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Antibody therapy reverses biological signatures of COVID-19 progression.

ABSTRACT: Understanding who is at risk of progression to severe coronavirus disease 2019 (COVID-19) is key to clinical decision making and effective treatment. We study correlates of disease severity in the COMET-ICE clinical trial that randomized 1:1 to placebo or to sotrovimab, a monoclonal antibody for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (ClinicalTrials.gov04545060). Laboratory parameters identify study participants at greater risk of severe disease, including a high neutrophil-to-lymphocyte ratio (NLR), a negative SARS-CoV-2 serologic test, and whole-blood transcriptome profiles. Sotrovimab treatment is associated with normalization of NLR and the transcriptomic profile and with a decrease of viral RNA in nasopharyngeal samples. Transcriptomics provides the most sensitive detection of participants who would go on to be hospitalized or die. To facilitate timely measurement, we identify a 10-gene signature with similar predictive accuracy. We identify markers of risk for disease progression and demonstrate that normalization of these parameters occurs with antibody treatment of established infection.

SUBMITTER: Maher MC

PROVIDER: S-EPMC9380250 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Antibody therapy reverses biological signatures of COVID-19 progression.

Maher M Cyrus MC Soriaga Leah B LB Gupta Anil A Chen Yi-Pei YP di Iulio Julia J Ledoux Sarah S Smithey Megan J MJ Cathcart Andrea L AL McKusick Kathleen K Sun David D Aldinger Melissa M Alexander Elizabeth E Purcell Lisa L Ding Xiao X Peppercorn Amanda A Austin Daren D Mogalian Erik E Yeh Wendy W WW Shapiro Adrienne E AE Corti Davide D Virgin Herbert W HW Pang Phillip S PS Telenti Amalio A

Cell reports. Medicine 20220801 8

Understanding who is at risk of progression to severe coronavirus disease 2019 (COVID-19) is key to clinical decision making and effective treatment. We study correlates of disease severity in the COMET-ICE clinical trial that randomized 1:1 to placebo or to sotrovimab, a monoclonal antibody for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (ClinicalTrials.gov04545060). Laboratory parameters identify study participants at greater risk of severe disease, ...[more]

PMID: 35977462

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Project description:SARS-CoV-2 is the causative agent of COVID-19 that has infected over 642 million and killed over 6.6 million people around the globe. Underlying a wide range of clinical manifestations of this disease, from moderate to extremely severe systemic conditions, could be genes or pathways differentially expressing in the hosts. It is therefore important to gain insights into pathways involved in COVID-19 pathogenesis and host defense and thus understand the host response to this pathogen at the physiological and molecular level. To uncover genes and pathways involved in the differential clinical manifestations of this disease, we developed a novel gene co-expression network based pipeline that uses gene expression obtained from different SARS-CoV-2 infected human tissues. We leveraged the network to identify novel genes or pathways that likely differentially express and could be physiologically significant in the COVID-19 pathogenesis and progression but were deemed statistically non-significant and therefore not further investigated in the original studies. Our network-based approach aided in the identification of co-expression modules enriched in differentially expressing genes (DEGs) during different stages of COVID-19 and enabled discovery of novel genes involved in the COVID-19 pathogenesis, by virtue of their transcript abundance and association with genes expressing differentially in modules enriched in DEGs. We further prioritized by considering only those enriched gene modules that have most of their genes differentially expressed, inferred by the original studies or this study, and document here 7 novel genes potentially involved in moderate, 2 in severe, 48 in extremely severe COVID-19, and 96 novel genes involved in the progression of COVID-19 from severe to extremely severe conditions. Our study shines a new light on genes and their networks (modules) that drive the progression of COVID-19 from moderate to extremely severe condition. These findings could aid development of new therapeutics to combat COVID-19.

Project description:Viral sepsis has been proposed as an accurate term to describe all multisystemic dysregulations and clinical findings in severe and critically ill COVID-19 patients. The adoption of this term may help the implementation of more accurate strategies of early diagnosis, prognosis, and in-hospital treatment. We accurately quantified 110 metabolites using targeted metabolomics, and 13 cytokines/chemokines in plasma samples of 121 COVID-19 patients with different levels of severity, and 37 non-COVID-19 individuals. Analyses revealed an integrated host-dependent dysregulation of inflammatory cytokines, neutrophil activation chemokines, glycolysis, mitochondrial metabolism, amino acid metabolism, polyamine synthesis, and lipid metabolism typical of sepsis processes distinctive of a mild disease. Dysregulated metabolites and cytokines/chemokines showed differential correlation patterns in mild and critically ill patients, indicating a crosstalk between metabolism and hyperinflammation. Using multivariate analysis, powerful models for diagnosis and prognosis of COVID-19 induced sepsis were generated, as well as for mortality prediction among septic patients. A metabolite panel made of kynurenine/tryptophan ratio, IL-6, LysoPC a C18:2, and phenylalanine discriminated non-COVID-19 from sepsis patients with an area under the curve (AUC (95%CI)) of 0.991 (0.986-0.995), with sensitivity of 0.978 (0.963-0.992) and specificity of 0.920 (0.890-0.949). The panel that included C10:2, IL-6, NLR, and C5 discriminated mild patients from sepsis patients with an AUC (95%CI) of 0.965 (0.952-0.977), with sensitivity of 0.993(0.984-1.000) and specificity of 0.851 (0.815-0.887). The panel with citric acid, LysoPC a C28:1, neutrophil-lymphocyte ratio (NLR) and kynurenine/tryptophan ratio discriminated severe patients from sepsis patients with an AUC (95%CI) of 0.829 (0.800-0.858), with sensitivity of 0.738 (0.695-0.781) and specificity of 0.781 (0.735-0.827). Septic patients who survived were different from those that did not survive with a model consisting of hippuric acid, along with the presence of Type II diabetes, with an AUC (95%CI) of 0.831 (0.788-0.874), with sensitivity of 0.765 (0.697-0.832) and specificity of 0.817 (0.770-0.865).

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Antibody therapy reverses biological signatures of COVID-19 progression.

Publications

Antibody therapy reverses biological signatures of COVID-19 progression.

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