Authors: Anisa Jafar, Daniel Darbyshire, Simon Carley, Charles Reynard and the RCEM COVID-19 CPD team / Editors: Govind Oliver, Anisa Jafar / Codes: CAP6, CAP9, CC16, HAP29, HAP6 / Published: 25/06/2020
Another week, another top 5! The team faced well over 2,000 papers this week, along with a couple of big-hitters, which sneaked themselves in. We’ve all noticed a jump in quality and so whittling down to just five hasnt been easy. Luckily, if you have the headspace for ten more which couldn’t quite fit the page, check out the Director’s Cut. If an interactive live journal club captures your interest then tune in to the webinars.
The following papers have been split into 3 categories that will allow you to focus on those that are most vital to your practice.
- Worth a peek: interesting, but not yet ready for prime time
- Head Turner: new concepts
- Game Changer: this paper should change practice
Game changer summary:
Mehra et al. signal trouble for HCQ, thank goodness no-one stockpiled… 4
ISARIC give us the headlines on 20,000 hospitalised UK patients with COVID-19 1
Wang et al. leave us hanging with a non-significant result using remdesivir 2
Zhu et al. have us brushing up on our vaccine science with a recombinant adenovirus offering 3
Holmes et al. throw us a curveball in the quest to understand where all the regular pathology went 5
Features of 20133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study by Docherty et al.1
Rating: Head turner
Scout: Dr Anisa Jafar
The benefit of being several months into the pandemic is of course potential for big data. Over 20,000 hospitalised UK patients with COVID-19. The headlines remind us of the independent risk factors for in-hospital mortality, which are increasing age, being male, and having chronic co-morbidities i.e. cardiovascular disease, liver disease, chronic kidney disease, chronic respiratory disease and dementia. One thing the authors are keen to highlight is that obesity was noted to be an independent risk factor. Interestingly diabetes didnt quite reach significance as an independent predictor of in-hospital mortality. So what else? Median of 4 days symptomatic pre-admission; median age of admission 73; 41% discharged alive (26% died, the rest still remain in hospital). If ventilated, 17% discharged alive (37% died, the rest remain in hospital). Too much to summarise here, definitely worth spending your next coffee break getting into the detail.
Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trialby Wang et al.2
Rating: Head turner
Scout: Dr Daniel Darbyshire
This is a well-designed and clearly reported negative trial of an antiviral therapy for patients with COVID-19 admitted to hospital in Wuhan. 237 patients split 2:1 remdesevir vs. placebo, enrolled if 12-days or less since symptoms started (so, again lots of late administration of the therapy). Underpowered overall however interim analysis at this number of patients was accounted for. The study used a 6-point severity scale: death=6; extracorporeal membrane oxygenation or mechanical ventilation=5; noninvasive ventilation or high-flow oxygen therapy=4; oxygen therapy (NOT high-flow/non-invasive ventilation)=3; hospital admission but not requiring oxygen therapy=2; discharged/reached discharge criteria=1. This is both objective and likely to be important to patients – a good candidate for something for all studies to report so we have a hope of any meaningful meta-analyses. The study found a numerically median reduction in time to improvement between the remdesivir and placebo group which was not statistically significant. Not sure this outcome means we should be writing remdesivir off just yet: watching closely.
Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, nonrandomised, first-in-human trial by Zhu et al.3
Rating: Worth a peek
Scout: Dr Anisa Jafar
We are going to see more and more of these studies as the months go on. Here we have a recombinant adenovirus expressing the infamous spike glycoprotein being used as a COVID-19 vaccine. 3 groups of healthy adults (36 in each) received different doses and immune response was measured. Mild to moderate side effects were experienced, none serious (but increasing severity with increased dose) and peak antibodies were seen at 28 days, specific T-cell response peaked at 14 days. A number of issues relating to pre-existing antibodies to the adenovirus itself and lower seroconversion rates in older adults were noted. The team admit it is a small group, with no-one aged over 60 and with no control group, furthermore as it is first-in-human it does not measure efficacy. Importantly the study was not powered for safety outcomes. Bear in mind that antibody response was only measured at the latest at 28-days, so let’s keep our eyes on the upcoming later measurements. Very much a work in progress.
Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis by Mehra et al.4
Rating: Game changer
Scout: Dr Anisa Jafar
Wow, big numbers alert! 6 continents, 621 hospitals, 96,032 eligible patients meeting the inclusion criteria. So far so good. 4 potential treatment groups: chloroquine; chloroquine + macrolide; hydroxychloroquine; hydroxychloroquine + macrolide. Note that over 81,000 ended up in the control group which is somewhat unbalanced and the treatment groups had anything from nearly 1900 to over 6000 patients, however propensity score-matching was used across all groups. Only those receiving treatment within 48h of a firm COVID-19 diagnosis were included – this will have excluded a lot of patients however it imposed some uniformity amongst the treatment groups. Top-line appears to be an increased mortality (and increase in ventricular arrhythmia) in all treatment groups as compared to control. Admittedly not all confounders could be accounted for, however the signal is concerning. Reasonably good evidence here against using these drugs in any context other than clinical trials. Meanwhile, somebody had better drop a line to the Oval Office whilst the WHO have certainly reacted to these findings.
Emergency ambulance services for heart attack and stroke during UKs COVID-19 lockdown by Holmes et al.5
Rating: Head turner
Scout: Dr Charles Reynard
Are patients with serious health conditions not calling 999? Anecdotally I thought so, Holmes et al challenges this. They examined the ambulance callout data for the West Midlands Ambulance Service, focusing on episodes coded as STEMI or stroke. They found no statistically significant drop in callouts looking back over the last two years. The absolute number has fallen slightly over the period of lock-down, however this is within normal variation seen over the last two years. There are a whole host of confounding factors that this simple but powerful analysis cannot account for. Has the total number of STEMI and strokes increased because patients are delaying treatment for chest pain and TIA type episodes? Either way this data defies the assumption that all sick patients are staying away.
RCEM CPD COVID-19 TEAM
- Dr Charles Reynard, NIHR Doctoral Research Fellow, University of Manchester
- Dr Anisa Jafar, NIHR Clinical Lecturer, University of Manchester
- Dr Govind Oliver, TERN & RCEM Learning editor, Preston
- Dr Mina Naguib, NIHR Academic Clinical Fellow, Manchester
- Dr Patricia van den Berg, NIHR Academic Clinical Fellow, Manchester
- Dr Tom Roberts, RCEM Trainee Emergency Research Network Fellow, Bristol
- Professor Pamela Vallely, Medical Virologist, University of Manchester
- Professor Richard Body, Consultant in EM, University of Manchester
- Professor Daniel Horner, Consultant in EM and ICU, Salford
- Professor Simon Carley, Consultant in EM, RCEM CPD Lead
- Docherty AB, Harrison EM, Green CA. Features of 20133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study. BMJ 2020;369:m1985 http:// dx.doi.org/10.1136/bmj.m1985
- Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020;395(10236):1569- 1578. doi:10.1016/S0140-6736(20)31022-9
- Zhu FC, Li YH, Guan XH, et al. Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, nonrandomised, first-in-human trial. Lancet. 2020. doi:10.1016/S0140-6736(20)31208-3
- Mehra MR, Desai SS, Ruschitzka F, et al. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. [published online ahead of print, 2020 May 22]. Lancet. 2020 doi: 10.1016/S0140-6736(20)31180-6
- Holmes JL, Brake S, Docherty M, Lilford R, Watson S. Emergency ambulance services for heart attack and stroke during UKs COVID-19 lockdown [published online ahead of print, 2020 May 14]. Lancet. 2020;S0140-6736(20)31031-X. doi:10.1016/S0140-6736(20)31031-X