Since the start of the covid-19 pandemic, mutations of SARS-CoV-2—the virus that causes covid-19—have spread to the United States and a host of other countries worldwide. Recent studies suggest that current covid-19 variants are up to 70% more contagious than the pandemic’s original strains.

A multidisciplinary team of scientists at Cleveland Clinic and Case Western Reserve University used genomic sequencing to track SARS-CoV-2 as it mutated in Northeast Ohio from March 11 to April 22, 2020. The research findings,1 published in JAMA Network Open, demonstrated that initial strains and subgroups of virus strains (called clades), seen during this time period, were associated with higher mortality while newer variants were associated with lower hospitalizations and deaths. Although these findings share insight into what researchers learned earlier in the pandemic, it could also help guide future studies to analyze how the newer variants impact patient outcomes as the virus continues to evolve.

This research collaborative, led by Frank Esper, MD, a pediatric infectious disease physician at Cleveland Clinic Children’s, included experts in cancer genomics, computer and data sciences, neurology, and pathology. Brian Rubin, MD, chair of Cleveland Clinic’s Robert J. Tomsich Pathology and Laboratory Medicine Institute, and Jing Li, PhD, the Leonard Case Jr. Professor in Case Western Reserve University’s Department of Computer and Data Sciences, were co-senior authors on the study.

To better understand how the earlier mutations and clades altered clinical outcomes, Esper and the team of researchers analyzed the RNA sequences of data from 302 patients with covid-19 during the first wave of the pandemic in Northeast Ohio. These clinical samples were obtained from Cleveland Clinic’s covid-19 registry, a collection of data from nearly 50,000 patients who had been tested for the disease.

By sequencing each specimen against the initial strain of the virus discovered in Wuhan, China,  Esper and the research team identified 488 unique mutations, correlating with six virus strains (clades Wuhan, S, L, V, G, GH).

Results revealed that during the initial six weeks of the pandemic in Cleveland, the early virus strains were well established and contributed to higher incidents of death from the disease. However, within weeks these early virus strains were outpaced by more transmissible strains that were associated with lower hospitalizations and increased patient survival even when hospitalized.

“This study offers a detailed description of how the different covid-19 clades evolved and competed once they were brought to Cleveland,” says Rubin. “The linkage of viral clades to outcomes is quite important and highlights the importance of viral genome sequencing to gain a deeper understanding of new diseases.”

The greatest diversity of covid-19 strains occurred in the first weeks before community strategies to limit viral spread were established. It is likely that state and federal responses may have prevented continued introduction of new variants from outside the community, and thereby decreased overall mortality.

“These findings offer greater insight into how covid-19 infections significantly outpaced the rates of covid-19 hospitalizations and deaths as the pandemic progressed,” says Esper. “The research also helps to validate how viral clades can play an important role in predicting patient outcomes.”

Li adds, “This study further confirms the importance of studying genomic variants of the virus throughout the pandemic. It also clearly demonstrates the value of team science—a highly integrated and interactive team with different strengths and expertise but a shared vision—in addressing the challenge.”

As the virus continues to mutate over time, experts are not certain of the disease severity or mortality the new variants will cause. Currently, just 34% of Americans are fully vaccinated, while 52% have received at least one dose, according to the US Centers for Disease Control and Prevention.

Funding for this research was supported in part by the National Science Foundation (NSF) and the Robert J. Tomsich Pathology and Laboratory Medicine Institute at Cleveland Clinic.

Featured image: This transmission electron microscope image shows SARS-CoV-2, the virus that causes covid-19, isolated from a patient in the U.S. Virus particles are shown emerging from the surface of cells cultured in the lab. The spikes on the outer edge of the virus particles give coronaviruses their name, crown-like. Credit: NIAID-RML


Esper FP, Cheng YW, Adhikari TM, et al. Genomic Epidemiology of SARS-CoV-2 Infection During the Initial Pandemic Wave and Association With Disease Severity. JAMA Netw Open. 2021;4(4):e217746. Published 2021 Apr 1. doi:10.1001/jamanetworkopen.2021.7746