PONE-D-20-38722

Simplified antibiotic regimens for young infants with possible serious bacterial infection when referral is not feasible in the Democratic Republic of the Congo

PLOS ONE

Dear Dr. Lokangaka,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Nov 08 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Mehreen Arshad, M.D.

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

Thank you for submitting this very interesting manuscript. The reviewers, while mostly appreciative of the data presented, had some minor comments noted below.

Journal Requirements:

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at 

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and 

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

3. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match. 

When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section.

4. Thank you for stating the following in the Competing Interests section: 

The authors declare no conflict of interest. Rajiv Bahl and Yasir Bin Nisar are staff members of the World Health Organization. The expressed views and opinions do not necessarily express the policies of the World Health Organization

Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: "This does not alter our adherence to  PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests).  If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared. 

Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf.

5. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For more information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. 

In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially sensitive information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

6. Please upload a copy of Supporting Information Supplementary Table 1 and 2 which you refer to in your text on page 28.

[Note: HTML markup is below. Please do not edit.]

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: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: N/A

Reviewer #5: Yes

**********

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: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

**********

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

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

**********

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: The authors have highlighted an important topic considering the problem of limited health care access to underprivileged population in the region. The manuscript has written in detail. However, I am unable to grab information on the Qualitative component of the project.

Methods:

Comment 1: They have mentioned that it was the mixed method study but how the study was conducted whether qualitative component conducted first or the Quantitative component ? i.e. is it the sequential mixed method study design? please clarify this in the methodology

It seems that during implementation of intervention they have conducted FGDS and KII and table 4 were their results but how many FGDs and KII conducted? this information is missing

Results:

Comment 2: This component is too long, authors have described each and everything in the text. it can be shortened by mentioning only key information in the text and for other variables it is better to direct the reader to the table.

Comment 3: There is discrepancy in proportions in text and tables. Refer to table 2 on page 17 and text in lines 385 and 394 on page 18

Tables:

Comment 4: if operational definitions of pneumonia, severe pneumonia and CSI or critical illness are mentioned in the methods then it can be removed from table 2 and 3 footnotes.

Reviewer #2: Thank you for inviting me to review the manuscript.

The manuscript is well written and provides interesting findings on the treatment of PSBI in young infants in outpatient settings. However, some clarifications are needed.

1- It may be important to precise the proportion of neonatal infections due to bacterial infections worldwide and/or in LMIC/DRC to appreciate the importance of the implementation of outpatient treatment for possible serious bacterial infections in young infants.

2-The authors did not indicate the proportion of patients identified by CHW in the study area. This information could be useful to evaluate their importance as with the current data this might be underestimated.

3- If we assume that the CHW work only in their health areas, all patients from outside the study area should be brought by their family to the health centers. So how could we have 426 patients from outside the study area and only 385 walk-in patients?

A total of total of 285 young infants with PSBI were identified in the study area and 346 were identified by the CHW. Did the CHW and/or nurses from other health areas also referred patients to health centers in the study area?

4- The authors have identified some challenges to the implementation of their protocol and have adopted certain solutions at the beginning of the study. However, there is no mention of the appropriateness and/or evaluation of these solutions: any delay in the transportation of patients due to unavailability of HCW or insufficient number of bikes (which might have influenced the outcome of patients treated at the district hospital)? Stock-outs of medications despite the expected higher number of patients?

5- The mortality in the group of participants treated in the referred hospital was higher compared to those treated at home or at the health centers. Moreover, this mortality is higher compared to previous studies. The authors have provided some interesting explanations to these findings; however, could the difference between the two groups also explain these results? For example, the distribution of comorbidities in the two groups, families with sicker patients more likely to accept referral.

6-Line 108: please define the acronym “PSBI” on its first occurrence in the text.

Reviewer #3: The manuscript is easy to understand, very descriptive, informative and generally well-written. Minor changes mainly relating to grammatical errors are required. The introduction should also be expanded to provide comprehensive information on other factors that may induce serious bacterial infections in infants such as the mother`s immunity and neonatal immunisation.

Reviewer #4: In the Abstract introduction, the author mentioned that injectable antibiotics may not be feasible in many low resource settings. Is there any reason, e.g access? Please indicate.

The author should add the WHO recommendation in the introduction and not just reference it.

