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Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure.

ABSTRACT: Proper management of COVID-19 mandates better understanding of disease pathogenesis. The sudden clinical deterioration 7-8 days after initial symptom onset suggests that severe respiratory failure (SRF) in COVID-19 is driven by a unique pattern of immune dysfunction. We studied immune responses of 54 COVID-19 patients, 28 of whom had SRF. All patients with SRF displayed either macrophage activation syndrome (MAS) or very low human leukocyte antigen D related (HLA-DR) expression accompanied by profound depletion of CD4 lymphocytes, CD19 lymphocytes, and natural killer (NK) cells. Tumor necrosis factor-? (TNF-?) and interleukin-6 (IL-6) production by circulating monocytes was sustained, a pattern distinct from bacterial sepsis or influenza. SARS-CoV-2 patient plasma inhibited HLA-DR expression, and this was partially restored by the IL-6 blocker Tocilizumab; off-label Tocilizumab treatment of patients was accompanied by increase in circulating lymphocytes. Thus, the unique pattern of immune dysregulation in severe COVID-19 is characterized by IL-6-mediated low HLA-DR expression and lymphopenia, associated with sustained cytokine production and hyper-inflammation.

SUBMITTER: Giamarellos-Bourboulis EJ

PROVIDER: S-EPMC7172841 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure.

Giamarellos-Bourboulis Evangelos J EJ Netea Mihai G MG Rovina Nikoletta N Akinosoglou Karolina K Antoniadou Anastasia A Antonakos Nikolaos N Damoraki Georgia G Gkavogianni Theologia T Adami Maria-Evangelia ME Katsaounou Paraskevi P Ntaganou Maria M Kyriakopoulou Magdalini M Dimopoulos George G Koutsodimitropoulos Ioannis I Velissaris Dimitrios D Koufargyris Panagiotis P Karageorgos Athanassios A Katrini Konstantina K Lekakis Vasileios V Lupse Mihaela M Kotsaki Antigone A Renieris George G Theodoulou Danai D Panou Vassiliki V Koukaki Evangelia E Koulouris Nikolaos N Gogos Charalambos C Koutsoukou Antonia A

Cell host & microbe 20200421 6

Proper management of COVID-19 mandates better understanding of disease pathogenesis. The sudden clinical deterioration 7-8 days after initial symptom onset suggests that severe respiratory failure (SRF) in COVID-19 is driven by a unique pattern of immune dysfunction. We studied immune responses of 54 COVID-19 patients, 28 of whom had SRF. All patients with SRF displayed either macrophage activation syndrome (MAS) or very low human leukocyte antigen D related (HLA-DR) expression accompanied by pr ...[more]

PMID: 32320677

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Project description:BackgroundThere is considerable variation in disease behavior among patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19). Genomewide association analysis may allow for the identification of potential genetic factors involved in the development of Covid-19.MethodsWe conducted a genomewide association study involving 1980 patients with Covid-19 and severe disease (defined as respiratory failure) at seven hospitals in the Italian and Spanish epicenters of the SARS-CoV-2 pandemic in Europe. After quality control and the exclusion of population outliers, 835 patients and 1255 control participants from Italy and 775 patients and 950 control participants from Spain were included in the final analysis. In total, we analyzed 8,582,968 single-nucleotide polymorphisms and conducted a meta-analysis of the two case-control panels.ResultsWe detected cross-replicating associations with rs11385942 at locus 3p21.31 and with rs657152 at locus 9q34.2, which were significant at the genomewide level (P<5×10-8) in the meta-analysis of the two case-control panels (odds ratio, 1.77; 95% confidence interval [CI], 1.48 to 2.11; P = 1.15×10-10; and odds ratio, 1.32; 95% CI, 1.20 to 1.47; P = 4.95×10-8, respectively). At locus 3p21.31, the association signal spanned the genes SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6 and XCR1. The association signal at locus 9q34.2 coincided with the ABO blood group locus; in this cohort, a blood-group-specific analysis showed a higher risk in blood group A than in other blood groups (odds ratio, 1.45; 95% CI, 1.20 to 1.75; P = 1.48×10-4) and a protective effect in blood group O as compared with other blood groups (odds ratio, 0.65; 95% CI, 0.53 to 0.79; P = 1.06×10-5).ConclusionsWe identified a 3p21.31 gene cluster as a genetic susceptibility locus in patients with Covid-19 with respiratory failure and confirmed a potential involvement of the ABO blood-group system. (Funded by Stein Erik Hagen and others.).

Dataset Information

Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure.

Publications

Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure.

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