Talk:WikiJournal of Medicine/Vitamin D as an adjunct for acute community-acquired pneumonia among infants and children: systematic review and meta-analysis

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WikiJournal of Medicine
Wikipedia-integrated • Public peer review • Libre open access

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<meta name='citation_doi' value='10.15347/wjm/2017.005'>

Arpagevticle information

Authors: Soumyadeep Bhaumik[a][i], Zohra Lassi[b]ORCID iD.svg 

Bhaumik, S; Lassi, Z. 




 


Initial Editorial comments

VitD CAP Wiki J Med 2017 -- initial Editor feedback.pdf

Editor-annotated pdf file

Comments by Michaël R. Laurent, MD PhD
Initial comments of the Editorial Board Member are available in PDF format (right)

Additional comment (January 23th, 2017) by Michaël R. Laurent:

As an additional comment, please find attached a PDF of a more recent RCT (Gupta et al. 2016) on this topic (published after the date of your final data analysis).

Perhaps it might be worth at least discussing or maybe even including this RCT, given its more adequate size and design?



Response

The authors' reply to these comments can be found here:
VitD CAP Wiki J Med 2017 with response February 2017.pdf.

External peer reviewer comments

  • Reviewer comments were finalized May 1st, 2017.
  • Rebuttal by the Authors received May 6th, 2017.

The reviewers were:

  • an MD PhD and biostatistician
  • a medical epidemiologist
  • an Associate Professor and consultant physician
  • a professor and medical director in infectious diseases

All wished to remain anonymous.

Reviewer 1

Review by anonymous peer reviewer ,
This review was submitted on , and refers to this previous version of the article


This paper represents a unique contribution to the literature focusing on a clinically significant problem of low-cost clinically efficacious attempts to reduce pneumonia or its severity and complications among children. This study takes a challenging topic in which there is a paucity of data, and handles these challenges well.

The authors may consider quantitatively testing for publication bias/heterogeneity to provide more comprehensive and defensible results such as graphically with the funnel plot and quantitatively with the Harbord-Egger and Begg-Mazumdar statistical tests. Consider further the Duval and Tweedie nonparametric “trim and fill" method or comparable to account for this heterogeneity.

Editor’s note (dr. Laurent): Heterogeneity is mentioned in the Methods section but not explicitly described in the results. Consider changes according to the reviewer’s suggestion.

Response

We thank the reviewer for the kind comments about the manuscript. As we already have mentioned in the manuscript (discussion second paragraph) "Assessment of publication bias, through funnel plots could not be done because of the small number of studies found." The Harbord-Egger and Begg-Mazumdar statistical tests can be performed validly only if there are more than 10 studies. For heterogeneity too we have used standard Cochrane methods. This is already mentioned in the manuscript as "A fixed effects model was used since no heterogeneity was detected". For the outcome of all-cause mortality data from three studies were pooled and no heterogeneity was found (evidence by I-squared 0 % and chi - squared statistic being non-significant as seen in Figure 4). For other outcomes meta-analyses was not possible and the question of heterogeneity does not arise.

Reviewer 2

Review by anonymous peer reviewer ,
This review was submitted on , and refers to this previous version of the article


The study by Bhaumik et al deals with the research-question whether addition of vitamin D would lead to any benefit during pneumonia in infants or children. This issue has not been systematically reviewed before and therefore the current study aims to fill this knowledge gap. The authors have screen 272 papers and 25 clinical registry records and identified 3 completed and 3 ongoing trials. The number of patients included in the final analysis was n=977. No effect was observed on clinical cure rate or on all cause-mortality. The conclusion was that there is insufficient evidence to justify the use of vitamin D as adjunctive treatment in children with pneumonia, although the evidence was considered to be of low quality.

The study is well performed and clearly reported. However, I have several concerns:

1. The rationale for this study should be better explained. In particular the authors need to expand their thoughts on the role for vitamin D as a preventive intervention or as an adjunct treatment. In fact, the field is much focussed on prevention, rather than adjunctive approach. The recent paper by Martineau et al in BMJ should also be properly referred to.

