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      Neprilysin inhibitor–angiotensin II receptor blocker combination (sacubitril/valsartan): rationale for adoption in SARS-CoV-2 patients

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          Abstract

          On 11 March 2020, the World Health Organization (WHO) declared the coronavirus disease 2019 (COVID-19) outbreak as a ‘pandemic’. 1 No valid therapy for COVID-19 is actually available. Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is empirically treated with antivirals, antimalarics, tocilizumab, etc. 2 Production of a vaccine for COVID-19 has been attempted, although approval needs time. We describe a possible, alternative approach for treating COVID-19. Lymphocyte count has been associated with increased disease severity risk. 3 Patients who died from COVID-19 showed a significantly lower lymphocyte count than survivors, therefore this should be closely monitored. 3 Repletion of lymphocytes could probably have beneficial effects on recovery. A recent hypothesis suggests that the inhibition of the angiotensin 1 receptor (AT1R) may provide benefits to COVID-19 patients. 4 This hypothesis is based on the observation that the SARS-CoV-2 virus uses angiotensin-converting enzyme 2 (ACE2) as a receptor to bind the virus to the bronchial cell membrane. The enzymes ACE and ACE2 belong to the same peptidase family but have two very different physiological functions. ACE cleaves angiotensin I to generate angiotensin II (Ang II), which binds to and activates AT1R, and thus promoting vasoconstriction. ACE2 cleaves Ang II and generates angiotensin 1-7, a powerful vasodilator acting through Mas receptors. AT1R antagonists are widely used in hypertensive patients but they increase the ACE2 cardiac expression in rats 5 and the urinary concentration of ACE2. 6 It has been demonstrated that the binding of virus to ACE2 leads to ACE2 down-regulation, which increases the production of Ang II but reduces angiotensin 1-7. This contributes to increased AT1-mediated pulmonary vascular permeability, thereby mediating increased lung pathology. 7 Therefore, higher ACE2 expression following chronic therapy with sartans may protect COVID-19 patients from acute lung injury rather than increasing the risk for SARS-CoV-2. Two complementary mechanisms may explain such a hypothesis: sartans will continue to block excessive angiotensin-mediated AT1R activation due to the viral infection, and, in parallel, they will up-regulate ACE2, thus increasing angiotensin 1-7 production. In such a setting, the role of neprilysin (NEP) and its inhibitor sacubitril should also be revised. Recently, Zhang et al. 8 demonstrated that sacubitril/valsartan reduced the concentration of pro-inflammatory cytokines and neutrophil count, while increasing lymphocyte count more than valsartan alone or placebo. 8 This finding might be related to the increase in plasma levels of atrial/brain/C-type natriuretic peptide, Ang I/II, substance P, bradykikin, and endothelin secondary to neprilisin inibition by sacubitril. 8 We have recently shown that early sacubitril/valsartan administration reduces high sensitivity C-reactive protein levels and increases lymphocyte count in patients with acute heart failure. 9 These pieces of evidence support the biological plausibility of early administration of sacubitril/valsartan in COVID-19 patients, in order to maximize the anti-inflammatory effects of sacubitril and contain the effect of Ang I on the lungs (Figure 1 ). Figure 1 Double interaction between sacubitril and NEP and between valsartan and the AT1 receptor and their consequences on the development of the inflammatory response due to COVID-19 infection. RAAS, renin–angiotensin–aldosterone system; SacVal, sacubitril/valsartan. Conflict of interest: none declared.

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          Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study

          Summary Background An ongoing outbreak of pneumonia associated with the severe acute respiratory coronavirus 2 (SARS-CoV-2) started in December, 2019, in Wuhan, China. Information about critically ill patients with SARS-CoV-2 infection is scarce. We aimed to describe the clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia. Methods In this single-centered, retrospective, observational study, we enrolled 52 critically ill adult patients with SARS-CoV-2 pneumonia who were admitted to the intensive care unit (ICU) of Wuhan Jin Yin-tan hospital (Wuhan, China) between late December, 2019, and Jan 26, 2020. Demographic data, symptoms, laboratory values, comorbidities, treatments, and clinical outcomes were all collected. Data were compared between survivors and non-survivors. The primary outcome was 28-day mortality, as of Feb 9, 2020. Secondary outcomes included incidence of SARS-CoV-2-related acute respiratory distress syndrome (ARDS) and the proportion of patients requiring mechanical ventilation. Findings Of 710 patients with SARS-CoV-2 pneumonia, 52 critically ill adult patients were included. The mean age of the 52 patients was 59·7 (SD 13·3) years, 35 (67%) were men, 21 (40%) had chronic illness, 51 (98%) had fever. 32 (61·5%) patients had died at 28 days, and the median duration from admission to the intensive care unit (ICU) to death was 7 (IQR 3–11) days for non-survivors. Compared with survivors, non-survivors were older (64·6 years [11·2] vs 51·9 years [12·9]), more likely to develop ARDS (26 [81%] patients vs 9 [45%] patients), and more likely to receive mechanical ventilation (30 [94%] patients vs 7 [35%] patients), either invasively or non-invasively. Most patients had organ function damage, including 35 (67%) with ARDS, 15 (29%) with acute kidney injury, 12 (23%) with cardiac injury, 15 (29%) with liver dysfunction, and one (2%) with pneumothorax. 37 (71%) patients required mechanical ventilation. Hospital-acquired infection occurred in seven (13·5%) patients. Interpretation The mortality of critically ill patients with SARS-CoV-2 pneumonia is considerable. The survival time of the non-survivors is likely to be within 1–2 weeks after ICU admission. Older patients (>65 years) with comorbidities and ARDS are at increased risk of death. The severity of SARS-CoV-2 pneumonia poses great strain on critical care resources in hospitals, especially if they are not adequately staffed or resourced. Funding None.
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            The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak

            Coronavirus disease (COVID-19) is caused by SARS-COV2 and represents the causative agent of a potentially fatal disease that is of great global public health concern. Based on the large number of infected people that were exposed to the wet animal market in Wuhan City, China, it is suggested that this is likely the zoonotic origin of COVID-19. Person-to-person transmission of COVID-19 infection led to the isolation of patients that were subsequently administered a variety of treatments. Extensive measures to reduce person-to-person transmission of COVID-19 have been implemented to control the current outbreak. Special attention and efforts to protect or reduce transmission should be applied in susceptible populations including children, health care providers, and elderly people. In this review, we highlights the symptoms, epidemiology, transmission, pathogenesis, phylogenetic analysis and future directions to control the spread of this fatal disease.
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              A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus–induced lung injury

              During several months of 2003, a newly identified illness termed severe acute respiratory syndrome (SARS) spread rapidly through the world 1,2,3 . A new coronavirus (SARS-CoV) was identified as the SARS pathogen 4,5,6,7 , which triggered severe pneumonia and acute, often lethal, lung failure 8 . Moreover, among infected individuals influenza such as the Spanish flu 9,10 and the emergence of new respiratory disease viruses 11,12 have caused high lethality resulting from acute lung failure 13 . In cell lines, angiotensin-converting enzyme 2 (ACE2) has been identified as a potential SARS-CoV receptor 14 . The high lethality of SARS-CoV infections, its enormous economic and social impact, fears of renewed outbreaks as well as the potential misuse of such viruses as biologic weapons make it paramount to understand the pathogenesis of SARS-CoV. Here we provide the first genetic proof that ACE2 is a crucial SARS-CoV receptor in vivo. SARS-CoV infections and the Spike protein of the SARS-CoV reduce ACE2 expression. Notably, injection of SARS-CoV Spike into mice worsens acute lung failure in vivo that can be attenuated by blocking the renin-angiotensin pathway. These results provide a molecular explanation why SARS-CoV infections cause severe and often lethal lung failure and suggest a rational therapy for SARS and possibly other respiratory disease viruses. Supplementary information The online version of this article (doi:10.1038/nm1267) contains supplementary material, which is available to authorized users.
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                Author and article information

                Journal
                Eur Heart J Cardiovasc Pharmacother
                Eur Heart J Cardiovasc Pharmacother
                ehjcvp
                European Heart Journal — Cardiovascular Pharmacotherapy
                Oxford University Press
                2055-6837
                2055-6845
                13 April 2020
                13 April 2020
                : pvaa028
                Affiliations
                [p1 ] Unit of Internal Medicine, San Francesco Hospital , Viale Europa 21, 82037 Telese Terme (BN), Italy
                [p2 ] Section of Cardiovascular Diseases, Department of Emergency and Organ Transplantation, University of Bari, School of Medicine , Bari, Italy
                [p3 ] Cardiology Unit, Hospital ‘F. Perinei’ ASL BA , Altamura, Bari, Italy
                [p4 ] Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila , L’Aquila, Italy
                Author notes
                Corresponding author. Cardiology Section, Hospital ‘F. Perinei’ ASL BA, Altamura, Bari, Italy. Tel.: +39 080 3108286, Email: piero.sc@ 123456hotmail.it ; pietrosc.83@ 123456libero.it
                Article
                pvaa028
                10.1093/ehjcvp/pvaa028
                7184416
                32282032
                c0f56079-de6a-4615-9945-9acf31403318
                Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.

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