Exploring the timeline and network interplay of immune mediators in COVID-19 patients according to disease outcome

Gabriel Macedo Costa Guimarães^1*Christiane Costa-Pereira¹Renan da Silva Faustino^1,2Lilian Santos Alves²Fabiana Rabe Carvalho²Thalia Medeiros²Joaquim Pedro Brito-de-Sousa¹Laurence Amaral³Vanessa Peruhype Pascoal¹Ana Carolina Campi-Azevedo¹Andréa Teixeira-Carvalho¹Andrea Alice Silva²Olindo Assis Martins Filho^1*

• ¹René Rachou Institute, Oswaldo Cruz Foundation (Fiocruz), Belo Horizonte, Brazil
• ²Universidade Federal Fluminense, Niterói, Brazil
• ³Universidade Federal de Uberlandia, Uberlândia, Brazil

The present study is an observational descriptive follow-up investigation designed to characterize the profile of serum immune mediators in COVID-19 patients further categorized according to disease outcome. A total of 92 COVID-19 patients were enrolled in a timeline kinetics, starting at hospital admission (Day 0) throughout consecutive time-point intervals (Day 3-7, Day 8-14 and Day 15-40). Immune mediators (chemokines, cytokines and growth factors) were quantified by a high-throughput multiplex assay and compared with a pre-pandemic healthy control group (HC). Data demonstrated that COVID-19 exhibited a classical immune mediator storm, with prominent increases of chemokines and pro-inflammatory cytokines. Longitudinal follow-up revealed that the “death” outcome was associated with a persistent increase of immune mediators across all timepoints, with higher imbalance at Day 8-14. Conversely, the “discharge” outcome evolved with a balanced temporal profile with progressive waning of pro-inflammatory cytokines. Integrative network architectures uncovered that the “death” outcome exhibited a selective high-density chemokine cluster, contrasting with the balanced pattern described for “discharge” subgroups. A set of serum immune mediators (CXCL8, CCL2, CXCL10, IL-6 and IFN-) emerged as relevant predictors of disease outcome (AUC ≥ 0.8). Decision tree stepwise algorithms pointed out the hierarchical power (accuracy = 83%) of IL-6, CCL2 and CXCL8 to sort out patients according to disease outcome. Overall, these findings support clinical applicability of measuring serum immune mediators as complementary prognostic biomarkers for early classification and prediction of disease outcome in COVID-19 patients.