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Calvin You Jia Chen,1 Min Sen Yew,2 John Arputhan Abisheganaden,3 Huiying Xu3 1Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore; 2Department of Cardiology, Tan Tock Seng Hospital, Singapore, Singapore; 3Department of Respiratory and Critical Care Medicine, Tan Tock Seng Hospital, Singapore, SingaporeCorrespondence: Huiying XuDepartment of Respiratory and Critical Care Medicine, Tan Tock Seng Hospital, 11 Jln Tan Tock Seng, Singapore, 308433, Tel +65 6256 6011Email Huiying_xu@ttsh.com.sgPurpose: Influenza infection is an important cause of acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Clinical features predicting influenza PCR positivity are unknown. We aim to identify predictors of influenza PCR positivity in AECOPD.Patients and Methods: A retrospective study of AECOPD cases admitted between 1st January 2016 to 30 June 2017 with combined nasal/throat swabs sent for influenza PCR (Xpert Xpress Flu/RSV) within 24 hours of admission was performed. Clinical parameters and investigations within 24 hours of admission were retrieved from electronic medical records.Results: Influenza PCR were sent for 925 AECOPD cases (mean age 75 years, 87.9% male). There were 90 PCR positive cases (68 Influenza A, 22 Influenza B). Influenza PCR positive cases had higher temperatures, higher heart rates, lower white cell and lower eosinophil counts. Age, gender, COPD severity, comorbidities and smoking status were similar in both groups. There were no differences in blood pressure, oxygen status, neutrophil or lymphocyte counts, C reactive protein, procalcitonin or chest X-ray consolidation between groups. Higher temperature, higher heart rate, white cell count in the lowest quartile (Q1 < 8.1 x109/L) and non-eosinophilic exacerbations predicted influenza PCR positivity on univariate logistic regression and these factors remained significant after multivariate adjustment (temperature adjusted odds ratio [adj OR] 1.324 [1.009– 1.737], p = 0.043; heart rate adj OR 1.017 [1.004– 1.030], p = 0.011; white cell count Q1 adj OR 3.330 [1.690– 6.562], p = 0.001; eosinophilic exacerbations adj OR 0.390 [0.202– 0.756], p = 0.005).Conclusion: Higher temperature, higher heart rate, low white cell count (especially when < 8.1 x109/L) and non-eosinophilic exacerbations are independent predictors of influenza PCR positivity in AECOPD cases.Keywords: chronic obstructive pulmonary disease, exacerbation, influenza, eosinophil

Background: Sensitisation to Aspergillus fumigatus is linked to worse outcomes in patients with COPD; however, its prevalence and clinical implications in domestic (residential) settings remains unknown., Methods: Individuals with COPD (n=43) recruited in Singapore had their residences prospectively sampled and assessed by shotgun metagenomic sequencing including indoor air, outdoor air and touch surfaces (a total of 126 specimens). The abundance of environmental A. fumigatus and the occurrence of A. fumigatus (Asp f) allergens in the environment were determined and immunological responses to A. fumigatus allergens determined in association with clinical outcomes including exacerbation frequency. Findings were validated in 12 individuals (31 specimens) with COPD in Vancouver, Canada, a climatically different region., Results: 157 metagenomes from 43 homes were assessed. 11 and nine separate Aspergillus spp . were identified in Singapore and Vancouver, respectively. Despite climatic, temperature and humidity variation, A. fumigatus was detectable in the environment from both locations. The relative abundance of environmental A. fumigatus was significantly associated with exacerbation frequency in both Singapore (r=0.27, p=0.003) and Vancouver (r=0.49, p=0.01) and individuals with higher Asp f 3 sensitisation responses lived in homes with a greater abundance of environmental Asp f 3 allergens (p=0.037). Patients exposed and sensitised to Asp f 3 allergens demonstrated a higher rate of COPD exacerbations at 1-year follow-up (p=0.021)., Conclusion: Environmental A. fumigatus exposure in the home environment including air and surfaces with resulting sensitisation carries pathogenic potential in individuals with COPD. Targeting domestic A. fumigatus abundance may reduce COPD exacerbations., Competing Interests: Conflict of interest: P.Y. Tiew and A. Tee have served on advisory boards for GlaxoSmithKline and AstraZeneca, outside the submitted work. M.S. Koh reports grant support from AstraZeneca, and honoraria for lectures and advisory board meetings paid to her hospital (Singapore General Hospital) from GlaxoSmithKline, AstraZeneca, Novartis, Sanofi, Boehringer Ingelheim and Roche, outside the submitted work. F.T. Chew reports grants from the National University of Singapore, Singapore Ministry of Education Academic Research Fund, Singapore Immunology Network, National Medical Research Council (NMRC) (Singapore), Biomedical Research Council (BMRC) (Singapore), National Research Foundation (NRF) (Singapore), Singapore Food Agency (SFA), and the Agency for Science Technology and Research (A*STAR) (Singapore), during the conduct of the study, and consulting fees from Sime Darby Technology Centre, First Resources Ltd, Genting Plantation, Olam International, Musim Mas and Syngenta Crop Protection, outside the submitted work. P.Y. Tiew reports grants from Singapore Ministry of Health's National Medical Research Council under its Transition Award (MOH- 001275-00). S.H. Chotirmall reports support for the present study from Singapore Ministry of Health's National Medical Research Council under its Clinician-Scientist Individual Research Grant (MOH-001356), Singapore Ministry of Health's National Medical Research Council under its Clinician Scientist Award (MOH-000710), Open Fund Individual Research Grant (MOH-000955) and Singapore Ministry of Education under its AcRF Tier 1 Grant (RT1/22), consultancy fees from CSL Behring, Boehringer Ingelheim and Pneumagen Ltd, payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca and Chiesi Farmaceutici, and participation on a data safety monitoring board or advisory board with Inovio Pharmaceuticals Inc. and Imam Abdulrahman Bin Faisal University. J.M. Leung and C. Carlsten report grants from Canada Research Chairs program. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024.)

