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Journal Article•DOI•

Transplantation of ACE2 - Mesenchymal Stem Cells Improves the Outcome of Patients with COVID-19 Pneumonia.

Zikuan Leng1, Rongjia Zhu2, Wei Hou3, Yingmei Feng3, Yanlei Yang4, Qin Han2, Guangliang Shan2, Fanyan Meng1, Dongshu Du1, Shihua Wang2, Junfen Fan2, Wenjing Wang3, Luchan Deng2, Hongbo Shi3, Hongjun Li3, Zhongjie Hu3, Fengchun Zhang4, Jinming Gao4, Hongjian Liu5, Xiaoxia Li6, Yangyang Zhao2, Kan Yin6, Xijing He7, Zhengchao Gao7, Yibin Wang7, Bo Yang5, Ronghua Jin3, Ilia Stambler, Lee Wei Lim8, Huanxing Su9, Alexey Moskalev10, Antonio Cano11, Sasanka Chakrabarti12, Kyung-Jin Min13, Georgina M. Ellison-Hughes14, Calogero Caruso15, Kunlin Jin16, Robert Chunhua Zhao •
Shanghai University1, Peking Union Medical College2, Capital Medical University3, Peking Union Medical College Hospital4, Zhengzhou University5, Qingdao University6, Xi'an Jiaotong University7, Li Ka Shing Faculty of Medicine, University of Hong Kong8, University of Macau9, Russian Academy of Sciences10, University of Valencia11, Maharishi Markandeshwar University, Mullana12, Inha University13, King's College London14, University of Palermo15, University of North Texas Health Science Center16
09 Mar 2020-Aging and Disease (Aging and Disease)-Vol. 11, Iss: 2, pp 216-228
TL;DR: The intravenous transplantation of MSCs was safe and effective for treatment in patients with COVID-19 pneumonia, especially for the patients in critically severe condition.
Abstract: A coronavirus (HCoV-19) has caused the novel coronavirus disease (COVID-19) outbreak in Wuhan, China. Preventing and reversing the cytokine storm may be the key to save the patients with severe COVID-19 pneumonia. Mesenchymal stem cells (MSCs) have been shown to possess a comprehensive powerful immunomodulatory function. This study aims to investigate whether MSC transplantation improves the outcome of 7 enrolled patients with COVID-19 pneumonia in Beijing YouAn Hospital, China, from Jan 23, 2020 to Feb 16, 2020. The clinical outcomes, as well as changes of inflammatory and immune function levels and adverse effects of 7 enrolled patients were assessed for 14 days after MSC injection. MSCs could cure or significantly improve the functional outcomes of seven patients without observed adverse effects. The pulmonary function and symptoms of these seven patients were significantly improved in 2 days after MSC transplantation. Among them, two common and one severe patient were recovered and discharged in 10 days after treatment. After treatment, the peripheral lymphocytes were increased, the C-reactive protein decreased, and the overactivated cytokine-secreting immune cells CXCR3+CD4+ T cells, CXCR3+CD8+ T cells, and CXCR3+ NK cells disappeared in 3-6 days. In addition, a group of CD14+CD11c+CD11bmid regulatory DC cell population dramatically increased. Meanwhile, the level of TNF-α was significantly decreased, while IL-10 increased in MSC treatment group compared to the placebo control group. Furthermore, the gene expression profile showed MSCs were ACE2- and TMPRSS2- which indicated MSCs are free from COVID-19 infection. Thus, the intravenous transplantation of MSCs was safe and effective for treatment in patients with COVID-19 pneumonia, especially for the patients in critically severe condition.

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Citations
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Journal Article•DOI•
Virology, Epidemiology, Pathogenesis, and Control of COVID-19.

