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Genomic Epidemiology of SARS-CoV-2 Infection During the Initial Pandemic Wave and Association With Disease Severity

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Key Points

Question  Are SARS-CoV-2 variants, virus clades, or clade groups associated with disease severity and patient outcomes?

Findings  In this cross-sectional study of 302 SARS-CoV-2 isolates, 6 different Global Initiative on Sharing All Influenza Data clades circulated in the community followed by a rapid reduction in clade diversity. Several variants, including 23403A>G (D614G), were significantly associated with lower hospitalization rates and increased patient survival.

Meaning  These findings suggest that SARS-CoV-2 clade assignment is an important factor that may aid in estimating patient outcomes.


Importance  Understanding of SARS-CoV-2 variants that alter disease outcomes are important for clinical risk stratification and may provide important clues to the complex virus-host relationship.

Objective  To examine the association of identified SARS-CoV-2 variants, virus clades, and clade groups with disease severity and patient outcomes.

Design, Setting, and Participants  In this cross-sectional study, viral genome analysis of clinical specimens obtained from patients at the Cleveland Clinic infected with SARS-CoV-2 during the initial wave of infection (March 11 to April 22, 2020) was performed. Identified variants were matched with clinical outcomes. Data analysis was performed from April to July 2020.

Main Outcomes and Measures  Hospitalization, intensive care unit (ICU) admission, mortality, and laboratory outcomes were matched with SARS-CoV-2 variants.

Results  Specimens sent for viral genome sequencing originated from 302 patients with SARS-CoV-2 infection (median [interquartile range] age, 52.6 [22.8 to 82.5] years), of whom 126 (41.7%) were male, 195 (64.6%) were White, 91 (30.1%) required hospitalization, 35 (11.6%) needed ICU admission, and 17 (5.6%) died. From these specimens, 2531 variants (484 of which were unique) were identified. Six different SARS-CoV-2 clades initially circulated followed by a rapid reduction in clade diversity. Several variants were associated with lower hospitalization rate, and those containing 23403A>G (D614G Spike) were associated with increased survival when the patient was hospitalized (64 of 74 patients [86.5%] vs 10 of 17 patients [58.8%]; χ21 = 6.907; P = .009). Hospitalization and ICU admission were similar regardless of clade. Infection with Clade V variants demonstrated higher creatinine levels (median [interquartile range], 2.6 [−0.4 to 5.5] mg/dL vs 1.0 [0.2 to 2.2] mg/dL; mean creatinine difference, 2.9 mg/dL [95% CI, 0.8 to 5.0 mg/dL]; Kruskal-Wallis P = .005) and higher overall mortality rates (3 of 14 patients [21.4%] vs 17 of 302 patients [5.6%]; χ21 = 5.640; P = .02) compared with other variants. Infection by strains lacking the 23403A>G variant showed higher mortality in multivariable analysis (odds ratio [OR], 22.4; 95% CI, 0.6 to 5.6; P = .01). Increased variants of open reading frame (ORF) 3a were associated with decreased hospitalization frequency (OR, 0.4; 95% CI, 0.2 to 0.96; P = .04), whereas increased variants of Spike (OR, 0.01; 95% CI, <0.01 to 0.3; P = .01) and ORF8 (OR, 0.03; 95% CI, <0.01 to 0.6; P = .03) were associated with increased survival.

Conclusions and Relevance  Within weeks of SARS-CoV-2 circulation, a profound shift toward 23403A>G (D614G) specific genotypes occurred. Replaced clades were associated with worse clinical outcomes, including mortality. These findings help explain persistent hospitalization yet decreasing mortality as the pandemic progresses. SARS-CoV-2 clade assignment is an important factor that may aid in estimating patient outcomes.

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Article Information

Accepted for Publication: March 7, 2021.

Published: April 26, 2021. doi:10.1001/jamanetworkopen.2021.7746

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Esper FP et al. JAMA Network Open.

Corresponding Author: Frank P. Esper, MD, Center for Pediatric Infectious Disease, Cleveland Clinic Children’s, 9500 Euclid Ave, R3, Cleveland, OH 44195 (

Author Contributions: Dr Esper had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Rubin and J. Li are co–senior authors.

Concept and design: Esper, Cheng, Adhikari, Farkas, Procop, Chan, Rubin, J. Li.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Esper, Adhikari, Farkas, Chan, J. Li.

Critical revision of the manuscript for important intellectual content: Esper, Cheng, Tu, D. Li, E. Li, Farkas, Procop, Ko, Chan, Jehi, Rubin, J. Li.

Statistical analysis: Esper, Adhikari, D. Li, E. Li, J. Li.

Obtained funding: Esper, Chan, Jehi, Rubin, J. Li.

Administrative, technical, or material support: Cheng, Adhikari, Tu, Farkas, Procop, Ko, Chan, Jehi, Rubin.

Supervision: Cheng, Farkas, Chan, Rubin, J. Li.

Conflict of Interest Disclosures: Dr Esper reported receiving personal fees from MSL Group for serving as an advisory board member outside the submitted work. Dr Cheng reported receiving grants from the National Cancer Institute and personal fees from GLG Consulting, Putnam Associates, and Health Advances outside the submitted work. Dr Adhikari reported receiving grants from National Science Foundation outside the submitted work. Dr Chan reported receiving stock from Gritstone Oncology, personal fees from NysnoBio, and grants from Pfizer, Illumina, and AstraZeneca outside the submitted work. No other disclosures were reported.

Funding/Support: This project was supported in part by National Science Foundation grants IIS-2027667 (to Drs J. Li and Esper), CCF-2006780 (to Dr J. Li), CCF-1815139 (to Dr J. Li), and NS097719 (to Dr J. Li), and through unrestricted funds from the Robert J. Tomsich Pathology and Laboratory Medicine Institute.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: Yamini Mandelia, MD (Department of Pediatrics, East Carolina University), and Lihui Yin, PhD, and Maureen Jakubowski, BS (Department of Molecular Pathology, Robert J. Tomsich Pathology and Laboratory Medicine Institute), provided excellent assistance in patient identification and virus genome sequencing. No compensation was provided for their assistance.

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