key: cord-0905352-u7cz1d8p authors: Chen, S.; Lu, C.; Li, P.; Wang, L.; Wang, H.; Yang, Q.; Chen, L.; Li, J.; Ma, H.; Sang, Q.; Xu, L.; Song, X.; Li, F.; Zhang, Y.; Kang, Y.; Xing, L.; Zhang, G. title: Effectiveness of Convalescent Plasma for Treatment of COVID-19 Patients date: 2020-08-04 journal: nan DOI: 10.1101/2020.08.02.20166710 sha: b2ed2ea45bc12733d8087b6ebba001093cbfac05 doc_id: 905352 cord_uid: u7cz1d8p Background and objective: The outbreak of COVID-19 has become a global health concern. In this study, we evaluate the effectiveness and safety of convalescent plasma therapy in patients with severe and critically ill COVID-19. Methods: Sixteen COVID-19 patients received transfusion of anti-COVID-19 antibody-positive convalescent plasma. The main outcome was time for viral nucleic acid amplification (NAA) test turning negative. Clinical laboratory parameters were measured at the baseline (d0) before plasma transfusion, and day 1 (d1), day 3 (d3) after transfusion as well. Results: Among the 16 patients, 10 of them had a consistently positive result of viral NAA test before convalescent plasma transfusion. Eight patients (8/10) became negative from day 2 to day 8 after transfusion. Severe patients showed a shorter time for NAA test turning negative after transfusion (mean rank 2.17 vs 5.90, P = 0.036). Two critically ill patients transfused plasma with lower antibody level remained a positive result of NAA test. CRP level demonstrated a decline 1 day after convalescent plasma treatment, compared with the baseline (P = 0.017). No adverse events were observed during convalescent plasma transfusion. Conclusions: Viral NAA test of most patients with COVID-19 who received convalescent plasma transfusion turned negative on the 2nd to 8th days after transfusion, and the negative time of severe patients was shorter than that of critically ill patients. An outbreak of viral pneumonia has been reported in Wuhan City, Hubei Province, P. R. China since December 2019. The disease was subsequently confirmed to be an infectious disease caused by a novel coronavirus infection which is now named as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 1 , and WHO names the disease induced by SARS-CoV-2 as coronavirus disease 2019 (COVID-19) 2 . COVID-19 has spread rapidly globally [3] [4] [5] [6] and a total of 82,880 confirmed cases and 4,633 deaths were reported in China before May 3, 2020, with a fatality rate of 5.59% 7 . A retrospective study of 52 critically ill COVID-19 patients in Wuhan Jin Yin-tan Hospital showed that mortality rate of critically ill cases was as high as 51·2% (32/52) 8 There are currently no specific antiviral drugs for COVID-19, the clinical effects of some drugs such as lopinavir/ritonavir, chloroquine phosphate, and abidol still need further validation in clinical trials although they have been included in the guideline published by National Health Commission of P. R. China 9, 10 . Convalescent plasma transfusion has been used for clinical treatment of acute viral infectious diseases for a long time, and it has been used in the Spanish influenza pneumonia more than 100 years ago. A meta-analysis shows that patients with Spanish influenza pneumonia transfusion with influenza-convalescent human blood products reduced the risk for . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted August 4, 2020. . death 11 . Moreover, convalescent plasma has also been used in the treatment of severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), H1N1 influenza, and Ebola disease [12] [13] [14] [15] . The 4th edition of COVID-19 and the later updated clinical diagnosis and treatment scheme by National Health Commission of P. R. China also mentioned that convalescent plasma transfusion can be recommended to treat severe and critically ill patients under the symptomatic treatment, respiratory support, and circulatory support treatment 10, 16, 17 . In this study, we analyzed 16 patients diagnosed as COVID-19 who received convalescent plasma in the First Affiliated Hospital of Zhengzhou University and Henan Provincial People's Hospital to evaluate the safety and effectiveness of convalescent plasma in COVID-19. This case series study was approved by the Ethics Committee of Scientific Research and Clinical Trials of the First Affiliated Hospital of Zhengzhou University and the Henan Provincial People's Hospital, respectively. The approval number is 2020-KY-060. Patients diagnosed as COVID-19 by the SARS-CoV-2 nucleic acid amplification (NAA) test were given the convalescent plasma treatment if they fulfilled the following criteria: Rapidly progressed, severe or critically ill patient 10 , with a written informed consent given by the patient or next-of-kin. Patients were excluded if they were hypersensitive to plasma or plasma products, were known to have immunoglobulin A deficiency. Patients received a transfusion of convalescent . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted August 4, 2020. . https://doi.org/10.1101/2020.08.02.20166710 doi: medRxiv preprint plasma according to the ABO-compatible principle, 200-400 mL convalescent plasma was transfused each time, and could be repeated transfused 2-3 times if necessary. Adverse events were closely observed during transfusion. Conventional treatment including supportive treatment, antiviral treatment, antibacterial treatment, traditional Chinese medicine treatment, and respiratory circulation support treatment, etc. were carried out according to the clinical diagnosis and treatment scheme of COVID-19 10 . The primary outcome is the time for viral NAA test turning negative (two consecutive negative tests for viral nucleic acid with an interval time not less than 24 hours) after convalescent plasma transfusion. Laboratory parameters at baseline (d0), one day (d1), and three days (d3) after transfusion were recorded, including white blood cell (WBC) counts, neutrophil (NEU) counts, lymphocyte (LYM) counts, C-reactive protein (CRP), procalcitonin (PCT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), Lactate dehydrogenase (LDH), creatine kinase (CK), creatine kinase isoenzyme (CKMB), hypersensitive troponin T (cTnT), and lactic acid (Lac). The ratios of d1/d0, and d3/d0 were calculated to describe the change. Clinical information such as invasive ventilation, application of extracorporeal membrane oxygenation (ECMO), comorbidities were also recorded. All plasma donors has diagnosed as COVID-19 by NAA test and recovered from infection, continued the quarantine for 2 weeks after discharge. The donors should also meet the following criteria: recovered patients aged 18-55 years old, with the weight more than 50Kg for males and 45Kg for females, no blood-borne diseases, . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 4, 2020. . assessed by a clinician to be able to donate plasma, and gave a written informed consent by the donor. The apheresis plasma machine was used to collect the plasma of donors at Henan Red Cross Blood Center (Zhengzhou, China). After the plasma was collected, pathogens were detected and the plasma was stored by the blood station in accordance with the relevant operating procedures. Qualified samples will be sent to the medical institution for detection of plasma antibody level using the method of magnetic particle chemiluminescence. All data were tested for distribution of normality. Data met the normal distribution were expressed as mean ± standard deviation, and compared using the t test. Data did not meet the normal distribution were expressed as median (minimum, maximum value), and compared using a non-parametric test (Wilcoxon or Mann-Whitney U test). SPSS (version 21.0; SPSS) was used for statistical computation. A P value of 0.05 was considered to represent significant difference. A total of 16 patients, including 5 female and 11 male patients, received convalescent plasma treatment ( Table 1) . Patients were aged 30-90 years , with an average age of (65 ± 19) years. Among the enrolled patients, 5 of them (31.25%, 5/16) were in a severe illness, and 11 (68.75%, 11/16) were critically illness; 62.50% (10/16) of the patients had comorbidities; the rates of invasive ventilation and use of extracorporeal membrane oxygenation (ECMO) in critically ill patients were 90.91% (10/11) and 45.46% (5/11) respectively. The convalescent plasma transfusion in this study started on the 12th to 36th days of the onset of symptoms, with an average (23 ± 7) days. The . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 4, 2020. . The convalescent plasma antibody level in this study was ranged from 10.93 to 114.7 AU/mL, with an average value of (56.44 ± 39.4) AU/mL. The average plasma antibody level and accumulated dose of antibody before NAA turned negative were calculated ( Table 2 ). In 10 severe and critically ill patients, plasma antibody level and accumulated dose showed a similar trend, and the median antibody level of the two consistently positive patients was the lowest (Figure 1A, 1B) . We then excluded 3 severe patients due to the differences in the time of viral NAA test turning negative between severe and critically ill patients. In 7 critically ill patients, a possible correlation trend was observed between the median plasma antibody level (or accumulated dose) and time of viral NAA test turning negative after convalescent . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 4, 2020. . https://doi.org/10.1101/2020.08.02.20166710 doi: medRxiv preprint plasma application (Figure 1C, 1D) . However, this trend was not sufficient to be statistically significant due to the limitation of the number of enrolled patients. For laboratory parameters (Table 3, 4) , CRP level demonstrated a decline 1 day after convalescent plasma treatment with the median ratio of 0.63, compared with the baseline (Figure 2 , 3 P = 0.017). WBC (P=0.014) and NEU ratio (P=0.009) at d1/d0 also showed a decline. No significance was found in the ratio of d3/d0 (Table S1, S2 in appendix; P＞0.05). No adverse events were found during convalescent plasma transfusion in 16 patients. This study analyzed and summarized the basic characteristics and laboratory parameters of patients with convalescent plasma transfusion in provincial medical institutions in Henan province, China. More than 1,000 COVID-19 patients have been diagnosed in the area. Not only in China, COVID-19 epidemic has become an international public concern and affected more than 90,000 people worldwide 18, 19 . We preliminary evaluated some of the effectiveness and safety of convalescent plasma treatment. Shortening viral carrying time is particularly important for the treatment and control of COVID-19. In our study, time for viral NAA test negation is an important observational parameter for evaluating the effectiveness of convalescent plasma in this study. We found that the time of viral negativity was 2-8 days after transfusion for most enrolled patients (8/10), in addition, this time was even shorter in severe patients than in critically ill patients. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 4, 2020. In addition to the early application of convalescent plasma therapy, concentration of antibody in convalescent plasma may be another factor closely associated with effectiveness. Two patients died with a persistently positive viral NAA test after plasma transfusion in the study, the plasma (200 mL for each) they transfused came from a same donor with an low antibody concentration of 16.79 AU/mL. Our small sample study found that there may be a correlation between the plasma antibody concentration and the time for viral turning negative in critically ill patients, patients transfused plasma with a higher antibody level may have a shorter time for viral test negation. In the above-mentioned paper, convalescent plasma treatment showed a . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 4, 2020. . https://doi.org/10.1101/2020.08.02.20166710 doi: medRxiv preprint negative conclusion in Ebola disease, we noticed the researchers did not detect and screen the antibody level in the plasma 13 None. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 4, 2020. . https://doi.org/10.1101/2020.08.02.20166710 doi: medRxiv preprint with baseline (day 0, d0). Data were expressed as box and whiskers (minimum to maximum). * represents a significant difference of P＜0.05. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 4, 2020. . https://doi.org/10.1101/2020.08.02.20166710 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted August 4, 2020. . https://doi.org/10.1101/2020.08.02.20166710 doi: medRxiv preprint Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2 Coronavirus disease (COVID-19) outbreak. World Health Organization Singapore Novel Coronavirus Outbreak Research Team. Epidemiologic Features and Clinical Course of Patients Infected With SARS-CoV-2 in Update: Public Health Response to the Coronavirus Disease Outbreak -United States Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding China Novel Coronavirus I, Research T. A Novel Coronavirus from Patients with Pneumonia in China Update on the epidemic situation of coronavirus disease Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study Efficacies of lopinavir/ritonavir and abidol in the treatment of novel coronavirus pneumonia The National Health and Health Commission of P. R. China. Clinical diagnosis and treatment scheme of novel coronavirus infected pneumonia (the 6th trial version) Meta-analysis: convalescent blood products for Spanish influenza pneumonia: a future H5N1 treatment? The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis Evaluation of Convalescent Plasma for Ebola Virus Disease in Guinea Retrospective comparison of convalescent plasma with continuing high-dose methylprednisolone treatment in SARS patients Feasibility, safety, clinical, and laboratory effects of convalescent plasma therapy for patients with Middle East respiratory syndrome coronavirus infection: a study protocol The National Health and Health Commission of P. R. China. Clinical diagnosis and treatment scheme of novel coronavirus infected pneumonia (the 4th trial version) The National Health and Health Commission of P. R. China. Clinical treatment plan of convalescent plasma of recovered patients in novel coronavirus pneumonia A Novel Coronavirus (COVID-19) Outbreak: A Call for Action A novel coronavirus outbreak of global health concern Prediction model for pneumonia in primary care patients with an acute respiratory tract infection: role of symptoms, signs, and biomarkers C-reactive protein as a potential biomarker for disease progression in dengue: a multi-country observational study Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A(H1N1) infection