‘High risk’ clinical and inflammatory clusters in COPD of Chinese descent

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this recordIntroduction COPD is a heterogeneous disease demonstrating inter-individual variation. A high COPD prevalence in Chinese populations is described but little is known about disease clusters and prognostic outcomes in the Chinese population across South-East Asia. We aim to determine if clusters of Chinese patients with COPD exist and their association with systemic inflammation and clinical outcomes. Methods Chinese patients with stable COPD were prospectively recruited into two cohorts (derivation and validation) from six hospitals across three South-East Asian countries (Singapore, Malaysia and Hong Kong; n=1,480). Each patient was followed over two-years. Clinical data (including co-morbidities) were employed in unsupervised hierarchical clustering (followed by validation) to determine the existence of patient clusters and their prognostic outcome. Accompanying systemic cytokine assessments were performed in a subset (n=336) of COPD patients to determine if inflammatory patterns and associated networks characterised the derived clusters. Results Five patient clusters were identified including (1) Ex-tuberculosis (2) Diabetic (3) Low co-morbidity: low-risk (4) Low co-morbidity: high-risk and (5) cardiovascular. The ‘cardiovascular’ and ‘ex-tuberculosis’ clusters demonstrate highest mortality (independent of GOLD assessment) and illustrate diverse cytokine patterns with complex inflammatory networks. Conclusions We describe novel ‘clusters’ of Chinese COPD patients, two of which represent ‘high-risk’ clusters. The ‘cardiovascular’ and ‘ex-tuberculosis’ patient clusters exhibit high mortality, significant inflammation and complex cytokine networks. Clinical and inflammatory risk stratification of Chinese patients with COPD should be considered for targeted intervention to improve disease outcomes.Singapore Ministry of Health - National Medical Research CouncilSingapore Ministry of EducationNanyang Technological University, SingaporeEngineering and Physical Sciences Research Council (EPSRC

Sex steroids induce membrane stress responses and virulence properties in pseudomonas aeruginosa

© 2020 Vidaillac et al. Estrogen, a major female sex steroid hormone, has been shown to promote the selection of mucoid Pseudomonas aeruginosa in the airways of patients with chronic respiratory diseases, including cystic fibrosis. This results in long-term persistence, poorer clinical outcomes, and limited therapeutic options. In this study, we demonstrate that at physiological concentrations, sex steroids, including testosterone and estriol, induce membrane stress responses in P. aeruginosa. This is characterized by increased virulence and consequent inflammation and release of proinflammatory outer membrane vesicles promoting in vivo persistence of the bacteria. The steroid-induced P. aeruginosa response correlates with the molecular polarity of the hormones and membrane fluidic properties of the bacteria. This novel mechanism of interaction between sex steroids and P. aeruginosa explicates the reported increased disease severity observed in females with cystic fibrosis and provides evidence for the therapeutic potential of the modulation of sex steroids to achieve better clinical outcomes in patients with hormone-responsive strains. IMPORTANCE Molecular mechanisms by which sex steroids interact with P. aeruginosa to modulate its virulence have yet to be reported. Our work provides the first characterization of a steroid-induced membrane stress mechanism promoting P. aeruginosa virulence, which includes the release of proinflammatory outer membrane vesicles, resulting in inflammation, host tissue damage, and reduced bacterial clearance. We further demonstrate that at nanomolar (physiological) concentrations, male and female sex steroids promote virulence in clinical strains of P. aeruginosa based on their dynamic membrane fluidic properties. This work provides, for the first-time, mechanistic insight to better understand and predict the P. aeruginosa related response to sex steroids and explain the interindividual patient variability observed in respiratory diseases such as cystic fibrosis that are complicated by gender differences and chronic P. aeruginosa infection

Geographic variation in the aetiology, epidemiology and microbiology of bronchiectasis

Bronchiectasis is a disease associated with chronic progressive and irreversible dilatation of the bronchi and is characterised by chronic infection and associated inflammation. The prevalence of bronchiectasis is age-related and there is some geographical variation in incidence, prevalence and clinical features. Most bronchiectasis is reported to be idiopathic however post-infectious aetiologies dominate across Asia especially secondary to tuberculosis. Most focus to date has been on the study of airway bacteria, both as colonisers and causes of exacerbations. Modern molecular technologies including next generation sequencing (NGS) have become invaluable tools to identify microorganisms directly from sputum and which are difficult to culture using traditional agar based methods. These have provided important insight into our understanding of emerging pathogens in the airways of people with bronchiectasis and the geographical differences that occur. The contribution of the lung microbiome, its ethnic variation, and subsequent roles in disease progression and response to therapy across geographic regions warrant further investigation. This review summarises the known geographical differences in the aetiology, epidemiology and microbiology of bronchiectasis. Further, we highlight the opportunities offered by emerging molecular technologies such as -omics to further dissect out important ethnic differences in the prognosis and management of bronchiectasis.NMRC (Natl Medical Research Council, S’pore)MOH (Min. of Health, S’pore)Published versio

Similarity network fusion (SNF) for the integration of multi-omics and microbiomes in respiratory disease

This is the author accepted manuscript; the final published version is available from European Respiratory Society via the DOI in this record.Take home message: Similarity Network Fusion (SNF) is an increasingly employed method for multi-omics and microbiome data integration that can assist in patient endotyping. Here, we describe how it is performed and explore its current and future application in respiratory medicineEngineering and Physical Sciences Research Council (EPSRC)Singapore Ministry of Health’s National Medical Research CouncilNTU Integrated Medical, Biological and Environmental Life Sciences (NIMBELS