Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study
BMJ 2020; 369 doi: https://doi.org/10.1136/bmj.m1985 (Published 22 May 2020) Cite this as: BMJ 2020;369:m1985Linked Editorial
Covid-19 care before, during, and beyond the hospital
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Dear Editor
Two aspects are surprising to me.
958 patients of those admitted to ICU/HDU died, leaving 4207 (i.e. 5165 minus 958, cf. Fig 4) who died prior to admission to ICU/HDU, yielding 81.5% of all deaths. The prose text tells of 3954 deaths among 15 297 who received "only ward care". The surprising issue is that, anyhow, the vast majority of those who died were not (yet) admitted to ICU/HDU. Did those who died with ward care only receive therapy? Which? During which time frame did they die?
The inclusion criterion was "proven or high likelihood of infection with ... SARS-CoV-.2". The methodology suggests that not all had a positive PCR test. Unfortunately, I was unable to identify information on the rate of positive PCR tests, i.e. the second surprise. Could the authors please add this information?
Bringing both aspects together: Was the rate of positive PCR tests of those who died with ward care only different from those with ICU/HDU care or mechanical ventilation?
Competing interests: No competing interests
Dear Editor,
The importance of completed outcomes when reporting mortality and survival.
The first report from the International Severe Acute Respiratory and Emerging Infections Consortium (ISARIC) provides valuable information about UK hospital admissions with COVID-19 and is admirable in its speed and breadth (1). It reports that 26% died, 41% of patients survived to hospital discharge and 34% remained in hospital. It is easy to miss the fact that the mortality rate for those with completed outcomes is 39%.
In the ISARIC study new patients were included up to 14 days before data analysis: at this time more than one third of all recruited patients and two of every five admitted to an intensive care (ICU) remained in hospital or ICU, respectively. Early reporting will favour capture of those with early outcomes (the sickest who die early and the least sick who recover promptly). The outcome of those still being treated may differ significantly and final mortality rates may therefore be quite different from the interim results.
Considering the intensive care cohort alone, most patients in the ISARIC study will be included within the ICNARC dataset which is reported weekly (2). Of 10,024 patients with COVID-19 admitted to ICU in the UK, at 14 days 26% had died and 30% were discharged from ICU: 43% remained in ICU. At 56 days 38% had died and 54% were discharged from ICU: 8% remained in ICU. At first glance it might appear the mortality rate had increased from 26% to 38%. However, considering only those with a completed ICU stay the ICU-mortality fell from 46% at 14 days to 41% at 56 days.
In a recent systematic review of ICU mortality in COVID-19 we found that up to 75% of patients were still in ICU when data were published (3). Some studies reporting high survival rates failed to account for the unknown outcomes of those patients still undergoing treatment, which can be very misleading. The ISARIC team have not done this but we caution that outcomes should focus on those patients with a ‘completed episode’, be that discharge from ICU (ICU survival), or hospital (hospital survival). In due course it will be equally important to follow patients up after discharge to examine whether excess deaths occur after hospital discharge.
Andrew D. Kane, Specialty Registrar, Department of Anaesthesia, James Cook University Hospital, Middlesbrough, United Kingdom
Richard A. Armstrong, Academic Clinical Fellow in Anaesthesia, Severn Deanery, Bristol, United Kingdom
Tim. M Cook, Consultant, Department of Anaesthesia and Intensive Care Medicine, Royal United Hospitals Bath NHS Foundation Trust, Bath, United Kingdom and Honorary Professor of Anaesthesia, University of Bristol, Bristol, United Kingdom
References:
1. Docherty AB, Harrison EM, Green CA, et al. Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study. BMJ 2020;369:m1985. doi: 10.1136/bmj.m1985
2. Intensive Care National Research and Audit Centre. ICNARC report on COVID-19 in critical care- 26th June 2020 2020 [Available from: https://www.icnarc.org/Our-Audit/Audits/Cmp/Reports accessed 30th June 2020.
