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Chronic obstructive pulmonary disease (COPD) is the end result of a series of dynamic and cumulative gene–environment interactions over a lifetime. The evolving understanding of COPD biology provides novel opportunities for prevention, early diagnosis, and intervention. To advance these concepts, we propose therapeutic trials in two major groups of subjects: “young” individuals with COPD and those with pre-COPD. Given that lungs grow to about 20 years of age and begin to age at approximately 50 years, we consider “young” patients with COPD those patients in the age range of 20–50 years. Pre-COPD relates to individuals of any age who have respiratory symptoms with or without structural and/or functional abnormalities, in the absence of airflow limitation, and who may develop persistent airflow limitation over time. We exclude from the current discussion infants and adolescents because of their unique physiological context and COPD in older adults given their representation in prior randomized controlled trials (RCTs). We highlight the need of RCTs focused on COPD in young patients or pre-COPD to reduce disease progression, providing innovative approaches to identifying and engaging potential study subjects. We detail approaches to RCT design, including potential outcomes such as lung function, patient-reported outcomes, exacerbations, lung imaging, mortality, and composite endpoints. We critically review study design components such as statistical powering and analysis, duration of study treatment, and formats to trial structure, including platform, basket, and umbrella trials. We provide a call to action for treatment RCTs in 1) young adults with COPD and 2) those with pre-COPD at any age.

Inhalation of nanoparticles emitted from toner-based printing equipment (TPE), such as laser printers and photocopiers, also known as PEPs, has been associated with systemic inflammation, hypertension, cardiovascular disease, respiratory disorders, and genotoxicity. Global serum metabolomics analysis in 19 healthy TPE operators found 52 dysregulated biomolecules involved in upregulation of inflammation, immune, and antioxidant responses and downregulation of cellular energetics and cell proliferation. Here, we build on the metabolomics study by investigating the association of a panel of nine urinary OS biomarkers reflecting DNA/RNA damage (8OHdG, 8OHG, and 5OHMeU), protein/amino acid oxidation (o-tyrosine, 3-chlorotyrosine, and 3-nitrotyrosine), and lipid oxidation (8-isoprostane, 4-hydroxy nonenal, and malondialdehyde [MDA]), as well as plasma total MDA and total protein carbonyl (TPC), with several nanoparticle exposure metrics in the same 19 healthy TPE operators. Plasma total MDA, urinary 5OHMeU, 3-chlorotyrosine, and 3-nitrotyrosine were positively, whereas o-tyrosine inversely and statistically significantly associated with PEPs exposure in multivariate models, after adjusting for age and urinary creatinine. Urinary 8OHdG, 8OHG, 5OHMeU, and total MDA in urine and plasma had group mean values higher than expected in healthy controls without PEPs exposure and comparable to those of workers experiencing low to moderate levels of oxidative stress (OS). The highest exposure group had OS biomarker values, most notably 8OHdG, 8OHG, and total MDA, that compared to workers exposed to welding fumes and titanium dioxide. Particle number concentration was the most sensitive and robust exposure metric. A combination of nanoparticle number concentration and OS potential of fresh aerosols is recommended for larger scale future studies.

The microbiology in bronchiectasis has been historically defined by culture-based analysis of the airway microbiome and to date has largely focused on the detection and eradication of specific bacterial pathogens. Although central to our current understanding of disease, microbial culture alone masks the holistic complexity of the microbiome and does not account for potential microbial interactions that define specific clinical phenotypes such as frequent exacerbators. Advances in next-generation sequencing including their analytical technologies can further complement and build upon our current understanding of the microbiology and microbiome in bronchiectasis providing improved patient stratification with prognostic significance.

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. Published version

The last decade of research has revolutionized our understanding of respiratory microbiology, revealing that the lungs and airways contain diverse and dynamic microbial communities in health and disease. This “respiratory ecosystem”—a densely interconnected environment of microbial and host interactions—represents a tremendous and under-appreciated source of biological and clinical heterogeneity across patients with acute and chronic lung disease. Unlike other major sources of heterogeneity, such as comorbidities and host genetics, the respiratory microbiome is readily modifiable by clinical interventions, and therefore represents an untapped opportunity for therapeutic manipulation. As a potential “treatable trait” in efforts to subphenotype patients and deliver precision medicine, the respiratory microbiome is a promising therapeutic target. In this Pulmonary Perspective, we identify and discuss multiple challenges, both conceptual and practical, that must be overcome before the respiratory microbiome can be effectively modulated as a therapeutic target. Barriers include: 1) the need to identify specific microbiologic and ecologic “targets” for therapeutic modulation; 2) the need for an improved understanding of the efficacy and persistence of response to respiratory microbiome-modulating interventions; 3) the need for clinicians to be able to access, understand and utilize microbiome data for sub-phenotyping patients, and 4) specific concerns in special populations (including children, patients with chronic lung disease, and critically ill patients). By delineating these barriers, we identify opportunities for prospective research to advance our understanding of the respiratory microbiome, its role in human respiratory disease, and its genuine potential as a therapeutic target.