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Yuefei Jin1, Haiyan Yang1, Wangquan Ji1, Weidong Wu2, Shuaiyin Chen1, Weiguo Zhang1, Weiguo Zhang3, Guangcai Duan1 •
Zhengzhou University1, Xinxiang Medical University2, Duke University3
27 Mar 2020-Viruses
TL;DR: The present understanding of COVID-19 is detailed and the current state of development of measures are introduced in this review to provide a comprehensive summary to public health authorities and potential readers worldwide.
Abstract: The outbreak of emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) in China has been brought to global attention and declared a pandemic by the World Health Organization (WHO) on March 11, 2020. Scientific advancements since the pandemic of severe acute respiratory syndrome (SARS) in 2002~2003 and Middle East respiratory syndrome (MERS) in 2012 have accelerated our understanding of the epidemiology and pathogenesis of SARS-CoV-2 and the development of therapeutics to treat viral infection. As no specific therapeutics and vaccines are available for disease control, the epidemic of COVID-19 is posing a great threat for global public health. To provide a comprehensive summary to public health authorities and potential readers worldwide, we detail the present understanding of COVID-19 and introduce the current state of development of measures in this review.

1,126 citations

Cites background from "Transplantation of ACE2 - Mesenchym..."

  • ...with immunoglobulin (IVIG), and systemic anti-inflammatory drugs to reduce cytokine storm are also potential therapeutic strategies for severe COVID-19 [61,79]....

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Journal Article•DOI•
The cytokine storm and COVID-19.

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Biying Hu1, Shaoying Huang1, Lianghong Yin1•
Jinan University1
01 Jan 2021-Journal of Medical Virology
TL;DR: The current understanding of the features of SARS‐CoV‐2 and the pathological features, pathophysiological mechanisms, and treatments of the cytokine storm induced by COVID‐19 are reviewed and it is suggested that the identification and treatment of theocyte storm are important components for rescuing patients with severe CO VID‐19.
Abstract: Coronavirus disease 2019 (COVID-19), which began in Wuhan, China, in December 2019, has caused a large global pandemic and poses a serious threat to public health More than 4 million cases of COVID-19, which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have been confirmed as of 11 May 2020 SARS-CoV-2 is a highly pathogenic and transmissible coronavirus that primarily spreads through respiratory droplets and close contact A growing body of clinical data suggests that a cytokine storm is associated with COVID-19 severity and is also a crucial cause of death from COVID-19 In the absence of antivirals and vaccines for COVID-19, there is an urgent need to understand the cytokine storm in COVID-19 Here, we have reviewed the current understanding of the features of SARS-CoV-2 and the pathological features, pathophysiological mechanisms, and treatments of the cytokine storm induced by COVID-19 In addition, we suggest that the identification and treatment of the cytokine storm are important components for rescuing patients with severe COVID-19

854 citations

Cites background from "Transplantation of ACE2 - Mesenchym..."

  • ...A clinical trial of MSC therapy revealed that MSCs were able to rapidly and significantly improve the clinical symptoms of COVID‐19 without any observed adverse effects.(72) Although the side effects of MSC treatment are rarely reported, the safety and...

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Journal Article•DOI•
SARS-CoV-2 infection: The role of cytokines in COVID-19 disease.

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Víctor J. Costela-Ruiz1, Rebeca Illescas-Montes1, Jose M. Puerta-Puerta, Concepción Ruiz1, Lucía Melguizo-Rodríguez1 •
University of Granada1
02 Jun 2020-Cytokine & Growth Factor Reviews
TL;DR: This study reviews published data on alterations in the expression of different cytokines in patients with COVID-19 who require admission to an intensive care unit to support the design of more effective approaches to the management of CO VID-19.

769 citations

Cites background from "Transplantation of ACE2 - Mesenchym..."

  • ...Another possible therapeutic approach is to use MSCs to inhibit TNF-α and IL1α, among other cytokines [145]....

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  • ...MSCs inhibit the secretion of IL-12, as well as IFN-γ and TNF-α, and have been proposed as an effective therapy against COVID-19 [144,145]....

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  • ...Besides VEGF, MSCs can also secrete VEGF, among others, which would be useful in the approach to respiratory distress syndrome and in the regeneration of lung tissue and treatment of lung fibrosis induced by infections [145]....

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Journal Article•DOI•
Insights into SARS-CoV-2 genome, structure, evolution, pathogenesis and therapies: Structural genomics approach.

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Ahmad Abu Turab Naqvi1, Kisa Fatima1, Taj Mohammad1, Urooj Fatima2, Indrakant K. Singh3, Archana Singh3, Shaikh M. Atif4, Gururao Hariprasad5, Gulam Mustafa Hasan6, Imtaiyaz Hassan1 •
Jamia Millia Islamia1, Aligarh Muslim University2, University of Delhi3, University of Colorado Boulder4, All India Institute of Medical Sciences5, Salman bin Abdulaziz University6
01 Oct 2020-Biochimica et Biophysica Acta
TL;DR: The analysis suggests a minimal variation in the genome sequence of SARS-CoV-2, may be responsible for a drastic change in the structures of target proteins, makes available drugs ineffective.

