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Observational Study
. 2025 May 14:20:1477-1492.
doi: 10.2147/COPD.S481406. eCollection 2025.

Sputum Microbiome, Potentially Pathogenic Organisms, and Clinical Outcomes in Japanese Patients with COPD and Moderate Airflow Limitation: The Prospective AERIS-J Study

Kazuhiro Yatera #  1 , Zhang Wang #  2 , Yoko Shibata  3 , Nobuhisa Ishikawa  4 , Tetsuya Homma  5 , Kiyoyasu Fukushima  6 , Osamu Hataji  7 , Yoshikazu Inoue  8   9 , Hiroki Kawabata  1 , Keisuke Miki  10 , Kazuhiro Sato  11 , Kazunori Tobino  12 , Makoto Yoshida  13 , Takeo Ishii  14 , Risako Ito  14 , Tamami Kobayashi  14 , Shinya Kawamatsu  14 , Chris H Compton  15 , Paul W Jones  15
Affiliations
Observational Study

Sputum Microbiome, Potentially Pathogenic Organisms, and Clinical Outcomes in Japanese Patients with COPD and Moderate Airflow Limitation: The Prospective AERIS-J Study

Kazuhiro Yatera et al. Int J Chron Obstruct Pulmon Dis. .

Abstract

Background: In Western studies, lung microbiome changes are reported in patients with chronic obstructive pulmonary disease (COPD) and are associated with poorer outcomes, but similar studies in Asian patients or those with less severe COPD are limited.

Methods: The Acute Exacerbation and Respiratory InfectionS in COPD Japan (AERIS-J; jRCT1080224632/NCT03957577) was a prospective, non-interventional study to evaluate sputum microbiome diversity at baseline and after 12 months (V2; exploratory analysis), in patients aged 40-80 years with stable COPD (June 2019-June 2022). Baseline sputum potentially pathogenic organisms (PPOs) were identified. Blood cell counts and COPD Assessment Test (CAT) scores were collected at baseline and COPD symptoms measured over 12 months using the Evaluating Respiratory Symptoms in COPD and EXAcerbations of Chronic pulmonary disease Tool, collected by eDiary.

Results: Patients (N=63) had a mean age of 72.8 years, and percent predicted post-bronchodilator forced expiratory volume in 1 second was 58.3%; 92% were male. Across 62 baseline sputum samples, microbiome composition was similar between 16S rRNA/metagenomic datasets. Patients graded Global Initiative for Chronic Obstructive Lung Disease (GOLD) III versus GOLD I/II had minimal differences in their microbial taxonomic profile and no differences in microbial diversity (Wilcoxon P=0.71). Alpha diversity (Shannon index) positively correlated with blood basophils (rho=0.41; P=0.0019) and negatively correlated with CAT score (rho=0.36; P=0.0069). Alpha diversity and sputum (rho: -0.0637; P=0.7836) or blood (rho: 0.1739; P=0.2043) eosinophils were not correlated. No difference in alpha (P=0.5) or beta (P=0.3) diversity or Operational Taxonomic Unit (Anosim R=-0.024; P=0.892) was observed between PPO-positive or -negative sputum.

Conclusion: A less diverse microbiome correlated with poorer health status and lower blood basophils in patients with COPD and moderate airflow limitation. There was no relationship between PPO presence and microbiome diversity.

Keywords: 16S rRNA; Asia; COPD assessment test; basophil; metagenomic; sputum.

Plain language summary

Chronic obstructive pulmonary disease (COPD) is a progressive lung condition resulting in breathing difficulties. Research has shown that patients with COPD experience changes in the diversity of bacteria in their lungs, leading to a worsening of symptoms. The lung microbiome includes different types of bacteria, and is involved in important roles, such as regulating the immune system and protecting the lung from invading pathogens. Many studies on the microbiome have been based in western countries, and there are few studies among Asian patients and populations with moderate COPD. The aim of this year-long study was to assess the diversity of the lung microbiome in Japanese patients with COPD and moderate airflow limitation, and how it affects patients’ immunity and disease severity. Patients’ sputum and blood samples were obtained at the start of the study and the different types of bacteria in the sputum and the number of immune cells in the blood were measured. Patients’ symptoms were also assessed at study start. Results showed that a less diverse lung microbiome was associated with lower levels of blood immune cells and worse COPD symptoms. These results improve our knowledge of the lung microbiome in an Asian population with COPD, providing insights into how lower bacterial diversity may worsen patient immunity and COPD severity.

