The effect of TRV027 on coagulation in COVID-19: A pilot randomized, placebo-controlled trial.

COVID-19 causes significant thrombosis and coagulopathy, with elevated D-dimer a predictor of adverse outcome. The precise mechanism of this coagulopathy remains unclear; one hypothesis is that loss of angiotensin-converting enzyme 2 activity during viral endocytosis leads to pro-inflammatory angiotensin-II accumulation, loss of angiotensin-1-7 and subsequent vascular endothelial activation. We undertook a double-blind randomized, placebo-controlled experimental medicine study to assess the effect of TRV027, a synthetic angiotensin-1-7 analogue on D-dimer in 30 patients admitted to hospital with COVID-19. The study showed a similar rate of adverse events in TRV027 and control groups. There was a numerical decrease in D-dimer in the TRV027 group and increase in D-dimer in the placebo group; however, this did not reach statistical significance (P = .15). A Bayesian analysis demonstrated that there was a 92% probability that this change represented a true drug effect.

Safety and immunogenicity of a self-amplifying RNA vaccine against COVID-19: COVAC1, a phase I, dose-ranging trial.

BACKGROUND: Lipid nanoparticle (LNP) encapsulated self-amplifying RNA (saRNA) is a novel technology formulated as a low dose vaccine against COVID-19. METHODS: A phase I first-in-human dose-ranging trial of a saRNA COVID-19 vaccine candidate LNP-nCoVsaRNA, was conducted at Imperial Clinical Research Facility, and participating centres in London, UK, between 19th June to 28th October 2020. Participants received two intramuscular (IM) injections of LNP-nCoVsaRNA at six different dose levels, 0.1-10.0µg, given four weeks apart. An open-label dose escalation was followed by a dose evaluation. Solicited adverse events (AEs) were collected for one week from enrolment, with follow-up at regular intervals (1-8 weeks). The binding and neutralisation capacity of anti-SARS-CoV-2 antibody raised in participant sera was measured by means of an anti-Spike (S) IgG ELISA, immunoblot, SARS-CoV-2 pseudoneutralisation and wild type neutralisation assays. (The trial is registered: ISRCTN17072692, EudraCT 2020-001646-20). FINDINGS: 192 healthy individuals with no history or serological evidence of COVID-19, aged 18-45 years were enrolled. The vaccine was well tolerated with no serious adverse events related to vaccination. Seroconversion at week six whether measured by ELISA or immunoblot was related to dose (both p<0.001), ranging from 8% (3/39; 0.1µg) to 61% (14/23; 10.0µg) in ELISA and 46% (18/39; 0.3µg) to 87% (20/23; 5.0µg and 10.0µg) in a post-hoc immunoblot assay. Geometric mean (GM) anti-S IgG concentrations ranged from 74 (95% CI, 45-119) at 0.1µg to 1023 (468-2236) ng/mL at 5.0µg (p<0.001) and was not higher at 10.0µg. Neutralisation of SARS-CoV-2 by participant sera was measurable in 15% (6/39; 0.1µg) to 48% (11/23; 5.0µg) depending on dose level received. INTERPRETATION: Encapsulated saRNA is safe for clinical development, is immunogenic at low dose levels but failed to induce 100% seroconversion. Modifications to optimise humoral responses are required to realise its potential as an effective vaccine against SARS-CoV-2. FUNDING: This study was co-funded by grants and gifts from the Medical Research Council UKRI (MC_PC_19076), and the National Institute Health Research/Vaccine Task Force, Partners of Citadel and Citadel Securities, Sir Joseph Hotung Charitable Settlement, Jon Moulton Charity Trust, Pierre Andurand, Restore the Earth.

Treatment of chronic or relapsing COVID-19 in immunodeficiency.

