Comparing outcomes of COVID-19 and influenza among hospitalized adults in the European severe acute respiratory infection vaccine effectiveness (EuroSAVE) network, 2021–2024: a retrospective cohort analysis

Background: Understanding changes in the severity of respiratory virus infections over time is critical for guiding public health interventions. Few studies have been conducted in middle-income countries (MICs), where healthcare infrastructure, COVID-19 and influenza vaccine coverage, and antiviral availability and use differ from high-income countries. Methods: We compared the odds of severe outcome and death by virus test result among patients ≥18 years old hospitalized with severe acute respiratory infection (SARI) in five MICs and areas (Albania, Georgia, Kyrgyzstan, North Macedonia, and Kosovo). Severe outcome included ICU admission, mechanical ventilation, ECMO, or death during hospitalization. We calculated adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for severe outcome and death by respiratory virus PCR test result. Influenza-positive patients were the reference group. We grouped SARS-CoV-2 patients into three periods based on COVID-19 activity and circulating Omicron subvariants [Period 1 (6 December 2021-18 December 2022), Period 2 (19 December 2022-9 July 2023), and Period 3 (10 July 2023-6 August 2024).] We adjusted for age, sex, comorbidities, COVID-19 vaccination status, and country. Findings: Of 7671 patients who met the inclusion criteria, 963 (13%) patients had a severe outcome; 749 (10%) were admitted to ICU, 202 (3%) received mechanical ventilation or ECMO and 285 (4%) died. Compared to influenza patients, SARS-CoV-2-positive patients had a higher odds of severe outcome in Period 1 [ aOR = 1.80 (95% CI 1.23-2.64)], P2 [aOR = 1.94 (95% CI 1.25-3.01)], and Period 3 [aOR = 1.63 (95% CI 1.05-2.54)]. COVID-19 patients in Period 1 (aOR = 2.80; 1.67-4.82) and Period 3 (aOR = 2.25; 95% CI 1.23-4.18) had a higher aOR for death compared to influenza-positive patients; for Period 2 the aOR was 1.04 (95% CI 0.48-2.15). Interpretation: The odds of severe outcome were higher for SARS-CoV-2 patients compared to influenza-positive patients for all periods, while the odds of death were higher during Period 1 and Period 3. These results underscore the continued severity of COVID-19, and need for COVID-19-related health interventions, including COVID-19 vaccination and in-hospital patient management. Funding: This study was funded by the World Health Organization/Regional Office for Europe, in part through a cooperative agreement with the U.S. Centers for Disease Control and Prevention.