Background/objectives: Qualitative research can be laborious and time consuming, presenting a challenge for practitioners and policymakers seeking rapid, actionable results. Data collection, transcription and analysis are the main contributors to the resource-intensive nature. OpenAI's Chat Generative Pre-trained Transformer (ChatGPT), have demonstrated potential to aid in data analysis. Our study aimed to compare themes generated by ChatGPT (3.5 and 4.0) with traditional human analysis from in-depth interviews., Methods: Three transcripts from an evaluation study to understand patients' experiences at a community eye clinic were used. Transcripts were first analysed by an independent researcher. Next, specific aims, instructions and de-identified transcripts were uploaded to ChatGPT 3.5 and ChatGPT 4.0. Concordance in the themes was calculated as the number of themes generated by ChatGPT divided by the number of themes generated by the researcher. The number of unrelated subthemes and time taken by both ChatGPT were also described., Results: The average time taken per transcript was 11.5 min, 11.9 min and 240 min for ChatGPT 3.5, ChatGPT 4.0 and researcher respectively. Six themes were identified by the researcher: (i) clinic's accessibility, (ii) patients' awareness, (iii) trust and satisfaction, (iv) patients' expectations, (v) willingness to return and (vi) explanation of the clinic by referral source. Concordance for ChatGPT 3.5 and 4.0 ranged from 66 to 100%., Conclusion: Preliminary results showed that ChatGPT significantly reduced analysis time with moderate to good concordance compared with current practice. This highlighted the potential adoption of ChatGPT to facilitate rapid preliminary analysis. However, regrouping of subthemes will still need to be conducted by a researcher., (© 2024. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Adherence to treatment plans is crucial for patients with diabetic foot ulcers (DFUs) to achieve positive outcomes. With limited understanding of nonadherence and its impacts on care outcomes, this study aimed to explore the reasons and factors associated with nonadherence in an integrated diabetic limb salvage (DLS) programme and evaluate its effects on care outcomes. This study included 2798 DFU patients who were enrolled in an integrated DLS programme across multiple institutions in central and northern Singapore from 2020 to 2021. Reasons for nonadherence were obtained via telephone interviews. Factors associated with nonadherence were identified using multiple logistic regression. Differences in one-year outcomes, including minor and major lower extremity amputation (LEA), mortality, LEA-free survival, and healthcare utilisation between adherent and nonadherent patients, were examined based on a significance level of P  < .05. Nonadherence was observed in 40.2% of patients, with higher rates among younger patients, Malays and Indians, and those with higher HbA1c levels. Patient-related factors were the most commonly reported reasons for missed appointments (50.4%). Compared to adherent patients, nonadherent patients exhibited a relatively higher minor LEA rate (13.0% vs 10.2%, OR = 1.18, 95% CI: 0.93, 1.51), lower mortality rate (8.6% vs18.1%, OR = 0.50, 95% CI: 0.39, 0.65), higher overall LEA-free survival (76.4% vs 71.1%, OR = 1.27, 95% CI: 1.06, 1.53), and more hospitalisations (IRR = 1.22, 95% CI: 1.11, 1.33) and emergency visits (IRR = 1.27, 95% CI: 1.16, 1.39). While nonadherent patients showed relatively higher minor LEA rates and more healthcare utilisation, they also exhibited lower mortality and higher LEA-free survival. This suggests that nonadherence in this population may be associated with complex patient characteristics and behaviours that warrant further investigation to tailor interventions effectively., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Artificial Intelligence (AI) is transforming systematic reviews (SRs) in health research by automating processes such as study screening, data extraction, and quality assessment. This perspective highlights recent advancements in AI tools that enhance efficiency and accuracy in SRs. It discusses the benefits, challenges, and future directions of AI integration, emphasising the need for human oversight to ensure the reliability of AI outputs in evidence synthesis and decision-making in healthcare., (© 2024. The Author(s).)

Background: Individuals with chronic lung disease (CLD) are more susceptible to respiratory viral infections; however, significant heterogeneity exists in the literature on CLD and COVID-19 outcomes. Data are lacking on outcomes with newer variants (eg, Omicron) and in vaccinated and boosted populations., Research Question: What are the outcomes of SARS-CoV-2 infection in individuals with CLD during Delta and Omicron transmission in a highly vaccinated and boosted population-based cohort?, Study Design and Methods: Outcomes of Delta and Omicron SARS-CoV-2 infection in a highly vaccinated and boosted cohort of adult Singaporeans with CLD (including asthma, COPD, bronchiectasis, and pulmonary fibrosis) were contrasted against matched population control participants. Calendar time-scale Cox regressions were used to compare risk of infection, COVID-19-related hospitalizations, and severe COVID-19 disease, adjusting for sociodemographic factors and comorbidities., Results: Overall, 68,782 individual patients with CLD and 534,364 matched population control participants were included. By the end of the Omicron wave, 92.7% of patients with CLD were boosted. Compared with control participants, patients with CLD showed higher risk of SARS-CoV-2 infection, COVID-19-related hospitalization, and severe COVID-19 during both the Delta wave (infection: adjusted hazards ratio [aHR], 1.22 [95% CI, 1.17-1.28]; hospitalization: aHR, 1.76 [95% CI, 1.61-1.92]; severe COVID-19: aHR, 1.75 [95% CI, 1.50-2.05]) and Omicron wave (infection: aHR, 1.15 [95% CI, 1.14-1.17]; hospitalization: aHR, 1.82 [95% CI, 1.74-1.91]; severe COVID-19: aHR, 2.39 [95% CI, 2.18-2.63]). During Omicron, significantly higher risk of infection, hospitalization, and severe COVID-19 was observed among patients with asthma (severe COVID-19: aHR, 1.31 [95% CI, 1.10-1.55]) and COPD (severe COVID-19: aHR, 1.36 [95% CI, 1.12-1.66]) compared with control participants. Severe exacerbation (requiring hospitalization) in the preceding year was associated with higher risk of poorer outcomes (Delta, severe COVID-19: aHR, 9.84 [95% CI, 6.33-15.28]; Omicron, severe COVID-19: aHR, 19.22 [95% CI, 15.35-24.06]). Risk was attenuated in the boosted group, with numerically lower HRs against hospitalization and severe COVID-19 in the four-dose group compared with the three-dose group., Interpretation: Increased risk of COVID-19-related hospitalization and severe COVID-19 was observed among patients with CLD compared with matched population control participants during Delta and Omicron predominance. Boosting attenuated serious COVID-19 outcomes., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: S. H. C. reports relationships with CSL Behring LLC, Pneumagen, Boehringer Ingelheim GmbH, Inovio Pharmaceuticals, Inc., and Imam Abdulrahman Bin Faisal University that include board membership and relationships with AstraZeneca Pharmaceuticals LP and Chiesi Pharmaceuticals, Inc., that include speaking and lecture fees. None declared (L. E. W., J. Y. J. T., C. J.C., J. A. A., D. C. B. L., K. B. T.)., (Copyright © 2024 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

This study assessed the cost-effectiveness of continuous positive airway pressure treatment for obstructive sleep apnea in Singapore from a health system perspective. The analysis evaluated a 5-year care pathway using a Markov model, considering per-patient costs of treatment, health system cost savings of obstructive sleep apnea and attributed conditions, the effectiveness measured in disability-adjusted life years with a discount rate of 3% and a weighted 5-year continuous positive airway pressure adherence of 74.1% from Singapore studies. Per-patient costs of treatment were from a large public hospital in Singapore. Efficacy of continuous positive airway pressure treatment, health system costs and disability-adjusted life years were obtained from literature; costs are in US dollars. We conducted probabilistic sensitivity analysis, one-way sensitivity analysis and what-if analysis. Based on a willingness-to-pay threshold of US $50,000 per disability-adjusted life year in USA, continuous positive airway pressure therapy was highly cost-effective, with an incremental cost-effectiveness ratio of $13,822 per disability-adjusted life year averted. Compared with the annual total costs of $856 for patients with continuous positive airway pressure treatment diagnosed by an inpatient sleep study, the total costs for those diagnosed by a home sleep test were $625, resulting in a remarkable 27% reduction per patient per year. One-way sensitivity analysis indicated that costs of treatment, effectiveness of continuous positive airway pressure treatment and adherence had a higher impact on the cost-effectiveness of continuous positive airway pressure therapy. The what-if analysis suggested that for continuous positive airway pressure treatment to be cost-effective, adherence rate should be at least 16.1%. These findings provide valuable insights for policymakers in making informed decisions on funding diagnosis and continuous positive airway pressure therapy within Singapore's healthcare system., (© 2024 European Sleep Research Society.)