3. Armstrong RA, Kane AD, Cook TM. Outcomes from intensive care in patients with COVID-19: a systematic review and meta-analysis of observational studies. Anaesthesia 2020;In press doi: 10.1111/anae.15201
Competing interests: No competing interests
Dear Editor
Beyond existing arguments [1], we wish to make use of this timely research [2] to advance ways of understanding the importance of inclusion in UK COVID-19 data sets of patients' ethnic origin.
First, we refer to a question raised by a Norway-based researcher [3] regarding inputting group ethnicity in UK data sets of hospitalised COVID-19 patients. This begs the question: Have researchers in Norway inputed such record item? It will be of interest also to find out how the European Union is handling this pandemic ethnic diversity issue.
Second, the US has recently announced that patients’ race and ethnic data will be recorded when testing people for COVID-19 from now on.
1. https://doi.org/10.1136/bmj.m2282
Competing interests: No competing interests
Dear Editor
Why is increasing age an independent risk factor for COVID-19?(1)
We hypothesise that age-associated thymic involution may explain this finding. Whilst an adaptive immune system is crucial for successful viral clearance(2), age-related immunosenescence results in impaired responsiveness to new/evolving pathogens in older people(3). The production of naïve T-cells and diversification of intra-thymic T-cell reservoir in the thymus, the central haematopoietic site for T-cell production and a major part of the adaptive immune system, declines with age(3). Extra-thymic production can maintain the T-cell pool primarily by expanding the memory cell reservoir whilst naïve T-cell numbers decline(4). Whilst peripheral proliferation can expand existing T-cell clones, only the thymus can create new T-cell specificities(5). Ultimately, the relative deficiency of naïve T cells in ageing immune systems impairs the immune response to novel viral infections.
We suggest that observational studies of the incidence and severity of novel infections in people with thymic aplasia or surgical thymectomy and/or laboratory experiments using molecular/cell culture studies may shed further light on thymic involution as a contributing factor to T-cell senescence and poor outcomes from novel pathogens such as SARS-CoV-2. This may provide further insight on why protecting this vulnerable patient group from exposure to such pathogens is of critical importance.
References
1. Docherty AB, Harrison EM, Green CA, et al. Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study. BMJ. 2020 May 22;369.
2. Newton AH, Cardani A, Braciale TJ. The host immune response in respiratory virus infection: balancing virus clearance and immunopathology. Semin Immunopathol. 2016 Jul 1;38(4):471–82.
3. Goronzy JJ, Lee W-W, Weyand CM. Aging and T-cell diversity. Exp Gerontol. 2007 May;42(5):400–6.
4. Britanova OV, Putintseva EV, Shugay M, et al. Age-Related Decrease in TCR Repertoire Diversity Measured with Deep and Normalized Sequence Profiling. The Journal of Immunology. 2014 Mar 15;192(6):2689–98.
5. den Braber I, Mugwagwa T, Vrisekoop N, et al. Maintenance of Peripheral Naive T Cells Is Sustained by Thymus Output in Mice but Not Humans. Immunity. 2012 Feb 24;36(2):288–97.
Competing interests: No competing interests
Dear Editor
The Obesity Pandemic and COVID-19 : Primary Care Network Social Prescribing Link Workers Present a New Opportunity to Tackle Morbidity.
Obesity is linked to an increased risk of serious COVID-19 related illness . The most recent English data indicates that almost two-thirds of adults in England were overweight or obese , with 28 % in the obese category. Obesity is also driving the rising levels of many long-term conditions including type 2 diabetes and respiratory disease. It is also a major cause of cancer.
Losing weight is difficult for most people, and many environmental and personal factors play a part. However, public understanding of the potential risks associated with excess weight may have changed during the current COVID-19 pandemic; with the result of more people now motivated to lose weight and improve physical fitness.
