Reply to Kesici et al. and Zeng et al.: Blocking the virus and reducing the inflammatory damage in COVID-19.

We appreciate the constructive comments from Kesici et al. (1) and Zeng et al. (2), which mainly focus on the key points about the optimal procedure of convalescent plasma (CP) transfusion in severe coronavirus disease 2019 (COVID-19) therapy and about how to improve the effectiveness.

First of all, this study was a pilot trial and the aim was to investigate the safety of CP transfusion, which was defined as the primary endpoint (3). We nevertheless also explored the possible therapeutic benefits of CP by examining its effectiveness in neutralizing the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and in ameliorating clinical symptoms and paraclinical criteria in recipients. Indeed, the adverse effect was minor, whereas a quickly improved outcome of 10 severe COVID-19 patients was observed. There are of course a number of issues to be addressed, such as the confirmation of the clinical effectiveness in a phase II controlled, randomized trial.

Second, the objective for CP transfusion in severe COVID-19 therapy is based on an in-depth understanding of disease mechanisms. The pathogenesis of this epidemic involves the interaction between viral replication of SARS-CoV-2 and human immune response (4). Particularly, in severe or critical COVID-19 cases, lung alveolar macrophages or epithelial cells could produce various proinflammatory cytokines and chemokines, which recruit monocytes and neutrophils to the infection site to clear the virus particles and infected cells, resulting in uncontrolled inflammation. The uncontrolled virus infection leads to more macrophage infiltration and a further worsening of lung injury. Therefore, the key point of CP therapy is to neutralize the virus and to interrupt the vicious cycle of excessive activation of the immune response in severe patients. In our study, 200 mL CP containing neutralized antibody above 1:640 rapidly cleared the viremia and achieved clinical improvement. Considering the accessibility of plasma donors, using CP as replacement fluid for the therapeutic plasma exchange may be not feasible.

Third, the optimal treatment time and dose of CP need to be determined by the knowledge on viral proliferative kinetics. Zhou et al. (5) reported that the median viral shedding time was 20.0 d in survival patients. Huang et al. (6) observed that the viral load gradually decreased in the respiratory tract after 7 d of illness onset but can be detected after 28 d of illness onset in two-thirds of critically ill patients. Chen et al. (7) found the serum viremia was detected in 29.4% (5/17) critically ill patients and was significantly correlated with the level of interleukin-6. Thus, monitoring the dynamic changes of interleukin-6 level, which was significantly elevated in COVID-19, may help to determine the optimal treatment time, generally within 2 wk.

Finally, the optimal time for collecting CP should be determined by the time and level of total antibody production in convalescent patients. The presence of antibodies was <40% among patients within 1 wk since onset and rapidly increased to 100.0% (antibody), 94.3% (immunoglobulin M), and 79.8% (immunoglobulin G [IgG]) since day 15 after onset (8). Also, the neutralizing antibody titer was correlated with the IgG antibodies (9). The median duration of hospitalization for COVID-19 patients was 12.0 d (10). In our study, all of the donors were recovered from the common type of COVID-19. Therefore, the collection of CP from the convalescent patients may be 3 wk after the illness onset, and routine inactivation of plasma should be performed for elimination of potential existing virus. The optimal dose of CP can be calculated based on an empirical formula: volume (liters) = weight of the recipient (kilograms) × the antibody titer of CP.