723 citations

Cites background from "Transplantation of ACE2 - Mesenchym..."

  • ...[148] on patients with COVID-19, suggested that intravenous transplantation of MSCs into patients is effective in the treatment of COVID-19 with lesser side effects....

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Journal Article•DOI•
COVID-19: Transmission, prevention, and potential therapeutic opportunities.

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Melika Lotfi1, Michael R. Hamblin2, Nima Rezaei3, Nima Rezaei2•
Zanjan University of Medical Sciences1, Education and Research Network2, Tehran University of Medical Sciences3
01 Sep 2020-Clinica Chimica Acta
TL;DR: Current therapeutic options, preventive methods and transmission routes of COVID-19 are discussed and infection prevention, early viral detection and identification of successful treatment protocols provide the best approach in controlling disease spread.

603 citations

References
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Journal Article•DOI•
Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

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Chaolin Huang1, Yeming Wang2, Xingwang Li3, Lili Ren4, Jianping Zhao5, Yi Hu5, Li Zhang1, Guohui Fan2, Jiuyang Xu6, Xiaoying Gu2, Zhenshun Cheng7, Ting Yu1, Jia'an Xia1, Yuan Wei1, Wenjuan Wu1, Xuelei Xie1, Wen Yin5, Li Hui2, Min Liu2, Yan Xiao4, Hong Gao4, Li Guo4, Jungang Xie5, Guang-Fa Wang8, Rongmeng Jiang3, Zhancheng Gao8, Qi Jin4, Jianwei Wang4, Bin Cao2 •
Wuhan Jinyintan Hospital1, China-Japan Friendship Hospital2, Capital Medical University3, Peking Union Medical College4, Huazhong University of Science and Technology5, Tsinghua University6, Wuhan University7, Peking University8
24 Jan 2020-The Lancet
TL;DR: The epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of patients with laboratory-confirmed 2019-nCoV infection in Wuhan, China, were reported.

36,578 citations

"Transplantation of ACE2 - Mesenchym..." refers background or methods in this paper

  • ...As reported by Cao’s team [11], the levels of serum IL-2, IL-7, G-SCF, IP10, MCP-1, MIP-1A and TNF-α in ICU patients were higher than those of normal patients....

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  • ...However, the immunomodulatory capacity may be not strong enough, if only one or two immune factors were used, as the virus can stimulate a terrible cytokine storm in the lung, such as IL-2, IL-6, IL-7, GSCF, IP10, MCP1, MIP1A, and TNFα, followed by the edema, dysfunction of the air exchange, acute respiratory distress syndrome, acute cardiac injury and the secondary infection [11], which may lead to death....

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  • ...This explains why not only all infected ICU patients are suffering from acute respiratory distress syndrome, but also complications such as acute myocardial injury, arrhythmia, acute kidney injury, shock, and death from multiple organ dysfunction syndrome [11] (Fig....

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  • ...All enrolled patients were confirmed by the realtime reverse transcription polymerase chain reaction (RTPCR) assay of HCoV-19 RNA in Chinese Center for Disease Control and Prevention using the protocol as described previously [11,20]....

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Journal Article•DOI•
A pneumonia outbreak associated with a new coronavirus of probable bat origin

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Peng Zhou1, Xing-Lou Yang1, Xian Guang Wang2, Ben Hu1, Lei Zhang1, Wei Zhang1, Hao Rui Si1, Yan Zhu1, Bei Li1, Chao Lin Huang2, Hui-Dong Chen2, Jing Chen1, Yun Luo1, Hua Guo1, Ren Di Jiang1, Meiqin Liu1, Ying Chen1, Xu Rui Shen1, Xi Wang1, Xiao Shuang Zheng1, Kai Zhao1, Quanjiao Chen1, Fei Deng1, Lin Lin Liu3, Bing Yan1, Fa Xian Zhan3, Yan-Yi Wang1, Gengfu Xiao1, Zhengli Shi1 •
Chinese Academy of Sciences1, Wuhan Jinyintan Hospital2, Centers for Disease Control and Prevention3
03 Feb 2020-Nature
TL;DR: Identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China, and it is shown that this virus belongs to the species of SARSr-CoV, indicates that the virus is related to a bat coronav virus.
Abstract: Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats1–4. Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans5–7. Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor—angiotensin converting enzyme II (ACE2)—as SARS-CoV. Characterization of full-length genome sequences from patients infected with a new coronavirus (2019-nCoV) shows that the sequences are nearly identical and indicates that the virus is related to a bat coronavirus.

