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Review 1: "Severity of Illness Caused by Severe Acute Respiratory Syndrome Coronavirus 2 Variants of Concern in Children: A Single-Center Retrospective Cohort Study"

This preprint offers a retrospective analysis evaluating correlations between SARS-CoV-2 Variants of Concern and disease severity in children. The study finds that neither alpha or delta variants were associated with severe COVID-19 symptoms. Reviewers deemed the study reliable.

Published onJan 25, 2022
Review 1: "Severity of Illness Caused by Severe Acute Respiratory Syndrome Coronavirus 2 Variants of Concern in Children: A Single-Center Retrospective Cohort Study"
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key-enterThis Pub is a Review of
Severity of Illness Caused by Severe Acute Respiratory Syndrome Coronavirus 2 Variants of Concern in Children: A Single-Center Retrospective Cohort Study

AbstractBackgroundRecent surges in coronavirus 2019 disease (COVID-19) is attributed to the emergence of more transmissible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs). However, the relative severity of SARS-CoV-2 VOCs in children is unknown.MethodsThis retrospective single-center cohort study was performed at the Ann & Robert H. Lurie Children’s Hospital of Chicago, academic free-standing children’s hospital. We included all children ≤ 18 years-old diagnosed with COVID-19 between October 15th, 2020 and August 31st, 2021 and whose SARS-CoV-2 isolate was sequenced using the Illumina platform. For each patient sample, we identified the SARS-CoV-2 lineage, which was assigned to one of the following groups: Non-VOC, alpha VOC, beta VOC, gamma VOC, or delta VOC. We measured frequency of 5 markers of COVID-19 severity: hospitalization; COVID-19 pharmacologic treatment; respiratory support; intensive care unit admission; and severe disease as classified by the COVID-19 World Health Organization (WHO) Clinical Progression Scale (severe disease; score ≥ 6). A series of logistic regression models were fitted to estimate odds of each severity marker with each VOC (in comparison to non-VOCs), adjusting for COVID-19 community incidence and demographic and clinical co-variates.ResultsDuring the study period, 2,025 patients tested positive for SARS-CoV-2; 1,422 (70.2%) had sufficient viral load to permit sequencing. Among the 499 (35.1%) patients whose isolate was sequenced, median (inter-quartile range) age was 7 (1,12) years; 256 (51.3%) isolates were a VOC: 96 (37.5%) alpha, 38 (14.8%) gamma, and 119 (46.5%) delta. After adjusting for age, Black race, Hispanic ethnicity, high-risk medical conditions, and COVID-19 community incidence, neither alpha nor delta was associated with severe COVID-19. Gamma was independently associated with hospitalization (OR 5.9, 95% CI 1.6-21.5, p=0.007), respiratory support (OR 8.3, 95% CI 1.5-56.3, p=0.02), and severe disease as classified by the WHO Clinical Progression Scale (OR 7.7, 95% CI 1.0-78.1, p=0.05).ConclusionsCompared to non-VOC COVID-19 infections, the gamma VOC, but not the alpha or delta VOCs, was associated with increased severity. These data suggest that recent increased in pediatric COVID-19 hospitalizations are related to increased delta COVID-19 incidence rather than increased delta virulence in children.

RR:C19 Evidence Scale rating by reviewer:



My recommendations and instructions for peer review are the following:

  1. Based on the Strength of  Evidence scale, this manuscript can be qualified as RELIABLE.  The preprint is justified by its methods and data, and their conclusions would likely be similar to a hypothetical ideal study.

  2. The structure of the investigation has been designed and conducted properly; therefore, the results are credible and reproducible in similar future studies (with similar epidemiological conditions, it is understood). Surely, similar results would be observed with a large sample in other studies made in occidental cities in the United States or Europe.

  3. Tables and graphs are structured correctly and are easy to read and interpret.  Regarding the figures,  Figure 1 is difficult to understand, and the legend does not clearly demonstrate the comparison with adults’ data enough.  At least, for me, it is not easy to translate the relationship between pictures and text. However, I have nothing to object to for Figure 2.

  1. The methods, singular definitions, and statistical analyses provide potential readers with an interesting tool for better interpretation of results. In addition, explanations about whole genomic sequencing would allow a clearer understanding of the rest of the manuscript.

  1. In their results, specific cohort data are adequate, and the note about markers of severity is revealing for further understanding in the subsequent discussion.  Establishing the association among different variants of concern and future outcomes is the main strength of this work.

  2. Regarding the discussion, I agree with the authors in the limitations that they recognize.  For me, the important limitations are the small sample size, single-center study, and poor comparison with adults, in that order.      On page 12, the paragraph that begins: “Perhaps reassuringly, as October 2021…………Brazil (6.1%) and Chile (4.3%).” This line is not clearly explained because of different percentages in text and several countries.

  3. Finally, while gamma exhibits worst outcomes and major severity, delta has, surprisingly, increased hospitalizations without complications while also occurring three times more frequently than gamma. This paradoxical situation is worth a more detailed explanation.


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