SARS-CoV-2 RNAemia and proteomic trajectories inform prognostication in COVID-19 patients admitted to intensive care

Gutmann, Clemens; Takov, Kaloyan; Burnap, Sean A.; Singh, Bhawana; Ali, Hashim; Theofilatos, Konstantinos; Reed, Ella; Hasman, Maria; Nabeebaccus, Adam; Fish, Matthew; McPhail, Mark; O’Gallagher, Kevin; Schmidt, Lukas; Cassel, Christian; Rienks, Marieke; Yin, Xiaoke; Auzinger, G.; Napoli, Salvatore; Mujib, Salma; Trovato, Francesca M.; Sanderson, Barnaby; Merrick, Blair; Niazi, Umar; Saqi, Mansoor; Dimitrakopoulou, Konstantina; Fernández-Leiro, Rafael; Braun, S.; Kronstein‐Wiedemann, Romy; Doores, Katie J.; Edgeworth, Jonathan D; Shah, Ajay M.; Bornstein, Stefan R.; Tonn, Torsten; Hayday, Adrian; Giacca, Mauro; Shankar-Hari, Manu; Mayr, Manuel

doi:10.1038/s41467-021-23494-1

Cited by 141 publications

(167 citation statements)

References 94 publications

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“…In addition, several key factors in the coagulation pathway, including factor III (F3), von Willebrand factor (vWF), and SERPINE1 (plasmin inhibitor), were elevated in the viremic group, in conjunction with a decrease in ADAMTS13, a metalloprotease enzyme that cleaves and inhibits the activity of vWF. The presence of endothelial cell damage and dysregulation of the coagulation cascade is consistent with results in patients with critical disease or after death (39)(40)(41). Our results not only demonstrate that these pathways become altered even in patients with early disease, but also provide the mechanistic link between plasma viremia and the hypercoagulable state observed in patients across the spectrum of COVID-19 disease severity (2,42,43).…”

Section: Resultssupporting

confidence: 85%

SARS-CoV-2 viremia is associated with distinct proteomic pathways and predicts COVID-19 outcomes

Li¹,

Schneider²,

Mehta³

et al. 2021

Journal of Clinical Investigation

109

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With coronavirus disease 2019 causing over 2 million deaths globally by early 2021 (1), there remains an urgent need to elucidate disease pathogenesis to improve clinical management and treatment. There is increasing evidence that COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), frequently manifests pathology beyond the pulmonary tract (2-4). In both immunocompromised and immunocompetent hosts, SARS-CoV-2 nucleic acids have been detected across a broad range of extrapulmonary sites, including spleen, heart, liver, and intestinal tract (5-9). In addition, endothelial cells are known to express ACE2, and some reports have suggested that direct infection of endothelial cells may be leading to a hypercoagulable state with vascular and downstream organ damage. Furthermore, viremia has been implicated in transplacental transmis-BACKGROUND. SARS-CoV-2 plasma viremia has been associated with severe disease and death in COVID-19 in small-scale cohort studies. The mechanisms behind this association remain elusive. METHODS.We evaluated the relationship between SARS-CoV-2 viremia, disease outcome, and inflammatory and proteomic profiles in a cohort of COVID-19 emergency department participants. SARS-CoV-2 viral load was measured using a quantitative reverse transcription PCR-based platform. Proteomic data were generated with Proximity Extension Assay using the Olink platform. RESULTS.This study included 300 participants with nucleic acid test-confirmed COVID-19. Plasma SARS-CoV-2 viremia levels at the time of presentation predicted adverse disease outcomes, with an adjusted OR of 10.6 (95% CI 4.4-25.5, P < 0.001) for severe disease (mechanical ventilation and/or 28-day mortality) and 3.9 (95% CI 1.5-10.1, P = 0.006) for 28-day mortality. Proteomic analyses revealed prominent proteomic pathways associated with SARS-CoV-2 viremia, including upregulation of SARS-CoV-2 entry factors (ACE2, CTSL, FURIN), heightened markers of tissue damage to the lungs, gastrointestinal tract, and endothelium/vasculature, and alterations in coagulation pathways. CONCLUSION.These results highlight the cascade of vascular and tissue damage associated with SARS-CoV-2 plasma viremia that underlies its ability to predict COVID-19 disease outcomes.

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Section: Resultssupporting

confidence: 85%

SARS-CoV-2 viremia is associated with distinct proteomic pathways and predicts COVID-19 outcomes

Li¹,

Schneider²,

Mehta³

et al. 2021

Journal of Clinical Investigation

109

View full text Add to dashboard Cite

show abstract

“…Furthermore, although these findings require further investigation, they are immediately relevant to research of C1-INH and α2M in individuals with kidney impairment, including patients with COVID-19. Recently, associations were identified between increased plasma C1-INH and COVID-19 RNAemia in samples from 123 hospitalized COVID-19 patients, 78 of whom required intensive care unit support [ 28 ]. On the basis of our data, these findings could be confounded by an increased burden of kidney impairment and renal replacement therapy in patients with high RNAemia and severe COVID-19.…”

Section: Discussionmentioning

confidence: 99%

Protease inhibitor plasma concentrations associate with COVID-19 infection

Medjeral-Thomas

Troldborg

Hansen

et al. 2021

Oxford Open Immunology

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Protease inhibitors influence a range of innate immunity and inflammatory pathways. We quantified plasma concentrations of key anti-inflammatory protease inhibitors in chronic haemodialysis patients with COVID-19. The samples were collected early in the disease course to determine whether plasma protease inhibitor levels associated with the presence and severity of COVID-19. We used antibody-based immunoassays to measure plasma concentrations of C1 esterase inhibitor (C1-INH), alpha2-macroglobulin (α2M), antithrombin, and inter-alpha-inhibitor heavy chain 4 (ITIH4) in 100 serial samples from 27 haemodialysis patients with COVID-19. ITIH4 was tested in two assays, one measuring intact ITIH4 and another also detecting any fragmented ITIH4 (total ITIH4). Control cohorts were 32 haemodialysis patients without COVID-19 and 32 healthy controls. We compared protease inhibitor concentration based on current and future COVID-19 severity and with CRP. Results were adjusted for repeated measures and multiple comparisons. Analysis of all available samples demonstrated lower plasma C1-INH and α2M and higher total ITIH4 in COVID-19 compared to dialysis controls. These differences were also seen in the first sample collected after COVID-19 diagnosis, a median of four days from diagnostic swab. Plasma ITIH4 levels were higher in severe than non-severe COVID-19. Serum CRP correlated positively with plasma levels of antithrombin, intact ITIH4, and total ITIH4. In conclusion, plasma protease inhibitor concentrations are altered in COVID-19.

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“…Conceptually, T cells do not recognize the virus but only recognize virus-infected cells (CD8 T cells) or cells that have internalized viral antigens produced after infection (CD4 T cells). This means that T cells do not prevent infection, but their role is linked to a reduction in viral load within the host and consequently shorter infection with lower pathogenicity [ 62 ]. Nevertheless, some data are starting to show the importance of vaccine-induced Spike-specific T cells in protection.…”

Section: Memory T Cell Response: Protection After Convalescence or Vaccinationmentioning

confidence: 99%

SARS-CoV-2-specific T cells in infection and vaccination

et al. 2021

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During viral infections, antibodies and T cells act together to prevent pathogen spread and remove virus-infected cells. Virus-specific adaptive immunity can, however, also trigger pathological processes characterized by localized or systemic inflammatory events. The protective and/or pathological role of virus-specific T cells in SARS-CoV-2 infection has been the focus of many studies in COVID-19 patients and in vaccinated individuals. Here, we review the works that have elucidated the function of SARS-CoV-2-specific T cells in patients and in vaccinated individuals. Understanding whether SARS-CoV-2-specific T cells are more linked to protection or pathogenesis is pivotal to define future therapeutic and prophylactic strategies to manage the current pandemic.

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SARS-CoV-2 RNAemia and proteomic trajectories inform prognostication in COVID-19 patients admitted to intensive care

Cited by 141 publications

References 94 publications

SARS-CoV-2 viremia is associated with distinct proteomic pathways and predicts COVID-19 outcomes

SARS-CoV-2 viremia is associated with distinct proteomic pathways and predicts COVID-19 outcomes

Protease inhibitor plasma concentrations associate with COVID-19 infection

SARS-CoV-2-specific T cells in infection and vaccination

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