Results and Discussion
Four patients, 14-18 years, were treated with CP during the study period. All patients were critically ill with COVID-19-associated acute respiratory distress syndrome (ARDS). All patients required intubation and ventilation; two required extra-corporeal membrane oxygenation (ECMO). None of the patients had Multisystem Inflammatory Syndrome in Children (MIS-C). All patients received other SARS-CoV-2 directed therapies in addition to CP. Graphical case summaries are presented in Figure 1. Further details are presented in Appendix S3. No patients experienced any treatment emergent adverse events (TEAE) related to CP infusion.
Longitudinal antibody titers are presented in Figure 2. Corresponding antibody titers for CP donors are displayed. At the time of CP infusion, patient CD4 had extremely high endogenous antibody titers (against SARS-CoV-2 RBD, S, and N). Antibody titers in this participant were sustained post-transfusion. This individual showed transient clinical improvement, decannulating from ECMO; however, died from cardiac causes by day 25 post-transfusion.
Patients CD15, CD17 and CD25 had low or undetectable RBD-specific antibody titers at the time of infusion. Serum antibodies against the SARS-CoV-2 RBD correlate with neutralizing activity, likely due to inhibition of the virus’ ability to bind and enter target cells.8-10 Of note, the donor plasma infused into patients CD15 and CD17 had relatively low RBD-specific antibody titer levels (<1:160). Both CP donors for CD15 and CD17 had substantial full-length IgG S titers (>1:1,000) and these may have conferred some neutralizing activity. It is unclear if CP with low RBD-specific and high full-length IgG S antibody titers would provide benefit. CD15 and CD17 both remain in intensive care and did not have significant clinical improvement following CP infusion. The donor for patient CD25 had higher SARS-CoV-2 RBD antibody titers (>1:6,000) than the donor for any of the other patients, making it more likely that this donor plasma could be beneficial. CD25 had the shortest period of admission and has been discharged from the hospital after being critically ill and on ECMO.
Prior to transfusion, three of the four recipients (CD15, CD17, and CD25) had undetectable IgG RBD antibody levels (<1:50 serum dilution). Upon transfusion all three participants eventually experienced a boost in IgG, IgM, and IgA antibodies against RBD that was sustained for 7-26 days post transfusion. In one participant (CD15), we detected antibodies against the full-length S protein before we detected antibodies against the RBD of the S protein. The boost in antibodies against N post-transfusion was similar to that of RBD and S-specific serum antibodies for patients CD15, CD17, and CD25. In all three patients, the serum levels of SARS-CoV-2-specific antibodies eventually surpassed the amount transfused, indicating that these patients mounted a post-transfusion de novo response and that CP did not eliminate the endogenous serological response.
In summary, CP was safely administered to four pediatric patients with severe COVID-19. There were no CP-related TEAE. The theoretical risks of ADE or elimination of endogenous antibody response did not occur. CP may be of greatest benefit for patients who are early in their illness and have not yet generated endogenous antibodies, and when the infused plasma has a high antibody titer. The patient who received the CP with the highest antibody titer had the best clinical response. The small sample size of our study precludes definitive conclusions about efficacy, however, the excellent clinical response in this patient is encouraging. The other patients had significant comorbidities that may have contributed to their clinical status. It is difficult to determine if CD15 and CD17 benefited, as it is possible without CP they could have continued to worsen. Future research should include randomized controlled trials to definitively examine the efficacy of convalescent plasma in children.