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ObjectiveTo assess whether FUT2 (secretor) genotype affects disease severity and airway infection in patients with non-cystic fibrosis bronchiectasis.ParticipantsInduced sputum samples were obtained from 112 adult patients with high-resolution CT scan-proven bronchiectasis and at least two exacerbations in the previous year, as part of an unrelated randomised control trial.Outcome measuresPresence of null FUT2 polymorphisms were determined by gene sequencing and verified by endobronchial biopsy histochemical staining. Outcome measures were FEV1% predicted, exacerbation frequency, and bacterial, fungal and viral components of the microbiota (measured by culture independent approaches).ResultsPatients were grouped by FUT2 loss-of-function genotype; categorised as non-secretors (n=27, sese), heterozygous secretors (n=54, Sese) or homozygous secretors (n=31, SeSe). FEV1% was significantly lower in SeSe patients compared with sese patients (mean 61.6 (SD 20.0) vs 74.5 (18.0); p=0.023). Exacerbation frequency was significantly higher in SeSe (mean count 5.77) compared with sese (4.07; p=0.004) and Sese (4.63; p=0.026) genotypes. The time until first exacerbation was significantly shorter in SeSe compared with Sese (HR=0.571 (95% CI 0.343 to 0.950); p=0.031), with a similar trend for sese patients (HR=0.577 (0.311 to 1.07); p=0.081). sese had a significantly reduced frequency of Pseudomonas aeruginosa-dominated airway infection (8.7%) compared with Sese (31%; p=0.042) and SeSe (36%; p=0.035). In contrast, fungal, viral and non-dominant bacterial components of the microbiome were not significantly different between FUT2 genotypes.ConclusionsFUT2 genotype in patients with non-cystic fibrosis bronchiectasis was significantly associated with disease outcomes, with homozygous secretors exhibiting lower lung function, higher exacerbation number and a higher frequency of P. aeruginosa-dominated infection.Trial registration numberACTRN12609000578202 (anzctr.org.au); Pre-results.

Bronchiectasis is characterised by pathological dilation of the airways. More specifically, the radiographic demonstration of airway enlargement is the common feature of a heterogeneous set of conditions and clinical presentations. No approved therapies exist for the condition other than for bronchiectasis caused by cystic fibrosis. The heterogeneity of bronchiectasis is a major challenge in clinical practice and the main reason for difficulty in achieving endpoints in clinical trials. Recent observations of the past 2 years have improved the understanding of physicians regarding bronchiectasis, and have indicated that it might be more effective to classify patients in a different way. Patients could be categorised according to a heterogeneous group of endotypes (defined by a distinct functional or pathobiological mechanism) or by clinical phenotypes (defined by relevant and common features of the disease). In doing so, more specific therapies needed to effectively treat patients might finally be developed. Here, we describe some of the recent advances in endotyping, genetics, and disease heterogeneity of bronchiectasis including observations related to the microbiome.

Patients with idiopathic bronchiectasis are predominantly female and have an asthenic body morphotype and frequent nontuberculous mycobacterial respiratory infections. They also demonstrate phenotypic features (scoliosis, pectus deformity, mitral valve prolapse) that are commonly seen in individuals with heritable connective tissue disorders. To determine whether lumbar dural sac size is increased in patients with idiopathic bronchiectasis as compared with control subjects, and to assess whether dural sac size is correlated with phenotypic characteristics seen in individuals with heritable connective tissue disorders. Two readers blinded to diagnosis measured anterior-posterior and transverse dural sac diameter using L1-L5 magnetic resonance images of 71 patients with idiopathic bronchiectasis, 72 control subjects without lung disease, 29 patients with cystic fibrosis, and 24 patients with Marfan syndrome. We compared groups by pairwise analysis of means, using Tukey's method to adjust for multiple comparisons. Dural sac diameter association with phenotypic and clinical features was also tested. The L1-L5 (average) anterior-posterior dural sac diameter of the idiopathic bronchiectasis group was larger than those of the control group (P < 0.001) and the cystic fibrosis group (P = 0.002). There was a strong correlation between increased dural sac size and the presence of pulmonary nontuberculous mycobacterial infection (P = 0.007) and long fingers (P = 0.003). A trend toward larger dural sac diameter was seen in those with scoliosis (P = 0.130) and those with a family history of idiopathic bronchiectasis (P = 0.149). Individuals with idiopathic bronchiectasis have an enlarged dural sac diameter, which is associated with pulmonary nontuberculous mycobacterial infection, long fingers, and family history of idiopathic bronchiectasis. These findings support our hypothesis that \"idiopathic\" bronchiectasis development reflects complex genetic variation in heritable connective tissue and associated transforming growth factor-β-related pathway genes.

