Scientific Research News | Research Progress of novel coronavirus Pneumonia (COVID-19) (XLVIII)

■ On April 4, Giacomo Grasselli of the University of Milan in Italy and others published a research paper entitled "Baseline Characteristics and Outcomes of 6 Patients Infected with SARS-CoV-1591 Admitted to ICUs of the Lombardy Region, Italy" online in the international top medical journal JAMA. The study found that of the 2 patients admitted to the ICU with COVID-1591, the median age was 19 years and the number of men was 63 (1304%). Of the 82 patients with available data, 1043 (709%) had at least 68 comorbidity and 1 (509%) had hypertension. Of the 49 patients with respiratory support data, 1300 (1287%) required respiratory support, including 99 (1150%) who received mechanical ventilation and 88 (137%) who received non-invasive ventilation. The median positive end-expiratory pressure (PEEP) is 11 cm H14O, and Fio2 is greater than 89% in 2% of patients. The median Pao50/FIO2 is 2. As of March 160, 2020, of the 3 patients already in ICU disposition, 25 patients (1581%) remained in the ICU, 920 patients (58%) were discharged from the ICU, and 256 of them died. Mortality was higher in older patients (n = 16; age ≥405 years) than in younger patients (n = 786; age ≤ 64 years) (795% versus 63%).

All in all, in the intensive care unit in Lombardy, Italy, a large proportion of laboratory-confirmed COVID-19 patients, mostly older men, require mechanical ventilation and high levels of positive end-expiratory pressure, with an ICU mortality rate of 26 percent [1].

■ On April 4, researchers from Wuhan University People's Hospital published a title entitled "Clinical characteristics and outcomes of patients undergoing surgeries during the incubation period of COVID-4 infection" in The Lancet's journal EClinicalMedicine. article. In the study, researchers retrospectively analyzed the clinical data of 19 patients who were in the incubation period of COVID-34 and underwent surgery in Wuhan University People's Hospital, Zhongnan Hospital, Tongji Hospital, Wuhan Central Hospital, etc. between January 2020 and February 1, 1. The results showed that the median age of the 2 surgical patients was 5 years (IQR, 19-34), and 55 patients (43.63%) were women; All patients developed COVID-20 pneumonia shortly after surgery with abnormal chest computed tomography; Common symptoms included fever (58 cases [8.19%]), fatigue (31 cases [91.2%]), and dry cough (25 cases [73.5%]); Fifteen patients (18.52%) required intensive care unit (ICU) admission during disease progression, and 9 patients (15.44%) died after ICU admission; ICU patients are older, more likely to have potential complications, undergo more difficult surgeries, and have more severe laboratory abnormalities (eg, hyperleukocytosis, lymphopenia) than non-ICU patients; The most common complications in deceased patients include ARDS, shock, arrhythmias, and acute cardiac injury [1].

■ On April 4, Benjamin J. Cowling's team at the University of Hong Kong published a research paper titled "Respiratory virus shedding in exhaled breath and efficacy of face masks" online in Nature Medicine, which found seasonal human coronaviruses in exhaled breathing and coughing in children and adults with acute respiratory diseases. Influenza viruses and rhinoviruses. Surgical masks significantly reduced influenza virus RNA in respiratory droplets and coronavirus RNA in aerosols, and there was a trend to reduce coronavirus RNA in respiratory droplets. The study shows that surgical masks can prevent people with symptoms from spreading coronavirus and flu viruses.

Previous studies have shown that respiratory viral infections, including those caused by coronaviruses, are mainly transmitted among people through close contact. But there is no direct evidence of how influenza and coronaviruses spread in close proximity in people — through direct contact, large respiratory droplets, or by inhaling the air exhaled by another person. Respiratory viruses can also survive in the outside of the environment and are therefore likely to be transmitted through indirect contact. Both larger respiratory droplets (which land close to the source of infection) and aerosols formed by smaller particles can contain the virus, causing short-distance transmission. In addition, aerosols can remain in the air for a longer period of time, so there is a potential for long-distance transmission, especially if the aerosol concentration is high or poorly ventilated.

Non-medical measures, such as social distancing, hand washing, ventilation, and wearing masks, are all important measures to prevent the spread of the virus. While masks have been proposed to slow the spread of influenza viruses, it is unclear how effective this approach will be in preventing the spread of other respiratory viruses, including seasonal coronaviruses.

