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      Effectiveness of convalescent plasma therapy in severe COVID-19 patients

      a , b , c , d , e , f , g , h , i , g , h , i , j , b , d , e , k , l , b , d , e , k , m , b , b , d , e , g , h , i , b , d , b , d , g , h , i , b , d , b , d , b , d , b , d , d , d , d , a , a , a , n , e , l , l , 2 , m , 2 , a , b , 2

      Proceedings of the National Academy of Sciences of the United States of America

      National Academy of Sciences

      COVID-19, convalescent plasma, treatment outcome, pilot project

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          COVID-19 is currently a big threat to global health. However, no specific antiviral agents are available for its treatment. In this work, we explore the feasibility of convalescent plasma (CP) transfusion to rescue severe patients. The results from 10 severe adult cases showed that one dose (200 mL) of CP was well tolerated and could significantly increase or maintain the neutralizing antibodies at a high level, leading to disappearance of viremia in 7 d. Meanwhile, clinical symptoms and paraclinical criteria rapidly improved within 3 d. Radiological examination showed varying degrees of absorption of lung lesions within 7 d. These results indicate that CP can serve as a promising rescue option for severe COVID-19, while the randomized trial is warranted.


          Currently, there are no approved specific antiviral agents for novel coronavirus disease 2019 (COVID-19). In this study, 10 severe patients confirmed by real-time viral RNA test were enrolled prospectively. One dose of 200 mL of convalescent plasma (CP) derived from recently recovered donors with the neutralizing antibody titers above 1:640 was transfused to the patients as an addition to maximal supportive care and antiviral agents. The primary endpoint was the safety of CP transfusion. The second endpoints were the improvement of clinical symptoms and laboratory parameters within 3 d after CP transfusion. The median time from onset of illness to CP transfusion was 16.5 d. After CP transfusion, the level of neutralizing antibody increased rapidly up to 1:640 in five cases, while that of the other four cases maintained at a high level (1:640). The clinical symptoms were significantly improved along with increase of oxyhemoglobin saturation within 3 d. Several parameters tended to improve as compared to pretransfusion, including increased lymphocyte counts (0.65 × 10 9/L vs. 0.76 × 10 9/L) and decreased C-reactive protein (55.98 mg/L vs. 18.13 mg/L). Radiological examinations showed varying degrees of absorption of lung lesions within 7 d. The viral load was undetectable after transfusion in seven patients who had previous viremia. No severe adverse effects were observed. This study showed CP therapy was well tolerated and could potentially improve the clinical outcomes through neutralizing viremia in severe COVID-19 cases. The optimal dose and time point, as well as the clinical benefit of CP therapy, needs further investigation in larger well-controlled trials.

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          Most cited references 9

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          Experience of using convalescent plasma for severe acute respiratory syndrome among healthcare workers in a Taiwan hospital

          Abstract Objectives: To describe the immunological responses and clinical outcome of coronavirus (SARS) infected healthcare workers (HCW) who had been administered with convalescent plasma as a treatment. Methods: Convalescent plasma (500 mL) was obtained from each of three SARS patients and transfused into the three infected HCW. Donors were blood type O and seronegative for hepatitis B and C, HIV, syphilis and human T-cell lymphotropic virus types I and II (HTLV-I and -II). Serum antibody (IgG) titre was >640. Apharesis was performed with a CS 3000 plus cell separator followed by the forming of the convalescent phase plasma. As part of the routine check with donated plasma, the convalescent plasma was confirmed free of residual SARS-CoV by RT–PCR. Serial serum samples obtained from the recipients of the convalescent plasma were collected to undertake real-time quantitative RT–PCR for SARS-CoV for direct measurement of viral concentration. Specific immunoglobulin IgM and IgG concentrations were titrated using an antigen microarray developed in-house. Results: Viral load dropped from 495 × 103, 76 × 103 or 650 × 103 copies/mL to zero or 1 copy/mL one day after transfusion. Anti-SARS-CoV IgM and IgG also increased in a time-dependent manner following transfusion. All three patients survived. One HCW became pregnant subsequently, delivering 13 months after discharge. Positive anti-SARS-CoV IgG was detected in the newborn. Passive transfer of anti-SARS-CoV antibody from the mother was considered as a possibility. Conclusions: All infected HCW whose condition had progressed severely and who had failed to respond to the available treatment, survived after transfusion with convalescent plasma.
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            Feasibility of Using Convalescent Plasma Immunotherapy for MERS-CoV Infection, Saudi Arabia

            Efficacy testing will be challenging because of the small pool of donors with sufficiently high antibody titers.
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              Dengue Antibody-Dependent Enhancement: Knowns and Unknowns.

