Background In 2021, new variants of the SARS-CoV-2 virus appeared with increased transmissibility and virulence as compared with the original wild variant. The first variants of concern (VoCs), Alpha (B1.1.7) and Gamma (P.1), first appeared in the United Kingdom and Brazil, respectively. The Delta (B.1.617.2) variant, seen in India in October 2020, dominated COVID-19 infections across all regions through the second half of 2021. Objective This research explores the degree to which SARS-CoV-2 VoCs generate waves of fluctuations in case-fatality rates (CFRs) across countries in several regions, increase the risk of mortality to persons with certain comorbidities, and decrease the risk of mortality as the percentage of fully vaccinated populations increases. Methods This analysis introduces a measure of the temporal dynamics of COVID-19 infections in the form of a proxy CFR (pCFR), which can be compared among countries. It uses economic and demographic data reported by the World Bank and International Monetary Fund, plus publicly available epidemiological and medical statistics reported to the relevant national and international public health authorities. From these ecological data, pandemic average and daily COVID-19 CFRs and their correlations with potential cofactors were computed for 2021, a year dominated by the spread of World Health Organization–designated VoCs. The study does not investigate disease pathology; rather, it compares the daily case rates and pCFRs to reveal underlying contributing factors that vary from country to country and region to region. Results The in-depth global regression analysis of cofactors found that the strongest single correlation with COVID-19 fatality was 0.36 (SD 0.02) with P<.001 for chronic kidney disease. No other single physiological cofactors display positive correlations exceeding 0.26 (SD 0.26), with P=.008 (asthma) and P=.01 (coronary disease). The study confirms that the pCFR is a valuable metric for tracking waves of infection due to different VoCs within countries. Conclusions The influence of social, economic, and medical cofactors on the CFR due to VoCs remains qualitatively similar, albeit strengthened, to the levels found for the wild strain. The strong regional variations of the influence of all cofactors observed for the wild strain persists in infections for all VoCs with very strong correlation coefficients seen in the Middle East for asthma (0.76), coronary heart disease (0.60), lung disease (0.70), and chronic kidney disease (0.52). Strong regional variations emphasize the influence on COVID-19 mortality due to regional differences in national economics, patterns of health care policies, and variations in cultural practices and environment. The pCFR-based analysis reveals clear patterns of the spread of VoCs across regions, but there is little evidence for the spread of the Lambda and Mu (B.1.621) variants of interest outside of South America.