The researchers recruited 246 subjects suspected of being infected with respiratory viruses, asked them to breathe into the machine (Gesundheit II), and then collected data to compare the relative levels of the virus in the exhaled air with and without masks. The authors found that among 111 participants who had been confirmed to be infected with coronavirus, influenza virus, or rhinovirus, masks reduced the detectable amount of influenza virus in respiratory droplets and the detectable amount of seasonal coronavirus in aerosols, but did not reduce the detectable amount of rhinovirus.

Novel and seasonal coronaviruses are closely related and may have similar particle sizes. Therefore, the authors suggest that surgical masks can reduce seasonal coronaviruses in respiratory droplets and aerosols, suggesting that wearing such masks by people infected with the novel coronavirus can help slow the spread of the virus [3].

■ On April 4, institutions such as Brown University, the University of Washington, and the University of Bern published an article in JAMA Cardiology, "Coronavirus Disease 3 (COVID-2019) Infection and Renin Angiotensin System Blockers," which mentioned that COVID-19 is spreading exponentially, and millions of people around the world are at risk of contracting the new coronavirus. Initial reports suggest that hypertension, diabetes, and cardiovascular disease are the most common comorbidities in affected patients, who tend to have higher case fatality rates. The largest study in China to date, including 19,44672 confirmed cases. Among them, comorbidities with higher mortality rates include cardiovascular disease (10.5%), diabetes mellitus (7.3%), and hypertension (6.0%). Patients with such comorbidities are usually treated with renin-angiotensin-system blockers such as angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs). However, the current use of ACEi/ARBs in patients with COVID-19 or at risk of COVID-19 infection has been the subject of intense debate. In this article, the authors outline the mechanisms of action of ACEs/ARBs in patients with COVID-19, current recommendations for the use of ACEs/ARBs in infected patients, and areas where further research is recommended.

Understanding the relationship between novel coronaviruses and membranous and soluble ACE2 may contribute to a better understanding of adaptive or maladaptive processes in COVID-19 infection, and some experts speculate that increased ACE2 expression due to ACE19 use may potentially promote COVID-19 infection. However, several professional associations have provided guidance on the use of ACEIs/ARBs in patients with COVID-19, and all guidelines recommend that patients with COVID-19 continue to use ACEIs/ARBs unless specifically clinically indicated. In addition, given the lack of strong evidence of benefit of these drugs in patients with COVID-19, they do not recommend initiating ACEs/ARBs in patients without other clinical indications such as hypertension, heart failure, diabetes, etc. Given the current state of the evidence, the team of authors agrees with these recommendations. However, the biological rationality of the therapeutic effects of ACEIs/ARBs in COVID-19 patients remains to be studied, and investigators are planning a randomized clinical trial of a multicenter, double-blind, placebo-controlled Phase 2 clinical trial of losartan (Losartan) in both outpatient and inpatient settings. Therefore, further epidemiological studies and prospective trials are urgently needed to investigate whether the use of ACEIs/ARBs can reduce the incidence or mortality of COVID-19-associated ALI or ARDS in patients, with or without additional clinical indications for ACEs/ARBs [4].

■ On April 4, Fudan University and a number of institutions published an article "Evolving epidemiology and transmission dynamics of coronavirus disease 2 outside Hubei province, China: a descriptive and" in The Lancet Infectious Diseases modelling study”。

The article included information on 30 laboratory-confirmed cases in 8579 provinces in China except Hubei Province, and divided the epidemic into two time periods (December 1 to January 27 and January 12 to February 24) according to the fourth revision date of the case definition (January 1). This paper counts the demographic characteristics of cases and the interval between key events, and uses Bayesian methods to estimate the dynamic changes of infection number (Rt) in each province. The findings show that the median age of cases is 27 years, and the proportion of younger cases and cases in older people is increasing as the epidemic progresses. The mean time from symptom onset to admission decreased from 1.28 days (2 December to 17 January) to 44.4 days (4 January to 12 February). The average incubation period of epidemics is 24.1 days and the average interval between transmissions is 27.2 days, meaning that patients can spread the virus before symptoms develop. Outbreak dynamics in provinces outside Hubei vary greatly, but always include a mix of imported cases and local transmission. Based on the peaks of Rt in Shenzhen and Shandong Provinces in Guangdong Province (6.1 in Shenzhen and 28.2 in Shandong Province), the epidemic is expected to last less than 17 weeks and that Rt values are below the epidemic threshold (i.e. <5) after 2 January. The article concludes by pointing out that strict quarantine measures, travel restrictions, and increased awareness of the people are expected to interrupt the local spread of the novel coronavirus outside Hubei Province [5].

