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1.
JCI Insight ; 2022 May 24.
Article in English | MEDLINE | ID: covidwho-1861743

ABSTRACT

The role of immune responses to previously seen endemic coronavirus epitopes in severe acute respiratory coronavirus 2 (SARS-CoV-2) infection and disease progression has not yet been determined. Here, we show that a key characteristic of fatal coronavirus disease (COVID-19) outcomes is that the immune response to the SARS-CoV-2 spike protein is enriched for antibodies directed against epitopes shared with endemic beta-coronaviruses, and has a lower proportion of antibodies targeting the more protective variable regions of the spike. The magnitude of antibody responses to the SARS-CoV-2 full-length spike protein, its domains and subunits, and the SARS-CoV-2 nucleocapsid also correlated strongly with responses to the endemic beta-coronavirus spike proteins in individuals admitted to intensive care units (ICU) with fatal COVID-19 outcomes, but not in individuals with non-fatal outcomes. This correlation was found to be due to the antibody response directed at the S2 subunit of the SARS-CoV-2 spike protein, which has the highest degree of conservation between the beta-coronavirus spike proteins. Intriguingly, antibody responses to the less cross-reactive SARS-CoV-2 nucleocapsid were not significantly different in individuals who were admitted to ICU with fatal and non-fatal outcomes, suggesting an antibody profile in individuals with fatal outcomes consistent with an original antigenic sin type-response.

2.
PLoS Pathog ; 17(9): e1009804, 2021 09.
Article in English | MEDLINE | ID: covidwho-1416909

ABSTRACT

Prior studies have demonstrated that immunologic dysfunction underpins severe illness in COVID-19 patients, but have lacked an in-depth analysis of the immunologic drivers of death in the most critically ill patients. We performed immunophenotyping of viral antigen-specific and unconventional T cell responses, neutralizing antibodies, and serum proteins in critically ill patients with SARS-CoV-2 infection, using influenza infection, SARS-CoV-2-convalescent health care workers, and healthy adults as controls. We identify mucosal-associated invariant T (MAIT) cell activation as an independent and significant predictor of death in COVID-19 (HR = 5.92, 95% CI = 2.49-14.1). MAIT cell activation correlates with several other mortality-associated immunologic measures including broad activation of CD8+ T cells and non-Vδ2 γδT cells, and elevated levels of cytokines and chemokines, including GM-CSF, CXCL10, CCL2, and IL-6. MAIT cell activation is also a predictor of disease severity in influenza (ECMO/death HR = 4.43, 95% CI = 1.08-18.2). Single-cell RNA-sequencing reveals a shift from focused IFNα-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.


Subject(s)
COVID-19/immunology , COVID-19/mortality , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Antigens, CD/immunology , Antigens, Differentiation, T-Lymphocyte/immunology , B-Lymphocytes/immunology , Biomarkers/blood , Blood Proteins/metabolism , Cohort Studies , Critical Illness/mortality , Female , Humans , Immunophenotyping , Influenza, Human/immunology , Lectins, C-Type/immunology , Lymphocyte Activation , Male , Middle Aged , Mucosal-Associated Invariant T Cells/immunology , Patient Acuity
3.
Kidney Int Rep ; 6(2): 265-271, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-1056576

ABSTRACT

INTRODUCTION: During the coronavirus disease 2019 (COVID-19) pandemic in 2020, high rates of acute kidney injury (AKI) in critically unwell patients are being reported, leading to an increased demand for renal replacement therapy (RRT). Providing RRT for this large number of patients is proving challenging, and so alternatives to continuous renal replacement therapies (CRRT) in the intensive care unit (ICU) are needed. Peritoneal dialysis (PD) can be initiated immediately after percutaneous insertion of the catheter, but there are concerns about impact on ventilation and RRT efficacy. We sought to describe our recent experience with percutaneous catheter insertion and peritoneal dialysis in patients in the ICU with COVID-19 infection. METHOD: Patients were selected according to local protocol, and catheters were inserted percutaneously by experienced operators using a Seldinger technique. Sequential Organ Failure Assessment (SOFA) score and ventilation requirements were recorded at the time of insertion and 24 hours later. Procedural complications, proportion of RRT provided by PD, renal recovery, and RRT parameters (serum potassium and maximum base excess) during PD were assessed. RESULTS: Percutaneous PD catheters were successfully inserted in 37 of 44 patients (84.1%) after a median of 13.5 days (interquartile range [IQR] = 10.0, 20.3 days) in the ICU. No adverse events were reported; SOFA scores and ventilation requirements were comparable before and after insertion; and adequate RRT parameters were achieved. The median proportion of RRT provided by PD following catheter insertion was 94.6% (IQR = 75.0, 100%). CONCLUSION: Peritoneal dialysis provides a safe and effective alternative to CRRT in selected patients with AKI and COVID-19 infection requiring ventilation on intensive care.

4.
Shock ; 55(6): 752-758, 2021 06 01.
Article in English | MEDLINE | ID: covidwho-835230

ABSTRACT

ABSTRACT: Critically ill patients with COVID-19 infection frequently exhibit a hyperinflammatory response and develop organ failures; however, the underlying mechanisms are unclear. We investigated the microcirculatory, endothelial, and inflammatory responses in critically ill COVID-19 patients and compared them to a group of patients with septic shock in a prospective observational case control study. Thirty critically ill patients with COVID-19 were compared to 33 patients with septic shock.Measurements of sublingual microcirculatory flow using Incident Dark Field video-microscopy and serial measurements of IL-6 and Syndecan-1 levels were performed. COVID-19 patients had significantly less vasoactive drug requirement and lower plasma lactate than those with septic shock. Microcirculatory flow was significantly worse in septic patients than those with COVID-19 (MFI 2.6 vs 2.9 p 0.02, PPV 88 vs 97% P < 0.001). IL-6 was higher in patients with septic shock than COVID-19 (1653 vs 253 pg/mL, P 0.03). IL-6 levels in COVID 19 patients were not elevated compared to healthy controls except on the day of ICU admission. Syndecan-1 levels were not different between the two pathological groups. Compared to patients with undifferentiated septic shock an overt shock state with tissue hypoperfusion does not appear typical of COVID-19 infection. There was no evidence of significant sublingual microcirculatory impairment, widespread endothelial injury or marked inflammatory cytokine release in this group of critically ill COVID-19 patients.


Subject(s)
COVID-19/blood , Endothelium, Vascular/metabolism , Interleukin-6/blood , Microcirculation , SARS-CoV-2/metabolism , Shock, Septic/blood , Syndecan-1/blood , Aged , COVID-19/pathology , Critical Illness , Endothelium, Vascular/pathology , Female , Humans , Inflammation/blood , Inflammation/pathology , Male , Middle Aged , Prospective Studies , Shock, Septic/pathology
5.
SSRN; 2020.
Preprint | SSRN | ID: ppcovidwho-1942

ABSTRACT

Background: Critically ill patients with COVID-19 infection frequently exhibit a hyperinflammatory response and develoorgan failures, however the underlyin

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