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      COVID-19 and hypertension: risks and management. A scientific statement on behalf of the British and Irish Hypertension Society

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          Abstract

          Hypertension is the single largest global contributor to disability-adjusted life years lost [1]. The majority of the population aged over 60 years have hypertension [2], and it has been suggested that they may be at increased risk from the effects of COVID-19. Despite this, and perhaps due to its ubiquity in the older population, current UK Government guidance does not identify people with hypertension as ʻat risk’ [3], however, other bodies such as the British Heart Foundation and the Health Service Executive in Ireland do [4, 5]. This article seeks to summarise and interpret the current evidence for and against an increase in COVID-19 risk and severity for those with raised blood pressure, and discusses the implications for the choice of anti-hypertensive treatment. Early small case series did not indicate an excess of hypertension in people admitted to hospital with COVID-19 [6]. The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team published a large case series from China; they found an overall case fatality rate of 2.3% (1023 of 44,672 confirmed cases), which increased to 6.0% for people with hypertension [7]. These data were reported without adjustment for age. Both COVID-19 case fatality rates and hypertension prevalence increase with age, reaching 8.0% and over 50% respectively for the 70–79 year age group [2]. New emerging evidence from the largest epidemiological study to date, examining over 17 million health records in England suggests that hypertension or a recorded blood pressure ≥140/90 mmHg taken together are not associated with COVID-19 in-hospital mortality after full adjustment: Hazard Ratio (HR) 0.95, (95% confidence interval (CI) 0.89–1.01). In sensitivity analyses, diagnosed hypertension alone was associated with slightly increased risk (HR 1.07, 95% CI 1.00–1.15) which might reflect residual confounding due to the strong age-related association [8]. Several other small case series that examine hypertension prevalence with and without severe COVID-19 have appeared in the literature [9]. In March 2020, a study-level meta-analysis of 2552 confirmed COVID-19 patients reported a pooled odds ratio (OR) of 2.49 (CI: 1.98–3.12; 11 studies) for severe disease in the presence of hypertension, with low heterogeneity between studies (I 2 = 24%). The OR for death was similar and weak evidence from meta-regression suggested that hypertension might be a clinical predictor of COVID-19 severity in people aged over 60 [10]. Likewise, a retrospective cohort analysis of 191 patients treated in hospital in China (not included in the meta-analysis) confirmed apparent high mortality in patients presenting with hypertension: 48% versus 23% of survivors [11]. Similar findings were reported with previous coronavirus infections, such as severe acute respiratory syndrome and Middle East Respiratory Syndrome [12, 13]. The mechanism by which hypertension leads to increased risk from COVID-19 is undoubtedly complex and may well relate to underlying co-morbidity. The prognosis for people with hypertension is markedly worse when COVID-19 infection is complicated by myocardial injury and in the presence of cardiovascular disease [8, 14]. End organ damage and cardiovascular events are associated with poorer control of high blood pressure, and mean blood pressure rises with age [15, 16]. It seems plausible, therefore, that older age, poorer blood pressure control and cardiovascular disease can explain the observed associations between age, hypertension and severity of COVID-19 infection. Are anti-hypertensive medications a risk for severity of COVID-19? The viral structural spike (S) protein binds to the angiotensin-converting enzyme 2 (ACE2) receptor to gain entry to cells; this has led to suggestions that use of ACE inhibitors and angiotensin II type-I receptor blockers (ARBs) may be implicated in poorer outcomes with COVID-19 [17, 18]. Whilst gaining much publicity, with attendant worry for patients and clinicians, this theory has been debated and ACE inhibitor and ARB treatment has also been associated with improved outcomes in some reports [19, 20]. Polymorphism in expression of the ACE2 receptor gene in association with hypertension and excess cardiovascular risk in ethnic minority groups has also been suggested as a partial explanation for observed excess mortality from COVID-19 in these populations [21, 22]. The National Institute for Health and Care Excellence are currently undertaking a rapid review of this topic [23]. Recent observational studies of confirmed COVID-19 patients have increased confidence that these drugs are not harmful: a case-control study of 6272 COVID-19 patients in Lombardy, Italy, matched to 30,759 controls, confirmed higher use of ACE inhibitors and ARBs in patients than controls, but after adjustment for greater prevalence of underlying