. Meta-analyses revealed that concomitant COPD was associated with poorer OS (HR, 1.17; 95% CI: 1.10-1.25, n = 20), which was independent of tumour staging, diagnostic criteria of COPD or location, and DFS (HR, 1.52; 95% CI: 1.04-2.23, n = 6) with high heterogeneity (I(2) = 78%). The presence of emphysema in patients with lung cancer predicted worse OS (HR, 1.66; 95% CI: 1.25-2.22, n = 7), but not poorer DFS. The presence of COPD and emphysema are robust predictors of poor survival in patients with lung cancer. Early detection of these diseases should be taken into account for lung cancer surveillance and management.

Aetiology of bronchiectasis in adults: A systematic literature review.

While identifying the underlying aetiology is a key part of bronchiectasis management, the prevalence and impact of identifying the aetiologies on clinical management remain unclear. We aimed to determine the etiological spectrum of bronchiectasis, and how often etiological assessment could lead to the changes in patients' management. A comprehensive search was conducted using MEDLINE (via PubMed) and EMBASE for observational studies published before October 2015 reporting aetiologies in adults with bronchiectasis. Of the 8216 citations identified, 56 studies including 8608 adults with bronchiectasis were relevant for this systematic review. The crude prevalence for the identified aetiologies ranged from 18% to 95%, which possibly resulted from the differences in the geographic regions and diagnostic workup. Post-infective (29.9%), immunodeficiency (5%), chronic obstructive pulmonary disease (3.9%), connective tissue disease (3.8%), ciliary dysfunction (2.5%), allergic bronchopulmonary aspergillosis (2.6%) were the most common aetiologies. In 1577 patients (18.3%), identifying the aetiologies led to changes in patient's management. Aetiologies varied considerably among different geographic regions (P < 0.001). Intensive investigations of these aetiologies might help change patient's management and therefore should be incorporated into routine clinical practice.

Aetiology of bronchiectasis in Guangzhou, southern China.

BACKGROUND AND OBJECTIVE: Aetiologies of bronchiectasis in mainland China and their comparisons with those in western countries are unknown. We aimed to investigate bronchiectasis aetiologies in Guangzhou, southern China, and to determine ethnic or geographic differences with reports from western countries. METHODS: Consecutive patients with steady-state bronchiectasis were randomly recruited. Past history was meticulously extracted. Patients underwent physical examination, saccharine test, humoral immunity assays, gastroesophageal reflux scoring and sputum culture. Fiberoptic bronchoscopy, total immunoglobin E (IgE) and Aspergillus fumigatus-specific IgE measurement, 24-h gastroesophageal pH monitoring and miscellaneous screening tests were performed, if indicated. This entailed comparisons on aetiologies with literature reports. RESULTS: We enrolled 148 patients (44.6 ± 13.8 years, 92 females), most of whom had mild to moderate bronchiectasis. Idiopathic (46.0%), post-infectious (27.0%) and immunodeficiency (8.8%) were the most common aetiologies. Miscellaneous aetiologies consisted of asthma (5.4%), gastroesophageal reflux (4.1%), aspergillosis (2.7%), congenital lung malformation (2.0%), Kartagener syndrome (1.4%), rheumatoid arthritis (1.4%), chronic obstructive pulmonary disease (0.7%), Young's syndrome (0.7%), yellow nail's syndrome (0.7%), eosinophilic bronchiolitis (0.7%) and foreign bodies (0.7%). No notable differences in clinical characteristics between idiopathic and known aetiologies were found. Ethnic or geographic variations of aetiologies were overall unremarkable. CONCLUSIONS: Idiopathic, post-infectious and immunodeficiency constitute major bronchiectasis aetiologies in Guangzhou. Clinical characteristics of patients between known aetiologies and idiopathic bronchiectasis were similar. Ethnicity and geography only account for limited differences in aetiologic spectra. These findings will offer rationales for early diagnosis and management of bronchiectasis in future studies and clinical practice in China.

Sputum matrix metalloproteinase-8 and -9 and tissue inhibitor of metalloproteinase-1 in bronchiectasis: clinical correlates and prognostic implications.

BACKGROUND AND OBJECTIVE: The triplet of airway infection, inflammation and bronchial wall destruction associated with excessive matrix metalloproteinases (MMP) release and imbalance of tissue inhibitor metalloproteinase-1 (TIMP-1) is implicated in bronchiectasis. We sought to determine the associations between sputum MMP (MMP-8, MMP-9) and TIMP-1 and the severity of bronchiectasis; the utility of MMP in predicting risks of future bronchiectasis exacerbations (BE); and the changes in MMP levels during BE. METHODS: We recruited 102 patients with stable bronchiectasis and 22 healthy subjects. For bronchiectasis patients, baseline measurements consisted of sputum inflammation and MMP measurements, bacterial culture, spirometry and chest high-resolution computed tomography (HRCT). Bronchiectasis patients were followed up for 1 year to determine the frequency of BE. Changes in MMP levels during BE were assessed in 36 bronchiectasis patients. RESULTS: Sputum MMP-8, MMP-9 and MMP-9/TIMP-1 ratio in bronchiectasis patients were significantly increased compared with healthy subjects. MMP-8 and MMP-9 levels, but not TIMP-1, were positively correlated with clinical measures, including HRCT scores, spirometry and Bronchiectasis Severity Index. Seventy-nine bronchiectasis patients were included in survival analyses of BE. Lower levels of baseline MMP-9 were associated with reduced risks of and a longer time to the first BE during follow-up. MMP-8 and MMP-9, but not TIMP-1 or MMP-9/TIMP-1 ratio, were significantly heightened during BE. CONCLUSIONS: Sputum MMP might be useful biomarkers for the assessment of bronchiectasis severity and the prediction of future risks of BE. Our results provide the rationales for the future clinical application of MMP inhibitors.

