key: cord-0270879-p6y6ud8b
authors: Fisman, D.; Tuite, A.
title: Age-Specific Changes in Virulence Associated with SARS-CoV-2 Variants of Concern
date: 2021-09-27
journal: nan
DOI: 10.1101/2021.09.25.21264097
sha: 7868db14a096b5329364076cde404c7c2d2be164
doc_id: 270879
cord_uid: p6y6ud8b

Background: Novel variants of concern (VOCs) have been associated with both increased infectivity and virulence of SARS-CoV-2. The virulence of SARS-CoV-2 is closely linked to age. Whether relative increases in virulence of novel VOCs is similar across the age spectrum, or is limited to some age groups, is unknown. Methods: We created a retrospective cohort of people in Ontario, Canada testing positive for SARS-CoV-2 and screened for VOCs, with dates of test report between February 7 and August 30, 2021 (n=233,799). Cases were classified as N501Y-positive VOC, probable Delta VOC, or VOC undetected. We constructed age-specific logistic regression models to evaluate the effects of N501Y-postive or Delta VOC infections on infection severity, using hospitalization, intensive care unit (ICU) admission, and death as outcome variables. Models were adjusted for sex, time, health unit, vaccination status, comorbidities, immune compromise, long-term care residence, healthcare worker status, and pregnancy. Results: Infection with either N501Y-positive or Delta VOCs was associated with significant elevations in risk of hospitalization, ICU admission, and death in younger and older adults, compared to infections where a VOC was not detected. Delta VOC increased hospitalization risk in children under 10 by a factor of 2.5 (adjusted odds ratio, 95% confidence interval: 1.2 to 5.1) compared to non-VOC. For most VOC-outcome combinations there was no heterogeneity in adverse outcomes by age. However, there was an inverse relationship between age and relative increase in risk of death with delta VOC, with younger age groups showing a greater relative increase in risk of death than older individuals. Interpretation: SARS-CoV-2 VOCs appear to be associated with increased relative virulence of infection in all age groups, though low absolute numbers of outcomes in younger individuals make estimates in these groups imprecise.

adverse outcomes by age. However, there was an inverse relationship between age and relative 43 increase in risk of death with delta VOC, with younger age groups showing a greater relative 44 increase in risk of death than older individuals. 45 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Emerging SARS-CoV-2 variants of concern (VOC) have displayed increased infectivity as well 52 as increased virulence relative to strains circulating early in the pandemic (1-7). In particular, the 53 emergence of the highly infectious and virulent Delta variant has led to revised expectations of 54 the pandemic's severity and duration (8-11). Notwithstanding the severe health and economic 55 toll the SARS-CoV-2 pandemic has taken worldwide, one relatively assuasive aspect of its 56 epidemiology had been decreased virulence of infection in children, with nearly 50% of infected 57 children experiencing asymptomatic infection (12, 13) . However, in the summer of 2021, both 58 the United Kingdom and the United States have reported an extraordinary surge in pediatric 59 hospitalizations related to SARS-CoV-2 infection (14) (15) (16) (17) . The coincidence of this surge with 60 Delta variant emergence in both countries has led some to suggest that this surge was driven by 61 Delta variant emergence. However, surging admissions could simply reflect the increased 62 infectivity of Delta variant, resulting in larger numbers of infected children without any change 63 in per-infection virulence. As such, it has been challenging to determine with certainty whether 64 infection with Delta VOC is more virulent in children than non-VOC SARS-CoV-2, or other 65 VOCs, such as those with the N501Y mutation (18 5   availability of a single master line list of all COVID-19 cases in the Canadian province of  74   Ontario, which includes patient outcomes (hospitalization, intensive care admission, and/or  75   death), important covariates including underlying medical conditions, and virological typing data  76 from February 2021 forward, provides an opportunity to evaluate age-specific risk associated 77 with VOC infection, and to determine whether there is heterogeneity in virulence across age 78 groups. Our objectives were to: (i) estimate age-specific risks of severe illness in individuals 79 infected with Delta or N501Y-positive VOC, relative to non-VOC SARS-CoV-2 infection; (ii) to 80 evaluate whether there is heterogeneity in differential risk by age group; and (iii) to explore the 81 sources of any such heterogeneity. 82 83 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint There has been an evolution in VOC screening and viral sequencing in Ontario over the course 99 of the pandemic. VOC cases were initially identified in Ontario in December 2020, with 100 subsequent targeted screening of isolates from individuals with a history suggestive of possible 101 VOC infection (e.g., travel). Systematic screening for VOCs with low cycle threshold (< 35) 102 began in February 2021. Initial screening focussed on the N501Y mutation, with screening for 103 both N501Y and E484K initiated in March 2020. At that time a 5% sampling of specimens was 104 subjected to all specimens, regardless of screen results, was initiated, with the fraction increased 105 to 50% by late May 2021. As of June 2021, routine WGS was discontinued on N501Y-106 POSITIVE/E484-specimens, which were presumed to be alpha lineage. Over 90% of infections 107 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint We constructed age-group-specific logistic regression models for the effects of N501Y-positive 119

