IMMUNE EXHAUSTION IS ASSOCIATED with PERSISTENT SARS-CoV-2 VIREMIA and SEVERE DISEASE

ABSTRACT

Background: SARS-CoV-2 viremia is associated with adverse outcomes in COVID-19. The immunologic mediators of this relationship remain under-explored. In this study, we aimed to evaluate the correlation between immune exhaustion markers, SARS-CoV-2 viremia clearance and clinical outcomes. Methods: We included 126 participants with confirmed SARS-CoV-2 infection who were hospitalized at an urban hospital in Boston, Massachusetts, during the first surge of the COVID-19 pandemic in early 2020. Plasma samples from days 0, 3, and 7 of hospitalization were available for analyses. The plasma SARS-CoV-2 viral load was determined by reverse transcription quantitative PCR (RT-qPCR). Proteomics data were generated using the Olink platform and neutralization level was assessed using a pseudovirus neutralization assay. Viremia persistence was defined as >40 copies/ml (detection limit) if the baseline detectable viremia was <1000 copies/ml, or >100 copies/ml (quantification limit) if the baseline viremia was ≥1000 copies/ml at day 7 of admission. Partial least-squares discriminant analysis (PLS-DA) was used to select exhaustion markers that could distinguish viremia persistence and clearance. An exhaustion score was generated based on features selected by PLS-DA and was divided into four quartiles. Differentially expressed proteins between 1st and 4th quartiles were determined by linear model adjusting for baseline characteristics. R (4.1.0) was used for statistics. Results: Viremia persistence was associated with a higher level of baseline viremia, a higher rate of severe diseases and mortality within 28 days of follow-up. Viremia persistence was associated with elevation of certain exhaustion protein markers including TIM3, PDL1, LGALS9, LAG3 and IL2RA. With PLS-DA, we selected TIM3, PDL1, and LGALS9 into the exhaustion score modeling. A higher exhaustion score was associated with higher baseline viremia, persistent viremia, severe disease, and death (Figure). When compared to the lowest exhaustion score (1st quartile), the highest exhaustion score (4th quartile) was associated with elevation in proteins belonging to IL-18 signaling pathway, lung fibrosis, and immune evasion in COVID-19. The immune exhaustion level was not associated with the neutralization level. Conclusion: In participants with COVID-19, soluble exhaustion markers are associated with delayed viremia clearance, immune evasion independent of humoral immunity development, and adverse outcomes.