Author's response to reviews

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1 Author's response to reviews Title:Differences upon admission and in hospital course of children hospitalized pneumonia: a retrospective cohort study Authors: Raquel Simbalista (r.simbalista@terra.com.br) Dafne C Andrade (andradedafne@yahoo.com.br) Igor C Borges (igorcms@gmail.com) Marcelo Araújo (image.maraujo@gmail.com) Cristiana M Nascimento-Carvalho (nascimentocarvalho@hotmail.com) Version:3Date:2 September 2015 Author's response to reviews: Salvador, September 2nd To Prof. Itzhak Brook BMC Pediatrics Dear Editor, I am submitting the re-revised version of the manuscript MS Differences upon admission and in hospital course of children hospitalized with community-acquired pneumonia with or without radiologically-confirmed pneumonia: a retrospective cohort study (26 references, 4 tables and 1 figure) as a Research Article to BMC Pediatrics. The re-revision was done taking into account the reviewers comments which are replied to below in a point-by-point style, in red. The new changes in the text are highlighted in red. Thank you very much for all valuable input. The files were formatted in accordance with BMC-series medical journal authors checklist for manuscript formatting. Kind regards, Cristiana M. Nascimento-Carvalho Rua Prof. Aristides Novis, No. 105/apto. 1201B, Federação, Salvador, Bahia, Brazil CEP Tel: Fax: nascimentocarvalho@hotmail.com 1st Reviewer's report Title: Differences upon admission and in hospital course of children hospitalized pneumonia: a retrospective cohort study Version:2

2 Date: 5 August 2015 Reviewer: Ariel Salas Reviewer's report: Major compulsory revisions Given that severity of disease was part of the exclusion criteria (i.e. cardiovascular compromise, need for transfer to another hospital), authors should acknowledge that most children included in this study were otherwise healthy and had no significant comorbidity. Reply: Thank you. This comment has been added to the first paragraph of the Discussion section. Minor essential revisions Delete word clinical in line 31. Text should read daily hospital course Reply: Thank you again. The word clinical in line 31 has been deleted. Level of interest: An article of limited interest Quality of written English: Acceptable Statistical review: No, the manuscript does not need to be seen by a statistician. Declaration of competing interests: I declare that I have no competing interests 2nd Reviewer's report Title: Differences upon admission and in hospital course of children hospitalized pneumonia: a retrospective cohort study Version:2 Date: 9 August 2015 Reviewer: Benn Sartorius Reviewer's report: Minor essential revisions Please change "multivariate" to "multi-variable". The former implies a data reduction technique (such as factor analysis). Reply: Thank you. The word multivariate has been changed to the word multi-variable. Sample size, lines : please move to this earlier in the methods section when you describe the study population. Unusual for it to come after the statistical analysis section. The sample size could be better presented. I suggest looking at another related publications as a guide. Reply: Sample size calculation was now moved to the end of the first paragraph in the Methods section, and has been re-written in accordance with other papers published in BMC Pediatrics (for example, Minossi V, Pellanda LC. The "Happy Heart" educational program for changes in health habits in children and their families: protocol for a randomized clinical trial. BMC Pediatr Mar 10;15:19.

3 doi: /s ) Please consistently present all p-values to 3 decimal places (both in the tables and results text). Reply: All p-values are now presented with 3 decimal places. Table 3: presentation of odds ratios and 95% confidence intervals to 4 decimal places is unnecessary. Pleas round to 2 decimal places. Reply: All OR and respective 95% CI have been rounded to 2 decimal places. Discretionary Revisions Given the number of individual hypothesis tests performed in tables 1,2 and supplementary table 1, please consider including an additional column with p-values adjusted for multiple testing (Bonferroni correction) to reduce likelihood of a type I error i.e. false positive finding. Reply: We restricted the presentation of data up to 48h of treatment, in accordance with another reviewer s suggestion. Level of interest: An article of limited interest Quality of written English: Needs some language corrections before being published Reply: Thank you. The manuscript has been proofread by a native British speaker. Statistical review: Yes, and I have assessed the statistics in my report. Declaration of competing interests: I declare that I have no competing interests 3rd Reviewer's report Title: Differences upon admission and in hospital course of children hospitalized pneumonia: a retrospective cohort study Version:2 Date: 1 August 2015 Reviewer: Jeffrey Pernica Reviewer's report: Major Compulsory Revisions. 1. Thank you for the details of the study period. 2. The explanation of the differences between cohorts is logical. 3. Logbook comments noted.

