Abstract
BACKGROUND: Extrapulmonary complications (EPCs) are common in patients hospitalized for coronavirus disease 2019 (COVID-19), but data on their clinical consequences and association with viral replication and systemic viral dissemination are lacking. METHODS: Patients hospitalized for COVID-19 and enrolled in the Therapeutics for Inpatients with COVID-19 (TICO) platform trial at 114 international sites between August 2020 and November 2021 were included in a prospective cohort study. We categorized EPCs into 39 event types within 9 categories and estimated their frequency through day 28 and their association with clinical outcomes through day 90. We analyzed the association between baseline viral burden (plasma nucleocapsid antigen [N-Ag] level and upper airway viral load) and EPCs, adjusting for other baseline factors. RESULTS: A total of 2625 trial participants were included in the study. Their median age was 57 years (interquartile range, 46-68 years), 57.7% were male, and 537 (20.5%) had ≥1 EPC. EPCs were associated with higher day-90 all-cause mortality rate (hazard ratio, 9.6 [95% confidence interval, 7.3-12.7]) after adjustment for other risk factors. The risk of EPCs increased with increasing baseline plasma N-Ag level (hazard ratio, 1.21 per log10 ng/L increase [95% confidence interval, 1.09-1.34]), and upper airway viral load (1.12 per log10 copies/mL increase [1.04-1.19), after adjustment for comorbid conditions, disease severity, inflammatory markers, and other baseline factors. Trial treatment allocation had no effect on EPC risk. CONCLUSIONS: Systemic viral dissemination as evidenced by high plasma N-Ag level and high respiratory viral burden are associated with development of EPCs in COVID-19, which in turn are associated with higher 90-day mortality rates.