16,857 citations

"Transplantation of ACE2 - Mesenchym..." refers background in this paper

  • ...Several reports demonstrated that the first step of the HCoV-19 pathogenesis is that the virus specifically recognizes the angiotensin I converting enzyme 2 receptor (ACE2) by its spike protein [2-4]....

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Journal Article•DOI•
Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China.

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Dawei Wang1, Bo Hu1, Chang Hu1, Fangfang Zhu1, Xing Liu1, Jing Zhang1, Binbin Wang1, Hui Xiang1, Zhenshun Cheng1, Yong Xiong1, Yan Zhao1, Yirong Li1, Xinghuan Wang1, Zhiyong Peng1 •
Wuhan University1
17 Mar 2020-JAMA
TL;DR: The epidemiological and clinical characteristics of novel coronavirus (2019-nCoV)-infected pneumonia in Wuhan, China, and hospital-associated transmission as the presumed mechanism of infection for affected health professionals and hospitalized patients are described.
Abstract: Importance In December 2019, novel coronavirus (2019-nCoV)–infected pneumonia (NCIP) occurred in Wuhan, China. The number of cases has increased rapidly but information on the clinical characteristics of affected patients is limited. Objective To describe the epidemiological and clinical characteristics of NCIP. Design, Setting, and Participants Retrospective, single-center case series of the 138 consecutive hospitalized patients with confirmed NCIP at Zhongnan Hospital of Wuhan University in Wuhan, China, from January 1 to January 28, 2020; final date of follow-up was February 3, 2020. Exposures Documented NCIP. Main Outcomes and Measures Epidemiological, demographic, clinical, laboratory, radiological, and treatment data were collected and analyzed. Outcomes of critically ill patients and noncritically ill patients were compared. Presumed hospital-related transmission was suspected if a cluster of health professionals or hospitalized patients in the same wards became infected and a possible source of infection could be tracked. Results Of 138 hospitalized patients with NCIP, the median age was 56 years (interquartile range, 42-68; range, 22-92 years) and 75 (54.3%) were men. Hospital-associated transmission was suspected as the presumed mechanism of infection for affected health professionals (40 [29%]) and hospitalized patients (17 [12.3%]). Common symptoms included fever (136 [98.6%]), fatigue (96 [69.6%]), and dry cough (82 [59.4%]). Lymphopenia (lymphocyte count, 0.8 × 109/L [interquartile range {IQR}, 0.6-1.1]) occurred in 97 patients (70.3%), prolonged prothrombin time (13.0 seconds [IQR, 12.3-13.7]) in 80 patients (58%), and elevated lactate dehydrogenase (261 U/L [IQR, 182-403]) in 55 patients (39.9%). Chest computed tomographic scans showed bilateral patchy shadows or ground glass opacity in the lungs of all patients. Most patients received antiviral therapy (oseltamivir, 124 [89.9%]), and many received antibacterial therapy (moxifloxacin, 89 [64.4%]; ceftriaxone, 34 [24.6%]; azithromycin, 25 [18.1%]) and glucocorticoid therapy (62 [44.9%]). Thirty-six patients (26.1%) were transferred to the intensive care unit (ICU) because of complications, including acute respiratory distress syndrome (22 [61.1%]), arrhythmia (16 [44.4%]), and shock (11 [30.6%]). The median time from first symptom to dyspnea was 5.0 days, to hospital admission was 7.0 days, and to ARDS was 8.0 days. Patients treated in the ICU (n = 36), compared with patients not treated in the ICU (n = 102), were older (median age, 66 years vs 51 years), were more likely to have underlying comorbidities (26 [72.2%] vs 38 [37.3%]), and were more likely to have dyspnea (23 [63.9%] vs 20 [19.6%]), and anorexia (24 [66.7%] vs 31 [30.4%]). Of the 36 cases in the ICU, 4 (11.1%) received high-flow oxygen therapy, 15 (41.7%) received noninvasive ventilation, and 17 (47.2%) received invasive ventilation (4 were switched to extracorporeal membrane oxygenation). As of February 3, 47 patients (34.1%) were discharged and 6 died (overall mortality, 4.3%), but the remaining patients are still hospitalized. Among those discharged alive (n = 47), the median hospital stay was 10 days (IQR, 7.0-14.0). Conclusions and Relevance In this single-center case series of 138 hospitalized patients with confirmed NCIP in Wuhan, China, presumed hospital-related transmission of 2019-nCoV was suspected in 41% of patients, 26% of patients received ICU care, and mortality was 4.3%.

