"High-Risk" Clinical and Inflammatory Clusters in COPD of Chinese Descent

Abstract

Background: 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 Southeast Asia. We aim to determine if clusters of Chinese patients with COPD exist and their association with systemic inflammation and clinical outcomes.

Research question: We aim to determine if clusters of Chinese patients with COPD exist and their association with clinical outcomes and inflammation.

Study design and methods: Chinese patients with stable COPD were prospectively recruited into two cohorts (derivation and validation) from six hospitals across three Southeast Asian countries (Singapore, Malaysia, and Hong Kong; n = 1,480). Each patient was followed more than 2 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 patients with COPD to determine if inflammatory patterns and associated networks characterized the derived clusters.

Results: Five patient clusters were identified including: (1) ex-TB, (2) diabetic, (3) low comorbidity: low-risk, (4) low comorbidity: high-risk, and (5) cardiovascular. The cardiovascular and ex-TB clusters demonstrate highest mortality (independent of Global Initiative for Chronic Obstructive Lung Disease assessment) and illustrate diverse cytokine patterns with complex inflammatory networks.

Interpretation: We describe clusters of Chinese patients with COPD, two of which represent high-risk clusters. The cardiovascular and ex-TB 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.

Keywords: COPD; Chinese; TB; cardiovascular; mortality.

Figure 1

Unsupervised clustering (of the derivation cohort) reveals five clinically relevant patient clusters of ethnic Chinese patients with COPD demonstrating variable prognostic outcome. Dendrogram illustrating the five derived COPD clusters using nonmetric multidimensional scaling followed by hierarchical clustering. Different clusters are represented by colors: ex-TB (red), diabetic (blue), low comorbidity: low-risk (gray), low comorbidity: high-risk (orange), and cardiovascular (light blue).

Figure 2

A, Kaplan-Meier curve demonstrating survival differences between clusters for 2-year all-cause mortality: worst prognosis in the cardiovascular and ex-TB (TB) clusters that (B) remains significant after adjustment for age, sex, BMI, FEV₁, and smoking pack-year exposure illustrated as Cox regression survival curves. (C) Cumulative incidence curves for each of the five derived COPD clusters for respiratory causes of death: greatest incidence of respiratory cause of death observed in the cardiovascular, ex-TB, and low comorbidity: high-risk clusters. Different clusters are represented by colors: Ex-TB (red), diabetic (blue), low comorbidity: low-risk (gray), low comorbidity: high-risk (orange), and cardiovascular (light blue). See Figure 1 legend for expansion of abbreviations.

Figure 3

Validation cohort (V; n = 569) of patients with COPD of Chinese ethnicity illustrates comparable comorbidity profiles by cluster when compared with the derivation (D; n = 911) cohort. Bubble size corresponds to the percentage of patients demonstrating each comorbidity within their respective cohort and bubble color represents cluster membership: ex-TB (red), diabetic (blue), low comorbidity: low-risk (gray), low comorbidity: high-risk (orange), and cardiovascular (light blue). AF = atrial fibrillation; Ca = lung, esophageal, pancreatic, or breast carcinoma; CAD = coronary artery disease; CHF = congestive heart failure; CKD = chronic kidney disease; CVA = cerebrovascular disease; DM = diabetes mellitus; other Ca = all other malignancies excluding lung, esophageal, pancreatic, or breast carcinoma; PAD = peripheral arterial disease; pTB = history of prior pulmonary TB; PUD = peptic ulcer disease.

Figure 4

Survival outcomes between the identified clusters in the validation cohort for 2-year all-cause mortality (as demonstrated independently in the derivation (D; n = 911) cohort; see Fig 2). A, Kaplan-Meier curves demonstrating worst prognosis in the cardiovascular and ex-TB clusters, which (B) remains significant after adjustment for age, sex, BMI, FEV₁, and smoking pack-year exposure illustrated as Cox regression survival curves. C, Comparable cumulative incidence curves for each of the five derived COPD clusters (as demonstrated independently in the derivation (D; n = 911) cohort; see Fig 2) for respiratory causes of death: greatest incidence of respiratory cause of death observed in the cardiovascular, ex-TB, and low co-morbidity: high-risk clusters. Different clusters are represented by color: ex-TB (red), diabetic (blue), low comorbidity: low-risk (gray), low comorbidity: high-risk (orange), and cardiovascular (light blue). See Figure 1 legend for expansion of abbreviations.

Figure 5

The five derived COPD clusters of Chinese ethnicity illustrate inflammatory signatures that associate with all cause and respiratory-related mortality. A, Radar plot illustrating variation in systemic cytokine profile between each of the five derived COPD clusters. The median normalized score for each selected cytokine (in the final assessed panel) is plotted on the radar chart for comparison between clusters. Each dot represents the median normalized value of the cytokine and the color indicates the specific cluster: ex-TB (red), diabetic (blue), low comorbidity: low-risk (gray), low comorbidity: high-risk (orange), and cardiovascular (light blue). PDGF = platelet-derived growth factor; TNF-R1 = tumor necrosis factor receptor 1; TNF-R2 = tumor necrosis factor receptor 2; VEGF = vascular endothelial growth factor. ∗P ≤ 0.05, #P <.1. B, Network plots demonstrating inflammatory grids detected within each cluster. Increased cytokine interaction and a greater number of positive cytokines are detectable in the cardiovascular, ex-TB and low comorbidity: high-risk clusters compared with the diabetic and low comorbidity: low-risk clusters (indicated by greater than [>] symbols). Each circle (node) represents a cytokine from the final assessed panel: circle size corresponds to percentage of patients within that cluster demonstrating a positive value. Lines connecting two nodes indicate positive detection of both cytokines and line thickness illustrates the proportion of patients with a positive result for both cytokines. Node color corresponds to the respective clinical cluster: ex-TB (red), diabetic (blue), low comorbidity: low-risk (gray), low comorbidity: high-risk (orange), and cardiovascular (light blue).

Figure 6

Cardiovascular and ex-TB clusters illustrate highest 2-year mortality. A, Tree map illustrating cluster-related mortality within each GOLD groups A through D. Rectangles represent the proportion of deceased patients within each group, presented as percentages. Rectangle color indicates cluster membership: ex-TB (red), diabetic (blue), low comorbidity: low-risk (gray), low comorbidity: high-risk (orange), and cardiovascular (light blue). B, The mortality differences remain significant after adjustment for age, sex, BMI, smoking pack-year exposure, lung function (by FEV₁), and GOLD group illustrated by forest plot using multivariate logistic regression. The dot represents the OR with color indicating significance levels: green (P < .05), gray (P > .05; NS). Error bar indicates the 95% CI. See Figure 1 legend for expansion of abbreviations.

Figure 7

Cardiovascular and ex-TB clusters demonstrate poorest 2-year survival irrespective of underlying COPD grade. Kaplan-Meir curves illustrating 2-year mortality of each cluster by conventional COPD staging (defined by FEV₁). ∗P ≤ .05, ∗∗P = .001 by log-rank test. Different clusters are represented by colors: ex-TB (red), diabetic (blue), low comorbidity: low-risk (gray), low comorbidity: high-risk (orange), and cardiovascular (light blue). See Figure 1 legend for expansion of abbreviations.