or Delta VOC infection, on infection severity, defined as hospitalization, ICU admission, or 120 death. Models were adjusted for male sex, time (modeled as a week-on-week linear trend), 121 vaccination status (in age groups 10 years and older), documented major comorbidity (including 122 asthma, COPD, hematological disease, liver disease, cardiac disease, diabetes, renal disease, 123 neurological disease, malignancy, or obesity), and immune compromise. In relevant age groups 124 we also adjusted for pregnancy, long-term care residence and healthcare worker status. Due to 125 geographic variation in timing of emergence of variants, we also adjusted for health unit region, 126 with health units classified as "Greater Toronto-Hamilton Area", "Ottawa", and "other". 127

All of these covariates were expected a priori to confound the association between VOC 128 exposure and disease severity. We considered odds ratios to approximate relative risks under the 129 "rare disease assumption" (24) . 130 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Adjusted odds ratios and confidence intervals for relative severity of VOC from age-131 group-specific models were incorporated into random effects meta-analyses to generate summary 132 estimates of effect, and to evaluate heterogeneity in effects by variant and age. Heterogeneity by 133 age was assessed by constructing meta-regression models in which age group was treated as an 134 ordinal variable in order to identify linear trends in effect across age groups. 135

We conducted regression analyses in R version 4.1.0; meta-analyses and meta-regression 136 were performed using the meta package in R (25, 26) . The study was conducted in accordance 137 with the STROBE guidelines for observational research (27) were more likely to be fully vaccinated, reflecting the fact that Delta became established in the 151 population in the spring of 2020, once vaccination programs were underway. For Delta VOC infections, significantly elevated hospitalization risk was seen in all age groups 162 except 10-to-19 year-olds. In children, the risk of hospitalization with Delta VOC was 2.5-fold 163 higher than that seen with non-VOC SARS-CoV-2. ICU admission risk could not be estimated 164 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Odds ratios for death with Delta could not be estimated for those aged less than 30 years; in 167 adults aged greater than 30 years the risk of death was elevated with Delta VOC infection though 168 confidence intervals for estimates in the 50-to-59 year and 80-and-over age groups overlapped 1. 169

In random effects meta-analyses, we found no significant heterogeneity in odds ratios across age 171 groups for death and ICU risk with N501Y-positive VOC, or for hospitalization and ICU risk 172 with Delta VOC. By contrast, significant heterogeneity in risk estimates was seen for 173 hospitalization risk across age groups with N501Y-positive VOC, and for death risk with Delta 174 VOC (Figure 1) . Across all outcomes, infection with Delta VOC was associated with elevated 175 risk, compared to N501Y-positive infections. 176

