Clinical Severity in Different Waves of SARS-CoV-2 Infection in Sicily: A Model of Smith’s “Law of Declining Virulence” from Real-World Data

Background: The COVID-19 epidemic had a rapid spread worldwide with a continuous and fast mutation of the virus, resulting in the emergence of several variants of concern (VOC). The aim of this study was to evaluate the severity of each VOC among SARS-CoV-2 infected subjects by investigating deaths, ICU admissions, intubations, and severe critical symptoms. Methods: An ecological observational study was performed to evaluate mortality rates and clinical characteristics of 321,490 unvaccinated Sicilian SARS-CoV-2 cases observed from 2 March 2020 to 27 March 2022. Odds ratios (OR) and 95% confidence intervals (CI) were calculated by multivariate logistic regression analysis evaluating factors determining a clinical worsening. Results: Delta (adj-OR 3.00, 95% Cls 2.70–3.33) and wild-type (adj-OR 2.41, 95% Cls 2.2–2.62) variants had a higher risk than the Omicron strain for developing critical COVID-19 necessitating intubation and eventually undergoing death. Moreover, males appeared to be significantly more susceptible to developing the worst clinical outcome considered, as did older subjects. Conclusions: The present study provides evidence of factors implicated in the worsening of SARS-CoV-2-infection-related clinical outcomes. The study highlighted the different roles of VOC, in particular Delta and wild-type, and being male and elderly in the development of a worse clinical outcome.