The COVIDTW3 Study: Impact of Variants of Concern and Vaccination on Mortality in Intubated Patients with COVID-19-Related Respiratory Failure from 2021 to 2023
Round 1
Reviewer 1 Report
Comments and Suggestions for Authors- A major limitation of the study is the absence of individual-level viral genomic sequencing. Variant classification is inferred based on the dominant circulating strain during specific calendar periods, which introduces potential misclassification bias. Although this approach is understandable given real-world constraints, the manuscript should more explicitly acknowledge how this limitation may affect the robustness of the observed association between Alpha variant infection and increased mortality risk. Sensitivity analyses or a more cautious interpretation of variant-specific hazard ratios would strengthen the credibility of the conclusions.
- The conclusion that vaccination status is not associated with improved survival among intubated patients requires a more nuanced discussion. By definition, the study population represents a subgroup in whom vaccination failed to prevent progression to critical illness, which may introduce collider bias. The manuscript would benefit from explicitly framing the findings within this context and avoiding interpretations that could be misconstrued as evidence against vaccine effectiveness. Emphasizing that vaccination primarily reduces progression to severe disease rather than mortality after intubation would improve interpretative balance.
- The comparison between Alpha and Omicron waves spans different time periods with potentially substantial differences in healthcare system strain, ICU capacity, treatment protocols, and clinical experience. These temporal factors may confound the observed differences in mortality risk attributed to viral variants. While some treatments are reported, a more explicit discussion of how evolving standards of care and resource availability could influence outcomes is warranted.
- The identification of low serum bicarbonate and lower BMI as independent predictors of mortality is intriguing; however, the biological and clinical interpretation remains underdeveloped. Serum bicarbonate may reflect underlying metabolic acidosis, renal dysfunction, or severity of respiratory failure, while BMI may act as a surrogate for frailty or nutritional reserve. Expanding the discussion to integrate these findings into established pathophysiological frameworks would substantially enhance the scientific depth of the manuscript.
Author Response
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Author Response.pdf
Reviewer 2 Report
Comments and Suggestions for AuthorsThis manuscript devoted the investigates the risk factors for mortality and vaccination status for COVID-19 in Taiwan among the intubated patients. The Alpha variant and variant Omicron were the main pathogens which caused the illness. The findings indicated that vaccination conferred no survival advantage (it is a daring affirmation), and the Alpha variant was associated with greater severity compared to the Omicron variant.
The authors presented a good discussion.
One suggestion: in the explanation of Figure 2 have to change "Orange bars" instead "Orange curve".
1. This study investigates the risk factors for mortality from COVID-19, including the variants of concern SARS-CoV-2 viruses and vaccination status of patients in Taiwan. The authors analysed only the patients, which were intubated.
2. It is realy actual topic becouse we need to understadnd realy importance the variant of virus, vaccination status of patients, other risk factors for mortality among the intubated COVID-19 patients. There are different opinions regarding this. Therefore this manuscript puts addition understanding of this item.
3. The authors proved that the older age, higher SOFA scores, Alpha variant infection, decreased serum bicarbonate levels and lower body mass index were associated with higer mortality amond intubated COVID-19 patients. Some of these data are new.
4. The methodolody is clear and fully appropriate.
5. The conclusions consistent with the evidence and arguments and reflected the main question.
6. The references are fully appropriate.
7. No additional comments regardig the tables and figures.
8. One proposition for improving the abstract: have to more clear wrote the main aim of this investigation.
Author Response
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Author Response File: Author Response.pdf
Reviewer 3 Report
Comments and Suggestions for AuthorsThe paper is well written. Methods are clearly described and conclusions supported by results. We suggest the Authors to add data (if available) on the subgroup of patients submitted to VV ECMo support. The novelty of the present findings should be highlightened
Author Response
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Reviewer 4 Report
Comments and Suggestions for AuthorsI appreciate the authors work, who attempted to retrospectively analyze the clinical and demographic profile of patients who were intubated following COVID-19 diagnosis.
After a detailed assessment of the author's work, I suggest the authors have to improve the article in terms of presentation.
Firstly, it appears that this retrospective study was carried out for 3 years (2021-2023)
All the patients included in this study appear to be above 60 years and therefore, the authors must reflect their article focused on such population instead of generalizing.
The introduction section must include arguments regarding the aged populations hospitalization and the need for mechanical ventilation and its implications on the outcomes with reference to the associated co-morbidities and vaccination status
Furthermore, it is important to include the vaccine type and analyzed for its effect. Interestingly, since the population recruited are old age, the concentrations of neutralizing antibodies following a single dose and double dose may be insufficient and therefore, such populations are advised booster doses, which was not mentioned by the authors
Moreover, the mention of older age predisposing to high mortality doesn't look appropriate considering the population studied are all above 60 years of age
The article might benefit from putting the focus on the geriatric age population and drive the discussion in that angle for a more meaningful addition to the available literature
Author Response
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Author Response File: Author Response.pdf
Reviewer 5 Report
Comments and Suggestions for AuthorsThis study is well conducted and complete the preceding ones. Thus I have two two questions.
Have some patients had co-respiratory infection such as flu, which would have worsened their respiratory status?
The interval ( 1year) between the peaks of alpha and omicron variants infections may have some consequence on administered vaccination: higher number of shots, different vaccine formulations (as booster). Would this have been considered as it may have consequence on the patient’s outcome?
Author Response
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Reviewer 6 Report
Comments and Suggestions for AuthorsThe COVIDTW3 Study: Impact of Variants of Concern and Vaccination on Mortality in Intubated Patients with COVID-19-Related Respiratory Failure from 2021 to 2023
The study reports on the impact of vaccination and VOCs (alpha and omicron) on mortality of intubated patients with COVID-19 acute respiratory distress (ARDS) from 2021 to 2023. Intubated patients infected with the alpha variant showed a higher mortality rate compared to those infected by omicron variant. Other risk factors included older age, low BMI, low bicarbonate level in the blood, acute kidney failure, high SOFA scores. Vaccination status did not affect mortality.
Overall, the paper is well written and presented. Even though the topic is not particularly novel, the work adds some interesting information about the Taiwan pandemic between 2021-2023 especially compared to other geographic areas.
Minor point:
Reference 10: list the authors.
Author Response
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Author Response File: Author Response.pdf
Round 2
Reviewer 1 Report
Comments and Suggestions for AuthorsThe manuscript is ready for publication.
Reviewer 4 Report
Comments and Suggestions for AuthorsI have no further comments
