SARS-CoV-2 variants and considerations of inferring causality on disease severity
Authors: Muge Cevik, Sharmistha Mishra
Journal: The Lancet Infectious Diseases (2021)

The SARS-CoV-2 B.1.1.7 variant that was first identified in Kent (UK) in December, 2020, has now spread to many countries and shown consistent fitness advantage over other variants in circulation at the time.1Davies NG Abbott S Barnard RC et al.Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England.Science. 2021; 372eabg3055Crossref PubMed Scopus (1570) Google Scholar This means an increase in transmission potential, which alone can lead to increased rates of hospitalisations and deaths. In The Lancet Infectious Diseases, Peter Bager and colleagues report the risk of hospitalisation with B.1.1.7 variant using the impressive population-level sequencing data in Denmark that include cases detected from both community-based and hospital-based testing.2Bager P Wohlfahrt J Fonager J et al.Risk of hospitalisation associated with infection with SARS-CoV-2 lineage B.1.1.7 in Denmark: an observational cohort study.Lancet Infect Dis. 2021; (published online June 22.)https://doi.org/10.1016/S1473-3099(21)00290-5Summary Full Text Full Text PDF PubMed Scopus (79) Google Scholar All SARS-CoV-2-positive cases confirmed by RT-PCR in Denmark, sampled between Jan 1 and March 24, 2021, with 14 days of follow-up for COVID-19 hospitalisation were assessed for this observational study. COVID-19 hospitalisation was defined as first admission lasting longer than 12 h within 14 days of a sample with a positive RT-PCR result, and the study population and main analysis were restricted to the proportion of cases with viral genome data. Bager and colleagues calculated crude and adjusted risk ratios (RRs) of hospital admission, with adjustments done for several important confounders such as sex, age, calendar time, region, and comorbidities. The analysis included 30 572 individuals with genomic data (60·0% of 50 958 positive cases with 14 days follow-up), of whom 10 544 (34·5%) had been infected with B.1.1.7. Compared with other lineages, the authors found a seemingly protective effect of B.1.1.7 (RR 0·79, 95% CI 0·72–0·87; p<0·0001) in the crude analyses but, after adjustment, B.1.1.7 was associated with increased risk of hospitalisation (1·42, 1·25–1·60; p<0·0001). These findings are consistent with early reports and strengthen the association between B.1.1.7 and increased disease severity observed previously (table).4Horby P Bell I Breuer J et al.NERVTAG update note on B.1.1.7 severity, 11 February. New & Emerging Respiratory Threats Advisory Group, 2021https://www.gov.uk/government/publications/nervtagupdate-note-on-b117-severity-11-february-2021Date accessed: May 31, 2021Google Scholar Particularly increased severity observed with B.1.1.7 appeared to be specific to adults older than 30 years,5Nyberg T Twohig KA Harris RJ Risk of hospital admission for patients with SARS-CoV-2 variant B.1.1.7: cohort analysis.BMJ. 2021; 373n1412Crossref PubMed Scopus (90) Google Scholar and pronounced among those older than 65 years.8Grint DJ Wing K Williamson E et al.Case fatality risk of the SARS-CoV-2 variant of concern B.1.1.7 in England, 16 November to 5 February.Euro Surveill. 2021; 262100256Crossref Scopus (131) Google ScholarTableSummary of studies assessing the association between B.1.1.7 and disease severityNumber of cases with B.1.1.7Data sourceAdjustments forRisk ratiosComorbiditiesDeprivationTime periodStudies assessing the risk of hospitalisation among those who tested positiveBager et al2Bager P Wohlfahrt J Fonager J et al.Risk of hospitalisation associated with infection with SARS-CoV-2 lineage B.1.1.7 in Denmark: an observational cohort study.Lancet Infect Dis. 2021; (published online June 22.)https://doi.org/10.1016/S1473-3099(21)00290-5Summary Full Text Full Text PDF PubMed Scopus (79) Google Scholar10 544Hospital and communityYesYesYes1·42 (1·25–1·60)Dabrera et al3Dabrera G Allen H Zaidi A et al.Assessment of mortality and hospital admissions associated with confirmed infection with SARS-CoV-2 variant of concern VOC-202012/01 (B.1.1.7) a matched cohort and time-to-event analysis.SSRN. 2021; (published online March 22.) (preprint).https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3802578Crossref Google Scholar6038Hospital and communityNoNoYes1·34 (1·07–1·66)PHS4Horby P Bell I Breuer J et al.NERVTAG update note on B.1.1.7 severity, 11 February. New & Emerging Respiratory Threats Advisory Group, 2021https://www.gov.uk/government/publications/nervtagupdate-note-on-b117-severity-11-february-2021Date accessed: May 31, 2021Google ScholarNAHospital and communityYesYesYes1·63 (1·48, 1·80)HOCI4Horby P Bell I Breuer J et al.NERVTAG update note on B.1.1.7 severity, 11 February. New & Emerging Respiratory Threats Advisory Group, 2021https://www.gov.uk/government/publications/nervtagupdate-note-on-b117-severity-11-february-2021Date accessed: May 31, 2021Google Scholar2386Hospital (ICU)NoNoNo1·15 (0·86–1·53)Nyberg et al5Nyberg T Twohig KA Harris RJ Risk of hospital admission for patients with SARS-CoV-2 variant B.1.1.7: cohort analysis.BMJ. 2021; 373n1412Crossref PubMed Scopus (90) Google Scholar27 710CommunityNoYesYes1·52 (1·47–1·57)Studies assessing the risk of death among those hospitalisedPatone et al6Patone M Thomas K Hatch R et al.Analysis of severe outcomes associated with the SARS-CoV-2 variant of concern 202012/01 in England using ICNARC Case Mix Programme and QResearch databases.medRxiv. 