Journal update Emerg Med J: first published as 10.1136/emermed-2021-211704 on 8 June 2021. Downloaded from EMJ COVID-19 monthly top five doi:10.1136/emermed-2021-211704 Ronan Callanan ‍ , Conor Deasy, Joe Slowey, Rory O’ Brien, Mike Dunphy, Kanti Dasari, Tom Brennan, Simon Walsh, Stephen Gilmartin, Iomhar O’ Sullivan, Gabrielle Prager

Introduction treatments in hospitalised patients in the also expensive and not readily available Following from the successful ‘RCEM UK NHS.1 It has now evaluated the effect worldwide. weekly top five’ series starting in April of tocilizumab in patients with severe A preplanned 6-month­ analysis may help 2020, this is the seventh of a monthly COVID-19 characterised by hypoxia and us appreciate the longer-­term outcomes. format for EMJ readers. We have under- substantial inflammation. Tocilizumab is taken a focused search of the PubMed an anti-­interleukin-6 receptor antibody, Bottom line literature using a standardised COVID-19 it may mitigate the hyperinflammatory In hospitalised patients with COVID-19 search string. Our search between 1 April response and associated cytokine ‘storm’ with hypoxia and systemic inflamma- 2021 and 30 April 2021 returned 3139 seen in severe COVID-19. It has shown tion, tocilizumab improved survival and papers limited to human subjects and promise in prior observational studies. discharge from hospital at 28 days. English language. We also searched high This intervention was offered as an impact journals for papers of interest. additional randomisation to trial partici- Our team have narrowed down the most pants within 21 days of initial randomis- Vaccine side-effects and SARS-CoV-2 interesting, relevant and important of the ation who had severe COVID-19, defined infection after vaccination in users of papers and provided a critical snapshot of as evidence of progressive COVID-19 the COVID Symptom Study app in the five of those we felt most deserved EMJ with oxygen saturation <92% on room UK: a prospective observational study reader attention. Importantly, we have air or receiving oxygen therapy and C-R­ e- Topic: vaccination highlighted not only the main findings active protein ≥75 mg/L. Rating: head turner from the papers but key limitations and Participants were randomised to current This prospective observational study considerations for emergency medicine management versus current management looked at the safety profile and efficacy of clinicians when interpreting the work. In plus tocilizumab at a dose of 400–800 mg the Pfizer–BioNTech and Oxford–Astra- doing so, we have created an accessible (weight-­based). Zeneca vaccines, building on data gath- window into pertinent research find- The primary outcome was all-­cause ered during phase 3 trials.2 This UK-based­ ings for our busy colleagues during this mortality at 28 days. Secondary outcomes trial was conducted between December fast-­paced and ever-changing­ COVID-19 were time to discharge from hospital and 2020 and March 2021. Anyone in the landscape. receipt of invasive ventilation or death in UK general population over 18 years old The papers are ranked in one of three those patients not receiving invasive venti- had the opportunity to download and sign http://emj.bmj.com/ categories, allowing you to focus on the lation at time of randomisation. up to the COVID Symptom Study app, papers that are most vital to your practice: Of the 4116 (19%) RECOVERY trial which records baseline health, employ- ►► Worth a peek: interesting, but not yet participants eligible for inclusion, 2022 ment and demographic characteristics. It ready for prime time were randomised to the tocilizumab group then prompts the user for further health ►► Head turner: new concepts and 2094 were allocated to controls. updates after receiving the vaccination or ►► Game changer: this paper could/ Mortality at 28 days in the intention-­ being tested for COVID-19. Use of the on September 23, 2021 by guest. Protected copyright. should change practice. to-­treat analysis was significantly lower app was driven by media, word of mouth, This month’s searches were undertaken in the tocilizumab group (31% vs 35%, referrals and charities. On downloading by the Emergency Innovation Research p=0.0028) and the proportion of patients the app, participants consented to non-­ Network (EIRN) at Cork Univer- discharged from hospital was higher (57% commercial use of their data. Primary sity Hospital Emergency Department, vs 50%, p<0.0001). Fewer patients