Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study
BMJ 2020; 368 doi: https://doi.org/10.1136/bmj.m1091 (Published 26 March 2020) Cite this as: BMJ 2020;368:m1091Read our latest coverage of the coronavirus outbreak
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Inhibitors of the renin-angiotensin-aldosterone system and CoViD-19-affected patients: A two-faced Janus?
Adriana Albini (1), Giovanni Di Guardo (2)* and Michele Lombardo (3)
1) Scientific and Technology Pole, IRCCS Multimedica, Milan, Italy; 2) University of Teramo, Faculty of Veterinary Medicine, Teramo, Italy; 3) Cardiology Unit, San Giuseppe Hospital-MultiMedica, Milan, Italy; *Corresponding author (E-mail address: gdiguardo@unite.it)
Dear Editor,
We have read the interesting article by Dr Chen and coworkers (1), reporting that hypertension and other cardiovascular comorbidities in CoViD-19 (CoronaVirus Disease 2019)-affected patients occurred in deceased subjects with a frequency approximately twice that seen in recovered ones. In this respect, among over 9,000 SARS-CoV-2-infected patients in Italy who succumbed, 73% were hypertensive, 28% suffered from ischemic heart disease and 31% were diabetic, with their median age being 78 years, in comparison to 63 years of those surviving (2). This may contribute to explain the increased CoViD-19-associated/related mortality rate in Italy (10.5%) as compared to that (2.5%) reported in infected cohorts from China (3). In Chinese cohorts, the most prevalent comorbidities are hypertension (24%), diabetes (16%) and cardiovascular disease (CVD) conditions (9%) (4). In another study by Dr Wu and coworkers (5), focused on 201 SARS-CoV-2-infected patients, the median age was 51 years and, among the 42% of them who developed acute respiratory distress syndrome, 27% had hypertension, 19% diabetes and 52% died. These observations pave the way to several issues of relevant concern. In this respect, while SARS-CoV-2-infected patients of older age with CVD comorbidities show a more severe clinical course and a worse prognosis, it should be adequately underscored that many of these patients in Italy are currently treated with ACE-inhibitors or angiotensin II receptor blockers (ARBs), which are considered the drugs of first choice for hypertension and other CVD conditions (6). Furthermore, the impact of SARS-CoV-2 infection on the cardiovascular system, highlighted by the occurrence of myocarditis, coronary plaque instability and myocardial infarction, coupled with heart failure exacerbation, makes a significant contribution to mortality in elderly patients (7). The antagonists of the renin-angiotensin-aldosterone system (RAAS) have been shown to interfere with angiotensin converting enzyme (ACE)-2 receptor expression in heart and kidney tissues. Therefore, are the aforementioned factors and conditions able to shape the clinical course of SARS-CoV-2 infection in CVD comorbid individuals? In other words, should these "intrinsically weaker" patients maintain or discontinue their ACE-inhibitor or ARB-based therapeutic regimens?
As already shown for SARS-CoV, the viral pathogen responsible for severe acute respiratory syndrome (SARS), ACE2 is the main cell receptor also for SARS-CoV-2. Within such framework, valuable insights into the molecular bases driving the complex interactions occurring at the SARS-CoV-2/ACE2 interface have been recently provided (8,9). Still noteworthy, experimental studies carried out both in vivo and in vitro have reported conflicting results. Indeed, normotensive rats treated with the ACE-inhibitor lisinopril and with the ARB losartan were shown to develop an increased cardiac ACE2 expression (10). By contrast, an ACE2 downregulation at mRNA and protein levels was reported in kidney and heart tissues from patients treated with ACE-inhibitors and ARBs (11).
Taken together, these experimental data add further concern to the fear that ACE-inhibitor or ARB-based treatments could worsen the prognosis of SARS-CoV-2 infection in patients suffering from simultaneously occurring CVD conditions. As a matter of fact, it has been additionally claimed that the ACE2 upregulation putatively induced by these two drug classes, although elicited through different mechanisms, could favour SARS-CoV-2 human lung tissue colonization (12). Conversely, it has been also hypothesized that ARBs could result potentially useful in the clinical course of SARS-CoV-2-infected patients (13).