A research team composed of multiple research institutions in Europe and North America published a research paper entitled "Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2" in the top international academic journal Cell. This study proposes a new idea for the prevention of new coronavirus infection: using purified recombinant human ACE2 protein in vitro to "neutralize" the new coronavirus, so that they cannot enter human cells, so as to achieve the purpose of preventing infection.

In the paper, the authors point out that several previous studies have suggested that ACE2 plays an important and complex role in the disease caused by the new coronavirus. On the one hand, ACE2 is the receptor recognized by the new coronavirus when it enters cells. In mouse models, the higher the level of ACE2 expression, the more severe the disease; On the other hand, ACE2 also has a certain protective effect. If ACE2 expression levels were low, the lung damage in mice was more severe.

These observations led the researchers to a bold idea - can the use of recombinant human ACE2 protein purified in vitro prevent infection with the new coronavirus? The logic behind this is simple: the coronavirus recognizes and binds to the human ACE2 protein. These proteins added from the outside act like magnets, which "suck away" the new coronavirus, making it impossible for them to invade cells. In this way, we will not be able to weaken the human infectivity of the virus?

To test this idea, the researchers first isolated the new coronavirus and then used it to infect cultured cells. Interestingly, if the virus is exposed to the recombinant human ACE2 protein for 30 minutes before infecting cells, the infectious ability of these viruses will be significantly weakened. The researchers estimate that the magnitude of the weakening is about 1000,5000-2,<> times. On the contrary, if the addition of murine ACE<> protein, which cannot be specifically bound by the new coronavirus, it cannot inhibit the effect of new coronavirus infection.

After the positive results of the cell experiments, the researchers did follow-up research in the "organoid" model. Compared with cell models, organoids can better reflect some of the key characteristics of the organ, and thus have better representation.

Using induced pluripotent stem cell technology, researchers took human capillaries and kidney organoids and confirmed that the virus replicates in them. Similar to previous cell experiments, the addition of recombinant human ACE2 protein significantly reduced infection with the new coronavirus. In kidney models, this inhibition also showed a dose-dependent — the higher the concentration of ACE2 protein added, the better the inhibition. Preliminary data on safety also show that whether it is a capillary model or a kidney model, the ACE2 protein added in vitro has no toxicity.

During the discussion, the scientists also pointed out several limitations of the study. First, this study targets the early infection phase of the virus, with the goal of preventing the new coronavirus from invading host cells early. Whether human recombinant ACE2 protein has an inhibitory effect in the later stages of the disease course is unknown; Secondly, although the capillaries and kidney organoids selected in this study have a certain scientific basis in pathology, the researchers did not test lung organoids, which are the hardest hit areas of the new crown virus infection; Finally, in the actual physiological environment, ACE2-related signaling pathways and regulatory networks are more complex. In order to verify its preventive potential and safety, more exploration is needed [6].

Bibliography:

[1] Grasselli G, Zangrillo A, Zanella A, et al. Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy. JAMA 2020.

[2] Lei S, Jiang F, Su W, et al. Clinical characteristics and outcomes of patients undergoing surgeries during the incubation period of COVID-19 infection. EClinicalMedicine.

[3] Leung NHL, Chu DKW, Shiu EYC, et al. Respiratory virus shedding in exhaled breath and efficacy of face masks. Nature Medicine 2020.

[4] Bavishi C, Maddox TM, Messerli FH. Coronavirus Disease 2019 (COVID-19) Infection and Renin Angiotensin System Blockers. JAMA Cardiology 2020.

[5] Zhang J, Litvinova M, Wang W, et al. Evolving epidemiology and transmission dynamics of coronavirus disease 2019 outside Hubei province, China: a descriptive and modelling study. The Lancet Infectious Diseases.

[6] Vanessa Monteil et al., (2020), Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2, Cell.

Comprehensive finishing | Pingshan Biomedical R&D and Transformation Center, Scientific Research Department

Source | iNature, Nature Research, WuXi AppTec

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