Impaired Cytotoxic Response in PBMCs From Patients With COVID-19 Admitted to the ICU: Biomarkers to Predict Disease Severity

Abstract

Infection by novel coronavirus SARS-CoV-2 causes different presentations of COVID-19 and some patients may progress to a critical, fatal form of the disease that requires their admission to ICU and invasive mechanical ventilation. In order to predict in advance which patients could be more susceptible to develop a critical form of COVID-19, it is essential to define the most adequate biomarkers. In this study, we analyzed several parameters related to the cellular immune response in blood samples from 109 patients with different presentations of COVID-19 who were recruited in Hospitals and Primary Healthcare Centers in Madrid, Spain, during the first pandemic peak between April and June 2020. Hospitalized patients with the most severe forms of COVID-19 showed a potent inflammatory response that was not translated into an efficient immune response. Despite the high levels of effector cytotoxic cell populations such as NK, NKT and CD8+ T cells, they displayed immune exhaustion markers and poor cytotoxic functionality against target cells infected with pseudotyped SARS-CoV-2 or cells lacking MHC class I molecules. Moreover, patients with critical COVID-19 showed low levels of the highly cytotoxic TCRγδ+ CD8+ T cell subpopulation. Conversely, CD4 count was greatly reduced in association to high levels of Tregs, low plasma IL-2 and impaired Th1 differentiation. The relative importance of these immunological parameters to predict COVID-19 severity was analyzed by Random Forest algorithm and we concluded that the most important features were related to an efficient cytotoxic response. Therefore, efforts to fight against SARS-CoV-2 infection should be focused not only to decrease the disproportionate inflammatory response, but also to elicit an efficient cytotoxic response against the infected cells and to reduce viral replication.

Impaired Antibody-Dependent Cellular Cytotoxicity in a Spanish Cohort of Patients With COVID-19 Admitted to the ICU

“…Furthermore, the analytical characterization of SARS-CoV-2 antibodies generated by the different individuals, as well as their ability to trigger an effective cytotoxic response, could be needed to further understand the differential progression of COVID-19 due to the composition of N-glycans and polymorphic allotype variations in the Ig gamma heavy chain gene may modify the binding affinity and also, the ADCC response ( 40 , 41 ). To our knowledge, this is the first time that impaired ADCC response has been described in patients with COVID-19 admitted to the ICU and it supports our previous observation that the cellular immune response against SARS-CoV-2 is compromised in these individuals with the most severe presentations of the disease ( 7 ).…”

“…Due to the impaired immune response presented in individuals with the most severe forms of COVID-19 ( 7 ), the reactivation of latent herpesviruses was analyzed in our cohorts of patients. We determined that 100% of the individuals recruited for this study were seropositive for VZV.…”

“…However, patients with severe outcomes of COVID-19 also show dysregulated immune responses associated to these cells. In fact, eosinopenia has been associated with high mortality due to COVID-19 ( 46 , 47 ) and we have shown that highly cytotoxic CD8γδ+ T cell levels are greatly diminished in critical patients ( 7 ). The low levels of essential cells involved in ADCC activity may at least partly explain the impaired cytotoxicity observed in the PBMCs of the individuals from our cohort.…”

“…ADCC via NK cells against SARS-CoV-2 spike glycoprotein has been observed previously in plasma from recovered or recovering COVID-19 patients ( 22 ). However, NK cells from patients with severe COVID-19 show reduced levels and a dysfunctional, altered expression of receptors ( 7 , 42 , 43 ). As a result, impaired NK functions, including ADCC response, are surely essential to get a better understanding in COVID-19 poor progression.…”

“…Accordingly, high levels of markers of inflammation in plasma such as interleukin (IL)-6, ferritin or C reactive protein (CRP) were described in patients with severe COVID-19 ( 5 , 6 ). However, patients with extremely severe disease also showed low levels of cytokines with antiviral potential such as IL-2, IL-12 or interferon (IFN)-γ ( 7 ). Therefore, despite of the critical role of the inflammatory response during COVID-19, other specific immunological features that also contribute to the different clinical outcomes remain to be understood.…”