Comment on: Nature and Dimensions of the Systemic Hyper-Inflammation and its Attenuation by Convalescent Plasma in Severe COVID-19

TO THE EDITOR—We read with great interest the article by Bandopadhyay et al [1], in which the effects of convalescent plasma (CP) on the inflammatory response in coronavirus disease 2019 (COVID-19) were evaluated. The authors reported that transfusion of CP was associated with a reduction of interleukin (IL) 6, interferon (IFN)–induced protein 10, and macrophage colony-stimulating factor. In addition, they showed that, compared with standard therapy, CP was associated with a rapid but transient improvement in the ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen. Although these results are of interest, we would like to emphasize some points.

We recently conducted an immunological study evaluating the effects of CP on cytokines and lymphocyte populations in 28-day follow-up [2]. We found that CP induces an early but transient effect on the antibody (ie, at 4 days after transfusion) and cytokine (at 4–7 days) profile of patients with severe disease, attenuates the exhausted phenotype, and increases memory T and B lymphocytes at day 28 after transfusion, together with a reduction in IL-6/IFN-γ and IL-6/IL-10 ratios (at 14–28 days). These results differ from those of Bandopadhyay et al [1], who observed an early decrease in inflammatory cytokines (IL-6, IFN- induced protein 10, and macrophage colony-stimulating factor) 3–4 days after transfusion. From 4 to 7 days after transfusion, we observed an increase in IFN-γ, granulocyte-macrophage colony-stimulating factor, IL-8, tumor necrosis factor α, and IL-17A but a late reduction in IL-6/IFN-γ and IL-6/IL-10 ratios, indicating that CP effects may take longer but modify parameters that have been previously associated with COVID-19 mortality rates and severity [3].

Bandopadhyay et al [1] state that the anti-inflammatory role of CP is independent of the content of neutralizing antibodies and that other components of CP could induce relevant biological effects. In our study, we did not observe differences between donors (ie, low immunoglobulin [Ig] G and IgA antibody titers) and “superdonors” (ie, those with high IgG and IgA antibody titers) in terms of cytokines, autoantibodies, and metabolomic profile [2]. In fact, total IgG and IgA antibodies against S1 severe acute respiratory syndrome coronavirus 2 are key factors for the selection of CP. We found that these antibodies were highly correlated with neutralizing antibodies. The use of CP with high titers modified the immune response of patients with COVID-19.

Results from Bandopadhyay et al [1] may differ from ours since they conducted paired tests for each group and did not evaluate intergroup differences. It would be of interest to know whether the reduction in cytokines in the plasma receptor group differed significantly from the reduction in those receiving standard therapy, and whether the effect persists for >4 days. The authors randomized patients with mild or severe disease to both therapy groups. However, randomization of patients with similar clinical characteristics (ie, confirmed viral pneumonia or severity according to validated classification criteria) may have allowed a better evaluation of the immune response. In addition, it is unknown whether patients received transfusions in early stages of the disease or in the first days of hospitalization. This has critical implications in the evaluation of cytokine kinetics.

The evaluation of lymphocyte populations may offer better information about the real therapeutic implications of CP. As our study showed, CP ameliorates activated T-cell and B-cell phenotypes, with an increase in memory cell subsets. All of these data suggest that early administration of CP influences the immune response, even after the resolution of the acute phase of the disease. However, it is unknown whether these phenomena persist 28 days after transfusion.