key: cord-0976472-59z5xaax
authors: Ward, I. L.; Bermingham, C.; Ayoubkhani, D.; Gethings, O. J.; Pouwels, K.; Yates, T.; Khunti, K.; Hippisley-Cox, J.; Banerjee, A.; Walker, A. S.; Nafilyan, V.
title: Risk of COVID-19 related deaths for SARS-CoV-2 Omicron (B.1.1.529) compared with Delta (B.1.617.2)
date: 2022-02-25
journal: nan
DOI: 10.1101/2022.02.24.22271466
sha: 14cc2cd3b2aefe3bc16984bbdedd03a5c3b77a19
doc_id: 976472
cord_uid: 59z5xaax

Objective: To assess the risk of death involving COVID-19 following infection from Omicron (B.1.1.539/BA.1) relative to Delta (B.1.617.2). Design: Retrospective cohort study. Setting: England, UK, 1 December 2021 to 25 January 2022. Participants: 1,035,163 people aged 18-100 years who tested positive for SARS-CoV-2 in the national surveillance programme, and had an infection identified as either Omicron- or Delta compatible. Main outcome measures: Death involving COVID-19 as identified from death certification records. The exposure of interest was the SARS-CoV-2 variant identified from NHS Test and Trace PCR positive tests taken in the community (pillar 2) and analysed by Lighthouse laboratories. Cause-specific Cox proportional hazard regression models were adjusted for sex, age, vaccination status, previous infection, calendar time, ethnicity, Index of Multiple Deprivation rank, household deprivation, university degree, keyworker status, country of birth, main language, region, disability, and comorbidities. Additionally, we tested for interactions between variant and sex, age, vaccination status and comorbidities. Results: The risk of death involving COVID-19 was 67% lower for Omicron compared to Delta and the reduction in the risk of death involving COVID-19 for Omicron compared to Delta was more pronounced in males than in females and in people under 70 years old than in people aged 70 years or over. Regardless of age, reduction of the risk of death from Omicron relative to Delta more was more pronounced in people who had received a booster than in those having received only two doses. Conclusions: Our results support early work showing the relative reduction in severity of Omicron compared to Delta in terms of hospitalisation and extends this research to assess COVID-19 mortality. Our work also highlights the importance of the vaccination booster campaign, where the reduction in risk of death involving COVID-19 is most pronounced in individuals who had received a booster.

The Omicron variant, which refers to the whole lineage (BA.1, BA.2, BA.3) had already been shown to be more transmissible than the Delta variant, but there is emerging evidence suggests that the risk of hospitalisation and risk of death within 28 days after a SARS-COV-2 test is lower. However, with a highly transmissible infection and high levels of population testing, definition of death within 28 days is more likely to be susceptible to misclassification bias due to asymptomatic or co-incidental infection. There is no study so far comparing the risk of COVID-19 death as identified from death certification records, with the cause of death assessed by the physician who attended the patient in the last illness.

Using data from a large cohort of COVID-19 infections that occurred in December 2021, we examined the difference in the risk COVID-19 death, as identified from death certification records, between the Delta and Omicron BA.1 variant. Our study shows that risk of death involving COVID-19 was reduced by 67% following infection with the Omicron BA.1 variant relative to the Delta variant after adjusting for a wide range of potential confounders, including vaccination status and comorbidities. Importantly, we found that the relative risk of COVID-19 mortality following Omicron versus Delta infection varied by age and sex, with lower relative risk in younger individuals and for males than females. The reduction in risk of death involving COVID-19 was also most pronounced in individuals who had received a booster. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

On 27 November 2021 the UK Health Security Agency (UKHSA) identified the first UK cases of coronavirus disease 19 (COVID-19) variant B.1.1.529/BA.1, a variant of concern named, together with its sub-variants BA.2 and BA.3, as Omicron (Department of Health and Social Care, 2021). As the Omicron variant, which refers to the whole lineage (BA.1, BA.2, BA. 3 ) had already been shown to be more transmissible, identifying whether the severity of disease, risk of hospitalisation, death or long-term complications is increased relative to Delta, is critical to enable pandemic and policy planning. Emerging data also indicate that risk of hospitalisation is lower following Omicron than Delta infection [4] , [5] , as is the risk of death within 28 days after a SARS-COV-2 test [5] . However, this analysis used death within 28 days of a positive test as a measure of COVID-19 death, rather than deaths involving COVID-19 identified using information from the death certificate, which include deaths at any time period and a cause of death classified by the physician who attended the patient in the last illness. Also, with a highly transmissible infection and high levels of population testing, definition of death within 28 days is more likely to be susceptible to misclassification bias due to asymptomatic co-incidental infection, than when infection rates are lower.

In this study, we compared the risk of COVID-19 death using death registration data in a large populationbased cohort of people infected in England in December 2021, a period where both Delta and Omicron BA.1 variants were circulating, but Omicron BA.2 remained rare. In addition, we adjusted for a range of potential confounders, including pre-existing health conditions which previous work has not assessed. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted February 25, 2022. ; https://doi.org/10.1101/2022.02.24.22271466 doi: medRxiv preprint obtained using probabilistic matching (overall linkage rate: 94.6%). All subsequent linkages were conducted using NHS number. The ONS Public Health Data Asset include data on 35 million adults, an estimated 79% of the population of England in 2020.

The study population included all individuals who had a positive PCR test for COVID-19 between 1 st December 2021 and 31 st December 2021, reported as part of pillar 2 of NHS Test and Trace and analysed by Lighthouse Laboratories, who were enumerated at the 2011 Census and were living in England and were registered with a general practitioner on 1 November 2019. We specifically selected people who 

Our main objective was to compare the risk of death involving COVID-19 between Delta and Omicron BA.1.

We adjusted for a wide range of potential confounders of the relationship between variant type and the risk of COVID-19 death once infected, either in relation to vulnerability or testing behaviours, to account for any bias in our sample of individuals presenting as positive in the national surveillance programme. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted February 25, 2022. ; https://doi.org/10.1101/2022.02.24.22271466 doi: medRxiv preprint Socio-demographic characteristics included age at time of infection (as a natural spline), sex, ethnicity (White/Black/South Asian/Other), region (North East, North West, Yorkshire and the Humber, East Midlands, West Midlands, East of England, London, South East, South West), disability, key worker status, Index of Multiple Deprivation rank (as a natural spline), country of birth (UK/Non-UK), university degree, household deprivation and English language ability. We also adjusted for baseline vaccination status (unvaccinated, one dose, two doses AstraZeneca ≤180 days previously, two doses mRNA vaccine (Pfizer or Moderna) ≤180 days previously, two doses AstraZeneca >180 days previously, two doses mRNA >180 days previously, any booster or third dose, which re refer to as boosters), previous infection (defined by a positive test at least 90 days before the date of the current positive test), for calendar date of infection using a natural spline, and for clinical risk factors by counting the number of conditions identified as being associated with an elevated risk of COVID-19 deaths in the QCovid 3 risk model (0 -8). Further details of the chronic conditions are in Supplementary Table S2 .

Characteristics of the study population were summarised overall, and stratified by variant type, using means for continuous variables and proportions for categorical variables.

We used cause-specific Cox proportional hazard regression model to estimate the hazard ratio of COVID-19 related death for individuals infected with Omicron versus Delta variants. For non-COVID-19 deaths, individuals were censored at the date of death if this occurred before the end of study date. We estimated four models, sequentially adjusted for age, sex, vaccination status and previous infection (Model 1); plus, calendar time (Model 2); plus, socio-economic factors (Model 3); and finally, plus pre-existing health conditions (Model 4).

To test whether the relative risk of mortality of Omicron varied by specific characteristics, we included interactions between variant type and age, and variant type and sex. In addition, we fitted separate fully adjusted models for aged 18-59, 60-69, 70+ years-olds to look at interactions between variant and vaccination status (unvaccinated, one dose, two doses and booster) an interaction between variant and health comorbidities (0, 1-2, 3+), grouped to have enough power to estimate the risk.

