RESUMO
BackgroundThe pathogenesis of COVID-19, caused by a novel strain of coronavirus (SARS-CoV-2), involves a complex host-virus interaction and is characterised by an exaggerated immune response, the specific components of which are poorly understood. Here we report the outcome of a longitudinal immune profiling study in hospitalised patients during the peak of the COVID-19 pandemic in the UK and show the relationship between immune responses and severity of the clinical presentation. MethodsThe Coronavirus Immune Response and Clinical Outcomes (CIRCO) study was conducted at four hospitals in Greater Manchester. Patients with SARS-CoV-2 infection, recruited as close to admission as possible, provided peripheral blood samples at enrolment and sequentially thereafter. Fresh samples were assessed for immune cells and proteins in whole blood and serum. Some samples were also stimulated for 3 hours with LPS and analysed for intracellular proteins. Results were stratified based on patient-level data including severity of symptoms and date of reported symptom onset. FindingsLongitudinal analysis showed a very high neutrophil to T cell ratio and abnormal activation of monocytes in the blood, which displayed high levels of the cell cycle marker, Ki67 and low COX-2. These properties all reverted in patient with good outcome. Unexpectedly, multiple aspects of inflammation were diminished as patients progressed in severity and time, even in ITU patients not recovering. InterpretationThis is the first detailed longitudinal analysis of COVID-19 patients of varying severity and outcome, revealing common features and aspects that track with severity. Patients destined for a severe outcome can be identified at admission when still displaying mild-moderate symptoms. We provide clues concerning pathogenesis that should influence clinical trials and therapeutics. Targeting pathways involved in neutrophil and monocyte release from the bone marrow should be tested in patients with COVID-19. FundingThe Kennedy Trust for Rheumatology Research, The Wellcome Trust, The Royal Society, The BBSRC, National Institute for Health Research (NIHR) Biomedical Research Centres (BRC). Research in contextO_ST_ABSEvidence before this studyC_ST_ABSAnalysis of the literature before the study via pubmed and bioRxiv searches using the terms COVID-19, SARS-CoV2, immune and inflammation (with the last search performed on 27th April 2020) showed evidence of an overactive immune response in a handful of studies in cross-sectional analyses all done at a single time point. Added value of this studyTo determine the role of the immune response in a disease process, it is necessary to correlate immune activity with clinical parameters dynamically. In this study patients presented to hospital at different stages of disease so we took samples at different time-points to provide an accurate picture of the relevant pathobiology. In order to avoid loss of large components of the immune system due to the processes of storage, longitudinal samples were interrogated in real time to reveal the full immune alterations in COVID-19. Implications of all the available evidenceRespiratory viruses continue to cause devastating global disease. The finding of altered myelopoiesis, with excess neutrophils and altered monocyte function, as dominant features in our study provides an incentive for clinical testing of therapeutics that specifically target this pathobiology. Given that inflammation is greatest prior to admission to intensive care, trials of specific immune-modulating therapies should be considered earlier in admission. Future studies of COVID-19 mechanisms should place more emphasis on longitudinal analyses since disease changes dramatically over time.
