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Cell-Type-Specific Immune Dysregulation in Severely Ill COVID-19 Patients.

ABSTRACT: Recent studies have demonstrated immunologic dysfunction in severely ill coronavirus disease 2019 (COVID-19) patients. We use single-cell RNA sequencing (scRNA-seq) to analyze the transcriptome of peripheral blood mononuclear cells (PBMCs) from healthy (n = 3) and COVID-19 patients with moderate disease (n = 5), acute respiratory distress syndrome (ARDS, n = 6), or recovering from ARDS (n = 6). Our data reveal transcriptomic profiles indicative of defective antigen presentation and interferon (IFN) responsiveness in monocytes from ARDS patients, which contrasts with higher responsiveness to IFN signaling in lymphocytes. Furthermore, genes involved in cytotoxic activity are suppressed in both natural killer (NK) and CD8 T lymphocytes, and B cell activation is deficient, which is consistent with delayed viral clearance in severely ill COVID-19 patients. Our study demonstrates that COVID-19 patients with ARDS have a state of immune imbalance in which dysregulation of both innate and adaptive immune responses may be contributing to a more severe disease course.

SUBMITTER: Yao C

PROVIDER: S-EPMC7744012 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Cell type-specific immune dysregulation in severely ill COVID-19 patients.

Project description:Coronavirus disease 2019 (COVID-19) has quickly become the most serious pandemic since the 1918 flu pandemic. In extreme situations, patients develop a dysregulated inflammatory lung injury called acute respiratory distress syndrome (ARDS) that causes progressive respiratory failure requiring mechanical ventilatory support. Recent studies have demonstrated immunologic dysfunction in severely ill COVID-19 patients. To further delineate the dysregulated immune response driving more severe clinical course from SARS-CoV-2 infection, we used single-cell RNA sequencing (scRNAseq) to analyze the transcriptome of peripheral blood mononuclear cells (PBMC) from hospitalized COVID-19 patients having mild disease (n = 5), developing ARDS (n = 6), and recovering from ARDS (n = 6). Our data demonstrated an overwhelming inflammatory response with select immunodeficiencies within various immune populations in ARDS patients. Specifically, their monocytes had defects in antigen presentation and deficiencies in interferon responsiveness that contrasted the higher interferon signals in lymphocytes. Furthermore, cytotoxic activity was suppressed in both NK and CD8 lymphocytes whereas B cell activation was deficient, which is consistent with the delayed viral clearance in severely ill COVID-19 patients. Finally, we identified altered signaling pathways in the severe group that suggests immunosenescence and immunometabolic changes could be contributing to the dysfunctional immune response. Our study demonstrates that COVID-19 patients with ARDS have an immunologically distinct response when compared to those with a more innocuous disease course and show a state of immune imbalance in which deficiencies in both the innate and adaptive immune response may be contributing to a more severe disease course in COVID-19.

| S-EPMC7386732 | biostudies-literature

Severely ill COVID-19 patients display impaired exhaustion features in SARS-CoV-2-reactive CD8+ T cells

Project description:The molecular properties of CD8+ T cells that respond to SARS-CoV-2 infection are not fully known. Here, we report on the single-cell transcriptomes of >80,000 virus-reactive CD8+ T cells, obtained using a modified Antigen-Reactive T cell Enrichment (ARTE) assay, from 39 COVID-19 patients and 10 healthy subjects. COVID-19 patients segregated into two groups based on whether the dominant CD8+ T cell response to SARS-CoV-2 was ‘exhausted’ or not. SARS-CoV-2-reactive cells in the exhausted subset were increased in frequency and displayed lesser cytotoxicity and inflammatory features in COVID-19 patients with mild compared to severe illness. In contrast, SARS-CoV-2-reactive cells in the dominant non-exhausted subset from patients with severe disease showed enrichment of transcripts linked to co-stimulation, pro-survival NF-κB signaling, and anti-apoptotic pathways, suggesting the generation of robust CD8+ T cell memory responses in patients with severe COVID-19 illness. CD8+ T cells reactive to influenza and respiratory syncytial virus from healthy subjects displayed polyfunctional features and enhanced glycolysis. Cells with such features were largely absent in SARS-CoV-2-reactive cells from both COVID-19 patients and healthy controls non-exposed to SARS-CoV-2. Overall, our single-cell analysis revealed substantial diversity in the nature of CD8+ T cells responding to SARS-CoV-2.