Rationale: Chronic infection and inflammation shapes the airway microbiome in bronchiectasis. Utilizing whole-genome shotgun metagenomics to analyze the airway resistome provides insight into interplay between microbes, resistance genes, and clinical outcomes. Objectives: To apply whole-genome shotgun metagenomics to the airway microbiome in bronchiectasis to highlight 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 multicenter cross-sectional Cohort of Asian and Matched European Bronchiectasis 2 (CAMEB 2) study ( n  = 251) and two independent cohorts, one describing patients experiencing acute exacerbation and a further cohort of patients undergoing Pseudomonas aeruginosa eradication treatment. Sputum was subjected to metagenomic sequencing, and the bronchiectasis resistome was evaluated in association with clinical outcomes and underlying host microbiomes. Measurements and Main Results: The bronchiectasis resistome features a unique resistance gene profile and increased counts of aminoglycoside, bicyclomycin, phenicol, triclosan, and multidrug 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 multidrug resistance genes, associate with shorter intervals to the next exacerbation, whereas 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 multidrug resistance, and P. aeruginosa. Successful targeted eradication in P. aeruginosa -colonized individuals mediated reversion from RT2 to RT1, a more clinically favorable resistome profile demonstrating reduced resistance gene diversity. Conclusions: 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.

Background: Variable clinical outcomes are reported with fungal sensitisation in chronic obstructive pulmonary disease (COPD), and it remains unclear which fungi and what allergens associate with the poorest outcomes. The use of recombinant as opposed to crude allergens for such assessment is unknown., Methods: A prospective multicentre assessment of stable COPD (n=614) was undertaken in five hospitals across three countries: Singapore, Malaysia and Hong Kong. Clinical and serological assessment was performed against a panel of 35 fungal allergens including crude and recombinant Aspergillus and non- Aspergillus allergens. Unsupervised clustering and topological data analysis (TDA) approaches were employed using the measured sensitisation responses to elucidate if sensitisation subgroups exist and their related clinical outcomes., Results: Aspergillus fumigatus sensitisation was associated with increased exacerbations in COPD. Unsupervised cluster analyses revealed two "fungal sensitisation" groups. The first was characterised by Aspergillus sensitisation and increased exacerbations, poorer lung function and worse prognosis. Polysensitisation in this group conferred even poorer outcome. The second group, characterised by Cladosporium sensitisation, was more symptomatic. Significant numbers of individuals demonstrated sensitisation responses to only recombinant (as opposed to crude) A. fumigatus allergens f 1, 3, 5 and 6, and exhibited increased exacerbations, poorer lung function and an overall worse prognosis. TDA validated these findings and additionally identified a subgroup within Aspergillus -sensitised COPD of patients with frequent exacerbations., Conclusion: Aspergillus sensitisation is a treatable trait in COPD. Measuring sensitisation responses to recombinant Aspergillus allergens identifies an important patient subgroup with poor COPD outcomes that remains overlooked by assessment of only crude Aspergillus allergens., Competing Interests: Conflict of interest: P.Y. Tiew received honoraria for lectures and advisory board meetings paid to her hospital (Singapore General Hospital) from AstraZeneca, GlaxoSmithKline and Boehringer Ingelheim, outside the submitted work. M.S. Koh received research grant support from AstraZeneca, and honoraria for lectures and advisory board meetings paid to her hospital (Singapore General Hospital) from GlaxoSmithKline, AstraZeneca, Novartis, Sanofi and Boehringer Ingelheim, outside the submitted work. K. Tsaneva-Atanasova reports EPSRC grant EP/T017856/1. F.T. Chew reports personal fees for consultancy from Sime Darby Technology Centre, First Resources Ltd, Genting Plantation and Olam International, outside the submitted work. S.H. Chotirmall is on advisory boards for CSL Behring, Pneumagen Ltd and Boehringer Ingelheim, serves on a data and safety monitoring board for Inovio Pharmaceuticals Inc. and Imam Abdulrahman Bin Faisal University, and has received personal fees from AstraZeneca, all outside of the submitted work. All other authors have no conflicts of interest to declare., (Copyright ©The authors 2023.)