We assessed the proportional hazard assumption by testing for the independence between the scaled Schoenfeld residuals and time-at-risk. We used Schoenfeld residuals from the fitted Cox models, smoothed using generalized additive models, to assess whether relative differences in the hazard of COVID-19 death between variant was constant over time following the positive test. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted February 25, 2022. ; https://doi.org/10.1101/2022.02.24.22271466 doi: medRxiv preprint

There were 1,035,163 people in our study population. Of these, 814,011 (78.6%) individuals had Omicroncompatible and 221,152 (21.4%) Delta-compatible infections, with the number of Omicron infections increasing per day across the study period [Supplementary Figure S1 ]. This covers 36.7% of all positive tests in England in December 2021 [6] . In our study population, 54% of infections were in females [ Table 1 , Supplementary Table S3 ]. The mean age at infection was two years younger in those infected with Omicron (39.9 years, SD=15.2) than Delta (42.2 years, SD=13.1). There were 128 deaths involving to COVID-19 and 53 deaths not involving COVID-19 in those infected with Omicron, and 189 and 28, respectively, in those infected with Delta [ Table 2 ]. The mean time from positive result to COVID-19 related death was 13 days (SD=7.0) for Omicron and 16 days (SD=9.6) for Delta. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted February 25, 2022. ; is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint Figure 1 ]. In our minimally adjusted model (Model 1) accounting for sex, vaccination status, age and previous infection, the risk of death was 78% lower is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint 

Estimates of the difference in the relative risk of death involving COVID-19 between Omicron and Delta by sex and age are presented in Figure 2 . The difference in mortality risk varied strongly by age (X 2 (4) = 22.8, p < 0.001) with greater reduction in COVID-19 mortality with Omicron compared to Delta for people under aged 18-59 (HR=0.13, 95%CI: 0.06, 0.30) and 60-69 years (HR=0.14, 95%CI: 0.05, 0.36) than aged 70 or over (HR=0.45, 95%CI: 0.16, 1.24, heterogeneity p-value = < 0.001). For the interaction between sex and variant (X 2 (1) = 5.65, p < 0.017), the reduction in mortality risk for COVID-19 is more pronounced in males (HR=0.25, 95%CI: 0.17, 0.37) than in females (HR=0.44, 95%CI: 0.28, 0.68, heterogeneity p-value = 0.016). is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint 

To assess whether the difference in risk of death between Omicron and Delta varied by age and comorbidities, we fitted fully adjusted models separately for different ages (18-59, 60-69, 70+ years-old) and tested for an interaction between variant and vaccination status, and separately between variant and number of health comorbidities within each age group [ Figure 3 ]. To assess the interaction between variant and vaccination, vaccination status was re-grouped to unvaccinated, one dose, two doses and booster. It was not possible to compute accurate confidence intervals for risk in the 'one dose' group due to lack of The risk of COVID-19 related death following Omicron infection was lower than Delta, for all age groups, regardless of the number of comorbidities (grouped to 0, 1-2 and 3+), but there was no evidence that the relative mortality risk varied by the number of comorbidities [ Figure 3 ].

We tested the proportional hazard assumption by testing for the independence between the scaled Schoenfeld residuals and time-at-risk. The test failed to reject the independence for the exposure (p = 0.07), suggesting that the proportional hazard assumption was unlikely to be violated. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint 

Using data from a large cohort of COVID-19 infections that occurred in December 2021, we examined the difference in mortality between the Delta and Omicron BA.1 variant. Our study shows that risk of death involving COVID-19 was reduced by 67% following infection with the Omicron BA.1 variant relative to the Delta variant after adjusting for a wide range of potential confounders, including vaccination status and comorbidities. Importantly, we found that the relative risk of COVID-19 mortality following Omicron versus Delta infection varies by age, with lower relative risk in younger individuals.

Early work exploring the clinical severity of COVID-19 Omicron variant in a South African cohort found significantly reduced odds of hospitalisation following SGTF versus non-SGTF infection across the same period [4] . A subsequent study in California on positive PCR tests between 30 November 2021 and 1 January 2022 also showed risk reductions for hospital admission, ICU admission and mortality following Omicron relative to Delta infections [7] . In Canada, in a matched sample, the risk of hospitalisation or death was found to be 65% lower among Omicron than Delta cases [8] .

