The cellular immune response to COVID-19 deciphered by single cell multi-omics across three UK centres (preprint)

The COVID-19 pandemic, caused by SARS coronavirus 2 (SARS-CoV-2), has resulted in excess morbidity and mortality as well as economic decline. To characterise the systemic host immune response to SARS-CoV-2, we performed single-cell RNA-sequencing coupled with analysis of cell surface proteins, providing molecular profiling of over 800,000 peripheral blood mononuclear cells from a cohort of 130 patients with COVID-19. Our cohort, from three UK centres, spans the spectrum of clinical presentations and disease severities ranging from asymptomatic to critical. Three control groups were included: healthy volunteers, patients suffering from a non-COVID-19 severe respiratory illness and healthy individuals administered with intravenous lipopolysaccharide to model an acute inflammatory response. Full single cell transcriptomes coupled with quantification of 188 cell surface proteins, and T and B lymphocyte antigen receptor repertoires have provided several insights into COVID-19: 1. a new non-classical monocyte state that sequesters platelets and replenishes the alveolar macrophage pool; 2. platelet activation accompanied by early priming towards megakaryopoiesis in immature haematopoietic stem/progenitor cells and expansion of megakaryocyte-primed progenitors; 3. increased clonally expanded CD8+ effector:effector memory T cells, and proliferating CD4+ and CD8+ T cells in patients with more severe disease; and 4. relative increase of IgA plasmablasts in asymptomatic stages that switches to expansion of IgG plasmablasts and plasma cells, accompanied with higher incidence of BCR sharing, as disease severity increases. All data and analysis results are available for interrogation and data mining through an intuitive web portal. Together, these data detail the cellular processes present in peripheral blood during an acute immune response to COVID-19, and serve as a template for multi-omic single cell data integration across multiple centers to rapidly build powerful resources to help combat diseases such as COVID-19.

SARS-CoV-2 testing of 11,884 healthcare workers at an acute NHS hospital trust in England: a retrospective analysis (preprint)

Healthcare workers (HCWs) are known to be at increased risk of infection with SARS-CoV-2, although whether these risks are equal across all roles is uncertain. Here we report a retrospective analysis of a large real-world dataset obtained from 10 March to 6 July 2020 in an NHS Foundation Trust in England with 17,126 employees. 3,338 HCWs underwent symptomatic PCR testing (14.4% positive, 2.8% of all staff) and 11,103 HCWs underwent serological testing for SARS-CoV-2 IgG (8.4% positive, 5.5% of all staff). Seropositivity was lower than other hospital settings in England but higher than community estimates. Increased test positivity rates were observed in HCWs from BAME backgrounds and residents in areas of higher social deprivation. A logistic regression model adjusting for these factors showed significant increases in the odds of testing positive in certain occupational groups, most notably domestic services staff, nurses and health-care assistants. PCR testing of symptomatic HCWs appeared to underestimate overall infection levels, probably due to asymptomatic seroconversion. Clinical outcomes were reassuring, with only a small minority of HCWs with COVID-19 requiring hospitalisation (2.3%) or ICU management (0.7%) and with no deaths. Despite a relatively low level of HCW infection compared to other UK cohorts, there were nevertheless important differences in test positivity rates between occupational groups, robust to adjustment for demographic factors such as ethnic background and social deprivation. Quantitative and qualitative studies are needed to better understand the factors contributing to this risk. Robust informatics solutions for HCW exposure data are essential to inform occupational monitoring.

COVID-19 management in a UK NHS Foundation Trust with a High Consequence Infectious Diseases centre: a detailed descriptive analysis (preprint)

BackgroundRecent large national and international cohorts describe the baseline characteristics and outcome of hospitalised patients with COVID-19, however there is little granularity to these reports. We aimed to provide a detailed description of a UK COVID-19 cohort, focusing on clinical decisions and patient journeys. MethodsWe retrospectively analysed the management and 28-day outcomes of 316 consecutive adult patients with SARS-CoV-2 PCR-confirmed COVID-19 admitted to a large NHS Foundation Trust with a tertiary High Consequence Infectious Diseases centre in the North of England. FindingsMost patients were elderly (median age 75) with multiple comorbidities. One quarter were admitted from residential or nursing care. Symptoms were consistent with COVID-19, with cough, fever and/or breathlessness in 90.5% of patients. Two thirds of patients had severe disease on admission. Mortality was 81/291 (27.8%). Most deaths were anticipated; decisions to initiate respiratory support were individualised after consideration of patient wishes, premorbid frailty and comorbidities, with specialist palliative care input where appropriate. 22/291 (7.6%) patients were intubated and 11/22 (50%) survived beyond discharge. Multiple logistic regression identified age as the most significant risk factor for death (OR 1.09 [95% CI 1.06 - 1.12] per year increase, p < 0.001). InterpretationThese findings provide important clinical context to outcome data. Deaths were anticipated, occurring in patients with advance decisions on ceilings of treatment. Age was the most significant risk factor for death, confirming that demographic factors in the population are a major influence on hospital mortality rates. FundingFunding was not required.