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Conflict of interest statement

KY has received lecture fees and honoraria from GSK. ZW and TI are former GSK employees and TI holds financial equities in GSK. YS has received lecture fees from GSK. NI has received lecture fees and honoraria from GSK. TH has received lecture fees from GSK. KF declares no conflict of interest. OH has received lecture fees from GSK, AstraZeneca, Boehringer Ingelheim, Eli Lilly, and Novartis. YI reports grants from Japanese Ministry of Health, Labour, and Welfare, grants from Japan Agency for Medical Research and Development, advisory board participation and lecture fees from Boehringer Ingelheim, Inc., lecture fees from Shionogi & Co. Ltd, Kyorin Pharmaceutical Co. Ltd, GSK, and Novartis, and advisory board participation for Roche/Promedior, Galapagos, Taiho Pharmaceutical, CSL Behring, and Vicore Pharma, outside the submitted work. HK declares no conflict of interest. KM declares no conflict of interest. KS has received lecture fees from GSK, AstraZeneca, Boehringer Ingelheim, Ono Pharmaceutical, and Sanofi. KT has received lecture fees from GSK, AstraZeneca, and Boehringer Ingelheim. MY declares no conflict of interest. RI and SK are employees of GSK. TK and CHC were employees of GSK at the time of the study and CHC holds financial equities in GSK. PWJ is an Emeritus Professor of Respiratory Medicine at St George’s, University of London, and a former full-time employee of GSK at the time of protocol development and contributed to study design and protocol on behalf of GSK. He is a part-time consultant at GSK and holds financial equities in GSK.

Figures

Figure 1
Figure 1
Study design. Patients completed a daily eDiary, which included screening questions for the detection of AECOPD during the study and the EXACT; the parameters captured in the eDiary are indicated in bold and all other parameters were captured using the eCRF, except for urine pregnancy test. Study visits were postponed or cancelled in the event of a positive COVID-19 diagnosis or presence of COVID-19 symptoms. If an AECOPD occurred at the date of study visit, the study visit was rescheduled, within the specified time frames, to ensure assessment of stable-state disease. aThe mod.ATS-DLD-078 assessed patients’ medical, family, smoking and occupational history; bspirometry data (in the 12 months prior to enrolment) in medical records was permitted to be used to assess patient eligibility; cincluding height and weight, medical conditions as specified in the eCRF, and pneumococcal and influenza vaccination status; dalso completed between study visits every 2 months; eif deemed necessary by the investigator; fsputum was taken at V1 where a sputum sample of ≥0.2 g was unable to be collected at the screening visit. V2 sputum samples were taken where available.
Figure 2
Figure 2
Taxonomic profiles (A) and alpha diversity between (B) GOLD I/II and III disease. Analysis of the metagenomic dataset, using baseline sputum samples. COPD severity according to GOLD guidelines.
Figure 3
Figure 3
Correlation between Shannon diversity and baseline blood basophils (A and CAT score (B). Shannon diversity assessed by 16S rRNA gene sequencing using baseline sputum samples. CAT scores and blood basophil were assessed at baseline. Analysis performed using Spearman’s rank correlation.
Figure 4
Figure 4
Correlation between microbial genera and baseline blood basophils (A) and CAT score (B). Microbial genera assessed by 16S rRNA gene sequencing, using baseline sputum samples. Blood basophils and CAT scores were assessed at baseline. Analysis performed using Spearman’s rank correlation. Significant correlations (P<0.01) between each genus and blood basophils and CAT score.
Figure 5
Figure 5
Baseline alpha (A) and beta (B) microbial diversity stratified by baseline PPO status. Alpha and beta diversity from 16S rRNA gene sequencing. PPO status, identified by qPCR or bacterial culture, was stratified by all negative (n=30) or any positive (n=26), using baseline sputum samples. Alpha diversity was assessed by Wilcoxon test. Beta diversity was assessed using Anosim R value.
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