Incidence Rates and Clinical Outcomes of SARS-CoV-2 Infection With the Omicron and Delta Variants in Children Younger Than 5 Years in the US

With the Omicron variant (B.1.1.529), SARS-CoV-2 infections and hospitalizations reached record levels.¹ Children younger than 5 years may be especially vulnerable because they are not eligible for COVID-19 vaccination.² We examined incidence rates and clinical outcomes of Omicron infection before and after Omicron became the predominant variant in the US.

This cohort study (September 1, 2021-January 31, 2022) was approved by the MetroHealth System institutional review board (IRB); the need for informed consent was waived owing to use of deidentified patient data. We used the TriNetX Analytics Platform to access aggregated and deidentified electronic health records of 90 million patients from 66 health care organizations. TriNetX built-in analytic functions permit patient-level analyses while only reporting population-level data. Patients represented 28% of the US population from 50 states covering diverse geographic, age, race, income, and insurance groups.³ Self-identified race and ethnicity were included owing to their association with SARS-CoV-2 infection risk and outcomes.

The study population contained 3 cohorts of children younger than 5 years with no prior SARS-CoV-2 infection: (1) Omicron cohort, who contracted SARS-CoV-2 infection between December 26, 2021, and January 25, 2022⁴; (2) Delta (B.1.617.2) cohort, who contracted SARS-CoV-2 infection between September 1, 2021, and November 15, 2021⁴; and (3) Delta2 cohort, who contracted SARS-CoV-2 infection between November 16 and November 30, 2021.⁴ Delta2 cohort was developed to control for later time periods and shorter infection window.

We examined monthly incidence rates of SARS-CoV-2 infection (new cases per 1000 persons per day) between September 1, 2021, and January 31, 2022, among children without prior infections, stratified by 2 age groups (0-2 and 3-4 years). We tested whether severe clinical outcomes differed between Omicron and Delta cohorts and between Delta2 and Delta cohorts. Cohorts were propensity-score matched for demographics (Table). Risk of death, emergency department visits, hospitalizations, intensive care unit (ICU) admissions, and the need for mechanical ventilation within 14 days after initial SARS-CoV-2 infection were compared between matched cohorts using hazard ratios (HRs) and 95% CIs. Statistical tests were conducted within the TriNetX Analytics Platform with significance set at a 2-sided P value <.05. TriNetX database and statistical analyses are in the eMethods in the Supplement. This study followed STROBE reporting guidelines.

This cohort study included a total of 651 640 children younger than 5 years: (1) Omicron cohort, 22 772 children; (2) Delta cohort, 66 692 children; and (3) Delta2 cohort, 10 496 children. The monthly incidence rate of SARS-CoV-2 infections was mostly stable (1.0-1.5 cases per 1000 persons per day) between September and November 2021 (Delta-predominant period) but rapidly increased to 2.4 to 5.6 cases per 1000 persons per day in December 2021, coincident with the emergence of Omicron variant. Monthly incidence rate of SARS-CoV-2 infections peaked at 8.6 cases per 1000 persons per day in the first half of January 2022 (Omicron-predominant period) and 8.2 in the second half of January 2022. Incidence rate of Omicron infection was higher in children aged 0 to 2 years than in those aged 3 to 4 years. Omicron cohort was younger and with fewer comorbidities than Delta cohort, but differences were eliminated after matching (Table). Risks for severe clinical outcomes in children infected with Omicron variant were significantly lower than those in the matched Delta cohort (Figure, A), whereas the risks for severe clinical outcomes in Delta2 cohort did not differ from those in Delta cohort (Figure, B). There were fewer than 10 deaths in all cohorts.

Results of this cohort study suggest that the incidence rate of SARS-CoV-2 infection with Omicron variant was 6 to 8 times that of Delta variant in children younger than 5 years, but severe clinical outcomes were less frequent than with Delta variant. Study limitations include potential biases introduced by the observational and retrospective analyses of electronic health records and the need for validation of the results from other data. Study findings may inform risk-benefit considerations about in-person school attendance, mask use, and vaccination implementation for young children.

Accepted for Publication: March 2, 2022.

Published Online: April 1, 2022. doi:10.1001/jamapediatrics.2022.0945

Corresponding Author: Rong Xu, PhD, Center for Artificial Intelligence in Drug Discovery, Case Western Reserve University School of Medicine, 2210 Circle Dr, Sears Tower T303, Cleveland, OH 44106 (rxx@case.edu).

Author Contributions: Dr Xu 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.

Concept and design: Berger, Davis, Kaelber, Volkow, Xu.

Acquisition, analysis, or interpretation of data: Berger, Kaelber, Xu, Wang.

Drafting of the manuscript: Berger, Volkow, Xu.

Critical revision of the manuscript for important intellectual content: Berger, Davis, Kaelber, Xu, Wang.

Statistical analysis: Wang.

Obtained funding: Berger, Kaelber, Xu.

Administrative, technical, or material support: Davis, Kaelber, Volkow, Xu.

Supervision: Berger, Kaelber, Volkow, Xu.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported by grants AG057557, AG061388, and AG062272 from the National Institute on Aging, grant R01AA029831 from the National Institute on Alcohol Abuse and Alcoholism, grant UG1DA049435 from the National Institute on Drug Abuse, grant 1UL1TR002548-01 from the Clinical and Translational Science Collaborative of Cleveland, and grants R25CA221718, P30 CA043703, and P20 CA2332216 from the National Cancer Institute Case Comprehensive Cancer Center.

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.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.