in the outcomes included the proportion of users Ireland. We look forward to next month’s tocilizumab group required invasive venti- reporting adverse events within 8 days of instalment by our colleagues from the lation (35% vs 42%, p<0.0001). vaccination. Secondary outcomes included Emergency Medicine Research Group The RECOVERY trial has contributed the infection rate in vaccinated individuals. Edinburgh. to international COVID-19 guidelines, Data were collected from more than and these results, in combination with 600 000 individuals receiving either previous studies, are already changing vaccine, with a subset of 28 207 having Tocilizumab in patients admitted to practice. There are, however, limita- received both Pfizer–BioNTech doses. hospital with COVID-19 (RECOVERY): tions. Clinicians were not blinded to About a quarter of recipients reported a randomised, controlled, open-label, allocations, and this could have resulted systemic adverse effects and two-thirds­ platform trial in differences in management decisions reported local adverse effects, both lower Topic: treatment (such as whether to continue care). Addi- than expected from phase 3 trial data. Rating: game changer tionally, 16% of the tocilizumab group Allergic skin reactions were reported The Randomised Evaluation of COVID did not receive the drug, with no expla- in less than 2% of individuals. Systemic - 19 Therapy (RECOVERY) trial is a nation given; therefore, we may not and local adverse effects were more large randomised control trial that has have a true representation of its effects. frequently reported in those with previous been evaluating potential COVID-19 We should remember that tocilizumab is SARS-­CoV-2 infection.

558 Callanan R, et al. Emerg Med J July 2021 Vol 38 No 7 Journal update Emerg Med J: first published as 10.1136/emermed-2021-211704 on 8 June 2021. Downloaded from A reduction in risk of SARS-­CoV-2 The authors analysed data on demo- evidence of disease, met specified criteria infection for both vaccinations was graphic covariates (age, sex, deprivation, for abnormal gas exchange demon- demonstrated from 12 days post vaccina- household size, primary care consulta- strating moderate to severe disease and tion with a risk reduction of 60% (95% tions in the past 12 months and geograph- met biochemical criteria for evidence of CI 49 to 68) for the Oxford–AstraZeneca ical region) and clinical covariates (body systemic inflammatory response. Patients vaccine and 58% (95% CI 62 to 72) for mass index, glycated haemoglobin, blood were allocated to either the treatment the Pfizer–BioNTech. Vaccine effective- pressure, smoking status and clinical arm (n=35) receiving intravenous methyl- ness is difficult to comment on within an comorbidities) prednisolone for 6 days or to standard of observational data set; however, the risk After accounting for all covariates, care management (n=29). Treatment was reduction over time is similar to that seen South Asian, black and mixed ethnicity commenced the same day as inclusion in in previous phase 3 trials.3 Limitations groups were more likely to be tested and the trial. include potential information bias due to to test positive for SARS-CoV­ -2 compared The primary outcome was a composite self-reported­ data, participants were self-­ with the white group. The risk of hospi- endpoint of in-­hospital mortality, ICU selected and older than the general popu- talisation was increased in all minority admission or progression to non-­invasive lation and only short-term­ side effects ethnic groups. The risk of ICU admis- ventilation. Patients were followed up for were recorded. There is a possibility of sion was two–three times higher in the 28 days. response bias as users are more likely to be four broad minority groups and two–five In the per-­protocol analysis, the treat- interested in health. The authors are clear times higher among South Asian, black, ment group demonstrated a statisti- that this paper is unable to allow an infer- mixed and other subcategories relative cally significant 20% risk reduction to ence of causality. to the White British group. Mortality the control (30% vs 50%) in reaching was increased by 22%–51% in the four the primary composite endpoint. In the broad minority ethnic groups. Differ- intention-to-­ ­treat analysis, the methyl- Bottom line ences between minority ethnic groups prednisolone group was less likely to reach Reassuringly, adverse events from both with regard to