cardiovascular disease, there was no evidence that ACE inhibitors (OR 0.96; 95% CI 0.87–1.07) or ARBs (OR 0.95; 95% CI 0.86–1.05) were associated with different risks of COVID-19 [24]. Two large retrospective cohort studies have also been published; one found no association between ACE inhibitor or ARB use and a positive coronavirus test in 18,472 people from Ohio and Florida (weighted OR 0.97; 95% CI 0.81–1.15), whist another study of 12,594 electronic health records from New York, found no association between any anti-hypertensive medication (ACE inhibitors, ARBs, beta-blockers, calcium-channel blockers, or thiazide diuretics) and increased likelihood of either a positive coronavirus test or an increased risk of severe COVID-19 illness [25, 26]. It is important to recognise that, to date, no randomised trial evidence exists to demonstrate either benefits or risks of continuing ACE inhibitors or ARBs on the incidence or outcomes of COVID-19. It must also be acknowledged that these observational data carry risks of residual confounding [27]. One retrospective cohort study found a positive association between ACE inhibitor or ARB use and admission to hospital (OR 1.93; 95% CI 1.38–2.71) or intensive care (OR 1.64; 95% CI 1.07–2.51) in small subgroup analyses (N = 421 and 161, respectively) [26]. These secondary outcomes are rightly viewed with caution due to the potential for residual confounding by co-morbidity and also imprecision (as evidenced by wide confidence intervals) due to small sample sizes [28]. Nevertheless, these studies taken together convey a consistent message of absence of harm associated with anti-hypertensive medications during infection with coronavirus, and clinical equipoise should therefore apply. Whilst these drugs appear increasingly unlikely to worsen COVID-19 severity, the consequences of poor blood pressure control, under normal circumstances, are well documented [16]. Consequently, the British and Irish Hypertension Society (BIHS), and our European and International partner societies, have issued clear position statements advising against cessation of anti-hypertensive therapy on the grounds of concern over risks with COVID-19 (available at: https://bihsoc.org/bihs-statement-on-acei-arb-and-covid19/) [29]. Current evidence does not support published opinions that doctors may consider stopping treatment with ACE inhibitors and ARBs in well-controlled patients with mild (Stage 1) hypertension and coronavirus infection [30]. The unintended consequences of discontinuing effective treatments for hypertension, without a suitable replacement titrated against appropriate blood pressure measurements and under direct medical supervision, could put patients at increased cardiovascular risk. In addition, managing such titration at a time when primary care is prioritising acute illness over routine contacts (including surgery blood pressure checks), makes the proposed strategy impractical and risks further diluting access to care. So, what can we say to hypertensive patients who may be anxious about taking anti-hypertensive medication and about their risks from infection during the COVID-19 pandemic? The evidence base remains incomplete, so strong recommendations are difficult. However, people with complications of hypertension, such as ischaemic heart disease, are already regarded as being at high risk from COVID-19. It seems reasonable to advise those with poorly controlled hypertension (i.e. blood pressure above guideline targets), particularly if prolonged, to also consider themselves to be at elevated risk, and, therefore, to follow appropriate social distancing advice [3]. For younger individuals with hypertension, there is an association of obesity with COVID-19 severity among Western populations [2, 8, 31, 32]. Generally, for people with good control of blood pressure, risks of undiagnosed cardiovascular disease are low, and they could therefore be reassured. All hypertensive patients should be strongly reassured that continuing their current medications is both safe and desirable. We should support all our hypertensive patients in continuing to strive for, and maintain, good blood pressure control by continuing to take their medications as prescribed, and by endeavouring to follow and maintain sensible lifestyle choices, including regular exercise [3]. Large numbers of people are being affected by COVID-19 with potentially profound consequences, however, their continued surveillance will also provide further data that will help us to understand the true risk from elevated blood pressure, its treatment and co-morbidities, on outcomes of the disease. Careful and continuous research is vital for an understanding of the mechanisms underlying any additional risk from hypertension with COVID-19, and to determine the best and safest ways to treat those with severe manifestations of disease. Our patients are best served when their treatment is based on available evidence rather than speculation, and the growing body of evidence suggests that continuation of ACE inhibitors and ARBs during the current COVID-19 pandemic is safe.