Exacerbations are key events in the natural history of bronchiectasis, but clinical predictors and outcomes of patients with frequently exacerbating disease are not well described. To establish if there is a \"frequent exacerbator phenotype\" in bronchiectasis and the impact of exacerbations on long-term clinical outcomes. We studied patients with bronchiectasis enrolled from 10 clinical centers in Europe and Israel, with up to 5 years of follow-up. Patients were categorized by baseline exacerbation frequency (zero, one, two, or three or more per year). The repeatability of exacerbation status was assessed, as well as the independent impact of exacerbation history on hospitalizations, quality of life, and mortality. A total of 2,572 patients were included. Frequent exacerbations were the strongest predictor of future exacerbation frequency, suggesting a consistent phenotype. The incident rate ratios for future exacerbations were 1.73 (95% confidence interval [CI], 1.47-2.02; P < 0.0001) for one exacerbation per year, 3.14 (95% CI, 2.70-3.66; P < 0.0001) for two exacerbations, and 5.97 (95% CI, 5.27-6.78; P < 0.0001) for patients with three or more exacerbations per year at baseline. Additional independent predictors of future exacerbation frequency were Haemophilus influenzae and Pseudomonas aeruginosa infection, FEV , radiological severity of disease, and coexisting chronic obstructive pulmonary disease. Patients with frequently exacerbating disease had worse quality of life and were more likely to be hospitalized during follow-up. Mortality over up to 5 years of follow-up increased with increasing exacerbation frequency. The frequent exacerbator phenotype in bronchiectasis is consistent over time and shows high disease severity, poor quality of life, and increased mortality during follow-up.

Airway inflammation plays a central role in bronchiectasis. Protease–antiprotease balance is crucial in bronchiectasis pathophysiology and increased presence of unopposed proteases activity may contribute to bronchiectasis onset and progression. Proteases’ over-reactivity and antiprotease deficiency may have a role in increasing inflammation in bronchiectasis airways and may lead to extracellular matrix degradation and tissue damage. Imbalances in serine proteases and matrix-metallo proteinases (MMPs) have been associated to bronchiectasis. Active neutrophil elastase has been associated with disease severity and poor long-term outcomes in this disease. Moreover, high levels of MMPs have been associated with radiological and disease severity. Finally, severe deficiency of α1-antitrypsin (AAT), as PiSZ and PiZZ (proteinase inhibitor SZ and ZZ) phenotype, have been associated with bronchiectasis development. Several treatments are under study to reduce protease activity in lungs. Molecules to inhibit neutrophil elastase activity have been developed in both oral or inhaled form, along with compounds inhibiting dipeptydil-peptidase 1, enzyme responsible for the activation of serine proteases. Finally, supplementation with AAT is in use for patients with severe deficiency. The identification of different targets of therapy within the protease–antiprotease balance contributes to a precision medicine approach in bronchiectasis and eventually interrupts and disrupts the vicious vortex which characterizes the disease.

