Characterizing ECOPD Phenotypes: Associations with In-Hospital Outcomes and Immunoinflammatory Mechanisms

Qin Wang,1,2,* Lei Wang,2,* Li Zhang,2 Chongyang Zhao,1 Ying Liu,2 Lei Liu,2 Lishan Yuan,2 Min Feng,3,4 Gang Wang,5 Li Li,1 Shuwen Zhang,6 Yulai Yuan,7 Deying Kang,1,8 Xin Zhang2 1Department of Evidence-Based Medicine and Clinical Epidemiology, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 2Division of Internal Medicine, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 3School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, Australia; 4Respiratory Cellular and Molecular Biology, Woolcock Institute of Medical Research, Sydney, Australia; 5Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden; 6Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 7The Department of Respirology of the Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, People’s Republic of China; 8Center of Biostatistics, Design, Measurement and Evaluation (CBDME), Department of Clinical Research Management, West China Hospital, Sichuan University, Chengdu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Deying Kang, Center of Biostatistics, Design, Measurement and Evaluation (CBDME), Department of Clinical Research Management, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China, Email [email protected] Xin Zhang, Division of Internal Medicine, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China, Email [email protected]: Hospitalization due to exacerbations of chronic obstructive pulmonary disease (ECOPD) is linked to substantial mortality rates.Objective: This study aimed to identify the clinical and inflammatory phenotypes of patients with ECOPD, as well as to examine their associations with in-hospital outcomes. We sought to explore the underlying mechanisms that contribute to the relationship between ECOPD phenotypes and these outcomes.Methods: A k-means cluster analysis was conducted on 20,890 recruited patients hospitalized for ECOPD. Logistic regression analyses were utilized to evaluate the associations between the identified phenotypes and in-hospital outcomes, such as mortality, invasive mechanical ventilation (IMV), and intensive care unit (ICU) admission. Additionally, a mediation analysis was performed to elucidate the immunoinflammatory mechanisms underlying the relationship between ECOPD phenotypes and in-hospital outcomes.Results: Three distinct phenotypes were identified: Cluster 1 (n=4,944, 23.67%) exhibited a “Female Eosinophilic Phenotype”, Cluster 2 (n=10,814, 51.77%) displayed a “Male Eosinophilic Phenotype”, and Cluster 3 (n=5,132, 24.57%) presented as an “Geriatric Multimorbidity-Associated Neutrophilic Systemic Inflammatory Phenotype”. Clusters 2 and 3 were associated with higher risks of in-hospital mortality (adjusted odds ratio [ORadj]=1.88 and 17.07, respectively) and IMV (ORadj=2.52 and 7.59, respectively) compared to Cluster 1. Patients in Cluster 3 also experienced an extended hospital stay (median of 13 days) and an increased risk of ICU admission (ORadj=7.72). Additionally, blood eosinophils, neutrophils, CRP, and albumin played a mediating role in the relationship between ECOPD phenotypes and the composite outcome.Conclusion: Our study identified three phenotypes stratified by sex, multimorbidity burden, and inflammatory endotypes, which advanced threshold definition for eosinophilic exacerbations and provided prognostic insights for ECOPD management.Keywords: exacerbations of chronic obstructive pulmonary disease, ECOPD, phenotype, cluster analysis, in-hospital outcome, immunoinflammation, endotype