Neisseria species are frequently identified in the bronchiectasis microbiome, but they are regarded as respiratory commensals. Using a combination of human cohorts, next-generation sequencing, systems biology, and animal models, we show that bronchiectasis bacteriomes defined by the presence of Neisseria spp. associate with poor clinical outcomes, including exacerbations. Neisseria subflava cultivated from bronchiectasis patients promotes the loss of epithelial integrity and inflammation in primary epithelial cells. In vivo animal models of Neisseria subflava infection and metabolipidome analysis highlight immunoinflammatory functional gene clusters and provide evidence for pulmonary inflammation. The murine metabolipidomic data were validated with human Neisseria-dominant bronchiectasis samples and compared with disease in which Pseudomonas-, an established bronchiectasis pathogen, is dominant. Metagenomic surveillance of Neisseria across various respiratory disorders reveals broader importance, and the assessment of the home environment in bronchiectasis implies potential environmental sources of exposure. Thus, we identify Neisseria species as pathobionts in bronchiectasis, allowing for improved risk stratification in this high-risk group., Competing Interests: Declaration of interests J.D.C. has received research grants from GSK, BI, AZ, Gilead Sciences, Grifols, and Insmed and has received personal fees from GSK, BI, AZ, Chiesi, Grifols, Napp, Novartis, Insmed, and Zambon, all outside the submitted work. S.H.C. is on advisory boards for CSL Behring, Pneumagen, and BI, serves on Data and Safety Monitoring Boards for Inovio Pharmaceuticals and Imam Abdulrahman Bin Faisal University, and has received personal fees from AZ, all outside of the submitted work., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Allergic bronchopulmonary aspergillosis (ABPA) is associated with frequent exacerbations and poor outcomes in chronic respiratory disease, but remains underdiagnosed. The role of fungal sensitization in bronchiectasis-COPD overlap (BCO) is unknown., Research Question: What is the occurrence and clinical relevance of Aspergillus sensitization and ABPA in BCO when compared with individuals with COPD or bronchiectasis without overlap?, Study Design: Prospective, observational, cross-sectional study., Methods: We prospectively recruited 280 patients during periods of clinical stability with bronchiectasis (n = 183), COPD (n = 50), and BCO (n = 47) from six hospitals across three countries (Singapore, Malaysia, and Scotland). We assessed sensitization responses (as specific IgE) to a panel of recombinant Aspergillus fumigatus allergens and the occurrence of ABPA in relationship to clinical outcomes., Results: Individuals with BCO show an increased frequency and clinical severity of ABPA compared with those with COPD and bronchiectasis without overlap. BCO-associated ABPA is associated with more severe disease, higher exacerbation rates, and lower lung function when compared with ABPA occurring in the absence of overlap. BCO with a severe bronchiectasis severity index (BSI; > 9) is associated significantly with the occurrence of ABPA that is unrelated to underlying COPD severity., Conclusions: BCO demonstrates a high frequency of ABPA that is associated with a severe BSI (> 9) and poor clinical outcomes. Clinicians should maintain a high index of suspicion for the potential development of ABPA in patients with BCO with high BSI., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Objectives: The Integrated Care for Advanced REspiratory Disorders (ICARE) service is a stay-in, post-acute care program for hospitalized patients with chronic, nonmalignant lung diseases. It provides palliative rehabilitation-a novel model integrating functional rehabilitation with early palliative care. We compare reduction of health care utilization among ICARE participants vs matched controls receiving usual care., Design: This is a prospective, propensity score-matched study. Primary outcomes were reduction in hospital readmissions and length of stay and emergency department (ED) visits, comparing the period 6 months before and after ICARE, or 6 months before and after hospital discharge (for controls). Secondary outcomes included 6-minute walking distance (6MWD) and Modified Barthel Index (MBI)., Setting: Participants were matched 1:1 to controls by age, respiratory diagnosis, socioeconomic strata, index hospitalization length of stay, frailty, and recent admissions into intensive care unit or noninvasive ventilation units., Methods: Multidisciplinary interventions focused on symptom relief, functional rehabilitation, targeted comorbidity management, and postdischarge care coordination., Results: One hundred pairs of patients were matched. Participants were older adults (mean age 73.9 ± 8.2 years) with prolonged index hospitalization (median 12.0 days; interquartile range 7-18). Overall, 57% had high Hospital Frailty Risk Scores and 71% had overlapping respiratory diagnoses, the most common commonest being COPD (89%), followed by interstitial lung disease (54%) and bronchiectasis (28%). Small reductions in health care utilization were observed among controls. ICARE was associated with a further 9.1 ± 19.9 days' reduction in hospitalization length of stay (P < .001), 0.8 ± 1.9 lesser admission (P < .001), and 0.6 ± 2.2 fewer ED visits (P < .02). Participants with longest index hospitalization were observed to have greatest reduction in length of stay. 6MWD and MBI scores improved by 41.0 ± 60.2 m and 12.3 ± 11.6 points, respectively (both P < .001). Greater improvement was observed in patients with lower baseline 6MWD and MBI scores. Prescription of slow-release opioids rose from 9% to 49%. Treatment for anxiety and depression rose from 5% to 19%., Conclusions and Implications: Integrating palliative care with postexacerbation functional rehabilitation was associated with short-term reduction in health care utilization, improved functional capacity, and increased treatment of dyspnea, anxiety, and depression., (Copyright © 2021 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Background and Objective: Little is known about the epidemiology and cost of bronchiectasis in Asia. This study describes the disease burden of bronchiectasis in Singapore., Methods: A nationwide administrative dataset was used to identify hospitalisations with bronchiectasis as a diagnosis. Population statistics and medical encounter data were used to estimate the incidence, mortality, prevalence and direct medical costs associated with bronchiectasis requiring hospitalisation., Results: There were 420 incident hospitalised bronchiectasis patients in 2017, giving an incidence rate of 10.6 per 100 000. Age-standardised incidence declined on average by 2.7% per year between 2007 and 2017. Incidence rates increased strongly with age in both men and women. Tuberculosis was a secondary diagnosis in 37.5% of incident hospitalisations in 2007, but has declined sharply since then. Patient survival was considerably lower in both men (5-year relative survival ratios (RSR) 0.63, 95% CI 0.59-0.66) and women (5-year RSR 0.75, 95% CI 0.72-0.78). The point prevalence of bronchiectasis was 147.1 per 100 000 in 2017, and increased sharply with age, with >1% of people aged ≥75 years having bronchiectasis. Total first-year costs among incident bronchiectasis patients in 2016 varied widely, with a mean±sd USD 7331±8863. Approximately 10% of the patients admitted in 2016 had total first-year costs of more than USD 14 380., Conclusion: Bronchiectasis is common and imposes a substantial burden on healthcare costs and survival rates of patients in Singapore., Competing Interests: Conflict of interest: H.P. Phua has nothing to disclose. Conflict of interest: W-Y. Lim has nothing to disclose. Conflict of interest: G. Ganesan has nothing to disclose. Conflict of interest: J. Yoong has nothing to disclose. Conflict of interest: K.B. Tan has nothing to disclose. Conflict of interest: J.A. Abisheganaden has nothing to disclose. Conflict of interest: A.Y.H. Lim has nothing to disclose., (Copyright ©The authors 2021.)

Introduction: Acute respiratory distress syndrome (ARDS) in COVID-19 is associated with a high mortality rate, though outcomes of the different lung compliance phenotypes are unclear. We aimed to measure lung compliance and examine other factors associated with mortality in COVID-19 patients with ARDS., Methods: Adult patients with COVID-19 ARDS who required invasive mechanical ventilation at 8 hospitals in Singapore were prospectively enrolled. Factors associated with both mortality and differences between high (<40mL/cm H 2 O) and low (<40mL/cm H 2 O) compliance were analysed., Results: A total of 102 patients with COVID-19 who required invasive mechanical ventilation were analysed; 15 (14.7%) did not survive. Non-survivors were older (median 70 years, interquartile range [IQR] 67-75 versus median 61 years, IQR 52-66; P <0.01), and required a longer duration of ventilation (26 days, IQR 12-27 vs 8 days, IQR 5-15; P <0.01) and intensive care unit support (26 days, IQR 11-30 vs 11.5 days, IQR 7-17.3; P =0.01), with a higher incidence of acute kidney injury (15 patients [100%] vs 40 patients [46%]; P <0.01). There were 67 patients who had lung compliance data; 24 (35.8%) were classified as having high compliance and 43 (64.2%) as having low compliance. Mortality was higher in patients with high compliance (33.3% vs 11.6%; P =0.03), and was associated with a drop in compliance at day 7 (-9.3mL/cm H 2 O (IQR -4.5 to -15.4) vs 0.2mL/cm H 2 O (4.7 to -5.2) P =0.04)., Conclusion: COVID-19 ARDS patients with higher compliance on the day of intubation and a longitudinal decrease over time had a higher risk of death.