BackgroundObservational studies have reported the association between tea consumption and the risk of lower respiratory tract infections (LRTIs). However, a consensus has yet to be reached, and whether the observed association is driven by confounding factors or reverse causality remains unclear.MethodA two-sample Mendelian randomization (MR) analysis was conducted to determine whether genetically predicted tea intake is causally associated with the risk of common LRTI subtypes. Genome-wide association study (GWAS) from UK Biobank was used to identify single-nucleotide polymorphisms (SNPs) associated with an extra cup of tea intake each day. The summary statistics for acute bronchitis, acute bronchiolitis, bronchiectasis, pneumonia, and influenza and pneumonia were derived from the FinnGen project.ResultsWe found that genetically predicted an extra daily cup of tea intake was causally associated with the decreased risk of bronchiectasis [odds ratio (OR) = 0.61, 95% confidence interval (CI) = 0.47–0.78, P < 0.001], pneumonia (OR = 0.90, 95% CI = 0.85–0.96, P = 0.002), influenza and pneumonia (OR = 0.91, 95% CI = 0.85–0.97, P = 0.002), but not with acute bronchitis (OR = 0.91, 95% CI = 0.82–1.01, P = 0.067) and acute bronchiolitis (OR = 0.79, 95% CI = 0.60–1.05, P = 0.100). Sensitivity analyses showed that no heterogeneity and pleiotropy could bias the results.ConclusionsOur findings provided new evidence that genetically predicted an extra daily cup of tea intake may causally associated with a decreased risk of bronchiectasis, pneumonia, and influenza and pneumonia.

Background Hereditary bronchiectasis refers to a subset of bronchiectasis related to genetic mutations, presenting with common clinical features. Historically, diagnosing this condition has been difficult due to the inaccessibility of diagnostic services coupled with a lack of awareness of the syndrome. We hypothesize that whole exome sequencing (WES) in patients with supporting clinical features, combined with non-genetic testing methods, will enhance the diagnosis of hereditary bronchiectasis. Results In total, 87 patients with clinical features suggestive of hereditary bronchiectasis, such as diffuse bronchiectasis (≥ 2 lobes) combined with early onset symptoms, recurrent otitis media, rhinosinusitis, infertility, organ laterality defects or a family history of bronchiectasis, were included in this study. Among them, 49.4% (43/87) were diagnosed with hereditary bronchiectasis, including 15 patients with cystic fibrosis, 27 patients with primary ciliary dyskinesia, and 1 patient with immunodeficiency-21. The combined use of WES and non-genetic testing methods significantly improved the diagnostic rate of hereditary bronchiectasis compared to non-genetic testing alone (47.1% vs. 25.3%, P  = 0.005). Re-analysis of negative commercial genetic tests led to two additional diagnoses, though this increase was not statistically significant (47.1% vs. 49.4%, P  = 0.879). Conclusions We have described the supporting clinical features of patients with hereditary bronchiectasis. Clinicians should recommend WES for patients exhibiting these characteristics, in combination with accessible non-genetic testing methods, to maximize diagnostic accuracy. For patients with negative initial genetic test results, re-analysis of WES data may facilitate obtaining a new diagnosis.

Background Epidemiological observational studies have elucidated a correlation between rheumatoid arthritis (RA) and bronchiectasis. However, the causal nature of this association remains ambiguous. To clarify this potential causal linkage, we conducted a two-sample Mendelian randomization (MR) analysis to explore the bidirectional causality between RA and bronchiectasis. Methods Summary statistics for RA and bronchiectasis were obtained from the IEU OpenGWAS database We employed various methods, including inverse variance weighting (IVW), MR-Egger, weighted median, weighted mode, and simple mode, to explore potential causal links between RA and bronchiectasis. Additionally, a series of sensitivity studies, such as Cochran’s Q test, MR Egger intercept test, and leave-one-out analysis, were conducted to assess the MR analysis’s accuracy further. Results In the forward MR analysis, the primary analysis indicated that a genetic predisposition to RA correlated with an increased risk of bronchiectasis in European populations (IVW odds ratio (OR): 1.28, 95% confidence interval (CI): 1.20–1.37, p  = 1.18E-13). Comparable results were noted in the East Asian subjects (IVW OR: 1.55, 95% CI: 1.30–1.34, p  = 8.33E-07). The OR estimates from the other four methods were consistent with those obtained from the IVW method. Sensitivity analysis detected no evidence of horizontal pleiotropy or heterogeneity. Conversely, in the reverse MR analysis, we found no evidence to support a genetic causality between bronchiectasis and RA in either European or East Asian populations. Conclusion This study indicates that genetic predisposition to RA correlates with a heightened risk of bronchiectasis in both European and East Asian populations. These results imply that routine screening for bronchiectasis in RA patients could be beneficial, and effective management of RA may contribute to a reduced risk of bronchiectasis. Future research should aim to clarify the underlying mechanisms linking these two conditions.

Background Bronchiectasis is a chronic respiratory condition characterized by irreversible dilation and damage of the bronchial walls, leading to impaired mucociliary clearance and recurrent infections. Its etiology is diverse; however, genetic factors are critical in its congenital and severe forms. Therefore, we aimed to identify two novel variants of the WFDC2 gene, known as antiprotease, from patients with bronchiectasis and/or related phenotypes using trio-based whole-genome sequencing analysis. Methods Patients with bronchiectasis were recruited as trio or quad, and their genomic DNA was isolated. The whole genome sequence was produced and analyzed to find causative genetic variants through an internal pipeline using GATK-DRAGEN-Hail. Variant interpretation and pathogenicity assessment using various in-silico tools were performed to identify causative variants. Clinical characteristics were collected from the patients with identified variants. Results In this discovery study involving four patients from three families, two novel variants in the WFDC2 gene were identified and suggested as causative pathogenic variants for bronchiectasis. The first variant (c.291 C > G, p.(Cys97Trp)) is a homozygous variant that was not found in the population genome data. However, the second variant (c.278G > C, p.(Cys93Ser)) was identified in another patient as a heterozygous variant, forming a compound heterozygous state with the first variant. Notably, both variants, located at cysteine residues that are conserved across many species, are crucial in forming disulfide bonds essential for protein structure and function. In-silico analyses classified both variants as pathogenic; they were also identified as likely pathogenic according to the American College of Medical Genetics and Genomic guidelines. Furthermore, in an expansion study, the homozygous variant was also found in two unrelated patients. Conclusion We identified two novel bi-allelic variants located at cysteine residues in the WFDC2 gene from patients with bronchiectasis who had previously not received a genetic diagnosis. Therefore, considering prior research on the pivotal role of the WFDC2 protein in the respiratory system, these two novel variants may serve as potential diagnostic markers and therapeutic targets for bronchiectasis. Clinical trial number Not Applicable

Background Sinopulmonary diseases are characterized by bronchiectasis (BE) and chronic rhinosinusitis, partly arising from clear genetic abnormalities such as cystic fibrosis (CF) and primary ciliary dyskinesia (PCD). However, the spectrum varies across ethnicities, and specifically, while considered rare in Southeast Asia, the current status in this region remains largely unknown. In this study, we investigated the clinical and genetic characteristics of patients with chronic symptoms affecting both the upper and lower airways in the northern region of Vietnam. Results We recruited 200 patients with chronic rhinosinusitis and productive cough in Vietnam. Clinical characteristics including pulmonary function measurements and high-resolution chest computed tomography findings were collected. The patients’ median age was 49.0 years, with a median productive cough duration of 3 years. BE was identified in 43.8% of cases, most commonly affecting the right and left middle lung lobes (74.7% and 70.1%, respectively), and was associated with older age and bronchiolar lesions (BL). Extensive BL/BE representing 15.5% of cases (31/200), was associated with impaired pulmonary function, and seven exhibited respiratory symptoms before the age of 20. To elucidate the genetic basis of sinopulmonary diseases in patients with early onset or situs inversus, we performed genetic analyses, including targeted resequencing of genes for CF and PCD, as well as other candidate genes. Pathogenic variants identified in the CFTR gene were p.Trp401Ter and p.Asp979Ala only in one patient. NM_012472.6( DNAAF11 ):c.1A>G; p.Met1?, NM_080860.4( RSPH1 ):c.365+1G>A, and NM_080860.4( RSPH1 ):c.407_410del; p.Lys136MetfsTer6, all causative of PCD, were identified in the homozygous or hemizygous state in three different patients, respectively. WFDC2 genetic abnormalities were not identified. An intron2 variant of MUC22 ( PBMUCL1 ), a candidate susceptibility gene for diffuse panbronchiolitis (DPB), was more frequently observed in patients with extensive BL/BE. Conclusions This is the first report in Vietnamese patients with non-specific upper and lower airway symptoms to identify genetic variants specific to CF and PCD, as well as another variant potentially associated with DPB. For the future management of sinopulmonary diseases or BE with unknown causes, ethnic differences based on their genetic etiology should be carefully considered.