Reviewer #5: Thank you for the opportunity to review this manuscript. The implications of which are important to improving child mortality especially in Africa. A few minor changes are suggested:

- The author could include a subheading in the methods with study definitions to describe what is meant by pneumonia, severe pneumonia, critical illness, presumed serious bacterial infection, young infant age ranges used, adequate treatment, etc. This may eliminate having to provide the definitions under each table in the article

- The age range of a young infant is included at every mention throughout the document which need not be so if defined at the beginning of the article

Abstract:

- This a mixed methods longitudinal study but in the results, no mention is made of the salient findings from the qualitative side of the study

Introduction:

- Line 99: should be “per 1000 live births”

-

Data Analysis:

- lines 343-347: was treatment failure (with the same/similar criteria as the secondary outcomes) a separate secondary outcome?

Results:

- As this was a mixed method intervention study, what were the findings from the interviews/focus groups of the families?

- What were the reasons given by parents for refusal of transfer to a health facility?

- lines 361-364 reword the sentence to simplify it

- lines 381 -397: Table 2 and 3 summarise your results of the primary and secondary outcomes so there is no need to mention all of the findings in the text. The day 4 and day 8 follow up would imply that a certain number of antibiotic doses were taken. This could be cumulatively summarized for the clinical syndromes analysed.

- Provide the overall case fatality rate of those infants hospitalised

Discussion:

- lines 447-448: “whereas from 23% errors in dose calculation and 15% classification 448 errors on assessment were reported from MaMoni project, Bangladesh” remove the word “from”

- Line 438: remove the reference in the middle of the statement, it has been referenced from the previous statement

- Lines 456-457: the other research sites have been mentioned in the previous paragraph, there is no need to re-list them if referenced

**********

6. 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: Yes: Sonia Qureshi

Reviewer #2: No

Reviewer #3: No

Reviewer #4: Yes: Nigel Aminake Makoah

Reviewer #5: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Attachments

Attachment

Submitted filename: Reviewer comments.pdf

PONE-D-20-38722R1

Simplified antibiotic regimens for young infants with possible serious bacterial infection when the referral is not feasible in the Democratic Republic of the Congo

PLOS ONE

Dear Adrien Lokangaka

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we are happy to accept your paper for publication conditional to your making  the minor revisions suggested by reviewers 1 and 6. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by May 13 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Nusrat Homaira

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

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: All comments have been addressed

Reviewer #3: All comments have been addressed

Reviewer #4: (No Response)

Reviewer #5: All comments have been addressed

Reviewer #6: All comments have been addressed

********** 

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

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

Reviewer #6: Yes

********** 

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: I Don't Know

Reviewer #5: Yes

Reviewer #6: Yes

********** 

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

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

Reviewer #6: Yes

********** 

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

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

Reviewer #6: 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: The authors have tried to address all the comments.

In methodology, it would be great if authors will describe and elaborate the qualitative component such as: how many FGDs and KII were conducted? What was the size of each FGD? Where FGDs were conducted etc.

Reviewer #2: Thank you for inviting me to review this paper. The authors have satisfactorily addressed my concerns.

Reviewer #3: The reviewed manuscript is entitled: “Simplified antibiotic regimens for young infants with possible serious bacterial infection when referral is not feasible in the Democratic Republic of the Congo”.

The manuscript is easy to understand, very descriptive, informative and generally well-written.

Reviewer #4: WHO recommendation on how much injectable antibiotics should be given was not added in the introduction, probably due to limitations on the number of words?

Reviewer #5: Thank you for the revised manuscript.

Some minor grammatical changes suggested:

Line 447: rather say " as an outpatient" or "on an outpatient basis"

Line 429: insert "and" between the two categories of infants in the sentence

Line 450: the reference number at the end of the sentence

Be consistent with the text format throughout the document especially Table 2

Reviewer #6: (No Response)

********** 

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: Yes: Sonia Qureshi

Reviewer #2: No

Reviewer #3: No

Reviewer #4: No

Reviewer #5: Yes: Harsha Lochan

Reviewer #6: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Attachments

Attachment

Submitted filename: Revised Reviewer comments .pdf

Simplified antibiotic regimens for young infants with possible serious bacterial infection when the referral is not feasible in the Democratic Republic of the Congo

PONE-D-20-38722R2

Dear Adrien Lokangaka

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.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

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,

Nusrat Homaira

Guest Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: