  Citation: Mendiola-Pastrana, I.R.; López-Ortiz, E.; Río de la Loza-Zamora, J.G.; González, J.; Gómez-García, A.; López-Ortiz, G. SARS-CoV-2 Variants and Clinical Outcomes: A Systematic Review. Life 2022, 12, 170. https://doi.org/ 10.3390/life12020170 Academic Editors: Romina Salpini, Valentina Svicher and Mohammad Alkhatib Received: 19 December 2021 Accepted: 20 January 2022 Published: 25 January 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). life Systematic Review SARS-CoV-2 Variants and Clinical Outcomes: A Systematic Review Indira R. Mendiola-Pastrana 1 , Eduardo López-Ortiz 1 , José G. Río de la Loza-Zamora 1 , James González 2 , Anel Gómez-García 3 and Geovani López-Ortiz 1, * 1 Subdivisión de Medicina Familiar, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de Mexico 04510, Mexico; indira.mendiola@imss.gob.mx (I.R.M.-P.); eduardolptz@gmail.com (E.L.-O.); joseguillermoriodelaloza@hotmail.com (J.G.R.d.l.L.-Z.) 2 Departamento de Biología Celular, Facultad de Ciencias, Universidad Nacional Autónoma de México, Ciudad de Mexico 04510, Mexico; james@ciencias.unam.mx 3 Centro de Investigación Biomédica de Michoacán, Instituto Mexicano del Seguro Social, Morelia 58351, Mexico; anel.gomez.garcia@gmail.com * Correspondence: geovani.lorz@fmposgrado.unam.mx Abstract: Background: From the start of the COVID-19 pandemic, new SARS-CoV-2 variants have emerged that potentially affect transmissibility, severity, and immune evasion in infected individuals. In the present systematic review, the impact of different SARS-CoV-2 variants on clinical outcomes is analyzed. Methods: A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020. Two databases (PubMed and ScienceDirect) were searched for original articles published from 1 January 2020 to 23 November 2021. The articles that met the selection criteria were appraised according to the Newcastle–Ottawa Quality Assessment Scale. Results: Thirty-three articles were included, involving a total of 253,209 patients and 188,944 partial or complete SARS-CoV-2 sequences. The most reported SARS-CoV-2 variants showed changes in the spike protein, N protein, RdRp and NSP3. In 28 scenarios, SARS-CoV-2 variants were found to be associated with a mild to severe or even fatal clinical outcome, 15 articles reported such association to be statistically significant. Adjustments in eight of them were made for age, sex and other covariates. Conclusions: SARS-CoV-2 variants can potentially have an impact on clinical outcomes; future studies focused on this topic should consider several covariates that influence the clinical course of the disease. Keywords: SARS-CoV-2 variants; mutations; clinical outcomes; outcome assessment; health care; severity; clinical presentations 1. Introduction Variability in organisms leads to important changes which will have an effect on the course of their evolution [1,2]. In viruses, changes can determine their pathogenicity and virulence [3,4]; even single base changes can markedly influence their spread and confer selective advantages [5]. Since the beginning of the COVID-19 pandemic, it has been reported that SARS-CoV-2 has presented multiple changes in its genetic sequence that can potentially increase its infectivity, pathogenicity and antigenic capacity. This could affect the individual’s immune response and increase the severity of the clinical outcomes in each of the outbreaks [6,7]. One of the first variants to be recognized was D614G in the spike protein [6,8], and as genome sequencing subsequently progressed in different countries, it was reported that different mutations influence the adaptation of the virus to environmental and population contexts, in addition to conferring various phenotypes of clinical interest [9,10]. The clinical course caused by SARS-CoV-2 is associated with country-specific epi- demiological and health contexts, age, pre-existing diseases, comorbidities, and host allelic Life 2022, 12, 170. https://doi.org/10.3390/life12020170 https://www.mdpi.com/journal/life