LETTER

REPLY TO KESICI ET AL. AND ZENG ET AL.: Blocking the virus and reducing the inflammatory LETTER damage in COVID-19 Kai Duana,b,1, Bende Liuc,1, Cesheng Lid,1, Huajun Zhange,1, Ting Yuf,1, Jieming Qug,h,i,1, Min Zhoug,h,i,1, Li Chenj,1, Zhu Chenk,2, Xinxin Zhangl,2, and Xiaoming Yanga,b,2

We appreciate the constructive comments from Kesici macrophage infiltration and a further worsening of et al. (1) and Zeng et al. (2), which mainly focus on the lung injury. Therefore, the key point of CP therapy is key points about the optimal procedure of convales- to neutralize the virus and to interrupt the vicious cycle cent plasma (CP) transfusion in severe coronavirus dis- of excessive activation of the immune response in se- ease 2019 (COVID-19) therapy and about how to vere patients. In our study, 200 mL CP containing neu- improve the effectiveness. tralized antibody above 1:640 rapidly cleared the First of all, this study was a pilot trial and the aim viremia and achieved clinical improvement. Consider- was to investigate the safety of CP transfusion, which ing the accessibility of plasma donors, using CP as was defined as the primary endpoint (3). We neverthe- replacement fluid for the therapeutic plasma ex- less also explored the possible therapeutic benefits of change may be not feasible. CP by examining its effectiveness in neutralizing the Third, the optimal treatment time and dose of CP severe acute respiratory syndrome coronavirus 2 need to be determined by the knowledge on viral (SARS-CoV-2) and in ameliorating clinical symptoms proliferative kinetics. Zhou et al. (5) reported that the and paraclinical criteria in recipients. Indeed, the ad- median viral shedding time was 20.0 d in survival pa- verse effect was minor, whereas a quickly improved tients. Huang et al. (6) observed that the viral load outcome of 10 severe COVID-19 patients was ob- gradually decreased in the respiratory tract after 7 d served. There are of course a number of issues to be of illness onset but can be detected after 28 d of ill- addressed, such as the confirmation of the clinical ef- ness onset in two-thirds of critically ill patients. Chen fectiveness in a phase II controlled, randomized trial. et al. (7) found the serum viremia was detected in Second, the objective for CP transfusion in severe 29.4% (5/17) critically ill patients and was significantly COVID-19 therapy is based on an in-depth under- correlated with the level of interleukin-6. Thus, moni- standing of disease mechanisms. The pathogenesis of toring the dynamic changes of interleukin-6 level, this epidemic involves the interaction between viral which was significantly elevated in COVID-19, may replication of SARS-CoV-2 and human immune re- help to determine the optimal treatment time, gener- sponse (4). Particularly, in severe or critical COVID- ally within 2 wk. 19 cases, lung alveolar macrophages or epithelial cells Finally, the optimal time for collecting CP should could produce various proinflammatory cytokines and be determined by the time and level of total antibody chemokines, which recruit monocytes and neutrophils production in convalescent patients. The presence of to the infection site to clear the virus particles and antibodies was <40% among patients within 1 wk since infected cells, resulting in uncontrolled inflammation. onset and rapidly increased to 100.0% (antibody), The uncontrolled virus infection leads to more 94.3% (immunoglobulin M), and 79.8% (immunoglobulin

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; kState 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; and lResearch 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 Author contributions: Z.C., X.Z., and X.Y. designed research; and K.D., B.L., C.L., H.Z., T.Y., J.Q., M.Z., and L.C. wrote the paper. The authors declare no competing interest. Published under the PNAS license. 1K.D., B.L., C.L., H.Z., T.Y., J.Q., M.Z., and L.C. contributed equally to this work. 2To whom correspondence may be addressed. Email: [email protected], [email protected], or [email protected].

www.pnas.org/cgi/doi/10.1073/pnas.2007408117 PNAS Latest Articles | 1of2 Downloaded by guest on September 25, 2021 G [IgG]) since day 15 after onset (8). Also, the neutralizing anti- convalescent patients may be 3 wk after the illness onset, and body titer was correlated with the IgG antibodies (9). The median routine inactivation of plasma should be performed for elimina- duration of hospitalization for COVID-19 patients was 12.0 d (10). tion of potential existing virus. The optimal dose of CP can be In our study, all of the donors were recovered from the common calculated based on an empirical formula: volume (liters) = weight type of COVID-19. Therefore, the collection of CP from the of the recipient (kilograms) × the antibody titer of CP.

1 S. Kesici, S. Yavuz, B. Bayrakci, Get rid of the bad first: Therapeutic plasma exchange with convalescent plasma for severe COVID-19. Proc. Natl. Acad. Sci. U.S.A., 10.1073/pnas.2006691117 (2020). 2 F. Zeng, X. Chen, G. Deng, Convalescent plasma for patients with COVID-19. Proc. Natl. Acad. Sci. U.S.A., 10.1073/pnas.2006961117 (2020). 3 K. Duan et al., Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc. Natl. Acad. Sci. U.S.A. 117, 9490–9496 (2020). 4 H. Li et al., SARS-CoV-2 and viral sepsis: Observations and hypotheses. Lancet, 10.1016/S0140-6736(20)30920-X (2020). 5 F. Zhou et al., Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study. Lancet 395, 1054–1062 (2020). 6 Y. Huang et al., SARS-CoV-2 viral load in clinical samples of critically ill patients. Am. J. Respir. Crit. Care Med., 10.1164/rccm.202003-0572LE (2020). 7 X. Chen et al., Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely correlated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients. Clin. Infect. Dis., 10.1093/cid/ciaa449 (2020). 8 J. Zhao et al., Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019. Clin. Infect. Dis., 10.1093/cid/ciaa344 (2020). 9 K. K. To et al., Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: An observational cohort study. Lancet Infect. Dis., 10.1016/S1473-3099(20)30196-1 (2020). 10 W. J. Guan et al.; China Medical Treatment Expert Group for Covid-19, Clinical characteristics of coronavirus disease 2019 in China. N. Engl. J. Med., 10.1056/ NEJMoa2002032 (2020).

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