positive testing and severe the study endpoint (relative risk: 0.68), vaccines were usually mild and brief, COVID-19 symptoms were small. but this was not statistically significant. occurring less frequently than previously The causes of these excess risks in both Participants had symptoms for a mean of expected in a study population consider- the UK and elsewhere are likely multifac- 12 days (SD: ±6) at inclusion. No signif- ably older than previous phase 3 trials. torial, with social deprivation, structural icant adverse events were reported aside inequalities, inequitable care and uptake of from hyperglycaemia in 12 patients. testing and vaccination all playing a role. While the study suggests that there Ethnic differences in SARS-CoV-2 Further work is needed to better appre- may be some beneficial effect to the use infection and COVID-19-related ciate and address the underlying mecha- of methylprednisolone in this patient hospitalisation, intensive care unit nisms at play to reduce these inequalities. group, there are some limitations. These admission and death in 17 million findings represent an interim analysis due adults in England: an observational Bottom line to declining patient numbers in the study cohort study using the OpenSAFELY location. For sufficient power, it had a

Minority ethnic groups in the UK have http://emj.bmj.com/ platform suffered disproportionally during the requirement of 180 participants. In addi- Topic: epidemiology COVID-19 pandemic. tion, the main driver for the endpoint was Rating: head turner critical care admission, which possesses A large cohort study has been conducted a degree of subjectivity. There was, Methylprednisolone in adults in the UK seeking to estimate the effect however, specific, easy to follow inclusion of ethnicity on testing and testing positive hospitalised with COVID-19 pneumonia: criteria, accepted standard of care proto- for SARS-­CoV-2, hospitalisation rates, an open-label randomised trial cols with both an intention-­to-­treat and on September 23, 2021 by guest. Protected copyright. intensive care unit (ICU) admissions and (GLUCOCOVID) per-­protocol analysis performed. mortality.4 Previous studies in the UK and North America have demonstrated higher Topic: corticosteroids and COVID-19 Bottom line levels of COVID-19 and more signifi- Rating: worth a peek This interim analysis will not change our cant disease in minority ethnic groups in Corticosteroids are a frequently used practice; we are still not any closer to the comparison to white groups. This study weapon in our emergency arsenal for answer of does steroid administration aimed to analyse different ethnic groups the treatment of respiratory conditions.5 worsen the disease at the viral stage of separately rather than as a single cohort, While the RECOVERY trial found that the illness. However, having the wheels using a large general population-based­ corticosteroids were beneficial in critically in motion to examine treatments for this sample. ill hospitalised patients with COVID-19,6 specific patient group is encouraging. The authors used the OpenSAFELY the role of steroids in the patient that platform, an electronic record of warrants hospital admission but is not yet 24 million patients registered with requiring critical care is unclear. Effectiveness of the BNT162b2 primary care in the UK NHS. The study This open-­label study was a partially COVID-19 vaccine against the B.1.1.7 comprised of data from 17 288 532 adults. randomised control trial with hospital- and B.1.351 variants 10 877 978(62.9%) White, 1 025 319 ised patients not requiring critical care. Topic: prognosis (5.9%) South Asian, 340 912 (2.0%) ‘Partially’, in that the treating team could Rating: head turner Black, 170 484 (1.0%) mixed ethnicity, allocate the patient to the intervention This study from Qatar looks at the effec- 320 788 (1.9%) were of other ethnicity, arm if they felt this was beneficial. Patients tiveness of the Pfizer–BioNTech vaccine and 4 553 051 (26.3%) were of unknown were included if they had a symptom against two COVID-19 variants of ethnicity. duration of at least 7 days, radiological concern, the B.1.1.7, first identified in