Pulmonary mycoses remain a global threat, causing significant morbidity and mortality. Patients with airways disease, including COPD and bronchiectasis, are at increased risks of pulmonary mycoses and its associated complications. Frequent use of antibiotics and corticosteroids coupled with impaired host defenses predispose patients to fungal colonization and airway persistence, which are associated with negative clinical consequences. Notably

Printers are everyday devices in both our homes and workplaces. We have previously found high occupational exposure levels to toner-based printer emitted nanoparticles (PEPs) at printing centers. To elucidate the potential health effects from exposure to PEPs, a total of 124 human serum samples were collected from 32 workers in the printing centers during the repeated follow-up measurements, and global serum metabolomics were analyzed in three ways: correlation between metabolic response and personal exposure (dose response exposure); metabolite response changes between Monday and Friday of a work week (short-term exposure), and metabolite response in relation to length of service in a center (long-term exposure). A total of 52 key metabolites changed significantly in relation to nanoparticle exposure levels. The primary dysregulated pathways included inflammation and immunity related arginine and tryptophan metabolism. Besides, some distinct metabolite expression patterns were found to occur during the transition from short-term to long-term exposures, suggesting cumulative effect of PEPs exposure. These findings, for the first time, highlight the inhalation exposure responses to printer emitted nanoparticles at the metabolite level, potentially serving as pre-requisites for whole organism and population responses, and are inline with emerging findings on potential health effects. Nanyang Technological University Submitted/Accepted version This study was supported by Nanyang Technological University – Harvard School of Public Health Initiative for Sustainable Nanotechnology (NTU-Harvard SusNano; Ref. No. NTU-HSPH 17001). This work was also funded by the Engineered Nanomaterials Resource and Coordination Core established at Harvard T. H. Chan School of Public Health (NIH grant # U24ES026946) as part of the Nanotechnology Health Implications Research (NHIR) Consortium.

Emerging data supports the existence of a microbial 'gut-lung' axis that remains unexplored in bronchiectasis.Prospective and concurrent sampling of gut (stool) and lung (sputum) was performed in a cohort of n=57 individuals with bronchiectasis and subjected to bacteriome (16S rRNA) and mycobiome (18S ITS) sequencing (total 228 microbiomes). Shotgun metagenomics was performed in a subset (n=15; 30 microbiomes). Data from gut and lung compartments were 'integrated' by weighted Similarity Network Fusion (wSNF), clustered and subjected to co-occurrence analysis to evaluate 'gut-lung' networks. Murine experiments were undertaken to validate specific Pseudomonas-driven 'gut-lung' interactions.Microbial communities in stable bronchiectasis demonstrate significant 'gut-lung' interaction. Multi-biome integration followed by unsupervised clustering reveals two patient clusters, differing by 'gut-lung' interactions and with contrasting clinical phenotypes. A 'high gut-lung interaction' cluster characterized by lung Pseudomonas, gut Bacteroides and gut Saccharomyces associates with increased exacerbations, greater radiological and overall bronchiectasis severity while the 'low gut-lung interaction' cluster demonstrates an overrepresentation of lung commensals including Prevotella, Fusobacterium and Porphyromonas with gut Candida. The lung Pseudomonas-gut Bacteroides relationship, observed in the 'high gut-lung interaction' bronchiectasis cluster, was validated in a murine model of lung Pseudomonas aeruginosa (PAO1) infection. This interaction was abrogated following antibiotic (imipenem) pre-treatment in mice confirming the relevance and therapeutic potential of targeting the gut microbiome to influence the 'gut-lung' axis. Metagenomics in a subset of individuals with bronchiectasis corroborated our findings from targeted analyses.A dysregulated 'gut-lung' axis, driven by lung Pseudomonas, associates with poorer clinical outcomes in bronchiectasis. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