Over the last year, Primary Care Network-based Social Prescribing Link Worker teams have been commissioned to work with people with long term conditions. Many clinicians are still unfamiliar with this new service. Link workers provide individual support to try and overcome the barriers to behaviour change that reduce people’s confidence, and deny them the chance to lose weight and improve fitness. Clinicians should maximise the potential of this opportunity.
It is important to take something good from the COVID-19 pandemic. We are at a unique pivotal point where our current circumstances could result in positive outcomes for the longer-standing pandemic of obesity.
(https://www.bmj.com/company/newsroom/age-male-sex-obesity-and-underlying...
https://digital.nhs.uk/data-and-information/publications/statistical/sta...)
Competing interests: No competing interests
Dear Editor
I have grave concerns about this paper. Approximately 40% of the population in England over 60 years have Hypertension and are taking Lipid Lowering medications. It appears that this study doesn't show any patients with these problems, This runs against all previous reports of co-morbidities in Italy and China reported in the BMJ. Hypertension is also listed as a co-morbidity in your Covid Package of information.
Competing interests: No competing interests
Dear Editor,
We read with interest the impressive study by Docherty et al study regarding COVID-19 hospital admissions in the UK (1). The authors find that only 11% of patients admitted to hospital with COVID-19 are obese. At the age of 73 (the median age for admission found in the study), national data suggests that 33% of the UK population are obese (2). It might therefore appear from this data that obesity is associated with a reduced incidence of hospital admission with COVID-19, although causality cannot be implied. Interestingly, the UK Intensive Care National Audit and Research Centre (ICNARC) data reports obesity in around 38% of patients being admitted to ITU (3). If both the Docherty et al and ICNARC data are correct, it suggests that once admitted to hospital, obese patients have increased likelihood of requiring ICU.
However, the Docherty et al study did not measure body mass index (BMI), with obesity instead being “defined by clinical staff.” In some cases, this may have resulted in healthcare professionals estimating whether or not the patient was obese, which might have led to underestimation in borderline cases. This might explain why only 11% of patients were classed as obese in the study, a seemingly small proportion compared to UK-wide data. If obesity is misclassified in the published cohort, conclusions regarding the degree of risk conferred may then be confounded.
The Docherty et al study generates an interesting hypothesis about the impact of obesity on COVID-19 outcomes in the UK. It also serves as a reminder of the need for accurate assessment of patient weight, not just for academic use but also in the clinical care of patients where it is can be of considerable importance in drug dosing and monitoring fluid balance.
References:
1) Docherty A, Harrsion E, Green C et al. Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study. BMJ 2020; 369: m1985
2) https://researchbriefings.files.parliament.uk/documents/SN03336/SN03336.pdf
3) https://www.icnarc.org/DataServices/Attachments/Download/96b455be-059e-e...
Competing interests: No competing interests
Dear Editor
I enjoyed reading about this important data set, but would like to know if ethnicity was extracted. I mention this as in the UK much has been made of BAME groups being at higher risk of being affected by Covid-19.
This particular data set would answer this question and help all people with behaviour change as the lockdown eases.
Competing interests: No competing interests
Dear Editor
Docherty et al should be congratulated on drilling down into the UK database of COVID-19 hospital related outcomes and comorbidities [1]. They reported a 14.5% UK prevalence of asthma and 17.7% prevalence of non asthmatic chronic pulmonary disease in hospitalised patients with COVID-19. Pointedly the presence of chronic pulmonary disease conferred a 17% greater likelihood of death.
Crucially this does not tell us whether the use of inhaled corticosteroids (ICS) might have influenced outcomes in COVID-19. This might clinically be relevant because in theory ICS might promote viral replication and predispose to secondary bacterial infections possibly leading to worse outcomes especially in COPD [2]. For example, the use of ICS in asthma was associated with a 45% increased bacterial pneumonia risk, while in COPD, taking fluticasone furoate as dual or triple combination therapy exhibited a 57% relative increase in pneumonia risk [3].