              Dengue provides the most abundant example in human medicine and the greatest human illness burden caused by the phenomenon of intrinsic antibody-dependent infection enhancement (iADE). In this immunopathological phenomenon infection of monocytes or macrophages using infectious immune complexes suppresses innate antiviral systems, permitting logarithmic intracellular growth of dengue virus. The four dengue viruses evolved from a common ancestor yet retain similar ecology and pathogenicity, but although infection with one virus provides short-term cross-protection against infection with a different type, millions of secondary dengue infections occur worldwide each year. When individuals are infected in the virtual absence of cross-protective dengue antibodies, the dengue vascular permeability syndrome (DVPS) may ensue. This occurs in around 2 to 4% of second heterotypic dengue infections. A complete understanding of the biologic mechanism of iADE, dengue biology, and the mechanism of host responses to dengue infection should lead to a comprehensive and complete understanding of the pathogenesis of DVPS. A crucial emphasis must be placed on understanding ADE. Clinical and epidemiological observations of DVPS define the research questions and provide research parameters. This article will review knowledge related to dengue ADE and point to areas where there has been little research progress. These observations relate to the two stages of dengue illnesses: afferent phenomena are those that promote the success of the microorganism to infect and survive; efferent phenomena are those mounted by the host to inhibit infection and replication and to eliminate the infectious agent and infected tissues. Data will be discussed as "knowns" and "unknowns."

                Author and article information

                Proc Natl Acad Sci U S A
                Proc. Natl. Acad. Sci. U.S.A
                Proceedings of the National Academy of Sciences of the United States of America
                National Academy of Sciences
                28 April 2020
                6 April 2020
                6 April 2020
                : 117
                : 17
                : 9490-9496
                aChina National Biotec Group Company Limited , 100029 Beijing, China;
                bNational Engineering Technology Research Center for Combined Vaccines, Wuhan Institute of Biological Products Co. Ltd. , 430207 Wuhan, China;
                cFirst People’s Hospital of Jiangxia District , 430200 Wuhan, China;
                dSinopharm Wuhan Plasma-derived Biotherapies Co., Ltd , 430207 Wuhan, China;
                eKey Laboratory of Special Pathogens, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences , 430071 Wuhan, China;
                fWuHan Jinyintan Hospital , 430023 Wuhan, China;
                gDepartment of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine , 200025 Shanghai, China;
                hNational Research Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine , 200025 Shanghai, China;
                iInstitute of Respiratory Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine , 200025 Shanghai, China;
                jClinical Research Center, Department of Gastroenterology, Ruijin Hospital North, Shanghai Jiao Tong University School of Medicine , 200018 Shanghai, China;
                kWuhan Blood Center , 430030 Wuhan, China;
                lState Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine , 200025 Shanghai, China;
                mResearch Laboratory of Clinical Virology, Ruijin Hospital and Ruijin Hospital North, National Research Center for Translational Medicine, Shanghai Jiao Tong University School of Medicine , 200025 Shanghai, China;
                nNational Institute for Food and Drug Control of China , 102629 Beijing, China
                Author notes
                2To whom correspondence may be addressed. Email: zchen@ , zhangx@ , or yangxiaoming@ .

                Contributed by Zhu Chen, March 18, 2020 (sent for review March 5, 2020; reviewed by W. Ian Lipkin and Fusheng Wang)

                Author contributions: Z.C., X. Zhang, and X. Yang designed research; S.M., Yong Hu, C.P., M.Y., Z.W., J.Y., X.G., D.W., L. Li, J.Z., X.W., B. Li, W.C., Y.P., Yeqin Hu, L. Lin, S.H., Z. Zhou, L.Z., Y.W., Z. Zhang, K. Deng, Z.X., Q.G., W.Z., X. Zheng, Y.L., H.Y., D.Z., D.Y., J. Hou, and Z.S. performed research; J. Huang, X. Yu, Y.X., X.L., S.C., and Z.C. analyzed data; and K. Duan, B. Liu, C.L., H.Z., T.Y., J.Q., M.Z., L.C., and Z.C. wrote the paper.

                Reviewers: W.I.L., Columbia University; and F.W., Beijing 302 Hospital.

                1K. Duan, B. Liu, C.L., H.Z., T.Y., J.Q., M.Z., and L.C. contributed equally to this work.

                Copyright © 2020 the Author(s). Published by PNAS.

                This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).

                Page count
                Pages: 7
                Funded by: Key Project of Ministry of Science and Technology of China
                Award ID: 2020YFC0841800
                Award Recipient : Xiaoming Yang
                Biological Sciences
                Medical Sciences
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