Background: Cardiac troponins (cTn), either conventional or high-sensitive (hscTn) assays, are often performed during acute exacerbations of chronic obstructive pulmonary disease (AECOPD)., Objectives: To compare factors affecting abnormal conventional cTn and hscTn., Methods: We retrospectively studied data from AECOPD patients with conventional or hscTn performed at presentation. Binary logistic regression was used to identify predictors for abnormal conventional cTn (>0.5 ug/L) and hscTn (>40 ng/L)., Results: There were 466 patients in the conventional cTn and 313 patients in the hscTn groups. Ischaemic electrocardiographic change was the only significant predictor for abnormal conventional cTn (OR 6.662 [CI 1.233-35.990], p = 0.028) while B-type natriuretic peptide levels (Adj OR 1.004 [CI 1.000-1.006], p = 0.010) and SpO 2 /FiO 2 ratio (Adj OR 0.115 [CI 0.017-0.069], p = 0.026) were significant predictors of abnormal hscTn., Conclusions: Predictors of abnormal cTn differ between assays and should be taken into consideration when interpreting cTn during AECOPD., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 Elsevier Inc. All rights reserved.)

We aim to describe a case series of critically and non-critically ill COVID-19 patients in Singapore. This was a multicentered prospective study with clinical and laboratory details. Details for fifty uncomplicated COVID-19 patients and ten who required mechanical ventilation were collected. We compared clinical features between the groups, assessed predictors of intubation, and described ventilatory management in ICU patients. Ventilated patients were significantly older, reported more dyspnea, had elevated C-reactive protein and lactate dehydrogenase. A multivariable logistic regression model identified respiratory rate (aOR 2.83, 95% CI 1.24-6.47) and neutrophil count (aOR 2.39, 95% CI 1.34-4.26) on admission as independent predictors of intubation with area under receiver operating characteristic curve of 0.928 (95% CI 0.828-0.979). Median APACHE II score was 19 (IQR 17-22) and PaO2/FiO2 ratio before intubation was 104 (IQR 89-129). Median peak FiO2 was 0.75 (IQR 0.6-1.0), positive end-expiratory pressure 12 (IQR 10-14) and plateau pressure 22 (IQR 18-26) in the first 24 h of ventilation. Median duration of ventilation was 6.5 days (IQR 5.5-13). There were no fatalities. Most COVID-19 patients in Singapore who required mechanical ventilation because of ARDS were extubated with no mortality.

Bronchiectasis, a progressive chronic airway disease, is characterized by microbial colonization and infection. We present an approach to the multi-biome that integrates bacterial, viral and fungal communities in bronchiectasis through weighted similarity network fusion ( https://integrative-microbiomics.ntu.edu.sg ). Patients at greatest risk of exacerbation have less complex microbial co-occurrence networks, reduced diversity and a higher degree of antagonistic interactions in their airway microbiome. Furthermore, longitudinal interactome dynamics reveals microbial antagonism during exacerbation, which resolves following treatment in an otherwise stable multi-biome. Assessment of the Pseudomonas interactome shows that interaction networks, rather than abundance alone, are associated with exacerbation risk, and that incorporation of microbial interaction data improves clinical prediction models. Shotgun metagenomic sequencing of an independent cohort validated the multi-biome interactions detected in targeted analysis and confirmed the association with exacerbation. Integrative microbiomics captures microbial interactions to determine exacerbation risk, which cannot be appreciated by the study of a single microbial group. Antibiotic strategies probably target the interaction networks rather than individual microbes, providing a fresh approach to the understanding of respiratory infection.

Introduction: The chronic obstructive pulmonary disease (COPD) bacteriome associates with disease severity, exacerbations and mortality. While COPD patients are susceptible to fungal sensitisation, the role of the fungal mycobiome remains uncertain., Methods: We report the largest multicentre evaluation of the COPD airway mycobiome to date, including participants from Asia (Singapore and Malaysia) and the UK (Scotland) when stable (n=337) and during exacerbations (n=66) as well as nondiseased (healthy) controls (n=47). Longitudinal mycobiome analysis was performed during and following COPD exacerbations (n=34), and examined in terms of exacerbation frequency, 2-year mortality and occurrence of serum specific IgE (sIgE) against selected fungi., Results: A distinct mycobiome profile is observed in COPD compared with controls as evidenced by increased α-diversity (Shannon index; p<0.001). Significant airway mycobiome differences, including greater interfungal interaction (by co-occurrence), characterise very frequent COPD exacerbators (three or more exacerbations per year) (permutational multivariate ANOVA; adjusted p<0.001). Longitudinal analyses during exacerbations and following treatment with antibiotics and corticosteroids did not reveal any significant change in airway mycobiome profile. Unsupervised clustering resulted in two clinically distinct COPD groups: one with increased symptoms (COPD Assessment Test score) and Saccharomyces dominance, and another with very frequent exacerbations and higher mortality characterised by Aspergillus , Curvularia and Penicillium with a concomitant increase in serum sIgE levels against the same fungi. During acute exacerbations of COPD, lower fungal diversity associates with higher 2-year mortality., Conclusion: The airway mycobiome in COPD is characterised by specific fungal genera associated with exacerbations and increased mortality., Competing Interests: Conflict of interest: P.Y. Tiew has nothing to disclose. Conflict of interest: A.J. Dicker has nothing to disclose. Conflict of interest: H.R. Keir has nothing to disclose. Conflict of interest: M.E. Poh has nothing to disclose. Conflict of interest: S.L. Pang has nothing to disclose. Conflict of interest: M. Mac Aogáin has nothing to disclose. Conflict of interest: B.Q.Y. Chua has nothing to disclose. Conflict of interest: J.L. Tan has nothing to disclose. Conflict of interest: H. Xu has nothing to disclose. Conflict of interest: M.S. Koh has nothing to disclose. Conflict of interest: A. Tee has nothing to disclose. Conflict of interest: J.A. Abisheganaden has nothing to disclose. Conflict of interest: F.T. Chew reports personal fees for consultancy from Sime Darby Technology Centre, First Resources Ltd, Genting Plantation and Olam International, outside the submitted work. Conflict of interest: B.E. Miller is an employee and shareholder of GlaxoSmithKline. Conflict of interest: R. Tal-Singer reports personal fees from Immunomet and VOCALIS Health, outside the submitted work; and is a former employee and current shareholder of GlaxoSmithKline. Conflict of interest: J.D. Chalmers reports grants and personal fees from GlaxoSmithKline, Boehringer Ingelheim, AstraZeneca, Grifols and Insmed, grants from Gilead Sciences, personal fees from Chiesi, Napp, Novartis and Zambon, outside the submitted work. Conflict of interest: S.H. Chotirmall has nothing to disclose., (Copyright ©ERS 2021.)