In converse, taking ICS as a class effect results in reduced ex vivo gene expression of COVID related cell entry receptors--namely, angiotensin converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) in airway epithelial cells [4]. Moreover, ICS may also inhibit local and systemic production of cytokines including interleukin-6 (IL6) [5 6]. This is relevant as circulating levels of IL6 are the strongest predictor of the need for mechanical ventilation in hospitalised patients with severe COVID-19 [7]. Finally, a more ICS specific effect is described whereby ciclesonide and mometasone furoate but not fluticasone propionate, beclomethasone dipripionate or budesonide suppresses in vitro replication of SARS-CoV-2 [8].
In particular we would be interested to know if those patients with COPD taking ICS as dual or triple therapy in conjunction with long acting bronchodilators compared to those taking long acting bronchodilators alone might have an altered risk of COVID-19 outcomes. In this regard use of ICS in COPD might be more relevant than in asthma in relation to COVID-19 as the former patients tend to be older, be smokers [9] with attendant comorbidities such as chronic cardiovascular disease [10], as well as having attenuated lung reserve, altered lung microbiome and impaired mucociliary clearance, all of which are likely risk factors for worse outcomes in relation to severe SARS-CoV-2 infection.
References
1. Docherty AB, Harrison EM, Green CA, et al. Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study. BMJ 2020;369:m1985. doi: 10.1136/bmj.m1985
2. Singanayagam A, Johnston SL. Long-term impact of inhaled corticosteroid use in asthma and chronic obstructive pulmonary disease (COPD): Review of mechanisms that underlie risks. J Allergy Clin Immunol 2020 doi: 10.1016/j.jaci.2019.12.907 [published Online First: 2020/01/19]
3. Qian CJ, Coulombe J, Suissa S, et al. Pneumonia risk in asthma patients using inhaled corticosteroids: a quasi-cohort study. Br J Clin Pharmacol 2017;83(9):2077-86. doi: 10.1111/bcp.13295 [published Online First: 2017/04/21]
4. Peters MC, Sajuthi S, Deford P, et al. COVID-19 Related Genes in Sputum Cells in Asthma: Relationship to Demographic Features and Corticosteroids. Am J Respir Crit Care Med 2020 doi: 10.1164/rccm.202003-0821OC [published Online First: 2020/04/30]
5. Suda K, Tsuruta M, Eom J, et al. Acute lung injury induces cardiovascular dysfunction: effects of IL-6 and budesonide/formoterol. American journal of respiratory cell and molecular biology 2011;45(3):510-6. doi: 10.1165/rcmb.2010-0169OC [published Online First: 2010/12/21]
6. Yamaya M, Nishimura H, Deng X, et al. Inhibitory effects of glycopyrronium, formoterol, and budesonide on coronavirus HCoV-229E replication and cytokine production by primary cultures of human nasal and tracheal epithelial cells. Respir Investig 2020 doi: 10.1016/j.resinv.2019.12.005 [published Online First: 2020/02/26]
7. Herold T, Jurinovic V, Arnreich C, et al. Elevated levels of interleukin-6 and CRP predict the need for mechanical ventilation in COVID-19. Journal of Allergy and Clinical Immunology doi: 10.1016/j.jaci.2020.05.008
8. Matsuyama S, Kawase M, Nao N, et al. The inhaled corticosteroid ciclesonide blocks coronavirus RNA replication by targeting viral NSP15. bioRxiv 2020:2020.03.11.987016. doi: 10.1101/2020.03.11.987016
9. Leung JM, Yang CX, Tam A, et al. ACE-2 Expression in the Small Airway Epithelia of Smokers and COPD Patients: Implications for COVID-19. Eur Respir J 2020 doi: 10.1183/13993003.00688-2020 [published Online First: 2020/04/10]
10. Mehra MR, Desai SS, Kuy S, et al. Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19. N Engl J Med 2020 doi: 10.1056/NEJMoa2007621 [published Online First: 2020/05/02]
Competing interests: BJL has received funding from companies who make inhaled steroids including AstraZeneca (research grants, giving talks, advisory boards, consulting, attending ATS and ERS ), Chiesi (research grants ,giving talks, advisory boards, consulting, attending BTS), Teva (research grants, advisory boards, giving talks, attending ERS), Novartis (advisory boards), Glenmark (consulting),Cipla (consulting), Vectura (consulting), Dr Reddys (consulting), Lupin (consulting). Son of BJL is an employee of AstraZeneca.