A recently released HFSA/AAC/AHA Statement has emphasized the need to continue ongoing treatments with RAAS antagonists in patients assuming these drugs, despite the herein highlighted concerns that their use might worsen CoViD-19 evolution and outcome in SARS-CoV-2-infected subjects (14).
Within such context, the data originating from the aforementioned studies might suggest that previously or concurrently administered treatments based upon ACE-inhibitors or ARBs could influence the clinical course of SARS-CoV-2-infection.
Given the aforementioned "dual" effects of ACE- inhibitors and ARBs on ACE2 expression, which could be defined a “two-faced Janus”, we strongly believe that a body of solid and robust , "science-evidence"-based data are urgently needed, in order to provide a "non-equivocal" reply to the crucial question whether RAAS antagonists can be safey maintained or removed in handling elderly, hypertensive, diabetic or cardiovascular comorbidity-affected, SARS-CoV-2-infected patients.
In this respect, we herein emphasize the cogent need of adequately funded studies aimed at evaluating the real impact, if any, of ACE-inhibitor and ARB drugs on SARS-CoV-2 infection's clinico-pathological evolution and outcome.
Last but not least, the post mortem investigations which will be performed (as much as possible, most hopefully!) on deceased patients with CoViD-19, will be of paramount relevance for providing adequate, science evidence-based answers to the many open issues concerning SARS-CoV-2 infection's pathogenesis, including those addressed in the present Letter to the Editor.
References
1. Chen T., et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ 2020;368:m1091.
2. Report sulle caratteristiche dei pazienti deceduti positivi a COVID-19 in Italia. Italian ISS Report, March 26, 2020.
3. Deng S.Q, Peng H.J. Characteristics of and Public Health Responses to the Coronavirus Disease 2019 Outbreak in China. J Clin Med 2020;9.
4. Guan W., et al. Clinical caracteristics of coronarovirus in China, N Engl J Med 2020;doi:10.1056Moa20020.
5. Wu C., et al. Risk factors associated with acute respiratory distress syndrome and death in patients with CoronaroVirus Disease 2019 Pneumonia in Wuhan, China, JAMA Intern Med. 2020;doi:10.1001/jamainternmed.20200994.
6. Williams B., et al.. 2018 ESC/ESH Guidelines for the Management of Arterial Hypertension. Eur Heart J 2018;39: 3021-3104.
7. Xiong T.-Y., et al. Coronaviruses and the cardiovascular system: acute and long-term implications. Eur Heart J 2020;doi: 10.1093/eurheartj/ehaa231.
8. Yan R., et al. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science 2020.
9. Hoffmann M., et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020.
10. Ferrario C.M., et al. Effects of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin converting enzyme 2. Circulation 2005;24:2605-2010.
11. Koka M., et al. Angiotensin II up-regulates angiotensin I-converting enzyme (ACE), but down-regulates ACE2 via the AT1-ERK/p38 MAP kinase pathway. Am J Pathol 2008;172:1174-1183.
12. Fang L., Karakiulakis G., Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med 2020.
13. Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug Dev Res 2020.
14. American College of Cardiology (AAC News Story). HFSA/AAC/AHA Statement adresses concerns: Using RAAS antagonists in CoViD-19, March 2020.
Competing interests: No competing interests
Dear Editor,
The world is facing an immense threat from novel coronavirus disease 2019 commonly known as COVID-19. The study published by Chen and colleagues has highlighted that older persons infected with COVID-19 were the group with highest mortality rate[1]. In fact, another report from the Chinese Center for Disease Control and Prevention described the characteristics of the disease based on 72 314 cases, updated through February 11, 2020. We as geriatricians find the results alarming - as the older population was among the most affected by the virus. The study has reported that of the total cases, 3% (1408 cases) were older adults ≥80 years and the case-fatality rate (CFR) was 14.8% (208 of 1408) for this population. Older population aged 70-79 years had a CFR of 8.0% (312 of 3918). Subjects with pre-existing comorbid conditions such as cardiovascular disease, diabetes, chronic respiratory disease, hypertension, and cancer had the highest CFR, of which most of them are most likely to be older individuals. Similar findings have been reported even in the Italian population[3].
