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Increased mortality in community-tested cases of SARS-CoV-2 lineage B.1.1.7

Our take —

S gene target failure (SGTF) is a hallmark of the B.1.1.7 variant. Among 2,245,263 individuals who tested positive for SARS-CoV-2 in the community in England between November 1, 2020 and February 14, 2021, 0.9% died, and 51% had conclusive SGTF test results (59% of whom had SGTF). SGTF was associated with >50% increased hazard of death across all analyses, accounting for covariates, missing data, and misclassification, but bias due to non-random missing data and residual confounding cannot be ruled out.

Study design

Retrospective Cohort

Study population and setting

This study includes 2,245,263 (54% female, 79% < 55 years old) individuals who had a positive SARS-CoV-2 test at a community testing site (“Pillar 2” testing) in England between November 1, 2020 and February 14, 2021. Data were combined across three Public Health England datasets: 1) specimen date and demographic information from community testing, 2) cycle threshold values for ORF1ab, N( nucleocapsid), and S (spike) genes from three national laboratories, and 3) deaths due to COVID-19 in England reported to the Office for National Statistics. S gene target failure (SGTF), a hallmark of the B.1.1.7 variant, was defined as a SARS-CoV-2 test result with cycle threshold (CT) values <30 for both ORF1ab and N targets, but no detectable S gene (CT>40). Complete case and inverse-probability weighted models (to account for missing SGTF status) estimated the hazard of death associated with SGTF were adjusted for several covariates, including age, sex, ethnicity, index of multiple deprivation, place of residence, national health service (NHS) England region, and test date. Absolute risks of death were estimated from the adjusted hazard ratios from complete case analysis and compared to “baseline” estimates of absolute risk of death for sex and age groups using data from individuals tested during August-October 2020. SGTF was used as a proxy for B.1.1.7 variant detection, and misclassification analyses explored potential biases resulting from this.

Summary of Main Findings

Fewer than 1% of people (N=19,615) in the study had a death recorded, and, overall, only 51% of had conclusive SGTF results; of those, 59% had SGTF (30% of the total study population). Prevalence of SGTF increased throughout the study period from 5.8% to 94.3%. For the 51% of individuals with known SGTF status, the death rate was higher among those with SGTF than those without (1.86 vs. 1.42 per 10,000 person-days), and this elevated death rate was consistently seen in nearly all (94%) analyses stratified for covariates. In adjusted models, SGTF was associated with increased risk of death in complete case analysis (hazard ratio (HR): 1.55, 95% confidence interval (CI): 1.39-1.72) and when using inverse probability weighting to account for missing SGTF status (HR: 1.58, 95% CI: 95% CI: 1.40-1.78). There was evidence of non-proportional hazards, indicating that as time since positive test increased, the hazard ratio for death comparing SGTF and non-SGTF groups also increased. For individuals <70, absolute risk of death was <1% for baseline and SGTF groups, though slightly elevated among individuals with SGTF, whereas absolute risk of death for SGTF vs. baseline was markedly increased among older individuals (females 70-84: 4.4% vs. 2.9%, females 85+: 19% vs. 13%, males 70-84: 7.2% vs. 4.7%, males 85+: 25% vs. 17%). Results were consistent in analyses that accounted for potential misclassification due to using SGTF as a proxy for the variant of concern B.1.1.7.

Study Strengths

This was a very large study, and included recent data on this variant of concern. Analyses were robust to different methods of handling missing data, non-proportionality of hazards over time, and misclassification of SGTF. Analyses were adjusted for several covariates that may skew the observed association between SGTF (a proxy for B.1.1.7) and death.

Limitations

Almost half of eligible participants were missing data on SGTF and were excluded from the analysis. The missingness was not random (i.e. related to several important covariates, including age and location of residence) which may lead to biased results. Additionally, the study population included only individuals who were tested for SARS-CoV-2 in the community, and thus may not be generalizable to individuals who first tested positive in the hospital, which is where most severe cases, including majority of cases leading to mortality, were first tested. Other variants lead to SGTF, and B.1.1.7 prevalence among SGTF samples was not confirmed via sequencing; results should be cautiously interpreted as B.1.1.7 specific.

Value added

This was a very large and robust study with data linked across Public Health England evaluating the impact of S gene target failure (as a proxy for the B.1.1.7 variant of concern) on mortality.

This review was posted on: 3 April 2021