International Changes in COVID-19 Clinical Trajectories Across 315 Hospitals and 6 Countries: a 4CE Consortium Study.

BACKGROUND Many countries have experienced two predominant waves of COVID-19-related hospitalizations. Comparing the clinical trajectories of patients hospitalized in separate waves of the pandemic enables further understanding of the evolving epidemiology, pathophysiology, and healthcare dynamics of the COVID-19 pandemic. OBJECTIVE In this retrospective cohort study, we analyzed electronic health record (EHR) data from patients with SARS-CoV-2 infections hospitalized in participating healthcare systems representing 315 hospitals across six countries. We compared hospitalization rates, severe COVID-19 risk, and mean laboratory values between patients hospitalized during the first and second waves of the pandemic. METHODS Using a federated approach, each participating healthcare system extracted patient-level clinical data on their first and second wave cohorts and submitted aggregated data to the central site. Data quality control steps were performed at the central site to correct for implausible values and harmonize units. Statistical analyses were performed by computing individual healthcare system effect sizes and synthesizing these using random effects meta-analyses to account for heterogeneity. We focused the laboratory analysis on C-reactive protein (CRP), ferritin, fibrinogen, procalcitonin, D-dimer, and creatinine based on their reported associations with severe COVID-19. RESULTS Data were available for 79,613 patients, of which 32,467 were hospitalized in the first wave and 47,146 in the second wave. The prevalence of male patients and patients aged 50-69 decreased significantly between the first and second wave. Patients hospitalized in the second wave had a 9.9% reduction in risk of severe COVID-19 compared to patients hospitalized in the first wave (95% CI: 8.5-11.3%). Demographic subgroup analyses indicated that patients aged 26-49 and 50-69; male and female patients; and Black patients had significantly lower risk for severe disease in the second wave compared to the first wave. At admission, the mean values of CRP were significantly lower in the second wave compared to the first. On the seventh hospital day, mean values of CRP, ferritin, fibrinogen, and procalcitonin were significantly lower in the second wave compared to the first. In general, countries exhibited variable changes in laboratory testing rates from the first to the second wave. At admission, there was a significantly higher testing rate for D-dimer in France, Germany, and Spain. CONCLUSIONS Patients hospitalized in the second wave were at significantly lower risk for severe COVID-19. This corresponded to mean laboratory values in the second wave that were more likely to be in typical physiological ranges on the seventh hospital day compared to the first wave. Our federated approach demonstrated the feasibility and power of harmonizing heterogeneous EHR data from multiple international healthcare systems to rapidly conduct large-scale studies to characterize how COVID-19 clinical trajectories evolve. CLINICALTRIAL