PONE-D-21-35679Vitamin D and SARS-CoV2 infection, severity and mortality: a systematic review and meta-analysisPLOS ONE

Dear Dr. Sara Gandini,

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Surasak Saokaew, PharmD, PhD, BPHCP, FACP

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: No

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: PONE-D-21-35679

Thank you for giving me the opportunity to review the article " Vitamin D and SARS-CoV2 infection, severity and mortality: a systematic review and meta-analysis."

Potential readers are interested in the topic, but there are some fundamental methodology to consider. Furthermore, numerous studies have suggested that vitamin D supplementation could be used to prevent SARS-CoV-2 infection and to treat COVID-19 patients. Aside from that, 25(OH)D or Vitamin D supplementation was associated to COVID-19 composite severity and mortality. For example as indicated below,

1) Crafa, Andrea et al. “Influence of 25-hydroxy-cholecalciferol levels on SARS-CoV-2 infection and COVID-19 severity: A systematic review and meta-analysis.” EClinicalMedicine vol. 37 (2021): 100967. doi:10.1016/j.eclinm.2021.100967

2) Kazemi, Asma et al. “Association of Vitamin D Status with SARS-CoV-2 Infection or COVID-19 Severity: A Systematic Review and Meta-analysis.” Advances in nutrition (Bethesda, Md.) vol. 12,5 (2021): 1636-1658. doi:10.1093/advances/nmab012

3) Rawat, Dimple et al. “"Vitamin D supplementation and COVID-19 treatment: A systematic review and meta-analysis".” Diabetes & metabolic syndrome vol. 15,4 (2021): 102189. doi:10.1016/j.dsx.2021.102189

4) Teshome, Amare et al. “The Impact of Vitamin D Level on COVID-19 Infection: Systematic Review and Meta-Analysis.” Frontiers in public health vol. 9 624559. 5 Mar. 2021, doi:10.3389/fpubh.2021.624559

5) Wang, Zhen et al. “Association of vitamin D deficiency with COVID-19 infection severity: Systematic review and meta-analysis.” Clinical endocrinology, 10.1111/cen.14540. 23 Jun. 2021, doi:10.1111/cen.14540

6) Borsche L, Glauner B, von Mendel J. COVID-19 Mortality Risk Correlates Inversely with Vitamin D3 Status, and a Mortality Rate Close to Zero Could Theoretically Be Achieved at 50 ng/mL 25(OH)D3: Results of a Systematic Review and Meta-Analysis. Nutrients. 2021; 13(10):3596. https://doi.org/10.3390/nu13103596

7) Margarucci, L. M., E. Montanari, G. Gianfranceschi, C. Caprara, F. Valeriani, A. Piccolella, V. Lombardi, E. Scaramucci, and V. Romano Spica. “The Role of Vitamin D in Prevention OF COVID-19 and Its Severity: an Umbrella Review: Vitamin D Versus COVID-19: An Umbrella Review”. Acta Biomedica Atenei Parmensis, vol. 92, no. S6, Oct. 2021, p. e2021451, doi:10.23750/abm.v92iS6.12216.

Whereas, the current evidence suggested that vitamin D deficiency or insufficiency was not significantly linked to susceptibility to COVID-19 infection or its associated death. Vitamin D supplements did not significantly improve clinical outcomes in patients with COVID-19. The overall GRADE evidence quality was low, they suggest that vitamin D supplementation was not recommended for patients with COVID-19.

1) Chen, J., Mei, K., Xie, L. et al. Low vitamin D levels do not aggravate COVID-19 risk or death, and vitamin D supplementation does not improve outcomes in hospitalized patients with COVID-19: a meta-analysis and GRADE assessment of cohort studies and RCTs. Nutr J 20, 89 (2021). https://doi.org/10.1186/s12937-021-00744-y

It is important to note that the emergence and severity of Covid-19 should be regarded as a potential current analysis that needs further investigation, including an Umbrella or Network Meta-Analysis.

Overall, this manuscript is poorly designed, and the work presented probably lacks originality, credibility, and impact. As a result, the authors must revise several points before acceptance.

The major comments are listed below.

Abstract:

1. The results from the analysis cannot provide the answer to the research background/question. The authors also should think about the PICO criteria.

2. The authors stated “We summarised data from 38 studies, including two RCT and 27 cohort-studies: 205565 patients with information on 25OHD status and 2022 taking vitamin D supplementation with a total of 1197 admitted to the ICU or who needed invasive mechanical ventilation or intubation and hospital stay, and more than 910 Covid-19 deaths”, However, this data was not correlated with the results.

Materials and Methods:

Sources of information and search strategies

1. "Vitamin D" may include the MeSH terms "25-OH-D" or "cholecalciferol" or "25-hydroxycholecalciferol" or "calcitriol" or "25-hydroxyvitamin D" or "hydroxycholecalciferols" or "25-hydroxyvitamin D3."

Eligibility criteria

2. What is the main selection criteria in included studies (PICO)? Please define "Low and High 25OHD" as well.

3. The authors should mention about the primary and secondary outcomes of this study (meta-analysis).

Results

Characteristics of eligible studies

1. Please explain Figure 1, and the reasons why studies were excluded from the analysis.

2. The authors did not show the main characteristics of the 38 selected studies. As a result, the reader cannot trust your meta-analysis data, even though the authors show the main characteristics and results of the selected studies in supplementary tables 7, 8, and 9, but the data is incorrect.

3. The potential reader cannot understand why the author select only 8 studied for analyzed in topic “Association between baseline serum vitamin D levels and risk of SARS-CoV-2 infection”, 16 studied for “Association between baseline serum vitamin D levels and severity of Covid-19”, 19 studies for “Association between vitamin D supplementation and the severity of Covid-19”, and 17 studies for “Association between vitamin D supplementation and mortality in patients with Covid-19”

Reviewer #2: This systematic review and meta-analysis assessed the evidence on SARS-CoV2 infection and Covid-19 in relation to deficiency and supplementation of vitamin D. They found significant associations of vitamin D supplementation with Covid-19, encompassing risks of disease worsening and mortality, especially in seasons characterized by 25OHD deficiency and with not severe patients. This study provides benefits for clinical management.

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Reviewer #1: No

Reviewer #2: No

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Vitamin D and SARS-CoV2 infection, severity and mortality: a systematic review and meta-analysis

PONE-D-21-35679R1

Dear Dr. Sara Gandini,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Surasak Saokaew, PharmD, RPh, PhD, BPHCP, FACP, FCPA

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Thank you for revising the article "Vitamin D and SARSCoV2 infection, severity and mortality: a systematic review and meta-analysis." The authors have adequately addressed all comments raised in the previous round of review. I recommend accepting this manuscript to be published in PLOS ONE.

Reviewer #2: It is a nice manuscript the present a meta-analysis about the effect of vitamin-D on mortality and severity of SARS-CoV2 infection. The study is well presented and cover an interesting topic.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: Yes: Asst. Prof. Sukrit Kanchanasurakit