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Authors: Giamarellos-Bourboulis et al. Link to paper: https://www.cell.com/pb-assets/products/coronavirus/CHOM2296_s50.pdf

Journal/ Pre-Print: CellPress

Key Words: immune dysregulation; interleukin-6; lymphopenia; HLA-DR; macrophage activation

Research Highlights

1. Stratification of immune responses on COVID-19 patients with severe respiratory failure (SRF), compared to bacterial sepsis or H1N1 patients, based on previously reported classification of critically ill patients: i) Macrophage-activation-syndrome (MAS); ii) Immune dysregulation characterized by low expression of the HLA-DR on CD14-monocytes; iii) Intermediate functional state.

2. All patients with SRF and infected with SARS-CoV-2 had either immune dysregulation or MAS. Immune dysregulation was triggered by monocyte hyperactivation associated with excessive release of interleukin(IL)-6, and profound lymphopenia;

3. IL-6 overproduction mediated low HLA-DR expression on CD14-monocytes in COVID-19 patients with immune dysregulation but not in COVID19 patients with an intermediate immune state of activation. This process was partially restored though IL-6 pathway blockade (Tocilizumab).

Summary

The article from Giamarellos-Bourboulis et al. reported a characterisation of immune responses in 54 COVID-19 patients, compared to patients with bacterial sepsis or infected with H1N1 suffering from pneumonia according to classification of critically ill patients. All COVID-19 patients with severe respiratory Failure (SRF) exhibited either acute immune dysregulation or macrophage-activation syndrome (MAS). Immune dysregulation was characterised by low HLA-DR expression on monocytes accompanied by profound depletion of CD4+, CD19+ and natural killer cells. This process was mediated by IL-6 and the blockade of IL-6 pathway partially restored the expression of HLA-DR on monocytes from all patients with immune dysregulation.

Impact for SARS-CoV2/COVID19 research efforts

Clinical symptoms and pathogenesis of SARS-Cov2/COVID19. Stratification of immune responses on COVID-19 patients with severe respiratory failure (SRF) based on previously reported classification of critically ill patients: i) Macrophage-activation-syndrome (MAS); ii) Immune dysregulation characterized by low expression of the HLA-DR on CD14-monocytes; iii) Intermediate functional state.

Understanding the immune response to SARS-CoV2/COVID19. Small cohort (n = 54) of COVID-19 patients confirming lower levels of CD4+ lymphocytes and natural killer (NK) cells in peripheral blood, especially in COVID-19 patients under immune dysregulation. Additionally, in this group of COVID-19 patients, there was a sustained production of TNFα and IL-6 by the PBMCs, in contrast to lower levels in PBMCS from patients affected by bacterial sepsis or H1N1.

Treatment of SARS-CoV2/COVID19 positive individuals. Based on immunological unique signature in COVID-19 patients with immune dysregulation, they suggest Sarilumab, Siltuximab, Tocilizumab (anti IL6R) as potential therapeutic strategies.

Study Type

· Clinical study related to the characterization of immune responses from COVID-19 patients, with SRF or not, compared to retrospective studies in patients affected by bacterial sepsis and H1N1.

Strengths and limitations of the paper

Novelty: All COVID-19 patients with severe respiratory Failure (SRF) exhibited either acute immune dysregulation or macrophage-activation syndrome (MAS). Immune dysregulation was characterised by low HLA-DR expression on CD14-monocytes in COVID-19 patients. This process was mediated by IL-6 and may be reversed trough IL-6 pathway blockade.

Standing in the field: It confirms existing literature on the nature of severe COVID-19- lymphopenia, high IL-6 levels.

Appropriate statistics: Yes.

Viral model used: Patients infected with SARS-CoV2.

Translatability: Moderate, further work is needed to define the use of Tocilizumab for COVID-19 treatment.

Main limitations:

· Relative small cohort of COVID-19 patients (n = 54, but only 28 COVID-19 patients under SRF)

· Combination of observational studies with retrospective studies

· Only six patients with immune dysregulation were treated with single intravenous infusion of 8mg/kg of Tocilizumab and it is not clear the clinical progression in these patients

· Not stated if SARS-CoV2 was confirmed via RTqPCR or ELISA or not at all

· SARS-CoV-2 Viral titers not monitored

· Missing gate strategy for FACS analysis and no representative dot plots

· Significant age difference between patients with bacterial and viral infection may have confounded results