Quality-of-Life Bronchiectasis Respiratory Symptom Scale Predicts the Risk of Exacerbations in Adults with Bronchiectasis: A Prospective Observational Study.

Rationale: The relationship between symptoms, measured using a validated disease-specific questionnaire, and longitudinal exacerbation risk has not been demonstrated in bronchiectasis. Objectives: The aim of this study is to investigate whether baseline symptoms, assessed using the Quality-of-Life Bronchiectasis Respiratory Symptom Scale (QoL-B-RSS) and its individual component scores, could predict future exacerbation risk in patients with bronchiectasis. Methods: The study included 436 adults with bronchiectasis from three tertiary hospitals. Symptoms were measured using the QoL-B-RSS, with scores ranging from 0 to 100, where lower scores indicated more severe symptoms. We examined whether symptoms as continuous measures were associated with the risk of exacerbation over 12 months. The analysis was also repeated for individual components of the QoL-B-RSS score. Results: The baseline QoL-B-RSS score was associated with an increased risk of exacerbations (rate ratio, 1.25 for each 10-point decrease; 95% confidence interval [CI], 1.15-1.35; P < 0.001), hospitalizations (rate ratio, 1.24; 95% CI, 1.05-1.43; P = 0.02), and reduced time to the first exacerbation (hazard ratio, 1.12; 95% CI, 1.03-1.21; P = 0.01) over 12 months, even after adjusting for relevant confounders, including exacerbation history. The QoL-B-RSS score was comparable to exacerbation history in its association with future frequent exacerbations (defined as three or more exacerbations per year) and hospitalization (area under the curve, 0.86 vs. 0.84; P = 0.46; and area under the curve, 0.81 vs. 0.83; P = 0.41, respectively). Moreover, patients with more severe symptoms in the majority of individual components of the QoL-B-RSS were more likely to experience exacerbations. Conclusions: Symptoms can serve as useful indicators for identifying patients at increased risk of exacerbation in bronchiectasis. Beyond relying solely on exacerbation history, a comprehensive assessment of symptoms could facilitate timely and cost-effective implementation of interventions for exacerbation prevention.

A phase 4 multicentre, 2×2 factorial randomised, double-blind, placebo-controlled trial to investigate the efficacy and safety of tobramycin inhalation solution for Pseudomonas aeruginosa eradication in bronchiectasis: ERASE.

Chronic Pseudomonas aeruginosa (PA) infection significantly contributes to morbidity and mortality in bronchiectasis patients. Initiating antibiotics early may lead to the eradication of PA. Here we outline the design of a trial (ERASE; NCT06093191) assessing the efficacy and safety of inhaled tobramycin, alone or with oral ciprofloxacin, in bronchiectasis patients with a new isolation of PA. This multicentre, 2×2 factorial randomised, double-blind, placebo-controlled, parallel-group trial includes a 2-week screening period, a 12-week treatment phase (with a combination of ciprofloxacin or a placebo at initial 2 weeks) and a 24-week follow-up. 364 adults with bronchiectasis and a new PA isolation will be randomly assigned to one of four groups: placebo (inhaled saline and ciprofloxacin placebo twice daily), ciprofloxacin alone (750 mg ciprofloxacin and inhaled saline twice daily), inhaled tobramycin alone (inhaled 300 mg tobramycin and ciprofloxacin placebo twice daily) or a combination of both drugs (inhaled 300 mg tobramycin and 750 mg ciprofloxacin twice daily). The primary objective of this study is to assess the proportion of patients successfully eradicating PA in each group by the end of the study. Efficacy will be evaluated based on the eradication rate of PA at other time points (12, 24 and 36 weeks), the occurrence of exacerbations and hospitalisations, time to first pulmonary exacerbations, patient-reported outcomes, symptom measures, pulmonary function tests and the cost of hospitalisations. To date no randomised trial has evaluated the benefit of different PA eradication strategies in bronchiectasis patients. The ERASE trial will therefore generate crucial data to inform future clinical guidelines.

The BED-Pro Tool: facilitating the detection of bronchiectasis exacerbations.

The Bronchiectasis Exacerbation Diary is an eight-item patient-reported outcome instrument for detecting exacerbations in bronchiectasis https://bit.ly/3k2IH4p.