16,635 citations

"Transplantation of ACE2 - Mesenchym..." refers background or methods in this paper

  • ...When the overactivated immune system kills the virus, it produces a large number of inflammatory factors, leading to the severe cytokine storms [20]....

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  • ...Several reports also focused on lymphopenia and high levels of C-reactive protein in COVID-19 patients [20,21]....

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  • ...All enrolled patients were confirmed by the realtime reverse transcription polymerase chain reaction (RTPCR) assay of HCoV-19 RNA in Chinese Center for Disease Control and Prevention using the protocol as described previously [11,20]....

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Journal Article•DOI•
Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

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Nanshan Chen1, Min Zhou2, Xuan Dong1, Jie-Ming Qu2, Fengyun Gong1, Yang Han1, Yang Qiu3, Jingli Wang1, Ying Liu1, Yuan Wei1, Jia'an Xia1, Ting Yu1, Xinxin Zhang2, Li Zhang1 •
Wuhan Jinyintan Hospital1, Shanghai Jiao Tong University2, Chinese Academy of Sciences3
30 Jan 2020-The Lancet
TL;DR: Characteristics of patients who died were in line with the MuLBSTA score, an early warning model for predicting mortality in viral pneumonia, and further investigation is needed to explore the applicability of the Mu LBSTA scores in predicting the risk of mortality in 2019-nCoV infection.

16,282 citations

"Transplantation of ACE2 - Mesenchym..." refers background in this paper

  • ...Moreover, the HCoV-19 is more likely to affect older males with comorbidities and can result in severe and even fatal respiratory diseases such as acute respiratory distress syndrome [21], like the critically severe case here....

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  • ...Several reports also focused on lymphopenia and high levels of C-reactive protein in COVID-19 patients [20,21]....

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Journal Article•DOI•
Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding.

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Roujian Lu1, Xiang Zhao1, Juan Li2, Peihua Niu1, Bo Yang3, Honglong Wu, Wenling Wang1, Hao Song4, Baoying Huang1, Na Zhu1, Yuhai Bi4, Xuejun Ma1, Faxian Zhan3, Liang Wang4, Tao Hu2, Hong Zhou2, Zhenhong Hu, Weimin Zhou1, Li Zhao1, Jing Chen5, Yao Meng1, Ji Wang1, Yang Lin, Jianying Yuan, Zhihao Xie, Jinmin Ma, William J. Liu1, Dayan Wang1, Wenbo Xu1, Edward C. Holmes6, George F. Gao1, George F. Gao4, Guizhen Wu1, Weijun Chen, Weifeng Shi2, Wenjie Tan1, Wenjie Tan4 •
Chinese Center for Disease Control and Prevention1, Peking Union Medical College2, Centers for Disease Control and Prevention3, Chinese Academy of Sciences4, Wenzhou Medical College5, University of Sydney6
22 Feb 2020-The Lancet
TL;DR: The 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.

9,474 citations

"Transplantation of ACE2 - Mesenchym..." refers background in this paper

  • ...Several reports demonstrated that the first step of the HCoV-19 pathogenesis is that the virus specifically recognizes the angiotensin I converting enzyme 2 receptor (ACE2) by its spike protein [2-4]....

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  • ...Both the novel coronavirus and SARS-2003 could enter the host cell by binding the S protein on the viral surface to the ACE2 on the cell surface [3,5]....

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

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How to cure pneumonia in lungs due to Covid?

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