Response

We thank the reviewer for the comment and agree that most of the field has focused on prevention, ignoring the adjunct plausibility for treatment. We have however consciously not engaged in expressing our thoughts on the role of Vitamin D as a preventive intervention as we believe it is an altogether different research question which is being actively researched already. We have, however, referenced the previous systematic reviews on the topic and we have now included the reference to the February 2017 paper in BMJ by Martineu et al. We thank the reviewer for notifying us about this article which we have used in the discussion too.

2. The validity of this meta-analysis is severely hampered by the few included studies. This should be properly stated in a section about “limitations”. I would favor a discussion-section with five paragraphs: 1. Statement of main findings; 2. Strengths; 3. Limitations; 4. Research in context and 5. Clinical implications. This will make the text easier to follow.

Response

We thank the reviewer for the comments and have reorganized the discussion with suitable sub-headings. However, we disagree that the validity of our systematic review and meta-analyses is hampered. We have used standard methodologies and searched in multiple databases and the limited number of studies is a reflection of the current research base and is not a limitation of the current piece of research in itself. We have also used the meta-analyses by Martineau et al. which the reviewer has kindly identified for preventing us in the section on research in context.

3. Why are unpublished studies without any data included? This does not add much to the final message.

Response

We have included Table 2 on ongoing studies and we agree that it is does not add any information in the final message other than contributing to the understanding of the trend of the dosage of the vitamin D used. We are happy to move it to the Supplementary Material or delete it if the Editor/Reviewer deems fit.

4. The conclusion of the paper does not match the conclusion in the abstract. In the abstract it is stated that there is not enough data to justify the use of vitamin D in infants and children with CAP, whereas in the conclusion in the paper it is stated that there is not enough information to support any clear conclusion. This discrepancy needs to be corrected, and I am in favor of the conclusion that not much can be said, since there is limited data available.

Response

We revisited our conclusion in abstract and main text. Although we think they are the same, we have still modified the two.

5. It is very good that the authors discuss how future trials should be designed to better answer the still unanswered research-question about vitamin D in infants and children with CAP. This part could actually be expanded even further, with a focus on relevant cohorts, doses, duration and endpoints.

Response

We have now added this important information in the discussion.

6. It would be relevant to include a section about which antibiotics or other treatment that was used in the various studies, although I fear that any such analysis would fail due to the few patients and limited number of studies.

Response

We thank the reviewer for the comment and agree that such information would have been useful. However, such analyses would require sensitivity analyses and sub-group analyses which is not possible due to the small number of studies.

To conclude, the paper has merits and is relevant for the field. However, the background needs to be expanded and should include recent papers in the field (Martineau et al). The results are fine but the discussion could benefit from expansion and a better structure based on above mentioned points. The limitations with this kind of small meta-analyses should be better explained for the reader.

Response

We thank the reviewer for the very constructive comments and we have modified the manuscript accordingly.

Reviewer 3

VitD CAP Wiki J Med 2017 -- Reviewer 3 comments.pdf

A

Reviewer-annotated pdf file.

Review by anonymous peer reviewer ,
This review was submitted on , and refers to this previous version of the article


The comments from Reviewer 3 can be found in PDF format (right, note that changes were copied by Editor dr. Laurent and as such appear with his name, although they are in fact derived from the Anonymous Reviewer)


  • Introduction Section: Comment 1: Before this citation author may add more recent citation: UNICEF. Committing to Child Survival: A Promise Renewed-Progress Report 2015. 1-104 p. Available from: [1]






Response

We thank the reviewer for the comment .We have added a reference 2 , where we have added the citation of the more recent 2016 UNICEF report, which the reviewer has kindly mentioned. UNICEF. One is too many: ending child deaths from pneumonia and diarrhoea. New York: UNICEF 2016 November. Available online at [2] (Last retrieved on 18 February 2017)

  • Comment 2: Long sentence and so difficult to follow, make it two sentences.
Response

We thank the reviewer for the comment and agree with him. We have now split it into two sentences and modified accordingly.

  • If author is only focusing on RCT it should reflect on the study title.
Response

We thank the reviewer for the comment and confirm we are focusing on RCT’s only. However, we have followed the PRISMA Reporting Guideline (http://www.prisma-statement.org/ ), which is the global standard for systematic reviews, which requires the title to reflect if it is a systematic review and/ or meta-analyses only without the need to mention the study design of the included studies in the title. We have hence left the title unchanged.

