Assessment of COVID-19 hospitalization risk during SARS-CoV-2 Omicron relative to Delta variant predominance, New York City, August 2021–January 2022

Importance Assessing relative disease severity of SARS-CoV-2 variants in populations with varied vaccination and infection histories can help characterize emerging variants and support healthcare system preparedness. Objective To assess COVID-19 hospitalization risk for patients infected with Omicron (BA.1 and sublineages) compared with Delta SARS-CoV-2 variants. Design Observational cohort study. Setting New York City Department of Health and Mental Hygiene population-based COVID-19 disease registry, linked with laboratory results, immunization registry, and supplemental hospitalization data sources. Participants New York City residents with positive laboratory-based SARS-CoV-2 tests during August 2021–January 2022. A secondary analysis restricted to patients with whole-genome sequencing results, comprising 1%–18% of weekly confirmed cases. Exposures Diagnosis during periods when ≥98% of sequencing results were Delta (August–November 2021) or Omicron (January 2022). A secondary analysis defined variant exposure using patient-level sequencing results. Main outcomes and measures COVID-19 hospitalization, defined as a positive SARS-CoV-2 test 14 days before or 3 days after hospital admission. Results Among 646,852 persons with a positive laboratory-based SARS-CoV-2 test, hospitalization risk was lower for patients diagnosed when Omicron predominated (16,025/488,053, 3.3%) than when Delta predominated (8,268/158,799, 5.2%). In multivariable analysis adjusting for demographic characteristics and prior diagnosis and vaccination status, patients diagnosed when Omicron relative to Delta predominated had 0.72 (95% confidence interval [CI]: 0.63, 0.82) times the hospitalization risk. In a secondary analysis of 55,138 patients with sequencing results, hospitalization risk was similar for patients infected with Omicron (2,042/29,866, 6.8%) relative to Delta (1,780/25,272, 7.0%) and higher among those who received two mRNA vaccine doses (adjusted relative risk 1.64, 95% CI: 1.44, 1.87). Conclusions and relevance Illness severity was lower for patients diagnosed when Omicron (BA.1 and sublineages) relative to Delta predominated. This finding was consistent after adjusting for prior diagnosis and vaccination status, suggesting intrinsic virologic properties, not population-based immunity, accounted for the lower severity. A secondary analysis demonstrated collider bias from the sequencing sampling frame changing over time in ways associated with disease severity. Investing in representative data collection is necessary to avoid bias in assessing relative disease severity as new variants emerge, immunity wanes, and additional COVID-19 vaccines are administered. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The authors received no specific funding for this work beyond their usual salaries. Dr. Greene was supported by the Public Health Emergency Preparedness Cooperative Agreement (grant No. NU90TP922035-03-03), funded by the US Centers for Disease Control and Prevention (CDC). Ms. Levin-Rector was supported by ELC CARES (grant No. NU50CK000517-01-09), funded by CDC. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Institutional Review Board of the New York City Department of Health and Mental Hygiene gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Line-level data are not publicly available in accordance with patient confidentiality and privacy laws. Publicly available data are linked below.