2021; (published online March 12.) (preprint).https://doi.org/10.1101/2021.03.11.21253364Google Scholar3400Hospital (ICU)YesYesYes0·93 (0·76–1·15)CO-CIN4Horby P Bell I Breuer J et al.NERVTAG update note on B.1.1.7 severity, 11 February. New & Emerging Respiratory Threats Advisory Group, 2021https://www.gov.uk/government/publications/nervtagupdate-note-on-b117-severity-11-february-2021Date accessed: May 31, 2021Google Scholar216HospitalNoYesYes0·63 (0·20–1·69)CO-CIN4Horby P Bell I Breuer J et al.NERVTAG update note on B.1.1.7 severity, 11 February. New & Emerging Respiratory Threats Advisory Group, 2021https://www.gov.uk/government/publications/nervtagupdate-note-on-b117-severity-11-february-2021Date accessed: May 31, 2021Google Scholar404HospitalNoYesYes0·67 (0·32–1·40)CO-CIN4Horby P Bell I Breuer J et al.NERVTAG update note on B.1.1.7 severity, 11 February. New & Emerging Respiratory Threats Advisory Group, 2021https://www.gov.uk/government/publications/nervtagupdate-note-on-b117-severity-11-february-2021Date accessed: May 31, 2021Google Scholar412HospitalNoYesYes0·81 (0·50–1·32)Frampton et al7Frampton D Rampling T Cross A et al.Genomic characteristics and clinical effect of the emergent SARS-CoV-2 B.1.1.7 lineage in London, UK: a whole-genome sequencing and hospital-based cohort study.Lancet Infect Dis. 2021; (published online April 12.)https://doi.org/10.1016/S1473-3099(21)00170-5Summary Full Text Full Text PDF PubMed Scopus (272) Google Scholar289HospitalYesNoYes1·12 (0·71–1·78)Studies assessing the risk of death among those who tested positiveDavies et al1Davies NG Abbott S Barnard RC et al.Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England.Science. 2021; 372eabg3055Crossref PubMed Scopus (1570) Google Scholar674 539CommunityNoYesYes1·55 (1·39–1·72)Patone et al6Patone M Thomas K Hatch R et al.Analysis of severe outcomes associated with the SARS-CoV-2 variant of concern 202012/01 in England using ICNARC Case Mix Programme and QResearch databases.medRxiv. 2021; (published online March 12.) (preprint).https://doi.org/10.1101/2021.03.11.21253364Google Scholar80 494Hospital and communityYesYesYes1·59 (1·25–2·03)Grint et al8Grint DJ Wing K Williamson E et al.Case fatality risk of the SARS-CoV-2 variant of concern B.1.1.7 in England, 16 November to 5 February.Euro Surveill. 2021; 262100256Crossref Scopus (131) Google Scholar91 775Primary careYesYesYes1·67 (1·34–2·09)Challen et al9Challen R Brooks-Pollock E Read JM Dyson L Tsaneva-Atanasova K Danon L Risk of mortality in patients infected with SARS-CoV-2 variant of concern 202012/1: matched cohort study.BMJ. 2021; 372: n579Crossref PubMed Scopus (513) Google Scholar54 906CommunityNoYesYes1·64 (1·32–2·04)Dabrera et al3Dabrera G Allen H Zaidi A et al.Assessment of mortality and hospital admissions associated with confirmed infection with SARS-CoV-2 variant of concern VOC-202012/01 (B.1.1.7) a matched cohort and time-to-event analysis.SSRN. 2021; (published online March 22.) (preprint).https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3802578Crossref Google Scholar6038Hospital and communityNoNoYes1·06 (0·82–1·38)PHS4Horby P Bell I Breuer J et al.NERVTAG update note on B.1.1.7 severity, 11 February. New & Emerging Respiratory Threats Advisory Group, 2021https://www.gov.uk/government/publications/nervtagupdate-note-on-b117-severity-11-february-2021Date accessed: May 31, 2021Google ScholarNAHospital and communityYesYesYes1·37 (1·02–1·84)CO-CIN=COVID-19 Clinical Information Network. HOCI=COVID-19 Genomics UK Consortium Hospital Onset COVID-19 Infection Study. ICU=intensive care unit. NA=not applicable. PHE=Public Health England. PHS=Public Health Scotland. Open table in a new tab CO-CIN=COVID-19 Clinical Information Network. HOCI=COVID-19 Genomics UK Consortium Hospital Onset COVID-19 Infection Study. ICU=intensive care unit. NA=not applicable. PHE=Public Health England. PHS=Public Health Scotland. The study highlights three key considerations when trying to attribute an increase in disease severity to a variant of concern that also increases transmission risk, in the context of surveillance data. First, potential confounders in this context include factors that increase acquisition risk overlapping with factors known to increase severity, irrespective of lineages, such as age or comorbidities. For example, because B.1.1.7 is associated with a higher secondary attack rate, then the outbreak setting could introduce confounding if not accounted for, especially if the setting, such as a congregate living or workplaces, is more likely to include individuals with comorbidities. Increased transmission potential with B.1.1.7 means that it has reached and concentrated, like the early lineages, among economically marginalised communities who might also have higher rates of comorbidities.10Sundaram ME Calzavara A Mishra S et al.The individual and social determinants of COVID-19 diagnosis in Ontario, Canada: a population-wide study.medRxiv. 