Background: COVID-19 is a systemic viral infection which mainly targets the human respiratory system with many secondary clinical manifestations especially affecting the hematopoietic system and haemostasis. Few studies have highlighted the prognostic value of blood findings such as lymphopenia, neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, LDH, CRP, cardiac troponin, low-density lipoproteins and chest radiographic abnormality. A study of progressions of blood and radiological results may help to identify patients at high risk of severe outcomes. This systematic review aimed to assess the temporal progression of blood and radiology findings of patients with COVID-19., Methods: Comprehensive systematic literature search was conducted on Medline, Embase and Cochrane databases to identify articles published for peripheral blood investigation and radiological results of COVID-19 patients., Results: A total of 27 studies were included in this review. The common laboratory features reported include lymphopenia, elevated levels of C-reactive proteins and lactate dehydrogenase. For radiological signs, ground-glass opacifications, consolidations, and crazy paving patterns were frequently reported. There is a correlation between lymphocyte count, neutrophil count and biomarkers such as C-reactive proteins and lactate dehydrogenase; at a later phase of the disease (more than 7 days since onset of symptoms), lymphopenia worsens while neutrophil count, C-reactive protein levels and lactate dehydrogenase levels increase. Frequencies of ground-glass opacifications and ground-glass opacifications with consolidations decrease at a later phase of the disease while that of consolidation and crazy paving pattern rises as the disease progresses. More extensive lung involvement was also seen more frequently in the later phases., Conclusion: The correlation between temporal progression and the reported blood and radiological results may be helpful to monitor and evaluate disease progression and severity.

Platypnea-orthodeoxia syndrome (POS) is a rare clinical syndrome characterized by orthostatic oxygen desaturation and positional dyspnea from supine to an upright position. We observed POS in 5 of 20 cases of severe 2019 novel coronavirus (COVID-19) pneumonia, which demonstrated persistently elevated shunt fraction even after liberation from mechanical ventilation. POS was first observed during physiotherapy sessions; median oxygen desaturation was 8 % (range: 8-12 %). Affected individuals were older (median 64 vs 53 years old, p = 0.05) and had lower body mass index (median 24.7 vs 27.6 kg/m 2 , p = 0.03) compared to those without POS. While POS caused alarm and reduced tolerance to therapy, this phenomenon resolved over a median of 17 days with improvement of parenchymal disease. The mechanisms of POS are likely due to gravitational redistribution of pulmonary blood flow resulting in increased basal physiological shunting and upper zone dead space ventilation due to the predominantly basal distribution of consolidative change and reported vasculoplegia and microthrombi in severe COVID-19 disease., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: Allergic sensitisation to fungi such as Aspergillus are associated to poor clinical outcomes in asthma, bronchiectasis and cystic fibrosis; however, clinical relevance in COPD remains unclear., Methods: Patients with stable COPD (n=446) and nondiseased controls (n=51) were prospectively recruited across three countries (Singapore, Malaysia and Hong Kong) and screened against a comprehensive allergen panel including house dust mites, pollens, cockroach and fungi. For the first time, using a metagenomics approach, we assessed outdoor and indoor environmental allergen exposure in COPD. We identified key fungi in outdoor air and developed specific-IgE assays against the top culturable fungi, linking sensitisation responses to COPD outcomes. Indoor air and surface allergens were prospectively evaluated by metagenomics in the homes of 11 COPD patients and linked to clinical outcome., Results: High frequencies of sensitisation to a broad range of allergens occur in COPD. Fungal sensitisation associates with frequent exacerbations, and unsupervised clustering reveals a "highly sensitised fungal predominant" subgroup demonstrating significant symptomatology, frequent exacerbations and poor lung function. Outdoor and indoor environments serve as important reservoirs of fungal allergen exposure in COPD and promote a sensitisation response to outdoor air fungi. Indoor (home) environments with high fungal allergens associate with greater COPD symptoms and poorer lung function, illustrating the importance of environmental exposures on clinical outcomes in COPD., Conclusion: Fungal sensitisation is prevalent in COPD and associates with frequent exacerbations representing a potential treatable trait. Outdoor and indoor (home) environments represent a key source of fungal allergen exposure, amenable to intervention, in "sensitised" COPD., Competing Interests: Conflict of interest: P.Y. Tiew has nothing to disclose. Conflict of interest: F.W.S. Ko has nothing to disclose. Conflict of interest: S.L. Pang has nothing to disclose. Conflict of interest: S.A. Matta has nothing to disclose. Conflict of interest: Y.Y. Sio has nothing to disclose. Conflict of interest: M.E. Poh has nothing to disclose. Conflict of interest: K.J.X. Lau has nothing to disclose. Conflict of interest: M. Mac Aogain has nothing to disclose. Conflict of interest: T.K. Jaggi has nothing to disclose. Conflict of interest: F.X. Ivan has nothing to disclose. Conflict of interest: N.E. Gaultier has nothing to disclose. Conflict of interest: A. Uchida has nothing to disclose. Conflict of interest: D.I. Drautz-Moses has nothing to disclose. Conflict of interest: H. Xu has nothing to disclose. Conflict of interest: M.S. Koh has nothing to disclose. Conflict of interest: D.S.C. Hui has nothing to disclose. Conflict of interest: A. Tee has nothing to disclose. Conflict of interest: J.A. Abisheganaden has nothing to disclose. Conflict of interest: S.C. Schuster has nothing to disclose. Conflict of interest: F.T. Chew has nothing to disclose. Conflict of interest: S.H. Chotirmall has nothing to disclose., (Copyright ©ERS 2020.)

Background: Chitinase activity is an important innate immune defence mechanism against infection that includes fungi. The 2 human chitinases: chitotriosidase (CHIT1) and acidic mammalian chitinase are associated to allergy, asthma, and COPD; however, their role in bronchiectasis and bronchiectasis-COPD overlap (BCO) is unknown., Research Question: What is the association between chitinase activity, airway fungi and clinical outcomes in bronchiectasis and bronchiectasis-COPD overlap?, Study Design and Methods: A prospective cohort of 463 individuals were recruited across five hospital sites in three countries (Singapore, Malaysia, and Scotland) including individuals who were not diseased (n = 35) and who had severe asthma (n = 54), COPD (n = 90), bronchiectasis (n = 241) and BCO (n = 43). Systemic chitinase levels were assessed for bronchiectasis and BCO and related to clinical outcomes, airway Aspergillus status, and underlying pulmonary mycobiome profiles., Results: Systemic chitinase activity is elevated significantly in bronchiectasis and BCO and exceed the activity in other airway diseases. CHIT1 activity strongly predicts bronchiectasis exacerbations and is associated with the presence of at least one Aspergillus species in the airway and frequent exacerbations (≥3 exacerbations/y). Subgroup analysis reveals an association between CHIT1 activity and the "frequent exacerbator" phenotype in South-East Asian patients whose airway mycobiome profiles indicate the presence of novel fungal taxa that include Macroventuria, Curvularia and Sarocladium. These taxa, enriched in frequently exacerbating South-East Asian patients with high CHIT1 may have potential roles in bronchiectasis exacerbations., Interpretation: Systemic CHIT1 activity may represent a useful clinical tool for the identification of fungal-driven "frequent exacerbators" with bronchiectasis in South-East Asian populations., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Rationale: Long-term antibiotic use for managing chronic respiratory disease is increasing; however, the role of the airway resistome and its relationship to host microbiomes remains unknown. Objectives: To evaluate airway resistomes and relate them to host and environmental microbiomes using ultradeep metagenomic shotgun sequencing. Methods: Airway specimens from 85 individuals with and without chronic respiratory disease (severe asthma, chronic obstructive pulmonary disease, and bronchiectasis) were subjected to metagenomic sequencing to an average depth exceeding 20 million reads. Respiratory and device-associated microbiomes were evaluated on the basis of taxonomical classification and functional annotation including the Comprehensive Antibiotic Resistance Database to determine airway resistomes. Co-occurrence networks of gene-microbe association were constructed to determine potential microbial sources of the airway resistome. Paired patient-inhaler metagenomes were compared ( n  = 31) to assess for the presence of airway-environment overlap in microbiomes and/or resistomes. Measurements and Main Results: Airway metagenomes exhibit taxonomic and metabolic diversity and distinct antimicrobial resistance patterns. A "core" airway resistome dominated by macrolide but with high prevalence of β-lactam, fluoroquinolone, and tetracycline resistance genes exists and is independent of disease status or antibiotic exposure. Streptococcus and Actinomyces are key potential microbial reservoirs of macrolide resistance including the ermX , ermF , and msrD genes. Significant patient-inhaler overlap in airway microbiomes and their resistomes is identified where the latter may be a proxy for airway microbiome assessment in chronic respiratory disease. Conclusions: Metagenomic analysis of the airway reveals a core macrolide resistome harbored by the host microbiome.

