Distinct 'Immuno-Allertypes' of Disease and High Frequencies of Sensitisation in Non-Cystic-Fibrosis Bronchiectasis

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.Ministry of Education (MOE)Ministry of Health (MOH)National Medical Research Council (NMRC)Published versionSupported by the Singapore Ministry of Health’s National Medical Research Council under its Transition Award NMRC/TA/0048/2016 (S.H.C.) and Changi General Hospital Research grant CHF2016.03-P (T.B.L.). The work performed at NUS was supported by the Singapore Ministry of Education Academic Research Fund, SIgN, and National Medical Research Council grants N-154-000-038-001, R-154-000-404-112, R-154-000-553-112, R-154-000-565-112, R-154-000-630-112, R-154-000-A08-592, R-154-000-A27-597, SIgN-06-006, SIgN-08-020, and NMRC/1150/2008 (F.T.C.); J.D.C. is supported by the GSK/British Lung Foundation Chair of Respiratory Research

Metagenomics reveals a core macrolide resistome related to microbiota in chronic respiratory disease

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this recordRationale: 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 Objective: To evaluate airway resistomes, and, relate them to host and environmental microbiomes using ultra-deep metagenomic shotgun sequencing Methods: Airway specimens from n=85 individuals with and without chronic respiratory disease (severe asthma, COPD and bronchiectasis) were subjected to metagenomic sequencing to an average depth exceeding twenty million reads. Respiratory and device-associated microbiomes were evaluated based on taxonomical classification and functional annotation including the Comprehensive Antibiotic Resistance Database (CARD) 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. 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 exist, 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. Conclusion: Metag

‘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

The role of acute and chronic respiratory colonization and infections in the pathogenesis of COPD

© 2017 Asian Pacific Society of Respirology COPD is a major global concern, increasingly so in the context of ageing populations. The role of infections in disease pathogenesis and progression is known to be important, yet the mechanisms involved remain to be fully elucidated. While COPD pathogens such as Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae are strongly associated with acute exacerbations of COPD (AECOPD), the clinical relevance of these pathogens in stable COPD patients remains unclear. Immune responses in stable and colonized COPD patients are comparable to those detected in AECOPD, supporting a role for chronic colonization in COPD pathogenesis through perpetuation of deleterious immune responses. Advances in molecular diagnostics and metagenomics now allow the assessment of microbe–COPD interactions with unprecedented personalization and precision, revealing changes in microbiota associated with the COPD disease state. As microbial changes associated with AECOPD, disease severity and therapeutic intervention become apparent, a renewed focus has been placed on the microbiology of COPD and the characterization of the lung microbiome in both its acute and chronic states. Characterization of bacterial, viral and fungal microbiota as part of the lung microbiome has the potential to reveal previously unrecognized prognostic markers of COPD that predict disease outcome or infection susceptibility. Addressing such knowledge gaps will ultimately lead to a more complete understanding of the microbe–host interplay in COPD. This will permit clearer distinctions between acute and chronic infections and more granular patient stratification that will enable better management of these features and of COPD

A clinical prediction model for hospitalized COPD exacerbations based on “treatable traits”