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          Most cited references 21

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          Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

          Summary Background A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. Methods All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by WHO and the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. Findings By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0–58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0–13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. Interpretation The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. Funding Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.
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            Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

            Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p<0·0001), and d-dimer greater than 1 μg/mL (18·42, 2·64–128·55; p=0·0033) on admission. Median duration of viral shedding was 20·0 days (IQR 17·0–24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors. The longest observed duration of viral shedding in survivors was 37 days. Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.
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              Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding

              Summary Background In late December, 2019, patients presenting with viral pneumonia due to an unidentified microbial agent were reported in Wuhan, China. A novel coronavirus was subsequently identified as the causative pathogen, provisionally named 2019 novel coronavirus (2019-nCoV). As of Jan 26, 2020, more than 2000 cases of 2019-nCoV infection have been confirmed, most of which involved people living in or visiting Wuhan, and human-to-human transmission has been confirmed. Methods We did next-generation sequencing of samples from bronchoalveolar lavage fluid and cultured isolates from nine inpatients, eight of whom had visited the Huanan seafood market in Wuhan. Complete and partial 2019-nCoV genome sequences were obtained from these individuals. Viral contigs were connected using Sanger sequencing to obtain the full-length genomes, with the terminal regions determined by rapid amplification of cDNA ends. Phylogenetic analysis of these 2019-nCoV genomes and those of other coronaviruses was used to determine the evolutionary history of the virus and help infer its likely origin. Homology modelling was done to explore the likely receptor-binding properties of the virus. Findings The ten genome sequences of 2019-nCoV obtained from the nine patients were extremely similar, exhibiting more than 99·98% sequence identity. Notably, 2019-nCoV was closely related (with 88% identity) to two bat-derived severe acute respiratory syndrome (SARS)-like coronaviruses, bat-SL-CoVZC45 and bat-SL-CoVZXC21, collected in 2018 in Zhoushan, eastern China, but were more distant from SARS-CoV (about 79%) and MERS-CoV (about 50%). Phylogenetic analysis revealed that 2019-nCoV fell within the subgenus Sarbecovirus of the genus Betacoronavirus, with a relatively long branch length to its closest relatives bat-SL-CoVZC45 and bat-SL-CoVZXC21, and was genetically distinct from SARS-CoV. Notably, homology modelling revealed that 2019-nCoV had a similar receptor-binding domain structure to that of SARS-CoV, despite amino acid variation at some key residues. Interpretation 2019-nCoV is sufficiently divergent from SARS-CoV to be considered a new human-infecting betacoronavirus. Although our phylogenetic analysis suggests that bats might be the original host of this virus, an animal sold at the seafood market in Wuhan might represent an intermediate host facilitating the emergence of the virus in humans. Importantly, structural analysis suggests that 2019-nCoV might be able to bind to the angiotensin-converting enzyme 2 receptor in humans. The future evolution, adaptation, and spread of this virus warrant urgent investigation. Funding National Key Research and Development Program of China, National Major Project for Control and Prevention of Infectious Disease in China, Chinese Academy of Sciences, Shandong First Medical University.
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                Author and article information

                Contributors
                c.e.clark@exeter.ac.uk
                Journal
                J Hum Hypertens
                J Hum Hypertens
                Journal of Human Hypertension
                Nature Publishing Group UK (London )
                0950-9240
                1476-5527
                22 January 2021
                22 January 2021
                : 1-4
                Affiliations
                [1 ]GRID grid.8391.3, ISNI 0000 0004 1936 8024, Primary Care Research Group, Institute of Health Services Research, College of Medicine & Health, , University of Exeter Medical School, ; Smeall Building, St Luke’s Campus, Magdalen Road, Exeter, Devon, England EX1 2LU UK
                [2 ]GRID grid.4991.5, ISNI 0000 0004 1936 8948, Nuffield Department of Primary Care Health Sciences, Radcliffe Primary Care Building, Radcliffe Observatory Quarter, , University of Oxford, ; Woodstock Road, Oxford, England OX2 6GG UK
                [3 ]GRID grid.6572.6, ISNI 0000 0004 1936 7486, Birmingham Medical School, Institute of Clinical Sciences, College of Medical and Dental Sciences, , University of Birmingham, ; Birmingham, B15 2TT UK
                Article
                451
                10.1038/s41371-020-00451-x
                7821986
                33483621
                © The Author(s) 2021

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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