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Effect of Convalescent Plasma Therapy on Viral Shedding and Survival in COVID-19 Patients
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Qing-Lei Zeng,1, Zu-Jiang Yu,1, Jian-Jun Gou,1, Guang-Ming Li,2, Shu-Huan Ma,2, Guo-Fan Zhang,3 Jiang-Hai Xu,4 Wan-Bao Lin,5 Guang-Lin Cui,6 Min-Min Zhang,2 Cheng Li,2 Ze-Shuai Wang,7 Zhi-Hao Zhang,1 Zhang-Suo Liu1
Abstract
Currently, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease 2019 (COVID-19) has been reported in almost all countries globally, and no effective therapy has been documented for COVID-19 and the role of convalescent plasma therapy is unknown. In current study, 6 COVID-19 subjects with respiratory failure received convalescent plasma at a median of 21.5 days after first detection of viral shedding, all tested negative for SARS-CoV-2 RNA by 3 days after infusion, and 5 died eventually. In conclusion, convalescent plasma treatment can discontinue SARS-CoV-2 shedding but cannot reduce mortality in critically end-stage COVID-19 patients, and treatment should be initiated earlier.
RESULTS
Patients Characteristics
A total of 21 contemporaneously critical COVID-19 patients were enrolled in current study (Table 1), all patients required intensive care unit admission. Of them, 6 patients received convalescent plasma treatment based on the limited convalescent plasma availability and ABO compatibility. There are 5 and 11 male patients in convalescent plasma treatment group and non-convalescent plasma treatment (control) group, respectively. The median ages were 61.5 and 73 years respectively. The treatment group and control group had the comparable characteristics, clinical parameters, and management strategies (Table 1).
Safety and Efficacy of Convalescent Plasma Treatment
The median volume of plasma infused was 300 ml (Table 2). No immediate and noticeable adverse effects were observed with convalescent plasma infusions. The mortality in the treatment group was 5/6 and in the control group was 14/15 (p = 0.184). Each group had one recovered patient, respectively. All the 6 patients in treatment group obtained viral clearance after convalescent plasma transfusions, and 100% (5/5) and 21.4% (3/14) of fatal patients had undetectable SARS-CoV-2 before death in treatment and control groups, respectively (p = 0.005). Additionally, the survival period of treatment group was longer than control group (p = 0.029).
First Patient Received Convalescent Plasma Therapy in Henan Province
In Henan Province, the first available convalescent plasma was transfused for a 30 years postpartum woman on February 19, 2020 (Supplementary Figure 1). She was engaged in beef and mutton selling business in Wuhan and came to Henan Province at 29 gestational weeks plus 3 days on January 21, 2020, and initiated the illness with fever and dry cough on January 24. Then, she visited the hospital for testing and management, her SARS-CoV-2 was first detectable from January 28. On February 2, she had the caesarean section because of fetal destress, fortunately, the premature newborn was living and negative for SARS-CoV-2 for one month after birth.
Meantime and unfortunately, her bilateral pneumonia were gradually severe from the onset of illness (Supplementary Figure 2), and respiratory failure was diagnosed and invasive mechanical ventilation was required from February 9, and extracorporeal membrane oxygenation was needed from February 10. On February 19 and 21, she was received 400 ml and 200 ml of convalescent plasma transfusions, respectively. Notably, previously detectable SARS-CoV-2 was undetectable from February 21 to eventual fatality on March 6, 2020.
DISCUSSION
Recent study indicated that SARS-CoV-2 was detectable until death in non-survivors [14], and whether undetectable SARS-CoV-2 before death can regress fatalities is unknown. In current study, to the best of our knowledge, we firstly indicate that the convalescent plasma treatment contributes to the discontinuation of SARS-CoV-2 shedding and longer survival duration in COVID-19 patients with respiratory failure; however, it cannot reduce the mortality in critically end-stage COVID-19 patients.
As the neighbor Province of Hubei and nearest outside Province of Wuhan City, Henan Province was affected by the SARS-CoV-2 infection severely. It is known that Henan Province had the third largest number of COVID-19 patients and second largest number of fatal patients in China [15]. However, in mid-February, 2020, the epidemic was closing to the end, therefore, the enrolled patients were the most critical and last series of COVID-19 cases in Henan Province.
Commonly, viraemia peaks in the first week after infection in most acute viral diseases, and patient usually develops a primary immune response by day 10 to 14, which is followed by virus clearance [8]. In the third week, and clinical deterioration is occurred to be the result of inflammatory or hyperimmune attacks rather than direct viral-induced tissue damage [8, 14, 16]. Hence, convalescent plasma should theoretically be more effective when given in the early course of disease (i.e., before day 14, or during the viremic and seronegative stage) [8]. The failure of reduce the mortality may be attributed to the late transfusion of convalescent plasma, which were given on median day 21.5 during viral shedding. On the contrary, one critical patient in treatment group infused on day 11 during viral shedding was finally recovered.
Based on the current findings, the convalescent plasma treatment should be given to the COVD-19 patients with right phase or severity at the right timepoint. It is known that most mild COVD-19 patients can be self-recovered, and convalescent plasma may be improper therapy for them. And for end-stage COVD-19 patients, the convalescent plasma treatment may unable to regress the poor outcome as demonstrated by current study. Hence, the convalescent plasma treatment should probably
be used in potentially critical COVD-19 patients at their early stage. Thus, the early recognition of the COVD-19 patients who would subsequently and potentially develop to critically illness is the key question before the convalescent plasma treatment.
Our study has several limitations. First, limited number of patients. It is important to note that the COVID-19 outbreak was nearly finished outside Wuhan in China at the convalescent plasma available date, i.e., February 19 in Henan Province. Then, the vast majority of patients were discharged and new cases were few, and these 21 patients were almost all the critically ill cases at that moment. Conversely, mild patients did not need plasma. Second, the amounts of viral antibodies given to each patient was unknown and not standardized, which may lead to different clinical outcomes. Nevertheless, all plasma receiving patients underwent viral clearance after transfusions. Third, it was not randomized. However, the limited plasma availability, timeliness, ABO compatibility resulted in almost only one suitable patient existed at each certain circumstance. Last, the SARS-CoV-2 RNA was not quantitated because of the technic limitation of testing.
In conclusion, the current study firstly suggests that convalescent plasma therapy can discontinue the viral shedding and contribute longer survival duration in COVID-19 patients with respiratory failure, although it cannot reduce the mortality in critically end-stage patients. Additionally, we suggest that convalescent plasma treatment should be infused for potentially critical COVD-19 patients at their early phase based on the current study. Future large-scale studies are needed to investigate whether early phase infusion of convalescent plasma in proper receiving populations can prevent clinical deterioration and improve survival rate.
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