Background: 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 Southeast Asia. We aim to determine if clusters of Chinese patients with COPD exist and their association with systemic inflammation and clinical outcomes., Research Question: We aim to determine if clusters of Chinese patients with COPD exist and their association with clinical outcomes and inflammation., Study Design and Methods: Chinese patients with stable COPD were prospectively recruited into two cohorts (derivation and validation) from six hospitals across three Southeast Asian countries (Singapore, Malaysia, and Hong Kong; n = 1,480). Each patient was followed more than 2 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 patients with COPD to determine if inflammatory patterns and associated networks characterized the derived clusters., Results: Five patient clusters were identified including: (1) ex-TB, (2) diabetic, (3) low comorbidity: low-risk, (4) low comorbidity: high-risk, and (5) cardiovascular. The cardiovascular and ex-TB clusters demonstrate highest mortality (independent of Global Initiative for Chronic Obstructive Lung Disease assessment) and illustrate diverse cytokine patterns with complex inflammatory networks., Interpretation: We describe clusters of Chinese patients with COPD, two of which represent high-risk clusters. The cardiovascular and ex-TB 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., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Rationale: Allergic sensitization is associated with poor clinical outcomes in asthma, chronic obstructive pulmonary disease, and cystic fibrosis; however, its presence, frequency, and clinical significance in non-cystic fibrosis bronchiectasis remain unclear., Objectives: To determine the frequency and geographic variability that exists in a sensitization pattern to common and specific allergens, including house dust mite and fungi, and to correlate such patterns to airway immune-inflammatory status and clinical outcomes in bronchiectasis., Methods: Patients with bronchiectasis were recruited in Asia (Singapore and Malaysia) and the United Kingdom (Scotland) (n = 238), forming the Cohort of Asian and Matched European Bronchiectasis, which matched recruited patients on age, sex, and bronchiectasis severity. Specific IgE response against a range of common allergens was determined, combined with airway immune-inflammatory status and correlated to clinical outcomes. Clinically relevant patient clusters, based on sensitization pattern and airway immune profiles ("immunoallertypes"), were determined., Measurements and Main Results: A high frequency of sensitization to multiple allergens was detected in bronchiectasis, exceeding that in a comparator cohort with allergic rhinitis (n = 149). Sensitization was associated with poor clinical outcomes, including decreased pulmonary function and more severe disease. "Sensitized bronchiectasis" was classified into two immunoallertypes: one fungal driven and proinflammatory, the other house dust mite driven and chemokine dominant, with the former demonstrating poorer clinical outcome., Conclusions: Allergic sensitization occurs at high frequency in patients with bronchiectasis recruited from different global centers. Improving endophenotyping of sensitized bronchiectasis, a clinically significant state, and a "treatable trait" permits therapeutic intervention in appropriate patients, and may allow improved stratification in future bronchiectasis research and clinical trials.

Inhaled antibiotic nanoparticles have emerged as an effective strategy to control infection in bronchiectasis lung owed to their mucus-penetrating ability. Using ciprofloxacin (CIP) as the model antibiotic, we evaluated dry powder inhaler (DPI) formulations of two classes of antibiotic nanoparticles (i.e. liposome and nanoplex) in their (1) physical characteristics (i.e. size, zeta potential, CIP payload, preparation efficiency), (2) dissolution in artificial sputum medium, (3) ex vivo mucus permeability, (4) antimicrobial activity against Pseudomonas aeruginosa in mucus, (5) cytotoxicity towards human lung epithelium cells, and (6) in vitro aerosolization efficiency. The results showed that the CIP nanoplex exhibited fast dissolution with CIP supersaturation generation, in contrast to the slower release of the liposome (80 versus 30% dissolution after 1 h). Both nanoparticles readily overcame the mucus barrier attributed to their nanosize and mucus-inert surface (50% permeation after 1 h), leading to their similarly high antipseudomonal activity. The CIP liposome, however, possessed much lower CIP payload than the nanoplex (84% versus 3.5%), resulting in high lipid contents in its DPI formulation that led to higher cytotoxicity and lower aerosolization efficiency. The CIP nanoplex thus represented a superior formulation owed to its simpler preparation, higher CIP payload hence lower dosage, better aerosolization, and lower cytotoxicity., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Non-cystic fibrosis bronchiectasis (NCFB) characterized by permanent bronchial dilatation and recurrent infections has been clinically managed by long-term intermittent inhaled antibiotic therapy among other treatments. Herein we investigated dry powder inhaler (DPI) formulation of ciprofloxacin (CIP) nanoplex with mannitol/lactose as the excipient for NCFB therapy. The DPI of CIP nanoplex was evaluated against DPI of native CIP in terms of their (1) dissolution characteristics in artificial sputum medium, (2) ex vivo mucus permeability in sputum from NCFB and healthy individuals, (3) antibacterial efficacy in the presence of sputum against clinical Pseudomonas aeruginosa strains (planktonic and biofilm), and (4) cytotoxicity towards human lung epithelial cells. Despite their similarly fast dissolution rates in sputum, the DPI of CIP nanoplex exhibited superior mucus permeability to the native CIP (5-7 times higher) attributed to its built-in ability to generate highly supersaturated CIP concentration in the sputum. The superior mucus permeability led to the CIP nanoplex's higher antibacterial efficacy (>3 log 10 CFU/mL). The DPI of CIP nanoplex exhibited similar cytotoxicity towards the lung epithelial cells as the native CIP indicating its low risk of toxicity. These results established the promising potential of DPI of CIP nanoplex as a new therapeutic avenue for NCFB., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Understanding the composition and clinical importance of the fungal mycobiome was recently identified as a key topic in a "research priorities" consensus statement for bronchiectasis.Patients were recruited as part of the CAMEB study: an international multicentre cross-sectional Cohort of Asian and Matched European Bronchiectasis patients. The mycobiome was determined in 238 patients by targeted amplicon shotgun sequencing of the 18S-28S rRNA internally transcribed spacer regions ITS1 and ITS2. Specific quantitative PCR for detection of and conidial quantification for a range of airway Aspergillus species was performed. Sputum galactomannan, Aspergillus specific IgE, IgG and TARC (thymus and activation regulated chemokine) levels were measured systemically and associated to clinical outcomes.The bronchiectasis mycobiome is distinct and characterised by specific fungal genera, including Aspergillus , Cryptococcus and Clavispora Aspergillus fumigatus (in Singapore/Kuala Lumpur) and Aspergillus terreus (in Dundee) dominated profiles, the latter associating with exacerbations. High frequencies of Aspergillus- associated disease including sensitisation and allergic bronchopulmonary aspergillosis were detected. Each revealed distinct mycobiome profiles, and associated with more severe disease, poorer pulmonary function and increased exacerbations.The pulmonary mycobiome is of clinical relevance in bronchiectasis. Screening for Aspergillus -associated disease should be considered even in apparently stable patients., Competing Interests: Conflict of interest: F.T. Chew reports personal fees from Sime Darby Technology Center, Olam International and First Resources Ltd, outside the submitted work. J.D. Chalmers reports grants from AstraZeneca, grants and personal fees from GlaxoSmithKline, Boehringer Ingelheim, Pfizer, Bayer Healthcare and Grifols, and personal fees from Napp, outside the submitted work., (Copyright ©ERS 2018.)

