Bifurcated monocyte states are predictive of mortality in severe COVID-19

Abstract

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection presents with varied clinical manifestations, ranging from mild symptoms to acute respiratory distress syndrome (ARDS) with high mortality. Despite extensive analyses, there remains an urgent need to delineate immune cell states that contribute to mortality in severe COVID-19. We performed high-dimensional cellular and molecular profiling of blood and respiratory samples from critically ill COVID-19 patients to define immune cell genomic states that are predictive of outcome in severe COVID-19 disease. Critically ill patients admitted to the intensive care unit (ICU) manifested increased frequencies of inflammatory monocytes and plasmablasts that were also associated with ARDS not due to COVID-19. Single-cell RNAseq (scRNAseq)-based deconvolution of genomic states of peripheral immune cells revealed distinct gene modules that were associated with COVID-19 outcome. Notably, monocytes exhibited bifurcated genomic states, with expression of a cytokine gene module exemplified by CCL4 (MIP-1β) associated with survival and an interferon signaling module associated with death. These gene modules were correlated with higher levels of MIP-1β and CXCL10 levels in plasma, respectively. Monocytes expressing genes reflective of these divergent modules were also detectable in endotracheal aspirates. Machine learning algorithms identified the distinctive monocyte modules as part of a multivariate peripheral immune system state that was predictive of COVID-19 mortality. Follow-up analysis of the monocyte modules on ICU day 5 was consistent with bifurcated states that correlated with distinct inflammatory cytokines. Our data suggests a pivotal role for monocytes and their specific inflammatory genomic states in contributing to mortality in life-threatening COVID-19 disease and may facilitate discovery of new diagnostics and therapeutics.

Alterations in Circulating Monocytes Predict COVID-19 Severity and Include Chromatin Modifications Still Detectable Six Months after Recovery

“…The longitudinal measurements in acute COVID-19 patients showed that the progressive increase of HLA-DR expression in monocytes paralleled an increasing specific T cell response, and this was mostly observed in patients who survived, whereas patients who failed to augment HLA-DR expression in monocytes also failed to mount protective anti-SARS-CoV-2 cellular immune responses and died. These results agree with previous data which suggested a mortality predictive value of dual monocyte state and gene modules in severe COVID-19 [ 56 ].…”

COVID-19 virtual patient cohort suggests immune mechanisms driving disease outcomes

“…Indeed, the ability of our model to recapitulate severe disease by, in part, regulating monocyte differentiation raises the possibility that patients with low monocyte levels [7] may benefit from treatments that better regulate monocyte differentiation. This is in line with recent studies identifying distinct transcriptional factors as regulators of differentiated monocyte fates in inflammatory conditions [74,75], and clinical observations that monocyte dysregulation is present in severe COVID-19 [76,77]. It also raises the possibility that modulation by exogenous cytokines, including macrophage colony-stimulating factor in combination with IL-4 and tumour necrosis factor-alpha (TNF-α), may be able to direct monocyte differentiation in favour of monocyte-derived dendritic cells and reduce this response [74].…”

Syrian hamsters as a model of lung injury with SARS-CoV-2 infection: Pathologic, physiologic, and detailed molecular profiling

“…3 A – C). However, other reports have noted the higher incidence of inflammatory monocytes in COVID-19 [ 60 , 61 ] and other viral illnesses [62] . A recent report noted neutrophilia in only 31% of patients with severe COVID-19 [63] .…”