Outcomes
myalgia, fever, chills, shortness of breath, sore throat, death, loss of smell), rash, acute illness, acral lesions, fatigue, diarrhea, loss of taste, ageusia, vomiting, cough, nasal congestion, swelling, anosmia, headache
SORE THROAT
The primary outcome for this study, prespecified in the statistical analysis plan for CSSC-004, was the difference in time to resolution of all symptoms by day 14, defined as the absence of all queried symptoms by day 14 of follow-up, between the CCP and control plasma treatment groups. Participants were censored at the time of symptom resolution, loss to follow-up, or death. The CSSC-004 trial participants were asked about the presence and severity of symptoms at days 0, 1, 3, 5, 7, 10, and 14 through a structured, self-report form administered via phone (days 1, 3, 5, 7, and 10) and in-person visits (days 0 and 14). Data were collected on self-reported cough, fatigue, shortness of breath, ageusia, anosmia, nasal congestion, headache, myalgia, neurologic changes (ie, changes in cognitive functioning), nausea/vomiting, sore throat, diarrhea, skin manifestations (ie, acral lesions, rash, or swelling), chills, and fever at each visit. Details on symptom severity can be found in We also examined the difference between treatment groups in the proportion of participants experiencing a symptom within specified symptom clusters at day 14. We took 4 approaches to define symptom clusters before analysis of day 14 data. Clusters 1 (any of cough, fatigue, shortness of breath, or headache) and 2 (any neurologic symptoms, loss of taste, or loss of smell) were defined based on common clinical presentations of symptoms. Cluster 3 was investigator defined, based on a symptom's potential to inhibit an individual's ability to return to work after acute illness. For cluster 3, we adjusted the severity levels for assessing the presence of symptoms before analysis in order to develop a clinically meaningful definition for symptom resolution. Specifically, cluster 3 consisted of any fever, fatigue (grade 2+), diarrhea, headache (grade 2+), myalgia (grade 2+), or vomiting.In addition, we took an unsupervised, machine learning, algorithmic approach to derive data-driven symptom clusters, based on the prevalence of each symptom at each visit in the CSSC-004 study population [The presence of a symptom cluster was determined when a participant experienced ≥1 of the component symptoms within a cluster. For example, a participant reporting grade 2 fatigue and grade 1 cough at day 14 would be counted as having cluster 1 (cough or fatigue) and cluster 3 (fatigue at grade 2 or higher) symptoms at day 14. Finally, we explored differences between treatment groups in the change in severity for cluster 1 symptoms between treatment groups.