2020-07-22 | GSE153931 | GEO

Gene expression profile of peripheral blood mononuclear cells from mild and severe COVID-19 patients, severely ill COVID-19 patients treated with dexamethasone and healthy controls

Project description:The objective of this experiment was to compare the transcriptomic profile (NanoString platform) of peripheral blood mononuclear cells (PBMCs) from COVID-19 patients with mild disease, and patients with severe COVID-19 with and without dexamethasone treatment, and healthy controls. We analyzed PBMCs from 4 mild COVID patients, 3 severe COVID patients,4 severe COVID patients treated with dexamethasone, and 5 healthy controls

2023-03-23 | GSE227341 | GEO

Transcriptomic clustering of critically-ill COVID-19 patients

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-02-28 | GSE197259 | GEO

Adjunct Immunotherapies for the Management of Severely Ill COVID-19 Patients.

Project description:Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has infected millions, with more than 275,000 fatal cases as of May 8, 2020. Currently, there are no specific COVID-19 therapies. Most patients depend on mechanical ventilation. Current COVID-19 data clearly highlight that cytokine storm and activated immune cell migration to the lungs characterize the early immune response to COVID-19 that causes severe lung damage and development of acute respiratory distress syndrome. In view of uncertainty associated with immunosuppressive treatments, such as corticosteroids and their possible secondary effects, including risks of secondary infections, we suggest immunotherapies as an adjunct therapy in severe COVID-19 cases. Such immunotherapies based on inflammatory cytokine neutralization, immunomodulation, and passive viral neutralization not only reduce inflammation, inflammation-associated lung damage, or viral load but could also prevent intensive care unit hospitalization and dependency on mechanical ventilation, both of which are limited resources.

| S-EPMC7190525 | biostudies-literature

Identification of immune correlates of fatal outcomes in critically ill COVID-19 patients

Project description:Single-cell RNA-sequencing reveals a shift from focused IFN alpha-driven signals in COVID-19 ICU patients who survive to broad pro-inflammatory responses in fatal COVID-19 – a feature not observed in severe influenza. We conclude that fatal COVID-19 infection is driven by uncoordinated inflammatory responses that drive a hierarchy of T cell activation, elements of which can serve as prognostic indicators and potential targets for immune intervention.

2021-06-18 | GSE178404 | GEO

Early predictors of mortality for moderate to severely ill patients with Covid-19.

Project description:BackgroundDetermining the factors affecting the mortality and clinical conditions of the patients with Covid-19 are indispensable needs in developing patient treatment algorithms. We aimed to determine the parameters that can predict the mortality of moderate to severely ill patients with laboratory confirmed Covid-19.MethodsModerate to severely ill, Covid-19 patients older than 18 years were included. Mild Covid-19 patients and the ones with negative polymerase chain reaction test results were excluded from the study. The primary outcome of the study was 30-day mortality rate and we aimed to determine the factors affecting mortality in moderate to severely ill Covid-19 patients.Results168 patient results were analyzed. Median age of the patients was 59.5 (48.3 to 76) and 90 (53.6%) were male. According to multivariate regression analysis results, the presence of any comorbid disease (p = 0.027, HR = 26.11 (95%CI: 1.45 to 471.31)), elevated C-reactive protein levels (CRP) (p < 0.001, HR = 1.24 (95%CI: 1.11 to 1.38)) and presence of dyspnea (p = 0.026, HR = 4.26 ((95%CI: 1.19 to 15.28)) were found to significantly increase the mortality, while high pulse O 2 saturation level (p < 0.001, HR = 0.90 (95%CI: 0.82 to 0.99) was found to decrease. When receiver operating characteristic curve was created for laboratory tests, it was determined that white blood cell counts, neutrophil counts, CRP levels and neutrophil/lymphocyte ratio predicted mortality while Lymphocyte levels did not.ConclusionDyspnea, the presence of any comorbid disease, elevated CRP levels, and low pulse O 2 saturation levels predict mortality in moderate to severely ill Covid-19 patients.

