RESUMO
BackgroundDetermining the severity of COVID-19 remains an unmet medical need. Our objective was to develop a blood-based host-gene-expression classifier for the severity of viral infections and validate it in independent data, including COVID-19. MethodsWe developed the classifier for the severity of viral infections and validated it in multiple viral infection settings including COVID-19. We used training data (N=705) from 21 retrospective transcriptomic clinical studies of influenza and other viral illnesses looking at a preselected panel of host immune response messenger RNAs. ResultsWe selected 6 host RNAs and trained logistic regression classifier with a cross-validation area under curve of 0.90 for predicting 30-day mortality in viral illnesses. Next, in 1,417 samples across 21 independent retrospective cohorts the locked 6-RNA classifier had an area under curve of 0.91 for discriminating patients with severe vs. non-severe infection. Next, in independent cohorts of prospectively (N=97) and retrospectively (N=100) enrolled patients with confirmed COVID-19, the classifier had an area under curve of 0.89 and 0.87, respectively, for identifying patients with severe respiratory failure or 30-day mortality. Finally, we developed a loop-mediated isothermal gene expression assay for the 6-messenger-RNA panel to facilitate implementation as a rapid assay. ConclusionsWith further study, the classifier could assist in the risk assessment of COVID-19 and other acute viral infections patients to determine severity and level of care, thereby improving patient management and reducing healthcare burden.
RESUMO
SARS-CoV-2 pandemic, the fourth pandemic of the decade, has underscored gaps in global pandemic preparedness and the need for generalizable tests to avert overwhelming healthcare systems worldwide, irrespective of a virus. We integrated 4,780 blood transcriptome profiles from patients infected with one of 16 viruses across 34 independent cohorts from 18 countries, and 71 scRNA-seq profiles of 264,224 immune cells across three independent cohorts. We found a myeloid cell-dominated conserved host response associated with severity. It showed increased hematopoiesis, myelopoiesis, and myeloid-derived suppressor cells with increased severity. We identified four gene modules that delineate distinct trajectories associated with mild and severe outcomes, and show the interferon response was decoupled from protective host response during severe viral infection. These modules distinguished non-severe from severe viral infection with clinically useful accuracy. Together, our findings provide insights into immune response dynamics during viral infection, and identify factors that may influence patient outcomes.