  • Methods Section: Comment 4: I am sure author intended pneumonia or bronchopneumonia
Response

We thank the reviewer for the comment but it is indeed meant to be (pneumon* OR bronchopneumon*). The * acts as a wild card in PubMed which allows us to search for all variations of the word.

  • Results Section (Table), Comment 5: Would it be pneumonia or severe pneumonia. According to WHO pocket book 2013 (new definition / classification of pneumonia) if it is presence of lower chest wall indrawing in children presenting with cough or difficult breathing it would be pneumonia it would be defined as pneumonia only.
Response

We thank the reviewer in the table and we have corrected it to Severe Pneumonia in both places within the table. We apologise for the typographical error.

  • Comment 6: Author should bring this in discussion. The way this study authors (Gupta et al) defined pneumonia and severe pneumonia did not follow the recent classification of pneumonia. Reference: WHO Pocket Book. Pocket Book of Hospital care for children: Guideline for the Management of Common Childhood Illness- 2nd ed. [Internet]. 2nd Editio. 2013. 1-412 p. Available from: [[3]]

In this study high dose vitamin D intervention was given in only pneumonia cases which differ from the study of Gupta 2012 where low dose intervention was given in severe pneumonia cases. This should be discussed in the discussion and compared.

Response

We thank the reviewer for the extremely thoughtful comment and have modified the last part of the discussion section towards the need for trials to use standard WHO definions. The issue of proper dosage is already in the manuscript.

Reviewer 4

Review by anonymous peer reviewer ,
This review was submitted on , and refers to this previous version of the article


The paper deals with looking for evidence in randomised controlled trials of usefulness of vitamin D in infants and children with CAP. The methodology of this research was based on electronic databases or grey literature. The authors established inclusion criteria which allowed them to screen enough papers to put in evidence the putative usefulness of vitamin D as an adjunct for the treatment of CAP in infants and children from 1 month to 5 years of age.

A total of 365 papers and 25 clinical registry records have been carefully taken into consideration, and in particular six clinical trials were identified and their characteristics presented in a proper Table. Each trial has been carefully presented and discussed according to the GRADE approach whose usefulness in rating the quality of evidence has been highlighted in the Section “Summary of findings”.

In the Section “Discussion” the main characteristics and the results of the studies are summarized in the light of the possibility to justify the use of vitamin D as above described. However, in this concern the authors’ conclusion is that evidence available is insufficient.

The study is well designed as well as it is well written. All the putative questions raised by the studies’ examination are carefully answered.

As a very small consideration, attention should be payed to some minor points. For exemplum, the reference (26) at the end of the Section “Discussion” should be changed (27).

As a final judgement, in my opinion the paper is suitable for print.

Response

We thank the reviewer for the very kind comments about the article and the extensive review on all aspects of the study. As pointed out by the reviewer, we have corrected the sequence of reference in the last part of the discussion and also reviewed all the references for accuracy too.

Additional comments from the Editorial Board

Comments by Dr. Gwinyai Masukume
1. In the methods section the authors write "We used the Cochrane methodology for assessing risk of bias and where adequate data was available conducted a meta-analysis using a random-effects model. We assessed overall evidence quality using the GRADE approach." However for the All-cause mortality section they write "A fixed effects model was used since no heterogeneity was detected. (Figure 4) (Table 5)." I think the abstract might be misleading regarding if a random or fixed effects model was used. (I suspect that if there is no heterogeneity the random and fixed effects models give the same result?). Nevertheless I suggest the authors also report heterogeneity stats e.g. I-squared in the abstract.

2. Also, the PRISMA flow chart figure 1 is presented. However it's unclear to me if the authors followed the PRISMA guidelines http://www.prisma-statement.org/. If so in my opinion, I think they should mention this explicitly and cite e.g. https://www.ncbi.nlm.nih.gov/pubmed/19622511 (and someone should check indeed that PRISMA guidelines were followed).

Reply by the authors (June 13th, 2017):

Response

We agree with the comments and have revised the manuscript accordingly. We have attached the PRISMA compliance checklist for the review , which can go as a Supplementary Data file 2 and modified the results section accordingly. We have modified the abstract to remove ambiguity as the Editor has rightly pointed out. We have however not included the information on heterogeneity in the abstract as it is not a common practice. We have explained the heterogeneity values I in the results section.