Our results extend these initial analyses quantifying intrinsic risk of Omicron severity in terms of hospital admissions, to COVID-19 mortality. Nyberg et al. 2022 report a reduction in death following Omicron infection (HR=0.31) relative to Delta, which is similar to our findings. Importantly, our results account for more sociodemographic factors and comorbidities, and highlight that the reduction in risk remains consistent even after adjusting for these additional variables. Furthermore, our study specifically quantifies the risk of cause-specific COVID-19 mortality, utilising death registration data, unlike previous work which has defined COVID-19 death as death within 28 days of a positive COVID-19 test, resulting in large is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted February 25, 2022. ; https://doi.org/10.1101/2022.02.24.22271466 doi: medRxiv preprint

First, we use a large sample of positive cases from the national testing programme, allowing to precisely estimate the relative risk of COVID-19 death following infection with Omicron BA.1 and Delta. Second, by linking these infection data to information on vaccination status, comprehensive socio-demographic characteristics from the Census and information on pre-existing conditions based on primary care and hospital data, we were able to estimate the difference in mortality between the Omicron BA.1 and Delta variants, adjusting for a wide range of potential confounders, including vaccination status with manufacturer type, and key worker status. We also tested for the relative mortality risk of Omicron depended on the vaccination status, by including interactions between variant type and vaccination status. Third, we use death certificate data to confirm COVID-19 mortality, preventing our sample being conflated with non-COVID-19 related deaths of individuals that die of other causes following a positive COVID-19 test. We also compared the outcomes during the same time periods overcoming any differences due to changes in management of infected patients over the time period of the pandemic.

The main study limitation is an ascertainment bias since the data do not cover all SARS-CoV-2 infections, but only a subset of people who tested positive as part of the national testing programme in the community and analysed by Lighthouse laboratories. Tests conducted in the community but processed by other laboratories and tests conducted in hospitals could not be used because they do not use the S-gene molecular diagnostic assay, which we used to identify the variant type. A limitation of our work is not having access data to derive COVID-19 variants from tests in hospital (NHS Pillar 1), and explains why our total sample is smaller than other research [5] . Differences in testing behaviours between groups may bias the estimates of risk of COVID-19 death among people who tested positive. If some people only get tested if they experience severe symptoms, the estimated risk of death would be higher in this group than in people who get tested more routinely, even if the population has the same underlying risk. To mitigate this issue, we also adjusted the models for factors that may affect the propensity to get tested and may also be related to the severity of a SARS-CoV-2 infection, including ethnicity, region, calendar date of infection, and key worker status. Socio-demographic information was used from Census 2011 as was the most up to date at time of publishing, however future validation work should be conducted once Census 2021 data has been released and potentially using more granular breakdowns of variables, such as region.

Because of death registration delays, not all deaths that occurred in the period may yet have been registered. Deaths that occurred amongst people who tested positive in late December are less likely to have been registered than those which occurred in people who tested positive at the beginning of the month. As the proportion of cases which are from the Omicron variant increased during December, the delay in death registration, if unaccounted for, could lead to underestimation of the severity of the Omicron variant. However, we accounted for the effect of registration delay in December by adjusting for calendar time of infection in our models, reducing the difference between Omicron compared to Delta as expected. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint 

Given the emergence of the more transmissible Omicron BA.1 variant, there was an urgent healthcare requirement to quantify the risk of COVID-19 death relative to other variants to support pandemic planning responses. Our results support early work showing the relative reduction in severity of Omicron compared to Delta in terms of hospitalisation and extends this research to assess COVID-19 mortality, being the first to our knowledge to assess cause-specific COVID-19 death using death certification to accurately capture COVID-19 deaths. Our work also highlights the importance of the vaccination booster campaign, where the reduction in risk of death involving COVID-19 is most pronounced in individuals who had received a booster. However, mortality is only one metric that should be considered when assessing of the impact of COVID-19 and subsequent work should investigate long-term outcomes of infection, such as the prevalence of long COVID following Omicron infection relative to Delta. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted February 25, 2022. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted February 25, 2022. ; https://doi.org/10.1101/2022.02.24.22271466 doi: medRxiv preprint

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UK Coronavirus Dashboard

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SARS-CoV-2 variants of concern and variants under investigation in England Technical briefing 34