Discussion
obesity, IgG-negative, fatigue, hospitalization/death, infections, cough, reinfection, shortness of breath
OBESITY, VIRUS, DISEASE COURSE, INFECTIONS, COVID-19 INFECTION, LOSS OF APPETITE, SECONDARY, REINFECTION, ACUTE VIRAL DISEASE, ACUTE COVID-19 INFECTION
This secondary analysis reports the results from a clinical trial designed to determine the effect of CAS + IMD treatment in outpatients with acute COVID-19We delineated the effect of treatment on individual symptoms that individually and collectively are important to consider when evaluating response to treatment in a clinical setting, showing that three symptom clusters were most responsive to CAS + IMD, as demonstrated by correlation analysis and hierarchical clustering. These symptom complexes appeared and resolved in different time periods after acute presentation.We found that the reduction in symptoms with CAS + IMD treatment compared to placebo varied according to the presence or absence of established risk factors associated with severe COVID-19 outcomes (e.g., age, obesity, and baseline viral load)Five symptoms (shortness of breath, cough, feeling feverish, fatigue, and loss of appetite) were strongly associated with occurrence of hospitalization/death. This confirms and extends findings of other studies that used independent data setsA feature of the statistical analysis pursued here is the application of a bootstrapping method. The results suggest the bootstrapping subsamples for the symptom of “feeling feverish” exhibited a wider variance in the treatment effect (i.e., probability difference) in some sub-groups compared with the other symptoms, noting that in the overall seronegative population, CAS + IMD provided clear evidence of resolution of the symptom of “feeling feverish”.Adaptive immunity data from vaccine responsesMeasurement of anti–SARS-CoV-2 antibodies also provided an opportunity to assess the effect of baseline antibody responses on time to symptom resolution. Results demonstrated clear differences in treatment response, with a greater magnitude of benefit in patients who were seronegative (i.e., negative on all anti-S1 IgA, anti-S1 IgG, and anti-N IgG antibodies at baseline) versus those who were seropositive at baseline across all five symptoms. A treatment benefit was also observed in patients who seroconverted by day 29 versus those who were seropositive at baseline, underscoring the importance of early administration of CAS + IMD in rescuing patients lacking early serologic responses to SARS-CoV-2.Our analyses also further clarify the role of Ig class and resolution of COVID-19 infection. The treatment benefits in the IgA-positive group were generally similar to the IgG-positive group, suggesting that IgA generated very early on contributes to virus neutralization, as previously suggested by othersThese findings also confirm and extend our understanding of the role of virus-neutralizing antibodies in the resolution of acute COVID-19 infection. The failure to generate NAbs early in the disease course has been shown to be a risk factor for mortality in natural infectionWhile there is a growing body of evidence of the roles T cells and non-neutralizing antibodies play in immunity against COVID-19, this largely applies to their adjunctive contributions to the overwhelmingly dominant role of neutralizing antibodies in clearing acute viral disease or in the case of the former, prophylaxis against reinfection or new infections after vaccinations when antibody responses have wanedAlthough endogenous NAbs were not specifically tested for antibody class, a relatively low percentage (~ 42%) of IgA-positive, IgG-negative patients had detectable NAb activity at baseline, whereas almost all dual IgA- and IgG-positive patients demonstrated neutralizing capacity. This highlights the importance of affinity maturation of antibody response reflected by emergence of detectable virus-specific IgG production, leading to highly effective anti-virus NAbs that are critical for symptom resolution and clinical outcomes. Although NAbs assessed in serum might underestimate the role of mucosal IgA with the potential to neutralize virus locallyIn summary, high severity and long duration of a set of symptoms identified here were found to be associated with poor COVID-19 outcomes. The effects of CAS + IMD treatment on symptoms and the role of antibody class revealed new relationships and extend previous reports of the benefit of this therapeutic with respect to associated morbidity and mortality, most notably in patients lacking an anti–SARS-CoV-2 serologic response at baseline