Critical COVID‐19 is associated with distinct leukocyte phenotypes and transcriptome patterns

Abstract

Background Prognostic markers for disease severity and identification of therapeutic targets in COVID‐19 are urgently needed. We have studied innate and adaptive immunity on protein and transcriptomic level in COVID‐19 patients with different disease severity at admission and longitudinally during hospitalization. Methods Peripheral blood mononuclear cells (PBMCs) were collected at three time points from 31 patients included in the Norwegian SARS‐CoV‐2 cohort study and analysed by flow cytometry and RNA sequencing. Patients were grouped as either mild/moderate ( n = 14), severe ( n = 11) or critical ( n = 6) disease in accordance with WHO guidelines and compared with patients with SARS‐CoV‐2‐negative bacterial sepsis ( n = 5) and healthy controls ( n = 10). Results COVID‐19 severity was characterized by decreased interleukin 7 receptor alpha chain (CD127) expression in naïve CD4 and CD8 T cells. Activation (CD25 and HLA‐DR) and exhaustion (PD‐1) markers on T cells were increased compared with controls, but comparable between COVID‐19 severity groups. Non‐classical monocytes and monocytic HLA‐DR expression decreased whereas monocytic PD‐L1 and CD142 expression increased with COVID‐19 severity. RNA sequencing exhibited increased plasma B‐cell activity in critical COVID‐19 and yet predominantly reduced transcripts related to immune response pathways compared with milder disease. Conclusion Critical COVID‐19 seems to be characterized by an immune profile of activated and exhausted T cells and monocytes. This immune phenotype may influence the capacity to mount an efficient T‐cell immune response. Plasma B‐cell activity and calprotectin were higher in critical COVID‐19 while most transcripts related to immune functions were reduced, in particular affecting B cells. The potential of these cells as therapeutic targets in COVID‐19 should be further explored.

Complex immune deregulation in severe COVID-19: More than a mechanism of pathogenesis

“…These data become even more important since the authors described an increase of mHLA-DR following corticosteroid treatment [6] . We have also described similar increase of mHLA-DR after the ex vivo treatment of monocytes with the IL-6 receptor antagonist tocilizumab [5] . These findings explain, at least partly, the mechanism of the clinical benefit provided by dexamethasone and tocilizumab in patients with SRF as this has been described in the RECOVERY and REMAP-CAP trials, respectively [ 7 , 8 ].…”

“…The CID of severe COVID-19 was distinct from sepsis-induced immunosuppression since PBMCs maintained their functionality for cytokine production, mainly for tumour necrosis factor-alpha (TNFα) and IL-6; in sepsis immunosuppression this functionality was lost [4] . Low mHLA-DR in severe COVID-19 has also been described in a small cohort of patients from Norway [5] .…”

“…SARS-CoV-2 viral load was spectacularly decreased following start of treatment with recombinant interferon-gamma (rhIFNγ); four patients were eventually discharged alive [9] . rhIFNγ has been suggested as treatment for patients with immunosuppression and septic shock [10] where low mHLA-DR is one main feature [5] . To this end, the importance of the IL-6/mHLA-DR ratio introduced by the authors may pave the way for future guided immunotherapy in COVID-19.…”

Application of omics technology to combat the COVID‐19 pandemic

“… 140 Besides, plasma B‐cell activity and calprotectin were higher in critical COVID‐19, whereas most transcripts related to immune functions were reduced, particularly in B cells. 141 …”

A meta-analysis of the association between calprotectin and the severity of COVID-19

“…Christensen et al reported that patients with severe Novel Coronavirus Pneumonia had higher plasma B cell activity and calprotectin levels, while transcripts related to immune function were mostly reduced, affecting B cells in particular. 6 Therefore, these data suggest a new exploratory direction for COVID-19 patient treatments in the future.…”