Accelerated by developments in DNA sequencing technologies, our understanding of the respiratory microbiome is advancing at pace, providing unprecedented opportunities for clinical translation. Building on the early observations of sub-clinical micro-aspiration in healthy individuals, and initial culture independent microbiome studies in respiratory disease, recent work reveals an expansive microbial ecosystem that encompasses bacterial, fungal and viral constituents. This has led to major paradigm shifts including the potential importance of airway microbial networks in chronic respiratory disease states. As a complex organ system, with varying topology and a mucosal surface area exceeding that of the gut, the respiratory tract is recognized as a key site of host-microbe interaction. The airway experiences dynamic and continuous microbial exposures on breathing, shaped by climate and environmental surroundings, and is further influenced by sub clinical micro-aspiration of resident upper-airway microbes. The respiratory microbiome exists as an ecological gradient from upper to lower airway, interacting with host epithelia in balance between immune homeostasis and pathology. Current models posit that a balanced host-microbe interaction establishes in early life with a protective immune response that become dysregulated in respiratory disease. Characterization of microbial aberration as early indicators of deteriorating respiratory health is therefore a fundamental concept underpinning its potential clinical applications. Detecting microbial dysbiosis from otherwise ‘healthy microbiomes’ represents a potential opportunity for personalized phenotyping, stratification and therapeutic intervention. Despite such promise, this relatively nascent field has inherent challenges that need addressing as we seek to translate research gains in our understanding of the airway microbiome into tangible clinical applications for respiratory medicine.

PURPOSE OF REVIEW Next-generation sequencing (NGS) has deepened our understanding of the respiratory microbiome in health and disease. The number of microbiome studies employing sputum as an airway surrogate has continued to increase over the past decade to include multiple large multicentre and longitudinal studies of the microbiome in chronic obstructive pulmonary disease (COPD). In this review, we summarize the recent advances to our understanding of the bacteriome, virome and mycobiome in COPD. RECENT FINDINGS Diverse microbiome profiles are reported in COPD. The neutrophilic Haemophilus-predominant bacteriome remains a prominent COPD phenotype, relatively stable over time and during exacerbations. Studies of the virome remain limited but reveal a potential involvement of viruses and bacteriophages particularly during COPD exacerbations and advancing disease severity. Mycobiome signatures, even in stable COPD are associated with poorer clinical outcomes including mortality. SUMMARY The sputum microbiome in COPD is being increasingly recognized for its clinical relevance, even in the stable state. Future studies integrating microbial kingdoms holistically (i.e. bacterial, viral and fungal) will provide deeper insight into its functionality including the relevance of microbial interactions and effect of treatment on microbiome-associated clinical outcomes.

BackgroundThere are few data to support accurate interpretation of spirometry data in South Asia, a major global region with a high reported burden of chronic respiratory disease.MethodWe measured lung function in 7453 healthy men and women aged ≥18 years, from Bangladesh, North India, South India, Pakistan and Sri Lanka, as part of the South Asia Biobank study. First, we assessed the accuracy of existing equations for predicting normal forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and FEV1/FVC ratio. Then, we used our data to derive (n=5589) and internally validate (n=1864) new prediction equations among South Asians, with further external validation among 339 healthy South Asians living in Singapore.ResultsThe Global Lung Initiative (GLI) and National Health and Nutrition Examination Survey consistently overestimated expiratory volumes (best fit GLI-African American, mean±sdz-score: FEV1−0.94±1.05, FVC −0.91±1.10; n=7453). Age, height and weight were strong predictors of lung function in our participants (p10.03±0.99, FVC 0.04±0.97, FEV1/FVC −0.03±0.99) and external validation (z-scores: FEV10.31±0.99, FVC 0.24±0.97, FEV1/FVC 0.16±0.91). Further adjustment for study regions improves the model fit, with highest accuracy for estimation of region-specific lung function in South Asia.ConclusionWe present improved equations for predicting lung function in South Asians. These offer the opportunity to enhance diagnosis and management of acute and chronic lung diseases in this major global population.

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. Ministry of Education (MOE) Ministry of Health (MOH) National Medical Research Council (NMRC) Published version This research is supported by the Singapore General Hospital Research Grant (SRG-OPN-06-2021) (P.Y. Tiew) and the Singapore Ministry of Health's National Medical Research Council under its Clinician-Scientist Individual Research Grant (MOH-000141) (S.H. Chotirmall) and Clinician-Scientist Award (MOH-000710) (S.H. Chotirmall). K. Tsaneva-Atanasova gratefully acknowledges the financial support of the EPSRC via grant EP/T017856/1. F.T. Chew (Singapore) received grants from the National University of Singapore (N-154-000-038-001), Singapore Ministry of Education Academic Research Fund (R-154-000-191-112, 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, R-154-000-A91-592, R-154-000-A95-592, R154-000-B99-114), Biomedical Research Council (Singapore) (BMRC/01/1/21/18/077, BMRC/04/1/21/19/315, BMRC/APG2013/108), Singapore Immunology Network (SIgN-06-006, SIgN-08-020), National Medical Research Council (Singapore) (NMRC/1150/2008), and the Agency for Science Technology and Research (Singapore) (H17/01/a0/008 and APG2013/108). Funding information for this article has been deposited with the Crossref Funder Registry.