The Impact of SARS-CoV-2 VOCs on Clinical Outcomes: an Overview of Reviews

Federico Fama^1,2Rebecca Fattore^1*Paolo Raimondo¹Fabio Brivio¹Darcy Holmes³TOUSSAINT MUHEBERIMANA²Tarek Nayfeh⁴Alessandra Bandera^3,5Andrea Gori^1,2,6Matteo Passerini^1,6Marta Colaneri^1,2,6

• ¹Department of Infectious Diseases, Luigi Sacco University Hospital, Milan, Italy
• ²Centre for Multidisciplinary Research in Health Science (MACH), University of Milan, Milan, Italy
• ³Infectious Diseases Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
• ⁴Evidence-based Practice Center, Mayo Clinic, Rochester, MN, United States
• ⁵Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
• ⁶Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy

Synthesizing data from existing literature is crucial for validating the robustness of associations, assessing data quality, and forming recommendations, especially given the vast amount of information available on SARS-CoV-2. This study aims to conduct an overview of reviews to evaluate the strength and validity of associations between VOCs and specific clinical outcomes in COVID-19 patients.An overview of reviews according to the principles of PRIOR protocol was performed searching multiple databases in January 2024 and an updated search was conducted in MEDLINE database in June 2025. Peer reviewed systematic reviews considering two or more VOCs and reporting on clinical outcomes such as mortality, hospitalization, severe disease, admission to ICU, and mechanical ventilation were included. Data on study population and measures of association between clinical outcome and VOCs were considered. The quality of the studies was assessed through the AMSTAR-2 tool. Effect sizes and confidence intervals for each association between VOCs and clinical outcomes were reported. Subgroup analyses were performed where feasible. A citation matrix was used to assess the overlap between the included systematic reviews.Twelve studies were included in the review, with a total of 24 comparisons, primarily between Omicron and Delta variants (19/24). Omicron was consistently associated with better clinical outcomes compared to Delta. The confidence in the results of 10/12 studies was rated critically low. The overlap between the included reviews was minimal, with 10% having significant overlap (> 15%).Our overview of reviews shows the lower hazard on human health of the Omicron compared to Delta variant. However, the quality of the reviews included was generally low, prompting the need for more rigorous systematic reviews. (This overview of reviews was registered in PROSPERO, registration number: CRD42024500841).