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Review 2: "Associations between SARS-CoV-2 variants and risk of COVID-19 hospitalization among confirmed cases in Washington State: a retrospective cohort study"

This preprint claims that, although vaccination may reduce the risk, infection with VOC results in a higher hospitalization risk. Both reviewers found it to be reliable but suggested an adjustment for calendar time in the primary analysis would have produced a better output.

Published onOct 22, 2021
Review 2: "Associations between SARS-CoV-2 variants and risk of COVID-19 hospitalization among confirmed cases in Washington State: a retrospective cohort study"
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key-enterThis Pub is a Review of
Associations between SARS-CoV-2 variants and risk of COVID-19 hospitalization among confirmed cases in Washington State: a retrospective cohort study

AbstractBackgroundThe COVID-19 pandemic is now dominated by variant lineages; the resulting impact on disease severity remains unclear. Using a retrospective cohort study, we assessed the risk of hospitalization following infection with nine variants of concern or interest (VOC/VOI).MethodsOur study includes individuals with positive SARS-CoV-2 RT-PCR in the Washington Disease Reporting System and with available viral genome data, from December 1, 2020 to July 30, 2021. The main analysis was restricted to cases with specimens collected through sentinel surveillance. Using a Cox proportional hazards model with mixed effects, we estimated hazard ratios (HR) for the risk of hospitalization following infection with a VOC/VOI, adjusting for age, sex, and vaccination status.FindingsOf the 27,814 cases, 23,170 (83.3%) were sequenced through sentinel surveillance, of which 726 (3.1%) were hospitalized due to COVID-19. Higher hospitalization risk was found for infections with Gamma (HR 3.17, 95% CI 2.15-4.67), Beta (HR: 2.97, 95% CI 1.65–5.35), Delta (HR: 2.30, 95% CI 1.69-3.15), and Alpha (HR 1.59, 95% CI 1.26–1.99) compared to infections with an ancestral lineage. Following VOC infection, unvaccinated patients show a similar higher hospitalization risk, while vaccinated patients show no significant difference in risk, both when compared to unvaccinated, ancestral lineage cases.InterpretationInfection with a VOC results in a higher hospitalization risk, with an active vaccination attenuating that risk. Our findings support promoting hospital preparedness, vaccination, and robust genomic surveillance.

RR:C19 Evidence Scale rating by reviewer:

  • Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.



In their manuscript, M. I. Paredes and colleagues retrospectively studied the association between 9 SARS-CoV-2 variants of concern/interest (VOC/VOI) and hospitalization using medical records and virologic data spanning ~ 7 months from Dec 2020 to July 2021. The authors assessed >23k cases with available PCR and genomic data, of whom ~3% were hospitalized.
The authors conclude that VOC infection is associated with elevated hospitalization risk, while vaccination reduces this risk. These findings have important implications. However, some aspects in this work require clarification to validate the results and interpretation as outlined below.

1) One unclear aspect is that the authors "chose not to include" the calendar date in their primary analysis. At the same time, the authors state in the discussion that "including time as a covariate uniformly attenuates the variant-specific effects on hospitalization risk," "but has no influence on risk by vaccination." Given that time is a critical parameter in most retrospective studies, and especially in a dynamically changing pandemic setting where time affects both VOC/VOI and vaccination rates, I would have preferred the main analysis to take into account time, but also show sub- analyses excluding "time" as a covariate.

2) The authors included only three a priori confounders associated with infection and/or hospitalization risk (age, sex, and vaccination status) in their models. However, there is no mention of other factors shown by several studies to be important for COVID-19 risk, including, e.g., comorbidities, ethnicity, and weight (BMI). These data should be available through the patient medical records; however, I do not see any mention of it in the manuscript.

3) The results of the vaccination/variant interaction analysis are unclear. Perhaps, it is merely the syntax/phrasing issue, but it should be revisited. For example, can the authors include the "vaccinated/ancestral lineage infected" category in this sub-analysis?

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