Clinical outcomes associated with SARS-CoV-2 Omicron (B.1.1.529) variant and BA.1/BA.1.1 or BA.2 subvariant infection in Southern California

Abstract

Epidemiologic surveillance has revealed decoupling of Coronavirus Disease 2019 (COVID-19) hospitalizations and deaths from case counts after emergence of the Omicron (B.1.1.529) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant globally. However, assessment of the relative severity of Omicron variant infections presents challenges because of differential acquired immune protection against Omicron and prior variants and because longer-term changes have occurred in testing and healthcare practices. Here we show that Omicron variant infections were associated with substantially reduced risk of progression to severe clinical outcomes relative to time-matched Delta (B.1.617.2) variant infections within a large, integrated healthcare system in Southern California. Adjusted hazard ratios (aHRs) for any hospital admission, symptomatic hospital admission, intensive care unit admission, mechanical ventilation and death comparing individuals with Omicron versus Delta variant infection were 0.59 (95% confidence interval: 0.51-0.69), 0.59 (0.51-0.68), 0.50 (0.29-0.87), 0.36 (0.18-0.72) and 0.21 (0.10-0.44), respectively. This reduced severity could not be explained by differential history of prior infection among individuals with Omicron or Delta variant infection and was starkest among individuals not previously vaccinated against COVID-19 (aHR = 0.40 (0.33-0.49) for any hospital admission and 0.14 (0.07-0.28) for death). Infections with the Omicron BA.2 subvariant were not associated with differential risk of severe outcomes in comparison to BA.1/BA.1.1 subvariant infections. Lower risk of severe clinical outcomes among individuals with Omicron variant infection should inform public health response amid establishment of the Omicron variant as the dominant SARS-CoV-2 lineage globally.

Figure 1:. SARS-CoV-2 infections during follow-up within the study cohort.

Plots illustrate total SARS-CoV-2 testing undertaken within the KPSC healthcare system across all clinical settings (a, along with the proportion of tests with positive results [inset]); total outpatient SARS-CoV-2 testing implemented using the ThermoFisher TaqPath COVID-19 Combo Kit assay along with the proportion of tests with SGTF identified (b; blue for SGTF detections and red for non-SGTF detections, with cases from 17 February to 17 March presented on an expanded scale for clarity [inset]); and new inpatient admissions of cases with SARS-CoV-2 infection (c; pink for new detections on or after the admission date and green for cases first ascertained by outpatient testing). Plotted data include 382,971 cases diagnosed over the study period, including 375,642 were tested in outpatient settings and 316,785 had samples processed using the ThermoFisher TaqPath COVID-19 Combo Kit assay.

Figure 2:. Severe clinical outcomes among cases.

Plots illustrate cumulative 30-day risk of severe clinical outcomes among cases first ascertained in outpatient settings, stratified by SGTF status for infecting variant or subvariant. Panels in the top row compare cases with Delta (non-SGTF; red) or Omicron (SGTF; blue) variant infections testing positive in an outpatient setting between 15 December, 2021 and 17 January, 2022, for endpoints of any hospital admission (a); symptomatic hospital admission (b); intensive care unit admission (c); mechanical ventilation (d), and death (e). Panels in the bottom row compare cases with BA.2 (non-SGTF; yellow) and BA.1* (SGTF; blue, comprising BA.1/BA.1.1/BA.1.1.529 lineages) subvariant Omicron infections diagnosed in an outpatient setting between 3 February and 17 March, 2022, for endpoints of any hospital admission (f); symptomatic hospital admission (g); intensive care unit admission (h); and death (i). Mechanical ventilation among BA.2 and BA1* Omicron subvariant cases is not included due to sparse observations. Shaded areas denote 95% confidence intervals around point estimates. Analyses include 23,305 cases with Delta variant infection and 222,688 cases with Omicron variant infection over the period of 15 December, 2021 to 17 January, 2022, and 1,905 cases with BA.2 Omicron subvariant infection and 12,756 cases with BA.1* Omicron subvariant infection over the period of 3 February to 17 March, 2022. Confidence intervals are obtained via bootstrap resampling.