4 4. The added details of total numbers screened are useful. 5. I still do not understand why those with peribronchial thickening or atelectasis were excluded. The exclusions I understand are: - children whose baseline prognosis are expected to vary dramatically from the 'normal' (1st exclusion and 3rd exclusion) - children who might not have bacterial nor viral disease (hilar adenopathy or calcification might implicate TB, for example) My impression is that the point of this article is to explore whether the presence of alveolar infiltrate (ie. pneumonia) is associated with a different overall prognosis than those without these changes, thereby lending support to the suggestion that a CXR is useful in routine care. I understand that atelectasis and/or peribronchial thickening are not part of the diagnostic criteria for CAP - but they are commonly found in viral disease, which presumably makes up the vast majority of the included participants without bacterial CAP. I would stratify the groups into 'radiologically confirmed pneumonia' and 'non-radiologically confirmed pneumonia' (rather than 'normal CXR') as this is what happens in real life - this is the comparison that matters to clinicians. Those 31 participants is a not-insignificant proportion of the total group and merits inclusion. Their exclusion significantly limits the generalizability of this study, given how commonly these findings are found in children admitted to hospital with these radiologic findings. Reply: The whole analysis has been repeated in accordance with the reviewer s suggestion above and these new results have been inserted in a 3rd column of results, in each table, with the respective p value. 6. Noted. 7. I do believe that the STUDY RADIOLOGIST was blinded. I just cannot see how the person abstracting the clinical data from the chart would truly have been blinded. If someone had to go through the entire medical chart of the admitted patient, writing down signs and symptoms each day, how could this person be blinded to the radiologic interpretation of the admitting paediatrician or radiologist? It is stated that this person 'did not look for radiologic information on purpose'...but would it not have been extremely easy for RS to see this information 'by accident'? In my experience, details of radiographic reporting are often added to patient care notes. Reply: Please, observe that the radiologic interpretation of the admitting paediatrician was not considered in this research project. Additionally, the radiologic interpretation of the radiologist was performed without any connection with the medical chart review: a different researcher (MA) read all chest radiographs for this study, while another independent researcher reviewed the medical charts (RS). Definitely, data collection from the medical charts was blinded to the radiologic reading by the radiologist member of this research team, as well as the radiologic reading by this radiologist was blinded to all clinical information. He did not have access to any medical chart nor completed pre-defined forms.

5 8. Thank you for adding those symptoms. 9. I am uncertain if my comment about multiple comparisons was understood. 11 different symptoms/signs were compared between groups on 6 days - this is a total of 66 comparisons. This means that - even if the two groups were completely identical in terms of prognosis - one would expect at least three 'statistically significant' differences if the p value is set at When one makes multiple comparisons, the p value for 'significance' must be adjusted. The most conservative way to do this would be with the Bonferroni correction, where one simply divides 0.05 by the number of comparisons - this means that, in your study, to say that something is 'statistically different', the p-value must be or smaller. Now, that is pretty conservative, and there are certainly other ways to do this (Holm, etc.) - but you cannot say that there are differences between the groups in terms of cough on day 5 or chest in drawing on day 6. This does not really make clinical sense (why would there not be differences in cough on day 3 or 4 or 6?) or statistical sense. I think you are probably OK saying that there are differences between the rates of fever on D1 and D2, but nothing else. Reply: We restricted the presentation of data up to 48h of treatment. I note that another reviewer raised an excellent point that I did not address. A lot of the non-pneumonias were less than a year of age, and had wheezing. This means that the overall analysis is comparing CAP in older kids with bronchiolitis in younger kids. It would be worthwhile doing a sensitivity analysis taking out every child with wheeze and seeing if the fever numbers change. You may not have power with all the wheezers out - but the p-value is not the most important thing - you can see if the point estimates for fever duration change significantly. If they do, this weakens your conclusions. You cannot accomplish the same thing by including age in a multivariable regression because there is not only a complex relationship between age and pneumonia prognosis - but young age is also associated with a completely different disease, which will influence prognosis. Reply: The analysis has been repeated after having excluded the wheezers and the results are now inserted in Table 2. Differences on fever remained after 48h of treatment. 10. I am uncertain of how you did the multivariable logistic regression. Was it forward or backward? Only variables that were 'significant' were included - what does that mean specifically (p<0.05??) I would omit most of that and just look at fever on day 2, as this would probably be the most interesting thing. Please note the number of observations in the model. As stated above, I would take age out of the model. If you're worried about age, do it once for those under age 1 and again for those over age 1, as those groups will likely behave very differently, given clinical experience. Reply: The multi-variable logistic regression was performed by the enter method as it was informed in the Methods section. We consulted a statistician and were advised to perform the multi-variable logistic regression analysis in order to

6 assess the factor present on admission together with the same factor during evolution; as age distribution was different between the studied subgroups, we were advised to control for age. Please, observe that this approach is recommended as it may be supposed that children who reported fever upon admission would be the ones to be feverish during evolution. By multi-variable logistic regression we could demonstrate that the association between radiologically-confirmed pneumonia was independent of the factor present upon admission. 11. Thank you for removing the effusions. 12. Microbiologic data noted. 13. Now, in the discussion, I would remove the bit about cough. The fever seems the most robust finding.. The comment about cough during hospital course was removed. 14. Ah, I see. I think many readers will understand better if you call the two things 'intercostal indrawing' and 'subcostal indrawing.' My colleagues tend to use the words 'indrawing' and 'retractions' interchangeably. Reply: I am sorry to disappoint you on this topic. We used internationally defined expressions, as it has been already informed in the previous point-by-point reply. It is also possible to check reference from the World Health Organization: World Health Organization. Integrated Management of Childhood Illness chart booklet (WC 503.2) Accessed 15 January Level of interest: An article of limited interest Quality of written English: Acceptable Statistical review: Yes, but I do not feel adequately qualified to assess the statistics. Reply: A statistician was consulted and checked our analysis. Declaration of competing interests: I declare that I have no competing interests