Abstract
Inflammatory cytokines and chemokines (CC) drive COVID-19 pathology. Yet, patients with similar circulating CC levels present with different disease severity. Here, we determined 171 microRNAomes from 58 hospitalised COVID-19 patients (Cohort 1) and levels of 25 cytokines and chemokines (CC) in the same samples. Combining microRNA (miRNA) and CC measurements allowed for discrimination of severe cases with greater accuracy than using miRNA or CC levels alone. Severity group-specific associations between miRNAs and COVID-19-associated CC (e.g. IL6, CCL20) or clinical hallmarks of COVID-19 (e.g. neutrophilia, hypoalbuminemia) separated patients with similar CC levels but different disease severity. Critically, analysis of an independent cohort of 108 patients from a different centre (Cohort 2) demonstrated feasibility of CC/miRNA profiling in leftover blood samples with similar severe disease CC and miRNA profiles, and revealed CCL20, IL6, IL10, and miR-451a as key correlates of fatal COVID-19. These findings highlight that systemic miRNA/CC networks underpin severe COVID-19.Funding: The study was funded by the UKRI MRC/NIHR award to the UK Coronavirus Immunology Consortium (UK-CIC, MR/V028448/1). Sample collection at Manchester NHS Trusts was supported by the NIHR Manchester Biomedical Research Centre (TH and AS) and 3M Global Giving award (JRG and TH). Sample collection at York and Scarborough NHS Trust was supported by the Wellcome Trust (ISSF grant WT204829 through the Centre for Future Health at the University of York) and the Hull York Medical School. JRG is supported by a senior fellowship by The Kennedy Trust for Rheumatology Research. This report contains independent research supported by the North West Lung Centre Charity and the NIHR Manchester Clinical Research Facility at Wythenshawe Hospital.Declaration of Interests: The authors declare no competing interests.Ethics Approval Statement: For the cohort 1, ethics approval was obtained from the North West-Haydock Research Ethics Committee for ManARTS (reference 15/NW/0409) and from the Wales Research Ethics Committee 4 for NCARC (reference 18/WA/0368). For the cohort 2, ethics approval was obtained from Yorkshire & The Humber - Leeds West Research Ethics Committee (REC reference 19/YH/0394 with approved 26 SA002 amendment of IRAS project 269597).
Highlights
The COVID-19 pandemic has caused more than 5.2 million deaths
Combining microRNA and cytokines and chemokines (CC) measurements allowed for discrimination of severe cases with greater accuracy than using miRNA or CC levels alone
Analysis of an independent cohort of 108 patients from a different center (Cohort 2) demonstrated feasibility of CC/miRNA profiling in leftover hospital blood samples with similar severe disease CC and miRNA profiles, and revealed CCL20, IL6, IL10, and miR-451a as key correlates of fatal COVID-19. These findings highlight that systemic miRNA/CC networks underpin severe COVID-19
Summary
The COVID-19 pandemic has caused more than 5.2 million deaths (as of 1st December 2021, https://coronavirus.jhu.edu). Consistent with the acute respiratory distress syndrome (ARDS) presentation of severe COVID-19, multiple studies have reported increased circulating levels of pro-inflammatory cytokines and chemokines (CC) associated with COVID-19 severity including IL6, IL10, CCL2, CXCL10, and GMCSF (COvid-19 Multi-omics Blood ATlas (COMBAT) Consortium, 2021; Del Valle et al, 2020; Laing et al, 2020; Mann et al, 2020; Thwaites et al, 2021; Zhao et al, 2020). Other CC, have been reported to predict severity, less consistently (Chi et al, 2020; COvid-19 Multi-omics Blood ATlas (COMBAT) Consortium, 2021; Del Valle et al, 2020; Laing et al, 2020; Lucas et al, 2020; Zhao et al, 2020)
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