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Background <p>Comorbidity-based risk stratification in Chronic Obstructive Pulmonary Disease (COPD) incompletely captures inherent biological heterogeneity, particularly in Asian populations that demonstrate high-risk clinical phenotypes including prior pulmonary tuberculosis. We investigated whether integrated sputum multi-omics could improve risk stratification in an Asian COPD cohort.</p> Methods <p>We conducted a prospective, multicenter assessment of <i>N</i> = 56 Asians with established COPD, classified as high- (<i>N</i> = 25; cardiovascular or ex-tuberculosis) or low-risk (<i>N</i> = 31; diabetic or low-comorbidity) based on established co-morbidity phenotyping. Sputum was subjected to mucus analysis (MUC5AC, MUC5B, mucus solids, rheology), metabo-lipidomics (LC-MS/MS) and microbiome assessment (shotgun metagenomics). Multivariate statistics was employed to integrate datasets.</p> Results <p>High-risk Asian COPD demonstrates abnormal mucus biochemistry characterized by elevated MUC5AC; extensive metabo-lipidomic alterations characterized by dysregulated tryptophan-kynurenine metabolism and lipid remodeling with enrichment of lysophosphatidylcholines and triacylglycerols. Microbial networks are disrupted in high-risk patients, typified by antagonistic interactions driven by <i>K. pneumoniae</i>, <i>H. influenzae</i> and <i>Neisseria spp.</i> Integrative assessment combining all datasets partitioned the cohort into two clusters: SNF 1 (<i>N</i> = 34) and SNF 2 (<i>N</i> = 22), the former representing an unfavorable group characterized by exacerbations, hospitalizations, mucus dysfunction, microbial pathogens and dysregulated metabo-lipidomic pathways. Remarkably, 42% (<i>N</i> = 13 of 31) of the originally classified low risk COPD exhibited the unfavorable SNF 1 endotype, distinguished by more severe exacerbations (hospitalizations), <i>K. pneumoniae</i> and elevated hypoxanthine, creatine, spermine and phosphatidylcholines.</p> Conclusion <p>Integrative multi-omics profiling of Asian COPD significantly refines clinical risk stratification identifying a novel ‘high-risk’ biological endotype. Substantial proportions of clinically low-risk COPD exhibit this endotype, suggesting that clinical and co-morbidity profiling in Asians with COPD should be supplemented by molecular assessment to ensure accurate risk stratification.</p>

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Integrated multi-omics profiling for risk stratification in Asians with COPD

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月28日

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  • Oliver W. Meldrum,
  • Pei Yee Tiew,
  • Huiying Xu,
  • Dorrain Yanwen Low,
  • Fransiskus Xaverius Ivan,
  • Jayanth Kumar Narayana,
  • Tavleen Kaur Jaggi,
  • Jianhong Ching,
  • Sanjay H. Chotirmall

摘要

Background

Comorbidity-based risk stratification in Chronic Obstructive Pulmonary Disease (COPD) incompletely captures inherent biological heterogeneity, particularly in Asian populations that demonstrate high-risk clinical phenotypes including prior pulmonary tuberculosis. We investigated whether integrated sputum multi-omics could improve risk stratification in an Asian COPD cohort.

Methods

We conducted a prospective, multicenter assessment of N = 56 Asians with established COPD, classified as high- (N = 25; cardiovascular or ex-tuberculosis) or low-risk (N = 31; diabetic or low-comorbidity) based on established co-morbidity phenotyping. Sputum was subjected to mucus analysis (MUC5AC, MUC5B, mucus solids, rheology), metabo-lipidomics (LC-MS/MS) and microbiome assessment (shotgun metagenomics). Multivariate statistics was employed to integrate datasets.

Results

High-risk Asian COPD demonstrates abnormal mucus biochemistry characterized by elevated MUC5AC; extensive metabo-lipidomic alterations characterized by dysregulated tryptophan-kynurenine metabolism and lipid remodeling with enrichment of lysophosphatidylcholines and triacylglycerols. Microbial networks are disrupted in high-risk patients, typified by antagonistic interactions driven by K. pneumoniae, H. influenzae and Neisseria spp. Integrative assessment combining all datasets partitioned the cohort into two clusters: SNF 1 (N = 34) and SNF 2 (N = 22), the former representing an unfavorable group characterized by exacerbations, hospitalizations, mucus dysfunction, microbial pathogens and dysregulated metabo-lipidomic pathways. Remarkably, 42% (N = 13 of 31) of the originally classified low risk COPD exhibited the unfavorable SNF 1 endotype, distinguished by more severe exacerbations (hospitalizations), K. pneumoniae and elevated hypoxanthine, creatine, spermine and phosphatidylcholines.

Conclusion

Integrative multi-omics profiling of Asian COPD significantly refines clinical risk stratification identifying a novel ‘high-risk’ biological endotype. Substantial proportions of clinically low-risk COPD exhibit this endotype, suggesting that clinical and co-morbidity profiling in Asians with COPD should be supplemented by molecular assessment to ensure accurate risk stratification.