2021; (published online March 19.) (preprint).https://doi.org/10.1101/2020.11.09.20223792PubMed Google Scholar Therefore, the attributable effect of variants of concern on disease severity should account for confounders in the pathway of infection risk, such as social determinants and outbreak settings, while also addressing confounders in the pathway to severity risk in the case of infection (age, sex, and comorbidities). Second, selection biases can play a major role in drawing inference on relative severity risks.11Griffith GJ Morris TT Tudball MJ et al.Collider bias undermines our understanding of COVID-19 disease risk and severity.Nat Commun. 2020; 115749Crossref PubMed Scopus (465) Google Scholar The key player here is the reason for testing, and thus the sample selected for discerning the relative severity of B.1.1.7. For example, if a study excludes cases detected and admitted to hospital at the time of testing,12Davies NG Jarvis CI Edmunds WJ et al.Increased mortality in community-tested cases of SARS-CoV-2 lineage B.1.1.7.Nature. 2021; 593: 270-274Crossref PubMed Scopus (624) Google Scholar then the study population might underestimate the severity of the lineage that causes more severe infection. Similarly, if the study is restricted to individuals admitted to hospital,7Frampton D Rampling T Cross A et al.Genomic characteristics and clinical effect of the emergent SARS-CoV-2 B.1.1.7 lineage in London, UK: a whole-genome sequencing and hospital-based cohort study.Lancet Infect Dis. 2021; (published online April 12.)https://doi.org/10.1016/S1473-3099(21)00170-5Summary Full Text Full Text PDF PubMed Scopus (272) Google Scholar we might not observe an increased risk of death among those hospitalised even if B.1.1.7 increases mortality risk among those diagnosed. Additionally, an important selection bias that is common across most studies with surveillance data is that only a subset of all cases will have information on lineages, and missing information on lineage might not be random. Third, increased transmission potential means that the lineage can take over and thus, some studies might be limited in comparing B.1.1.7 cases with historical cases of other lineages. This difference in timing of comparator cases could lead to confounding if other factors, such as hospital pressure, influence mortality.13Rossman H Meir T Somer J et al.Hospital load and increased COVID-19 related mortality in Israel.Nat Commun. 2021; 121904Crossref PubMed Scopus (56) Google Scholar Timing of cases and comparators might also affect how readily cases of B.1.1.7 can be compared with those in a similar transmission network (confounders on the pathway of infection risk) when increased transmission potential leads to variant replacement. Therefore, evaluating the attributable relative risks of severity is particularly challenging when the risk factor in question also increases transmission potential. Determining relative severity across emerging variants will become increasingly challenging with SARS-CoV-2 vaccination, in the context of variable effectiveness, by factors such as vaccine coverage by social determinants of acquisition and transmission risks and differential vaccine effectiveness by lineages. The mechanisms by which increased transmission potential might challenge our ability to estimate attributable severity further emphasise the crucial role that increased transmissibility potential plays in hospitalisations and mortality—irrespective of any direct effect of the variant on severity. As Bager and colleagues show, careful consideration of all three potential challenges requires detailed data and a systematic approach to matching or adjusting for confounding. Not all surveillance systems can support this, and an investment in data platforms that enable rapid and robust analyses of relative transmission potential and relative severity remain crucial as new variants emerge. MC is a member of the New & Emerging Respiratory Threats Advisory Group. SM declares no competing interests. Risk of hospitalisation associated with infection with SARS-CoV-2 lineage B.1.1.7 in Denmark: an observational cohort studyInfection with SARS-CoV-2 lineage B.1.1.7 was associated with an increased risk of hospitalisation compared with that of other lineages in an analysis adjusted for covariates. The overall effect on hospitalisations in Denmark was lessened due to a strict lockdown, but our findings could support hospital preparedness and modelling of the projected impact of the epidemic in countries with uncontrolled spread of B.1.1.7. Full-Text PDF