These findings are of immense concern to us, particularly because the number of older adults in China and other parts of the world has increased considerably in the last decade. Older people who are also widely known to be frail (i.e., a geriatric syndrome with increased vulnerability to stressors) or with multimorbidity (i.e., with multiple chronic conditions) are the most vulnerable population even in the absence of an epidemic disease. In fact, we could only speculate the psychological effect of the current situation relating them as the highest fatality rate group and reports of biased allocation of medical services for older patients[4]. For instance, evidence from the post-Severe Acute Respiratory Syndrome (SARS) study has shown older people to have a very high prevalence of psychological conditions such as post-traumatic stress disorder (PTSD)[5]. Furthermore, it is undeniable that during the current state of the COVID-19 epidemic, the majority of the older adults are locked indoors for the fear of becoming infected. Lack of proper physical exercise or social interaction (leading to loneliness) could have a huge negative impact on their health such as added vulnerability to conditions such as depression and frailty.
Lessons could be learned from the Chinese government initiatives such as online mental services to support older people [6], which is laudable. A similar approach to address physical inactivity such as online physical exercise training programs where applicable may be beneficial, particularly to boost their immunity. Older adults are known to have a weak immune system, hence, other strategies to maintain their immunity in older age such as advice on proper diet and healthy lifestyle may be disseminated through media (including in a non-epidemic scenario). Indeed, all older populations may not have access to online resources or may not have enough knowledge to use internet tools. Governments of the infected regions should mobilize resources to help these vulnerable populations, including in getting the correct information, assistance in meeting their other daily needs, and the most important is facilitate them in testing for the virus. Undeniably, such services will be difficult to be dispersed in many low and middle income countries[7].
There have been several reports of ongoing research to develop vaccines or therapeutics against COVID-19. Here we would like to bring the attention of the concerned agencies to prioritize the inclusion of older persons in clinical trials of such potential treatments. As clinical trials are largely known to be biased, recruiting mostly younger populations leaving the neediest still at risk[8]. Besides, suitable planning should be done to protect older people in long-term care facilities, which is a major concern for the geriatric community[9]. We welcome the recent NICE guideline of frailty assessment of older adults upon admission to hospital irrespective of age and COVID-19 status, to make proper use of available resources based on medical benefit[10].
Older populations represent the most vulnerable group for COVID-19 infection. Public health strategies in favor of the most disadvantaged and exposed older individuals should be a present global priority.
Conflict of interest: None
Role of funding source: None
References:
1 Chen T, Wu D, Chen H, et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ 2020;368. doi:10.1136/bmj.m1091
2 Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention. JAMA Published Online First: 24 February 2020. doi:10.1001/jama.2020.2648
3 Remuzzi A, Remuzzi G. COVID-19 and Italy: what next? The Lancet 2020;0. doi:10.1016/S0140-6736(20)30627-9
4 Orecchio-Egresitz H. Faced with tough choices, Italy is prioritizing young COVID-19 patients over the elderly. That likely ‘would not fly’ in the US. Business Insider. https://www.businessinsider.com/prioritizing-covid-19-patients-based-age... (accessed 25 Mar 2020).