Anthony CA Yii,1 CH Loh,1 PY Tiew,2,3 Huiying Xu,4 Aza AM Taha,1 Jansen Koh,1 Jessica Tan,5 Therese S Lapperre,6,7 Antonio Anzueto,8 Augustine KH Tee1 1Department of Respiratory and Critical Care Medicine, Changi General Hospital, Singapore; 2Department of Respiratory and Critical Care Medicine, Singapore General Hospital, Singapore; 3Translational Respiratory Research Laboratory, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; 4Department of Respiratory and Critical Care Medicine, Tan Tock Seng Hospital, Singapore; 5Department of General Medicine, Sengkang General Hospital, Singapore; 6Department of Respiratory Medicine, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark; 7Duke-National University of Singapore Medical School, Singapore; 8Division of Pulmonary Diseases and Critical Care Medicine, Department of Medicine, UT Health Science Center, San Antonio, TX, USA Background: Assessing risk of future exacerbations is an important component in COPD management. History of exacerbation is a strong and independent predictor of future exacerbations, and the criterion of ≥2 nonhospitalized or ≥1 hospitalized exacerbation is often used to identify high-risk patients in whom therapy should be intensified. However, other factors or “treatable traits” also contribute to risk of exacerbation.Objective: The objective of the study was to develop and externally validate a novel clinical prediction model for risk of hospitalized COPD exacerbations based on both exacerbation history and treatable traits.Patients and methods: A total of 237 patients from the COPD Registry of Changi General Hospital, Singapore, aged 75±9 years and with mean post-bronchodilator FEV1 60%±20% predicted, formed the derivation cohort. Hospitalized exacerbation rate was modeled using zero-inflated negative binomial regression. Calibration was assessed by graphically comparing the agreement between predicted and observed annual hospitalized exacerbation rates. Predictive (discriminative) accuracy of the model for identifying high-risk patients (defined as experiencing ≥1 hospitalized exacerbations) was assessed with area under the curve (AUC) and receiver operating characteristics analyses, and compared to other existing risk indices. We externally validated the prediction model using a multicenter dataset comprising 419 COPD patients.Results: The final model included hospitalized exacerbation rate in the previous year, history of acute invasive/noninvasive ventilation, coronary artery disease, bronchiectasis, and sputum nontuberculous mycobacteria isolation. There was excellent agreement between predicted and observed annual hospitalized exacerbation rates. AUC was 0.789 indicating good discriminative accuracy, and was significantly higher than the AUC of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) risk assessment criterion (history of ≥1 hospitalized exacerbation in the previous year) and the age, dyspnea, and obstruction index. When applied to the independent multicenter validation cohort, the model was well-calibrated and discrimination was good.Conclusion: We have derived and externally validated a novel risk prediction model for COPD hospitalizations which outperforms several other risk indices. Our model incorporates several treatable traits which can be targeted for intervention to reduce risk of future hospitalized exacerbations. Keywords: exacerbations, clinical prediction model, risk assessment &nbsp

Sensitisation to recombinant Aspergillus fumigatus allergens and clinical outcomes in COPD.

This is the author accepted manuscript. The final version is available from the European Respiratory Society via the DOI in this recordBACKGROUND: Variable clinical outcomes are reported with fungal sensitisation in COPD, and it remains unclear which fungi and what allergens associate with poorest outcomes. The use of recombinant as opposed to crude allergens for such assessment is unknown. METHODS: A prospective multicenter 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 sub-groups exist and their related clinical outcomes. RESULTS: Aspergillus fumigatus sensitisation associates with increased exacerbations in COPD. Unsupervised cluster analyses reveal two "fungal sensitisation" groups, one characterized by Aspergillus sensitisation and increased exacerbations, poorer lung function and worse prognosis. Polysensitisation in this group confers even poorer outcome. The second group, characterized by Cladosporium sensitisation is more symptomatic. Significant numbers of individuals demonstrate sensitisation responses to only recombinant (as opposed to crude) Aspergillus fumigatus allergens 1, 3, 5, and 6, and exhibit higher exacerbations, poorer lung function and an overall worse prognosis. TDA validated these findings and additionally identified a sub-group within "Aspergillus sensitised COPD" enriched for frequent exacerbators. 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 remain overlooked by assessment of only crude Aspergillus allergens.Engineering and Physical Sciences Research Council (EPSRC)Singapore General Hospital Research GrantSingapore Ministry of Health's National Medical Research CouncilSingapore Ministry of Health's National Medical Research CouncilNational University of SingaporeSingapore Ministry of Education Academic Research FundSingapore Ministry of Education Academic Research FundSingapore Ministry of Education Academic Research FundSingapore Ministry of Education Academic Research FundSingapore Ministry of Education Academic Research FundSingapore Ministry of Education Academic Research FundSingapore Ministry of Education Academic Research FundSingapore Ministry of Education Academic Research FundSingapore Ministry of Education Academic Research FundSingapore Ministry of Education Academic Research FundBiomedical Research Council (BMRC) (Singapore)Biomedical Research Council (BMRC) (Singapore)Biomedical Research Council (BMRC) (Singapore)Singapore Immunology NetworkSingapore Immunology NetworkNational Medical Research Council (NMRC) (Singapore)Agency for Science Technology and Research (A*STAR) (Singapore)Agency for Science Technology and Research (A*STAR) (Singapore