ABSTRACT
Treatment of severe COVID-19 is currently limited by clinical heterogeneity and incomplete understanding of potentially druggable immune mediators of disease. To advance this, we present a comprehensive multi-omic blood atlas in patients with varying COVID-19 severity and compare with influenza, sepsis and healthy volunteers. We identify immune signatures and correlates of host response. Hallmarks of disease severity revealed cells, their inflammatory mediators and networks as potential therapeutic targets, including progenitor cells and specific myeloid and lymphocyte subsets, features of the immune repertoire, acute phase response, metabolism and coagulation. Persisting immune activation involving AP-1/p38MAPK was a specific feature of COVID-19. The plasma proteome enabled sub-phenotyping into patient clusters, predictive of severity and outcome. Tensor and matrix decomposition of the overall dataset revealed feature groupings linked with disease severity and specificity. Our systems-based integrative approach and blood atlas will inform future drug development, clinical trial design and personalised medicine approaches for COVID-19.
Subject(s)
COVID-19 , SepsisABSTRACT
BackgroundThere has been great concern amongst clinicians and patients that immunomodulatory treatments for IBD may increase risk of SARS-CoV-2 susceptibility or progression to severe disease. MethodsSera from 640 patients attending for maintenance infliximab or vedolizumab infusions between April and June 2020 at the John Radcliffe Hospital (Oxford, UK) and Royal London Hospital (London, UK) were tested using the Abbott SARS-CoV-2 IgG assay. Demographic and clinical data were collated from electronic patient records and research databases. ResultsSeropositivity rates of 3.0% (12/404), 7.2% (13/180), and 12.5% (7/56) were found in the Oxford and London adult IBD cohorts and London paediatric IBD cohorts respectively. Seroprevalence rates in the Oxford adult IBD cohort were lower than that seen in non-patient facing health-care workers within the same hospital (7.2%). Seroprevalence rates of the London paediatric IBD cohort were comparable to a contemporary healthy cohort collected at the same hospital (54/396, 13.6%). ConclusionsSARS-CoV-2 seropositivity rates are not elevated in patients with IBD receiving maintenance infliximab or vedolizumab infusions. There is no rationale based on these data for elective interruption of maintenance therapy, and we recommend continuation of maintenance therapy. These data do not address the efficacy of vaccination in these patients.
ABSTRACT
A major issue in identification of protective T cell responses against SARS-CoV-2 lies in distinguishing people infected with SARS-CoV-2 from those with cross-reactive immunity generated by exposure to other coronaviruses. We characterised SARS-CoV-2 T cell immune responses in 168 PCR-confirmed SARS-CoV-2 infected subjects and 118 seronegative subjects without known SARS-CoV-2 exposure using a range of T cell assays that differentially capture immune cell function. Strong ex vivo ELISpot and proliferation responses to multiple antigens (including M, NP and ORF3) were found in those who had been infected by SARS-CoV-2 but were rare in pre-pandemic and unexposed seronegative subjects. However, seronegative doctors with high occupational exposure and recent COVID-19 compatible illness showed patterns of T cell responses characteristic of infection, indicating that these readouts are highly sensitive. By contrast, over 90% of convalescent or unexposed people showed proliferation and cellular lactate responses to spike subunits S1/S2, indicating pre-existing cross-reactive T cell populations. The detection of T cell responses to SARS-CoV-2 is therefore critically dependent on the choice of assay and antigen. Memory responses to specific non-spike proteins provides a method to distinguish recent infection from pre-existing immunity in exposed populations.