5 Lee TMC, Chi I, Chung LWM, et al. Ageing and psychological response during the post-SARS period. Aging Ment Health 2006;10:303–11. doi:10.1080/13607860600638545
6 Liu S, Yang L, Zhang C, et al. Online mental health services in China during the COVID-19 outbreak. Lancet Psychiatry Published Online First: 18 February 2020. doi:10.1016/S2215-0366(20)30077-8
7 Lloyd-Sherlock P, Ebrahim S, Geffen L, et al. Bearing the brunt of covid-19: older people in low and middle income countries. BMJ 2020;368. doi:10.1136/bmj.m1052
8 Chhetri JK. Immunisation of older adults: where are the frail? Lancet Public Health 2017;2:e449. doi:10.1016/S2468-2667(17)30155-X
9 Dosa D, Jump RLP, LaPlante K, et al. Long-Term Care Facilities and the Coronavirus Epidemic: Practical Guidelines for a Population at Highest Risk. Journal of the American Medical Directors Association 2020;0. doi:10.1016/j.jamda.2020.03.004
10 NICE publishes first rapid COVID-19 guidelines | News and features | News. NICE. https://www.nice.org.uk/news/article/nice-publishes-first-rapid-covid-19... (accessed 23 Mar 2020).
Competing interests: No competing interests
A Highest Quality Scientific Paper.
Dear Editor:
The article published 4 days ago, on March 26th, in the research section of the last BMJ issue, and entitled Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study, is an excellent example of the correct structural format of a scientific paper. In it, authors present the results obtained in a serious and nowadays meaningful research work. Using the classic and traditional IMRAD format (Introduction, Methodology, Results, Analysis of results and Discussion), they describe the most relevant characteristics, demographic, personal history, patients habits, comorbidity, signs and symptoms of CoViD19 disease at patients admission, its natural course during the subjects stay in clinic, and other data produced by them during their stance at hospital Tongji located in the town of Wuhan in China.
CoViD19, has produced devastating effects on health systems in more than 50 countries. In several European ones, such as Italy and Spain, the number of deaths per 100 cases of people SARSCoVi2 infected has exceeded 10 per cent, and current data suggest that the rate of spread of the disease is so high that it is also causing serious damage to populations far from China, located mainly south of the Asian continent and in the east of the United States, in populous cities such as New York, New Jersey and Connecticut.
As can be seen, the format of this paper makes very easy the process of its reading; it shows the logic procedure of how the authors designed and did the study, from the formulation of the problem in the introduction, until the discussion of the results obtained. It reflects, very well, how they analyzed the information produced by the patients. We were very pleased to read the introduction, which contains the classic elements that must be present in that section: definitions of terms, statement of the problem to study, epidemiological data, general description of what has been done until now for solving the great problem generated by the coronavirus dynamics in the new millennium; what is being done and what needs to be done. It also states very well what the objective of the study was and how they justify the needs for making this research.
In the methodological section the authors, in a detailed manner, convince their readers that the study was carried out with the due level of care and accuracy. They describe the patients' characteristics, how the information was collected, how the PCR for the reverse transcriptase was done, how to quantify the various laboratory parameters studied; how they managed and treated the patients in hospital; how they did the data statistical analysis, what statistical model was used and what statistics were interpreted to make extrapolations.
What impressed us most was the way as authors presented the results and especially how they organized them, in a great table, and most surprising, the way as elementary, simple and pleasant way they interpret each of the variables presented in that wonderful table. It was so easy to manage the information that even we made the respective contingency tables to confirm the authors' findings. In order to better support the statements made by the authors in the Discussion section we think it would have been more spectacular if they, in that section, had written the results obtained after calculating the t student and chi square for various variables of the study. For instance, for the gender variable the chi squared is
X-squared = 9.9957, df = 1, p-value = 0.001569; for patients with ages > o = to 60 years and younger than 60 The X-squared = 58.321, df = 1, and p-value = 2.226 e-14, and so on.
CoViD19 disease is wreaking havoc on social dynamics, both individually and collectively, in many countries around the world. It is producing a very negative impact on the world economy, particularly in countries where unemployment, misery, and poverty prevail and where there are no state social protection systems. Understanding the pathogenesis and evolution of this disease is essential for the construction of good medical guidelines for the proper management of those patients. This article is a valuable reference document to better understand the CoViD19 characteristics, the epidemiological situation, its etiology, the behavior of the virus in the alveoli, the radical and rapid changes that occur in other organic systems of the body, the dynamics of the immune system against the virus and the secondary infection generated, so it is wonderful tool for proposing better strategies to diagnose, prevent, and treat patients with this disease.
Competing interests: No competing interests