Temporal Associations of Plasma Levels of the Secreted Phospholipase A2 Family and Mortality in Severe COVID-19

Previous research suggests that group IIA secreted phospholipase A2(sPLA2-IIA) plays a role in and predicts severe COVID-19 disease. The current study reanalyzed a longitudinal proteomic data set to determine the temporal (days 0, 3 and 7) relationship between the levels of several members of a family of sPLA2 isoforms and the severity of COVID-19 in 214 ICU patients. The levels of six secreted PLA2 isoforms, sPLA2-IIA, sPLA2-V, sPLA2-X, sPLA2-IB, sPLA2-IIC, and sPLA2-XVI, increased over the first 7 ICU days in those who succumbed to the disease. sPLA2-IIA outperformed top ranked cytokines and chemokines as predictors of patient outcome. A decision tree corroborated these results with day 0 to day 3 kinetic changes of sPLA2-IIA that separated the death and severe categories from the mild category and increases from day 3 to day 7 significantly enriched the lethal category. In contrast, there was a time-dependent decrease in sPLA2-IID and sPLA2-XIIB in patients with severe or lethal disease, and these two isoforms were at higher levels in mild patients. Taken together, proteomic analysis revealed temporal sPLA2 patterns that reflect the critical roles of sPLA2 isoforms in severe COVID-19 disease.

Group IIA Secreted Phospholipase A2 Plays a Central Role in the Pathobiology of COVID-19

There is an urgent need to identify cellular and molecular mechanisms responsible for severe COVID-19 disease accompanied by multiple organ failure and high mortality rates. Here, we performed untargeted/targeted lipidomics and focused biochemistry on 127 patient plasma samples, and showed high levels of circulating, enzymatically active secreted phospholipase A2 Group IIA (sPLA2-IIA) in severe and fatal COVID-19 disease compared with uninfected patients or mild illness. Machine learning demonstrated that sPLA2-IIA effectively stratifies severe from fatal COVID-19 disease. We further introduce a PLA-BUN index that combines sPLA2-IIA and blood urea nitrogen (BUN) threshold levels as a critical risk factor for mitochondrial dysfunction, sustained inflammatory injury and lethal COVID-19. With the availability of clinically tested inhibitors of sPLA2-IIA, our study opens the door to a precision intervention using indices discovered here to reduce COVID-19 mortality.