Blood Cell Ratio Biomarkers of Non-type 2 Inflammation in Chronic Obstructive Pulmonary

Background The majority of COPD patients are characterized by non-type 2 inflammation, yet there are no available non-type 2 biomarkers, as opposed to blood eosinophil count for type 2 inflammation. We aimed to test readily obtainable immune cell ratios as biomarkers for clinical phenotypes in COPD and to determine pathways represented by these ratios using multi-omics data. Methods Using complete blood counts with differential collected at the Phase 2 (5-year) visit in the COPDGene Study, we calculated three immune cell ratios previously described in COPD and other diseases: the neutrophil-lymphocyte ratio (NLR), the platelet-lymphocyte ratio (PLR), and the Systemic Immune-Inflammation Index (SII = NLR*platelets). We tested for associations with COPD outcomes, including lung function, chest CT scan phenotypes, and exacerbations. Blood RNA-sequencing and proteomics data were used to identify genes, proteins and pathways associated with the ratios. Results In univariate analyses, the three biomarkers were associated with COPD severity measures. In zero inflated Poisson regression models, all three were associated with increased odds of having an exacerbation but were not associated with exacerbation counts. Conversely, the three biomarkers were generally associated with prospective exacerbation counts, but not the zero-inflation term. In logistic regression models, the three biomarkers were significantly associated with having two or more exacerbations in the prior year; however, receiver operating characteristic analyses did not lead to clear cutoff values. Complement and PI3K signaling pathways were enriched across more than one ratio in both the RNA-sequencing and proteomics results. Other inflammatory pathways relevant in COPD appeared in different enrichment sets in either omics data type. Conclusions Higher levels of three easily obtained blood cell ratios were associated with COPD severity and exacerbations outcomes; however, there are not clear thresholds which would be required for clinical application. Blood RNA-sequencing and proteomics identified inflammatory pathways associated with the three biomarkers, including targets for COPD therapies currently in human trials.