BACKGROUND: Patients with some types of immunodeficiency can experience chronic or relapsing infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). This leads to morbidity and mortality, infection control challenges, and the risk of evolution of novel viral variants. The optimal treatment for chronic coronavirus disease 2019 (COVID-19) is unknown. OBJECTIVE: Our aim was to characterize a cohort of patients with chronic or relapsing COVID-19 disease and record treatment response. METHODS: We conducted a UK physician survey to collect data on underlying diagnosis and demographics, clinical features, and treatment response of immunodeficient patients with chronic (lasting ≥21 days) or relapsing (≥2 episodes) of COVID-19. RESULTS: We identified 31 patients (median age 49 years). Their underlying immunodeficiency was most commonly characterized by antibody deficiency with absent or profoundly reduced peripheral B-cell levels; prior anti-CD20 therapy, and X-linked agammaglobulinemia. Their clinical features of COVID-19 were similar to those of the general population, but their median duration of symptomatic disease was 64 days (maximum 300 days) and individual patients experienced up to 5 episodes of illness. Remdesivir monotherapy (including when given for prolonged courses of ≤20 days) was associated with sustained viral clearance in 7 of 23 clinical episodes (30.4%), whereas the combination of remdesivir with convalescent plasma or anti-SARS-CoV-2 mAbs resulted in viral clearance in 13 of 14 episodes (92.8%). Patients receiving no therapy did not clear SARS-CoV-2. CONCLUSIONS: COVID-19 can present as a chronic or relapsing disease in patients with antibody deficiency. Remdesivir monotherapy is frequently associated with treatment failure, but the combination of remdesivir with antibody-based therapeutics holds promise.

Ethnicity and acute hospital admissions: Multi-center analysis of routine hospital data.

Background: The effects of ethnic and social inequalities on patient outcomes in acute healthcare remain poorly understood. Methods: Prospectively-defined analysis of registry data from four acute NHS hospitals in east London including all patients ≥ 18 years with a first emergency admission between 1st January 2013 and 31st December 2018. We calculated adjusted one-year mortality risk using logistic regression. Results are presented as n (%), median (IQR), and odds ratios (OR) with 95% confidence intervals. Findings: We included 203,182 patients. 43,101 (21%) patients described themselves as Asian, 21,388 (10.5%) Black, 2,982 (1.4%) Mixed, 13,946 (6.8%) Other ethnicity, and 100,065 (49%) White. We excluded 21,700 (10.7%) patients with undisclosed ethnicity. 16,054 (7.9%) patients died within one year. Non-white patients were younger (Asian: 43 [31-62] years; Black: 48 [33-63] years; Mixed 36 [26-52] years) than White patients (55 [35-75] years), with a higher incidence of comorbid disease. In each age-group, non-white patients were more likely to be admitted to hospital. This effect was greatest in the ≥ 80 years age-group (32% non-white admitted to hospital versus 23% non-white in community population). Deprivation was associated with increased mortality in all ethnic groups (OR 1.41 [1.33-1.50]; p < 0.001). However, when adjusted for age, Asian (0.69 [0.66-0.73], p < 0.0001) and Black patients (0.79 [0.74-0.85]; p < 0.0001) experienced a lower mortality risk than White patients. Interpretation: Ethnic and social disparities are associated with important differences in acute health outcomes. However, these differences are masked by statistical adjustment because patients from ethnic minorities present at a younger age. Funding: None.

Emergency hospital admissions associated with non-communicable diseases 1998-2018 in England, Wales and Scotland: an ecological study.

BACKGROUND: Non-communicable diseases (NCDs) are increasingly prevalent and were responsible for 40.5 million deaths (71%) globally in 2016. We examined the number of NCD-related emergency hospital admissions during the years 1998 to 2018 in the UK. METHODS: Demographic features for those admitted as an emergency with NCDs as their primary diagnosis were collated for all admissions in England, Wales and Scotland. NCDs recorded as secondary diagnoses for all admissions in England from 2012 to 2018 were additionally recorded. RESULTS: We identified 120,662,155 emergency episodes of care. From 1998 to 2018 there was an increase from 1,416,233 to 1,892,501 in annual emergency admissions due to NCDs. This, however, represented a fall in the proportion of NCD among all emergency admissions, from 33.4% to 26.9%. Mean age of all patients admitted increased from 46.3 to 53.8 years. CONCLUSION: Despite a fall in proportion of NCD admissions, the population acutely admitted to hospital was increasingly elderly and increasingly comorbid.