We evaluated the contribution of age to heterogeneity in estimates by constructing meta-178 regression models with age group treated as a 9-level ordinal variable. For hospitalization risk 179 and N501Y-positive VOC, we found no relationship between age and odds ratio (relative OR per 180 10-year increase in age 1.01, 95% CI 0.97 to 1.05). For mortality risk and Delta VOC, there was 181 an inverse association between age group and relative OR (0.69, 95% CI 0.50 to 0.94). 182 183 184 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The landscape of SARS-CoV-2 infection continues to change rapidly, with novel variants of 187 concern impacting both transmissibility and virulence of infection. In this analysis, we evaluated 188 the relative impact of earlier N501Y-positive VOC, and subsequent Delta VOC infections on 189 severity of infection by age group. We find that, as reported previously, Delta VOC infection is 190 more virulent than infection with both N501Y-positive VOC and non-VOC SARS-CoV-2 strains 191 (7, 10, 28). We find no statistical evidence that the increase in virulence of Delta VOC in the 192 population as a whole is diminished in younger people. The absence of significant elevations of 193 risk in younger age groups for some outcomes is likely to reflect lower absolute risk (and 194 numbers of events) in these groups, with consequent lack of precision in estimates. Notably, the 195 risk of hospitalization with Delta VOC appears significantly increased in children. The relative 196 rarity of ICU admissions and deaths in younger age groups makes us unable to generate relative 197 risk estimates for these outcomes with Delta in children, but an increase in virulence as well as 198 transmissibility with Delta VOC in children would be consistent with recent observed surges in 199 pediatric hospitalizations reported in the United States and United Kingdom (14) (15) (16) (17) . 200 201 For most combinations of VOC and outcomes, we found no evidence of variation in increased 202 risk by age, but for Delta VOC, we also found an inverse, age-related gradient in relative risk of 203 death with Delta infection with VOC, in contrast to non-VOC infection. This does not indicate 204 that there is no excess risk associated with VOC in older individuals; indeed, we find significant 205 increases in risk of severe outcomes with both N501Y-positive and Delta VOC in older 206 individuals. Rather, this signifies that relative increase in mortality risk with Delta increases as 207 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted September 27, 2021. ;  https://doi.org/10.1101/2021.09.25.21264097 doi: medRxiv preprint age diminishes for Delta VOC, though our analysis was limited to age groups 40 and older. If 208 this effect proves generalizable, it suggests that the Delta variant will enhance mortality of 209 SARS-CoV-2 infection in younger age groups, which have been (and remain) less likely to 210 experience critical illness than older age groups. 211 212 Our analysis is subject to important limitations: first, the relative rarity of severe outcomes in 213 younger age groups means that our estimates for these groups are imprecise. Furthermore, our 214 failure to identify heterogeneity in severity by age, when evaluating effects in children and teens, 215 may simply be related to the imprecision of estimates in these age groups, rather than true lack of 216 heterogeneity. A second limitation is the degree to which frequency of testing, particularly in 217 younger age groups, has been dynamic in Ontario during the COVID-19 pandemic (21) . 218

Increasing frequency of testing in under-tested younger age groups over time, as VOC emerged 219 in the population, could increase the fraction of mild cases identified, and may have served to 220 mask increases in severity. 221

In summary, however, we find no evidence to suggest that the apparent increase in virulence of 223 SARS-CoV-2 VOC is limited to a particular age group; indeed, we present evidence that the 224 relative virulence of Delta VOC, as represented by mortality risk, may be inversely related to 225 age. The relative rarity of severe outcomes in children and teens means that more study is needed 226 to assess the robustness and generalizability of these findings. 227 228 Acknowledgements 229 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint NOTE: Linear trend estimated by treating age category as a 9-level ordinal variable. *Estimated amount of residual heterogeneity due to between-age group variation. *Fraction of heterogeneity accounted for by including age in meta-regression models. Models were adjusted for sex, health unit region, age group, vaccination status, comorbidity, immune compromise, and (in relevant age groups) long-term care residence, healthcare worker status, and pregnancy.

VOC, variant of concern

P-values based on chi-squared test

*Vaccination status is defined as in methods. †Comorbidities include one or more of asthma, COPD, hematological disease, liver disease, cardiac disease, diabetes, renal disease, neurological disease, malignancy, or obesity. Immune compromise was included as a separate covariate in models

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