Severity of COVID-19 Omicron Variants: A Global Systematic Review

INTRODUCTION: The continual emergence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants drives the need to update evidence on coronavirus disease 2019 (COVID-19) severity and disease burden, and better understand the impact on prevention, treatment, and healthcare systems. METHODS: This systematic review aimed to determine relative disease severity, through comparative measures of hospitalization, intensive care unit admission and mortality, between SARS-CoV-2 variants of concern emerging since Omicron was first identified. A protocol was registered a priori (PROSPERO ID: CRD42024619193). Systematic searches of MEDLINE and EMBASE databases were conducted in November 2024 and supplemented by conference searches from 2022-2024. Population, Exposure, Comparisons, Outcomes (PECO) criteria were used to screen publications for inclusion. Critical appraisal tools published in the Joanna Briggs Institute (JBI) Handbook for Evidence Synthesis were used to assess the risk of bias of the primary studies included. The outcomes associated with Omicron variants, identified by sequencing or predominance periods, included hospitalization, admission to intensive care, death, and various composite endpoints. RESULTS: Thirty-two studies fulfilled the eligibility criteria, most reported on relative disease severity for early Omicron BA.5 (n = 23) and XBB (n = 24) variants. Overall, COVID-19 severity appeared largely comparable across the various Omicron subvariants. Among the subset of studies that directly compared various severity outcomes to earlier SARS-CoV-2 variants (n = 7), some reported modest increases or decreases in severity. However, these differences were generally not statistically significant. Five studies stratifying outcomes by the presence of comorbid conditions noted that comorbidities were predictors of significantly worse COVID-19 disease outcomes (p = 0.000-0.027). CONCLUSIONS: Overall, this systematic review found the severity of COVID-19 disease to be comparable among Omicron subvariants. As SARS-CoV-2 subvariants continue to emerge, these results highlight the continuing need for vaccination against SARS-CoV-2 infection alongside early antiviral intervention to support short-term management and long-term reduction of COVID-19-associated morbidity and mortality.