The dynamic changes and sex differences of 147 immune-related proteins during acute COVID-19 in 580 individuals

Keypoints COVID-19 is associated with changes in cytokines, interleukins, and other immune-related proteins. However, previous research has failed to account for the dynamic nature of these changes over the course of infection, leading to often contradictory results. We measured 147 immune-related protein in 580 individuals in three large academic centers to precisely map the evolution of these proteins during acute COVID-19. COVID-19 was associated with a clear change in 69 proteins. More importantly, 3 of them may also help explain sex-differences in COVID-19 outcomes. These results provide greater insight into the COVID-19 immune response, and how it leads to severe illness. Introduction Severe COVID-19 leads to important changes in circulating immune-related proteins. To date it has been difficult to understand their temporal relationship and identify cytokines that are drivers of severe COVID-19 outcomes and underlie differences in outcomes between sexes. Here, we measured 147 immune-related proteins during acute COVID-19 to investigate these questions. Methods We measured circulating protein abundances using the SOMAscan nucleic acid aptamer panel in two large independent hospital-based COVID-19 cohorts in Canada and the United States. We fit generalized additive models with cubic splines from the start of symptom onset to identify protein levels over the first 14 days of infection which were different between severe cases and controls, adjusting for age and sex. Severe cases were defined as individuals with COVID-19 requiring invasive or non-invasive mechanical respiratory support. Results 580 individuals were included in the analysis. Mean subject age was 64.3 (sd 18.1), and 47% were male. Of the 147 proteins, 69 showed a significant difference between cases and controls (p < 3.4 x 10(-4)). Three clusters were formed by 108 highly correlated proteins that replicated in both cohorts, making it difficult to determine which proteins have a true causal effect on severe COVID-19. Six proteins showed sex differences in levels over time, of which 3 were also associated with severe COVID-19: CCL26, IL1RL2, and IL3RA, providing insights to better understand the marked differences in outcomes by sex. Conclusions Severe COVID-19 is associated with large changes in 69 immune-related proteins. Further, five proteins were associated with sex differences in outcomes. These results provide direct insights into immune-related proteins that are strongly influenced by severe COVID-19 infection.

Automated summary

COVID-19 is associated with changes in cytokines, interleukins, and other immune-related proteins. This study provides insights into the dynamic nature of these changes and their impact on severe illness and sex differences in COVID-19 outcomes.