Plasma Levels of CXCL9 and MCP-3 are Increased in Asthma-COPD Overlap (ACO) Patients

Abstract

Purpose: Asthma and chronic obstructive pulmonary disease overlap patients (ACO) have more exacerbations and a worse prognosis than pure asthma or COPD, and it is of great interest to identify differential biomarkers of ACO. We compared blood eosinophil counts, plasma IgE and protein levels among patients with asthma, ACO, COPD, and healthy subjects to identify those associated with ACO.

Patients and methods: 397 adults (age 40-90 years) were recruited from two Colombian cities: asthma (n=123), COPD (n=100), ACO (n=74) and healthy control (HC, n=100). Plasma protein levels were measured using the Proximity Extension Assay (Olink Proteomics).

Results: There were no differences in blood eosinophil counts between the patient groups. Total and specified IgE levels were higher in patients with ACO than in those with COPD. Ten plasma proteins showed significant differences between the patients with ACO and HC. In patients above 60 years old, CXCL9 discriminates ACO from asthma patients with AUC 0.73 (0.63-0.82, DeLong test p=0.007), and in patients below 60 years old, MCP-3 discriminates ACO from COPD patients with AUC 0.84 (0.62-1.0, DeLong test p=0.006). CUB domain-containing protein 1 (CDCP1) levels (OR, 0.47; p=0.008) and age > 60 years (OR, 0.25; p=0.001) were negatively associated with ACO.

Conclusion: CXCL9 levels could be used to discriminate ACO from asthma patients and MCP-3 to discriminate ACO from COPD. Protein inflammatory signatures in plasma of ACO patients were similar to the COPD group. This study revealed novel biomarkers that may help characterize patients with ACO.

Keywords: COPD; CXCL9; MCP-3; PEA; biomarkers; chronic obstructive pulmonary disease; circulating inflammatory mediators; proximity extension assay.

Figure 1

Type 2 biomarkers in healthy controls (HC), and patients with Asthma, ACO and COPD. (A) total IgE levels, (B) specific IgE levels to house dust mite Dermatophagoides pteronyssinus, (C) blood eosinophil counts, (D) periostin levels. Each dot corresponds to an individual, error bars indicate median and interquartile range; asterisk denote P values: *p < 0.05; **p < 0.01; ***p < 0.001.

Figure 2

Differentially expressed proteins in ACO patients. (A) Volcano plot showing the differences of 67 inflammatory biomarkers between ACO patients and healthy controls. FDR: False Discovery Rate. (B) Venn diagram summarizing differentially expressed proteins in each disease group.

Figure 3

Comparison of plasma levels in immune mediators in healthy controls (HC) and patients with asthma, ACO and COPD. (A) CXCL1, (B) CXCL9, (C) MCP-3 (D) CDCP1. NPX: Normalized Protein Levels; asterisks denote P values: *P < 0.05; **P < 0.01; ***P < 0.001.

Figure 4

Predictive capacity of the models for (A) Asthma vs ACO and (B) COPD vs ACO.

Figure 5

ROC curves for the predictive capacity of plasma mediators to discriminate respiratory phenotypes according to the age of patients: (A) CXCL9 in ACO vs Asthma. (B) MCP-3 in ACO vs COPD. Blue line indicates results in subjects with age above 60 years old and Orange line indicates results in subjects with age below 60 years old. The DeLong test P value denotes the difference between the AUC curves.Plasma levels of CXCL9 and MCP-3 are increased in asthma-COPD overlap (ACO) patients.