Re: Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study
Dear Editor,
I have concerns regarding this article’s seemingly purposeful omission of recording hypertension as a comorbidity for COVID-19, as well as its vague terminology and lack of definitions in the methodology.
Several studies before its publication reported hypertension to be one of the most prevalent comorbidities amongst hospitalised patients with laboratory-confirmed COVID-19. Indeed, this was observed in the very first description of hospitalised patients with PCR-confirmed COVID-19 in Wuhan, China, where its prevalence was 32% (1). Since then, many observational studies and meta-analyses have confirmed a similar importance of hypertension as a comorbidity (2–6).
I was therefore shocked to see ‘Chronic Cardiac Disease’ stated as the most prevalent comorbidity within the UK’s population of hospitalised COVID-19 patients in this paper. This goes against most of the findings observed for the rest of the world.
Part of me even wondered whether hypertension was included under ‘Chronic Cardiac Disease’, which, though technically incorrect as a definition, would corroborate most of the observational studies and meta-analyses published to date.
Being a medical student myself (and knowing my place on the Dunning-Kruger curve), I took this question to twitter. Whilst I accept that this is not the pinnacle of research methodologies, my followers are predominantly healthcare professionals, and I had no intention of writing this response at the time.
I set up an anonymous poll with the following scenario:
“You read 'Chronic Cardiac Disease' as a comorbidity in a cohort study (with no definitions). Does this include hypertension?”
There was no consensus.
Herein lies one issue with this paper. ‘Chronic Cardiac Disease’ is not a standardised term and consequently warrants a definition in the methodology. After examining the supplementary material for any such thing, I came across the Case Report form, which under ‘Chronic Cardiac Disease’ explicitly states, ‘not hypertension’ (but still provides no definition). This alludes to two things: the creators’ acknowledgment of possible confusion with this definition, as well as intentional omission of recording hypertension as a comorbidity.
I believe the design of this study is flawed, especially in context of the works that came before it. Its omission of recording hypertension as a comorbidity may well mean the findings of this paper are misrepresentative of the UK cohort. Furthermore, clearer definitions of potentially ambiguous terms are required.
References:
1. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet [Internet]. 2020 Feb 15;395(10223):497–506. Available from: https://doi.org/10.1016/S0140-6736(20)30183-5
2. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet [Internet]. 2020 Mar 28;395(10229):1054–62. Available from: https://doi.org/10.1016/S0140-6736(20)30566-3
3. Yang J, Zheng Y, Gou X, Pu K, Chen Z, Guo Q, et al. Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis. Int J Infect Dis IJID Off Publ Int Soc Infect Dis. 2020 May;94:91–5.
4. Fu L, Wang B, Yuan T, Chen X, Ao Y, Fitzpatrick T, et al. Clinical characteristics of coronavirus disease 2019 (COVID-19) in China: A systematic review and meta-analysis. J Infect [Internet]. 2020/04/10. 2020 Jun;80(6):656–65. Available from: https://pubmed.ncbi.nlm.nih.gov/32283155
5. Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW, et al. Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA [Internet]. 2020;323(20):2052–9. Available from: https://doi.org/10.1001/jama.2020.6775
6. Reilev M, Kristensen KB, Potteg\r ard A, Lund LC, Hallas J, Ernst MT, et al. Characteristics and predictors of hospitalization and death in the first 9,519 cases with a positive RT-PCR test for SARS-CoV-2 in Denmark: A nationwide cohort. medRxiv [Internet]. 2020; Available from: https://www.medrxiv.org/content/early/2020/05/26/2020.05.24.20111823
Competing interests: No competing interests