Figure 3:. Adjusted hazard ratios of severe clinical endpoints within strata defined by vaccination status.

Points and lines denote estimates and accompanying 95% confidence intervals for the adjusted hazard ratio of each endpoint, comparing cases with Omicron versus Delta variant infection, in case strata defined by history of COVID-19 vaccination. Analyses are restricted to individuals tested diagnosed in outpatient settings by RT-PCR testing using the ThermoFisher TaqPath COVID-19 combo kit; adjusted hazard ratios are estimated using Cox proportional hazards regression models, controlling for covariates listed in Table S2 and stratifying on positive test date. Analyses include 23,305 cases with Delta variant infection and 222,688 cases with Omicron variant infection. Confidence intervals are obtained using Cox proportional hazards regression models.

Figure 4:. Changes in risk of severe clinical outcomes and in symptoms history among cases during the study period.

Panels illustrate proportions of cases experiencing each clinical outcome over the course of follow-up (30 days for endpoints of hospital admission [a] or symptomatic hospital admission [b]; 60 days for ICU admission [c], mechanical ventilation [d], and mortality [e]). Gray lines denote 95% confidence intervals around estimates for each day based on bootstrap resampling; 7-day moving averages are plotted in red lines. Polygons at the bottom of panels a-e illustrate probability densities of change point timings (blue), while inset panels illustrate fitted slopes for adjusted hazard ratio (aHR) estimates for each endpoint as a function of testing date (red; lines indicating point estimates and polygons delineating 95% confidence intervals). Bottom panels illustrate the proportion of cases tested in outpatient settings indicating symptoms onset on or before their testing date (f); mean time from symptoms onset to outpatient testing, among symptomatic cases (g); and mean time from the testing date to hospital admission, among admitted cases (h). Changes in the proportion of cases ascertained in inpatient settings are plotted separately in Figure S4. Analyses include 316,038 outpatient-diagnosed cases. Confidence intervals around proportions of cases experiencing severe outcomes, by testing date, are obtained by bootstrap resampling; confidence intervals in inset plots around the adjusted hazard ratio of severe outcomes are obtained using Cox proportional hazards regression models.

Figure 5:. Durations of hospital stay.

Top panels illustrate times from hospital admission to discharge to home without skilled care (a), discharge to skilled care or against medical advice (b), and in-hospital death or discharge to hospice (c) among cases testing positive in outpatient settings and subsequently admitted to hospital on or after the date of symptoms onset over the period from 15 December, 2021 to 17 January, 2022; lines and polygons indicate point estimates and 95% confidence intervals, respectively, based on bootstrap resampling for cases with Delta (red) and Omicron (blue) variant infection. Below, panels illustrate histograms of the total length of stay for cases with Delta variant infection (d) and Omicron variant infection (e) within this sample, as well as distributions of the likelihood ratio for cases with Delta vs. Omicron infection to have hospital stays lasting >5 days, >10 days, >15 days, and >20 days (f). The bottom set of panels illustrates times from admission to discharge to home (g), and discharge to skilled care or against medical advice (h), among cases testing positive in outpatient settings and subsequently admitted to hospital on or after the date of symptoms onset over the period from 3 February to 17 March, 2022; lines and polygons indicate point estimates and 95% confidence intervals, respectively, based on bootstrap resampling for cases with BA.2 (yellow) and BA.1* (blue) Omicron subvariant infection. Below, panels illustrate histograms of the total length of stay for cases with BA.2 Omicron subvariant infection (i) and BA.1* Omicron subvariant infection (j) within this sample, as well as distributions of the likelihood ratio for cases with BA.2 vs. BA.1* Omicron subvariant infection to have hospital stays lasting >5 days, >10 days, >15 days, and >20 days (k). Analyses include 208 cases with Delta variant infection and 703 cases with Omicron variant infection for the period of 15 December, 2021 to 17 January, 2022, and 23 cases with BA.2 Omicron subvariant infection and 146 cases with BA.1* Omicron subvariant infection for the period of 3 February to 17 March, 2022. Confidence intervals are computed via bootstrap resampling.