Circulating Eosinophils Are a Biomarker, Mediator for COPD and FEV1/FVC Decline

An elevated blood eosinophil count (BEC) is a risk factor for the onset of chronic obstructive pulmonary disease (COPD), particularly among younger individuals. Elevated BEC is also a risk factor for a decline in forced expiratory volume in 1 second/forced vital capacity (FEV₁/FVC) ratio and hospitalization for COPD, according to the results of a Mendelian randomization (MR) study published in the journal Computers in Biology and Medicine.

Blood leukocyte counts (eg, eosinophil counts) are key biomarkers for the onset, classification, and exacerbation of COPD; however, the causal relationship among them remains unclear. Researchers therefore sought to implement a 2-sample, bidirectional MR and multivariable MR to evaluate these causal associations. In the present study, the causal relationships among 6 leukocyte traits and 5 COPD-associated outcomes were examined. The 6 leukocyte traits included white blood cell, neutrophil, monocyte, lymphocyte, basophil, and eosinophil counts.

Initially, the effects of the 6 leukocyte traits on risk for COPD and FEV₁/FVC ratio were assessed. Next, 3 additional COPD-related outcomes were explored, including risk for development of COPD in the young and in the elderly, along with risk for COPD hospitalization. Further, reverse MR was performed to examine whether onset of COPD or FEV₁/FVC ratio is a determinant of each of the blood leukocyte counts.

Per univariable MR, elevated BEC increased the risk for COPD (odds ratio [OR], 1.22; 95% CI, 1.14-1.30; P =1.54×10^–09) and COPD-associated hospitalizations (OR, 1.44; 95% CI, 1.15-1.80; P =1.36×10^–03). Additionally, elevated BEC significantly decreased the FEV₁/FVC ratio (OR, 0.942; 95% CI, 0.914-0.971; P =1.02×10^–04). Multivariable MR results fully supported these findings.

Of note, univariable MR demonstrated a weak causal relationship between elevated BEC and risk for COPD in younger individuals (ie, <65 years of age; OR, 1.39; 95% CI, 1.10-1.75; P =5.52×10^–03), but not in older individuals (OR, 1.20; 95% CI, 0.926-1.550; P =.17). The reverse univariable MR also revealed that COPD onset and reduced FEV₁/FVC ratio both were associated with increased blood neutrophil counts (OR, 1.03; 95% CI, 1.01-1.05; P =3.40×10^–03 and OR, 0.947; 95% CI, 0.910-0.986; P =8.75×10^–03, respectively).

A limitation of the MR approach that warrants mention is the fact that the 3 assumptions are difficult to fulfill, with pleiotrophy biases the main reasons for violating these assumptions. In the current analysis, the instrumental variables reported to be associated with exposure risks are directly excluded, with 4 additional univariable MR methods being used that are more robust against violations or MR assumptions.

The researchers concluded that their findings provided genetic evidence to support “the role of circulating eosinophil as a biomarker and mediator for COPD and the FEV₁/FVC ratio. “These findings indicate a fundamental difference between eosinophilic COPD and neutrophilic COPD, and highlight the importance of non-neutrophil-targeted therapeutic strategy for the neutrophilic COPD,” the study authors noted.