| S-EPMC7452846 | biostudies-literature

Potential therapeutic effects of dipyridamole in the severely ill patients with COVID-19.

Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can cause acute respiratory distress syndrome, hypercoagulability, hypertension, and multiorgan dysfunction. Effective antivirals with safe clinical profile are urgently needed to improve the overall prognosis. In an analysis of a randomly collected cohort of 124 patients with COVID-19, we found that hypercoagulability as indicated by elevated concentrations of D-dimers was associated with disease severity. By virtual screening of a U.S. FDA approved drug library, we identified an anticoagulation agent dipyridamole (DIP) in silico, which suppressed SARS-CoV-2 replication in vitro. In a proof-of-concept trial involving 31 patients with COVID-19, DIP supplementation was associated with significantly decreased concentrations of D-dimers (P < 0.05), increased lymphocyte and platelet recovery in the circulation, and markedly improved clinical outcomes in comparison to the control patients. In particular, all 8 of the DIP-treated severely ill patients showed remarkable improvement: 7 patients (87.5%) achieved clinical cure and were discharged from the hospitals while the remaining 1 patient (12.5%) was in clinical remission.

| S-EPMC7169892 | biostudies-literature

Increased circulating levels of angiotensin-(1-7) in severely ill COVID-19 patients.

Project description:This letter reports an unexpected increase of the ACE2 product angiotensin-(1-7) and a parallel decrease of its substrate angiotensin II, suggesting a dysregulation of the renin-angiotensin system towards angiotensin-(1-7) formation in #COVID19 patients https://bit.ly/3xFXuTU.

| S-EPMC8326714 | biostudies-literature

Matched Cohort Study of Convalescent COVID-19 Plasma Treatment in Severely or Life Threateningly Ill COVID-19 Patients.

Project description:BackgroundThe utility of convalescent coronavirus disease 2019 (COVID-19) plasma (CCP) in the current pandemic is not well defined. We sought to evaluate the safety and efficacy of CCP in severely or life threateningly ill COVID-19 patients when matched with a contemporaneous cohort.MethodsPatients with severe or life-threatening COVID-19 were treated with CCP according to Food and Drug Administration criteria, prioritization by an interdisciplinary team, and based on CCP availability. Individual-level matched controls (1:1) were identified from patients admitted during the prior month when no CCP was available. The safety outcome was freedom from adverse transfusion reaction, and the efficacy outcome was a composite of death or worsening O2 support. Demographic, clinical, and laboratory data were analyzed by univariate and multivariable regression analyses accounting for matched design.ResultsStudy patients (n = 94, 47 matched pairs) were 62% male with a mean age of 58, and 98% (90/94) were minorities (53% Hispanic, 45% Black, non-Hispanic) in our inner-city population. Seven-day composite and mortality outcomes suggested a nonsignificant benefit in CCP-treated patients (adjusted hazard ratio [aHR], 0.70; 95% CI, 0.23-2.12; P = .52; aHR, 0.23; 95% CI, 0.04-1.51; P = .13, respectively). Stratification by pretransfusion mechanical ventilation status showed no differences between groups. No serious transfusion reactions occurred.ConclusionsIn this short-term matched cohort study, transfusion with CCP was safe and showed a nonsignificant association with study outcomes. Randomized and larger trials to identify appropriate timing and dosing of CCP in COVID-19 are warranted.Trial registration?ClinicalTrials.gov Identifier: NCT04420988.

| S-EPMC7798482 | biostudies-literature

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