International Changes in COVID-19 Clinical Trajectories Across 315 Hospitals and 6 Countries: Retrospective Cohort Study
Authors: Weber Griffin M , Zhang Harrison G , L'Yi Sehi , Bonzel Clara-Lea , Hong Chuan , Avillach Paul , Gutiérrez-Sacristán Alba , Palmer Nathan P , Tan Amelia Li Min , Wang Xuan , Yuan William , Gehlenborg Nils , Alloni Anna , Amendola Danilo F , Bellasi Antonio , Bellazzi Riccardo , Beraghi Michele , Bucalo Mauro , Chiovato Luca , Cho Kelly , Dagliati Arianna , Estiri Hossein , Follett Robert W , García Barrio Noelia , Hanauer David A , Henderson Darren W , Ho Yuk-Lam , Holmes John H , Hutch Meghan R , Kavuluru Ramakanth , Kirchoff Katie , Klann Jeffrey G , Krishnamurthy Ashok K , Le Trang T , Liu Molei , Loh Ne Hooi Will , Lozano-Zahonero Sara , Luo Yuan , Maidlow Sarah , Makoudjou Adeline , Malovini Alberto , Martins Marcelo Roberto , Moal Bertrand , Morris Michele , Mowery Danielle L , Murphy Shawn N , Neuraz Antoine , Ngiam Kee Yuan , Okoshi Marina P , Omenn Gilbert S , Patel Lav P , Pedrera Jiménez Miguel , Prudente Robson A , Samayamuthu Malarkodi Jebathilagam , Sanz Vidorreta Fernando J , Schriver Emily R , Schubert Petra , Serrano Balazote Pablo , Tan Byorn WL , Tanni Suzana E , Tibollo Valentina , Visweswaran Shyam , Wagholikar Kavishwar B , Xia Zongqi , Zöller Daniela ,   The Consortium For Clinical Characterization Of COVID-19 By EHR (4CE), Kohane Isaac S , Cai Tianxi , South Andrew M , Brat Gabriel A 
Published: September 2021

Background
Many countries have experienced 2 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 health care 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 health care systems representing 315 hospitals across 6 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 health care 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 adopted at the central site to correct for implausible values and harmonize units. Statistical analyses were performed by computing individual health care system effect sizes and synthesizing these using random effect 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 to 69 years decreased significantly between the first and second waves. Patients hospitalized in the second wave had a 9.9% reduction in the 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 to 49 years and 50 to 69 years; male and female patients; and black patients had significantly lower risk for severe disease in the second wave than in the first wave. At admission, the mean values of CRP were significantly lower in the second wave than in the first wave. On the seventh hospital day, the mean values of CRP, ferritin, fibrinogen, and procalcitonin were significantly lower in the second wave than in the first wave. 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 health care systems to rapidly conduct large-scale studies to characterize how COVID-19 clinical trajectories evolve.