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.