Callanan R, et al. Emerg Med J July 2021 Vol 38 No 7 559 Journal update Emerg Med J: first published as 10.1136/emermed-2021-211704 on 8 June 2021. Downloaded from Kent, England and B.1.351, first identified is younger, with a greater proportion To cite Callanan R, Deasy C, Slowey J, et al. in South Africa.7 These variants account of males, than in other populations. Emerg Med J 2021;38:558–560. for the majority of infections in Qatar. However, the population is also very Received 25 May 2021 The authors estimated vaccine efficacy diverse with large number of expats from Accepted 26 May 2021 using a test-negative­ case–control study. many nationalities, a potential strength. Published Online First 8 June 2021 Testing in Qatar has been conducted in Emerg Med J 2021;38:558–560. symptomatic individuals, as part of contact doi:10.1136/emermed-2021-211704 tracing, routine testing and random Bottom line This study provides reassurance that the ORCID iD testing campaigns. Cases and controls Ronan Callanan http://orcid.​ ​org/0000-​ ​0001-5211-​ ​ were matched 1:1 by age, sex, nationality Pfizer–BioNTech vaccine provides good 7268 and reason for PCR testing. protection against severe disease caused After one dose, the Pfizer–BioNTech by these new variants of concern. REFERENCES vaccine had an estimated effectiveness 1 RECOVERY Collaborative Group. Tocilizumab in patients against subsequent SARS-CoV­ -2 infection Twitter Ronan Callanan @ro_calla admitted to hospital with COVID-19 (recovery): a randomised, controlled, open-­label, platform trial. Lancet of 29.5% (95% CI 22.9 to 35.5) for the Contributors All of the authors contributed to this B.1.1.7 variant and 16.9% (95% CI 10.4 2021;397:1637–45. review. 2 Menni C, Klaser K, May A, et al. Vaccine side-effects­ to 23.0) for B.1.351 variant. Funding The authors have not declared a specific and SARS-­CoV-2 infection after vaccination in users Fourteen days after the second vacci- grant for this research from any funding agency in the of the COVID symptom study APP in the UK: a nation dose, the Pfizer–BioNTech vaccine public, commercial or not-for­ -profit­ sectors. prospective observational study. Lancet Infect Dis 2021. had an estimated efficacy of 89.5% (95% doi:10.1016/S1473-3099(21)00224-3. [Epub ahead of Competing interests None declared. print: 27 Apr 2021]. CI 85.9 to 92.3) against infection from the Patient and public involvement Patients and/or 3 Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy B.1.1.7 variant and 75% (95% CI 70.5 to the public were not involved in the design, or conduct, of the BNT162b2 mRNA Covid-19 vaccine. N Engl J 78.9) against infection from the B.1.351 or reporting, or dissemination plans of this research. Med 2020;383:2603–15. 4 Mathur R, Rentsch CT, Morton CE, et al. Ethnic variant. This is lower than the 95% effi- Patient consent for publication Not required. cacy against infection reported in the differences in SARS-­CoV-2 infection and COVID-19-­ Provenance and peer review Not commissioned; related hospitalisation, intensive care unit admission, phase 3 trial conducted before these vari- and death in 17 million adults in England: an 3 internally peer reviewed. ants emerged. observational cohort study using the OpenSAFELY This article is made freely available for use in platform. Lancet 2021;397:1711–24. Vaccine effectiveness against severe, accordance with BMJ’s website terms and conditions 5 Corral-Gudino­ L, Bahamonde A, Arnaiz-­Revillas critical or fatal disease (14 days after for the duration of the covid-19 pandemic or until second vaccination) from all variants of F. Methylprednisolone in adults hospitalized with otherwise determined by BMJ. You may use, download COVID-19 pneumonia : An open-­label randomized trial SARS-CoV­ -2 in Qatar was 97.4% (95% and print the article for any lawful, non-­commercial (GLUCOCOVID). Cent Eur J Med 2021;133:303–11. CI 92.2 to 99.5). Despite reduced effec- purpose (including text and data mining) provided that 6 RECOVERY Collaborative Group, Horby P, Lim WS, et al. tiveness against infection primarily for the all copyright notices and trade marks are retained. Dexamethasone in hospitalized patients with Covid-19. B.1.351 variant, it remained effective in © Author(s) (or their employer(s)) 2021. No commercial N Engl J Med 2021;384:693–704. re-use­ . See rights and permissions. Published by BMJ. 7 Abu-­Raddad LJ, Chemaitelly H, Butt AA. Effectiveness preventing severe illness and death. of the BNT162b2 Covid-19 vaccine against the There are limitations to the study. B.1.1.7 and B.1.351 variants. N Engl J Med http://emj.bmj.com/ The population demographic in Qatar 2021:NEJMc2104974. on September 23, 2021 by guest. Protected copyright.

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