High dimensional profiling identifies specific immune types along the recovery trajectories of critically ill COVID19 patients

Abstract

The COVID-19 pandemic poses a major burden on healthcare and economic systems across the globe. Even though a majority of the population develops only minor symptoms upon SARS-CoV-2 infection, a significant number are hospitalized at intensive care units (ICU) requiring critical care. While insights into the early stages of the disease are rapidly expanding, the dynamic immunological processes occurring in critically ill patients throughout their recovery at ICU are far less understood. Here, we have analysed whole blood samples serially collected from 40 surviving COVID-19 patients throughout their recovery in ICU using high-dimensional cytometry by time-of-flight (CyTOF) and cytokine multiplexing. Based on the neutrophil-to-lymphocyte ratio (NLR), we defined four sequential immunotypes during recovery that correlated to various clinical parameters, including the level of respiratory support at concomitant sampling times. We identified classical monocytes as the first immune cell type to recover by restoration of HLA-DR-positivity and the reduction of immunosuppressive CD163 + monocytes, followed by the recovery of CD8 + and CD4 + T cell and non-classical monocyte populations. The identified immunotypes also correlated to aberrant cytokine and acute-phase reactant levels. Finally, integrative analysis of cytokines and immune cell profiles showed a shift from an initially dysregulated immune response to a more coordinated immunogenic interplay, highlighting the importance of longitudinal sampling to understand the pathophysiology underlying recovery from severe COVID-19. Supplementary Information The online version contains supplementary material available at 10.1007/s00018-021-03808-8.

Alterations of blood monocyte subset distribution and surface phenotype are linked to infection severity in COVID‐19 inpatients

“…In addition, the intermediate monocyte compartment was substantially, yet not significantly, larger in COVID‐19 patients (median, % of CD45 + cells, moderate: 5.6 [IQR: 3.4–7.8], severe: 5.1 [IQR: 3.7–8.7]) than in control individuals (2.1 [IQR: 2–2.6]) (Figure 3 ). Of note, neutrophil expansion [ 14 , 16 – 19 ] along with a profound reduction of nonclassical monocyte levels [ 11 , 15 – 18 , 21 – 23 , 31 – 33 ] has been described as a characteristic of acute COVID‐19.…”

“…Specifically, low levels of CD4 + and CD8 + cells, impaired antiviral type I IFN response and polymorphisms in the genes involved in antigen presentation and immune cell communication were associated with the risk of severe COVID‐19 [ 7 , 8 , 9 , 10 ]. Furthermore, aberrant monocyte and neutrophil accumulation along with systemic inflammation and altered systemic iron homeostasis have been linked to the disease severity and a poor prognosis [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. This pertains to the key role of myeloid leukocytes, that is, macrophages, monocytes, and neutrophils in the SARS‐CoV‐2 pathogen control and orchestration of the inflammatory response [ 13 , 16 , 17 , 21 – 24 ].…”

“…These subsets display differences in the pattern to activate stimuli and immune effector functions such as phagocytosis, antigen presentation, and cytokine production [ 28 ]. Alterations in the monocyte subset distribution and surface molecule repertoire were observed in multiple inflammatory conditions, including COVID‐19, and were proposed to correlate with the disease course and prognosis [ 11 , 15 – 18 , 21 – 23 , 28 – 33 ].…”

Human immune diversity: from evolution to modernity

“…Clonal cross-reactivity explains a proportion of protection 102,103 ; however, other factors have been linked to differential immunological response configurations. Cytokine bias, driven by an altered myeloid compartment [104][105][106] , appears to significantly alter the risk of severe disease, with type I interferons being protective and IL-6 or TNF being detrimental 104,105,107 . In the lymphoid compartment, susceptibility to severe disease is associated with elevated activation and clonal expansion of CD8 + T cells 104,108,109 .…”

“Multiomics” Approaches to Understand and Treat COVID-19: Mass Spectrometry and Next-Generation Sequencing

“…COVID-19 transmission and infection kinetics appear to map onto a biphasic progression wherein there is an asymptomatic phase that may end the disease progression or, if virion titre is sufficient and co-morbidities obtain, there can be a second phase where frank respiratory disease presents with a sizable increase in cytokine and chemokine expression and secretion followed by a hyperimmune response [88].…”