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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is known to present with pulmonary and extra-pulmonary organ complications. In comparison with the 2009 pandemic (pH1N1), SARS-CoV-2 infection is likely to lead to more severe disease, with multi-organ effects, including cardiovascular disease. SARS-CoV-2 has been associated with acute and long-term cardiovascular disease, but the molecular changes govern this remain unknown. In this study, we investigated the landscape of cardiac tissues collected at rapid autopsy from SARS-CoV-2, pH1N1, and control patients using targeted spatial transcriptomics approaches. Although SARS-CoV-2 was not detected in cardiac tissue, host transcriptomics showed upregulation of genes associated with DNA damage and repair, heat shock, and M1-like macrophage infiltration in the cardiac tissues of COVID-19 patients. The DNA damage present in the SARS-CoV-2 patient samples, were further confirmed by {gamma}-H2Ax immunohistochemistry. In comparison, pH1N1 showed upregulation of Interferon-stimulated genes (ISGs), in particular interferon and complement pathways, when compared with COVID-19 patients. These data demonstrate the emergence of distinct transcriptomic profiles in cardiac tissues of SARS-CoV-2 and pH1N1 influenza infection supporting the need for a greater understanding of the effects on extra-pulmonary organs, including the cardiovascular system of COVID-19 patients, to delineate the immunopathobiology of SARS-CoV-2 infection, and long term impact on health.
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BackgroundRobust biomarkers that predict disease outcomes amongst COVID-19 patients are necessary for both patient triage and resource prioritisation. Numerous candidate biomarkers have been proposed for COVID-19. However, at present, there is no consensus on the best diagnostic approach to predict outcomes in infected patients. Moreover, it is not clear whether such tools would apply to other potentially pandemic pathogens and therefore of use as stockpile for future pandemic preparedness. MethodsWe conducted a multi-cohort observational study to investigate the biology and the prognostic role of interferon alpha-inducible protein 27 (IFI27) in COVID-19 patients. FindingsWe show that IFI27 is expressed in the respiratory tract of COVID-19 patients and elevated IFI27 expression is associated with the presence of a high viral load. We further demonstrate that systemic host response, as measured by blood IFI27 expression, is associated with COVID-19 severity. For clinical outcome prediction (e.g. respiratory failure), IFI27 expression displays a high positive (0.83) and negative (0.95) predictive value, outperforming all other known predictors of COVID-19 severity. Furthermore, IFI27 is upregulated in the blood of infected patients in response to other respiratory viruses. For example, in the pandemic H1N1/09 swine influenza virus infection, IFI27-like genes were highly upregulated in the blood samples of severely infected patients. InterpretationThese data suggest that prognostic biomarkers targeting the family of IFI27 genes could potentially supplement conventional diagnostic tools in future virus pandemics, independent of whether such pandemics are caused by a coronavirus, an influenza virus or another as yet-to-be discovered respiratory virus. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched the scientific literature using PubMed to identify studies that used the IFI27 biomarker to predict outcomes in COVID-19 patients. We used the search terms "IFI27", "COVID-19, "gene expression" and "outcome prediction". We did not identify any study that investigated the role of IFI27 biomarker in outcome prediction. Although ten studies were identified using the general terms of "gene expression" and "COVID-19", IFI27 was only mentioned in passing as one of the identified genes. All these studies addressed the broader question of the host response to COVID-19; none focused solely on using IFI27 to improve the risk stratification of infected patients in a pandemic. Added value of this studyHere, we present the findings of a multi-cohort study of the IFI27 biomarker in COVID-19 patients. Our findings show that the host response, as reflected by blood IFI27 gene expression, accurately predicts COVID-19 disease progression (positive and negative predictive values; 0.83 and 0.95, respectively), outperforming age, comorbidity, C-reactive protein and all other known risk factors. The strong association of IFI27 with disease severity occurs not only in SARS-CoV-2 infection, but also in other respiratory viruses with pandemic potential, such as the influenza virus. These findings suggest that host response biomarkers, such as IFI27, could help identify high-risk COVID-19 patients - those who are more likely to develop infection complications - and therefore may help improve patient triage in a pandemic. Implications of all the available evidenceThis is the first systemic study of the clinical role of IFI27 in the current COVID-19 pandemic and its possible future application in other respiratory virus pandemics. The findings not only could help improve the current management of COVID-19 patients but may also improve future pandemic preparedness.
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ImportanceThere is a paucity of data that can be used to guide the management of critically ill patients with coronavirus disease 2019 (COVID-19). Global collaboration offers the best chance of obtaining these data, at scale and in time. In the absence of effective therapies, insights derived from real-time observational data will be a crucial means of improving outcomes. ObjectiveIn response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, a research and data-sharing collaborative has been assembled to harness the cumulative experience of intensive care units (ICUs) worldwide. The resulting observational study provides a platform to rapidly disseminate detailed data and insights. DesignThe COVID-19 Critical Care Consortium observational study is an international, multicenter, prospective, observational study of patients with confirmed or suspected SARSCoV-2 infection admitted to ICUs. SettingThis is an evolving, open-ended study that commenced on January 1st, 2020 and currently includes more than 350 sites in over 48 countries. The study enrolls patients at the time of ICU admission and follows them to the time of death, hospital discharge, or 28 days post-ICU admission, whichever occurs last. ParticipantsAll subjects, without age limit, requiring admission to an ICU for SARS-CoV-2 infection, confirmed by real-time polymerase chain reaction (PCR) and/or next-generation sequencing or with high clinical suspicion of the infection. Patients admitted to an ICU for any other reason are excluded. Main outcomes and measuresKey data, collected via an electronic case report form devised in collaboration with the ISARIC/SPRINT-SARI networks, include: patient demographic data and risk factors, clinical features, severity of illness and respiratory failure, need for non-invasive and/or mechanical ventilation and/or extracorporeal membrane COVID-19 CCC observational study protocol oxygenation (ECMO), and associated complications, as well as data on adjunctive therapies. Final outcomes of in-hospital death, discharge or continuing admissions at 28 days. DiscussionThis large-scale, observational study of COVID-19 in the critically ill will provide rapid international characterization. Open-ended accrual will increase the power to answer hypothesis-led questions over time. Several sub-studies have already been initiated, examining hemostasis, neurological, cardiac, and long-term outcomes.