Background: Non-tuberculous mycobacteria (NTM) infection is an increasing problem worldwide. The epidemiology of NTM in most Asian countries is unknown. This study investigated the epidemiology, and clinical profile of inpatients in whom NTM was isolated from various anatomical sites in a Singaporean population attending a major tertiary referral centre., Methods: Demographic profile, clinical data, and characteristics of patients hospitalized with NTM isolates at a major tertiary hospital over two-year period were prospectively assessed (2011-2012). Data collected included patient demographics, ethnicity, smoking status, co-morbidities, NTM species, intensive care unit (ICU) treatment, and mortality., Results: A total of 485 patients (62.1% male) with 560 hospital admissions were analysed. The median patient age was 70 years. Thirteen different NTM species were isolated from this cohort. Mycobacterium abscessus (M. abscessus) (38.4%) was most frequently isolated followed by Mycobacterium fortuitum (M. fortuitum) (16.6%), Mycobacterium avium complex (MAC) (16.3%), Mycobacterium kansasii (M. kansasii) (15.4%), and Mycobacterium gordonae (M. gordonae) (6.8%). Most (91%) NTM was isolated from the respiratory tract. The three most common non-pulmonary sites were; blood (2.7%), skin wounds and abscesses (2.1%), and gastric aspirates (1.1%). A third (34.4%) of the study population had prior pulmonary tuberculosis (PTB). There was a significant association between isolated NTM species, and patient age (p = 0.0002). Eleven (2.2%) patients received intensive care unit (ICU) treatment during the study period and all cause mortality within 1 year of the study was 16.9% (n = 82). Of these, 72 (87.8%) patients died of pulmonary causes., Conclusions: The profile of NTM species in Singapore is unique. M. abscessus is the commonest NTM isolated, with a higher prevalence in males, and in the elderly. High NTM prevalence is associated with high rates of prior PTB in our cohort.

Background: Despite the strong association of asthma exacerbations with rhinovirus (RV) infection, inoculation of asthmatic subjects with RV only causes small changes in lower airway function, suggesting that RV infection is not itself sufficient to provoke asthma exacerbations., Objective: Our purpose was to test whether allergic inflammation increases the airway response to RV infection., Methods: We compared the severity of RV type 16-induced colds in 2 groups of 10 subjects with allergic rhinitis. One group received 3 nasal challenges with allergen and the other received challenges with placebo over the week before nasal inoculation with RV type 16 (4000 tissue culture infective dose 50% per subject). Subjects kept symptom diaries and were assessed with spirometry, methacholine challenge, nasal lavage, and sputum induction on days 2, 4, 7, 10, 15, and 30 after inoculation., Results: The 2 groups developed equal rates of infection (90%), similar cold symptoms (Jackson score median [interquartile range], 11 [6-33] vs 20.5 [6-42] for allergen and placebo groups respectively, P =.54), and similar changes in cellular profile and in IL-6 and IL-8 concentrations in nasal lavage fluid and induced sputum after RV inoculation. The incubation period was significantly longer in the allergen group (2.5 [1-5.5] vs 1 [1-1] day, P =.03) and the duration of cold symptoms was shorter (5 [4-7] vs 8.5 [6-10] days, P =.008). We also found an inverse correlation between the percent of eosinophils in nasal lavage fluid before inoculation and the severity of cold symptoms (r = -0.58, P =. 008)., Conclusion: In subjects with allergic rhinitis, augmented nasal allergic inflammation before inoculation with RV type 16 does not worsen the severity of cold symptoms but delays their onset and shortens their duration.

Purpose: Macrolide antibiotics are frequently prescribed to patients with symptoms of a common cold. Despite their lack of proven antiviral activity, macrolide antibiotics may have anti-inflammatory actions, such as inhibition of mucus secretion and production of interleukins 6 and 8 by epithelial cells. Because the symptoms of rhinovirus colds are attributed to the inflammatory response to infection, we studied the effects of treatment with clarithromycin on the symptomatic and inflammatory response to nasal inoculation with rhinovirus., Subjects and Methods: We performed a prospective, double-blind, controlled trial in 24 healthy subjects who were seronegative for antibodies to rhinovirus-16. Subjects were randomly assigned to receive either clarithromycin (500 mg) or trimethoprim-sulfamethoxazole (800/160 mg, as a control antibiotic) twice a day for 8 days, beginning 24 hours before inoculation with rhinovirus-16., Results: All 12 subjects in each group were infected and developed symptomatic colds. The groups did not differ in the intensity of cold symptoms (median [25th to 75th percentile] score in the clarithromycin group of 25 [5 to 33] versus 21 [11 to 26] in the trimethoprim-sulfamethoxazole group, P = 0.86), weight of nasal secretions (25 g [8 to 56 g] versus 12 g [5 to 28 g], P = 0.27), or decline in nasal peak flow during the 8 days following viral inoculation. In both groups, similar and significant increases from baseline were observed in the numbers of total cells and neutrophils, and in the concentrations of interleukins 6 and 8, in nasal lavage fluid during the cold. The changes that we observed did not differ from those in an untreated historical control group., Conclusions: We conclude that clarithromycin treatment has little or no effect on the severity of cold symptoms or the intensity of neutrophilic nasal inflammation in experimental rhinovirus-16 colds.