An international observational study to assess the impact of the Omicron variant emergence on the clinical epidemiology of COVID-19 in hospitalised patients

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    Evaluation Summary:

    This manuscript compares COVID-19 mortality during the pre-Omicron and Omicron emergence periods in several countries and finds evidence suggesting the Omicron variant was associated with lower mortality than previous dominant variants. This paper will be of interest to infectious disease scientists both for its content and its methods, as it validates that population-level variant frequency can be a good proxy for individual-level variant data to derive insights on variant biology with population data.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)

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Abstract

Whilst timely clinical characterisation of infections caused by novel SARS-CoV-2 variants is necessary for evidence-based policy response, individual-level data on infecting variants are typically only available for a minority of patients and settings.

Methods:

Here, we propose an innovative approach to study changes in COVID-19 hospital presentation and outcomes after the Omicron variant emergence using publicly available population-level data on variant relative frequency to infer SARS-CoV-2 variants likely responsible for clinical cases. We apply this method to data collected by a large international clinical consortium before and after the emergence of the Omicron variant in different countries.

Results:

Our analysis, that includes more than 100,000 patients from 28 countries, suggests that in many settings patients hospitalised with Omicron variant infection less often presented with commonly reported symptoms compared to patients infected with pre-Omicron variants. Patients with COVID-19 admitted to hospital after Omicron variant emergence had lower mortality compared to patients admitted during the period when Omicron variant was responsible for only a minority of infections (odds ratio in a mixed-effects logistic regression adjusted for likely confounders, 0.67 [95% confidence interval 0.61–0.75]). Qualitatively similar findings were observed in sensitivity analyses with different assumptions on population-level Omicron variant relative frequencies, and in analyses using available individual-level data on infecting variant for a subset of the study population.

Conclusions:

Although clinical studies with matching viral genomic information should remain a priority, our approach combining publicly available data on variant frequency and a multi-country clinical characterisation dataset with more than 100,000 records allowed analysis of data from a wide range of settings and novel insights on real-world heterogeneity of COVID-19 presentation and clinical outcome.

Funding:

Bronner P. Gonçalves, Peter Horby, Gail Carson, Piero L. Olliaro, Valeria Balan, Barbara Wanjiru Citarella, and research costs were supported by the UK Foreign, Commonwealth and Development Office (FCDO) and Wellcome [215091/Z/18/Z, 222410/Z/21/Z, 225288/Z/22/Z]; and Janice Caoili and Madiha Hashmi were supported by the UK FCDO and Wellcome [222048/Z/20/Z]. Peter Horby, Gail Carson, Piero L. Olliaro, Kalynn Kennon and Joaquin Baruch were supported by the Bill & Melinda Gates Foundation [OPP1209135]; Laura Merson was supported by University of Oxford’s COVID-19 Research Response Fund - with thanks to its donors for their philanthropic support. Matthew Hall was supported by a Li Ka Shing Foundation award to Christophe Fraser. Moritz U.G. Kraemer was supported by the Branco Weiss Fellowship, Google.org, the Oxford Martin School, the Rockefeller Foundation, and the European Union Horizon 2020 project MOOD (#874850). The contents of this publication are the sole responsibility of the authors and do not necessarily reflect the views of the European Commission. Contributions from Srinivas Murthy, Asgar Rishu, Rob Fowler, James Joshua Douglas, François Martin Carrier were supported by CIHR Coronavirus Rapid Research Funding Opportunity OV2170359 and coordinated out of Sunnybrook Research Institute. Contributions from Evert-Jan Wils and David S.Y. Ong were supported by a grant from foundation Bevordering Onderzoek Franciscus; and Andrea Angheben by the Italian Ministry of Health “Fondi Ricerca corrente–L1P6” to IRCCS Ospedale Sacro Cuore–Don Calabria. The data contributions of J.Kenneth Baillie, Malcolm G. Semple, and Ewen M. Harrison were supported by grants from the National Institute for Health Research (NIHR; award CO-CIN-01), the Medical Research Council (MRC; grant MC_PC_19059), and by the NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool in partnership with Public Health England (PHE) (award 200907), NIHR HPRU in Respiratory Infections at Imperial College London with PHE (award 200927), Liverpool Experimental Cancer Medicine Centre (grant C18616/A25153), NIHR Biomedical Research Centre at Imperial College London (award IS-BRC-1215-20013), and NIHR Clinical Research Network providing infrastructure support. All funders of the ISARIC Clinical Characterisation Group are listed in the appendix.

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  1. Author Response

    Reviewer #2 (Public Review):

    According to the authors, the goal is to identify a method to study changes in hospital presentation and outcomes of new COVID-19 variants using publicly available population-level data on variant relative frequency to infer SARS-CoV variants likely responsible for clinical cases. This would assist in answering questions asked by public health authorities as to differences in disease severity and risk factors and vaccine protection.

    Authors use patients' data collected prospectively in 30 countries in their pre-Omicron period (Omicron variant is less than 10% of SARS-CoV2 variants) to the Omicron period (Omicron variant prevalence is >90% of circulating variants). The following factors are analyzed and adjusted for: age/gender, symptoms, comorbidities, vaccination, and outcomes during …

  2. Evaluation Summary:

    This manuscript compares COVID-19 mortality during the pre-Omicron and Omicron emergence periods in several countries and finds evidence suggesting the Omicron variant was associated with lower mortality than previous dominant variants. This paper will be of interest to infectious disease scientists both for its content and its methods, as it validates that population-level variant frequency can be a good proxy for individual-level variant data to derive insights on variant biology with population data.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)

  3. Reviewer #1 (Public Review):

    This manuscript analyzes COVID-19 associated mortality in the pre-Omicron and Omicron eras to assess whether there is evidence of lower mortality associated with the Omicron variant in a large population spanning multiple countries. They used population-level data on variant frequency to infer the time periods when Omicron emerged in different countries. While there are weaknesses associated with this assumption which are well discussed by the authors, they provide a validation analysis with individual-level data from a smaller subsample suggesting that the categorization of pre-Omicron and Omicron periods is able to correctly discriminate between patients infected with different variants in the vast majority of cases. We can therefore have high confidence that the patients in the analysis are in most cases …

  4. Reviewer #2 (Public Review):

    According to the authors, the goal is to identify a method to study changes in hospital presentation and outcomes of new COVID-19 variants using publicly available population-level data on variant relative frequency to infer SARS-CoV variants likely responsible for clinical cases. This would assist in answering questions asked by public health authorities as to differences in disease severity and risk factors and vaccine protection.

    Authors use patients' data collected prospectively in 30 countries in their pre-Omicron period (Omicron variant is less than 10% of SARS-CoV2 variants) to the Omicron period (Omicron variant prevalence is >90% of circulating variants). The following factors are analyzed and adjusted for: age/gender, symptoms, comorbidities, vaccination, and outcomes during pre and Omicron periods.

  5. Reviewer #3 (Public Review):

    The authors combine outcomes data from patients hospitalised with COVID-19 across 30 countries to investigate differences in likelihood of death from the Omicron variant vs pre-Omicron variants. Data are from the ISARC COVID-19 database; variant status is inferred from country-specific GISAID data. The principal finding is a 36% reduced risk of 14-day death in the Omicron period (OR 0.64 (0.59 - 0.69)) compared with the pre-Omicron period, after multiple adjustment.

    The strengths of this paper are the large N and large number of participating countries from different regions, and also the careful and thorough analytical approaches. The main findings are stress-tested through a range of sensitivity analyses using different variant-dominance thresholds and statistical approaches and found to be robust. The …