PONE-D-20-17173

Clinical signs of possible serious infection and associated mortality among young infants presenting at first-level health facilities

PLOS ONE

Dear Dr. Nisar,

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.

Specifically, both reviewers have asked for additional methodological details and further information and clarification of some of the results and observations from the study. In addition, they have provide suggestions to better place your submission in context of previously published work. 

Please submit your revised manuscript by Apr 01 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

We look forward to receiving your revised manuscript.

Kind regards,

Nicola Stead

Senior Editor

PLOS ONE

Journal requirements:

When submitting your revision, we need you to address these additional 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. 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 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 identifying or sensitive patient information) 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. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. 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.

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

"YBN and RB are WHO employees. All other authors declare no competing interests."

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.

[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: Partly

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: 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: No

Reviewer #2: 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

**********

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: Thank you for the invitation to review the study „Clinical signs of possible serious infection and associated mortality among young infants presenting at first-level health facilities“. The study estimates the case fatality rate of different signs of possible severe bacterial infections in infants. The authors found that the mortality risk differs with clinical signs and young infants with serious infection can be grouped into those with lower mortality risk signs; higher mortality risk signs; or signs of critical illness and that only for more severely ill children, inpatient treatment is advantageous compared to outpatient treatment. This is a clinically relevant work that can inform future guidelines on management of PSBI and a well-written manuscript.

I have the following comments:

1. Introduction: “Unfortunately, in many low-resource settings families may not accept referral advice, and sick young infants are not taken to hospital (9-12).” Is refusal by families the major reason for which young infants are not admitted or are there any further barriers to be considered?

2. Methods: „For this analysis, 7129 young infants classified as pneumonia, severe pneumonia, clinical severe infection, or critical illness by IMCI trained nurses at first-level health facilities were selected“ Patients were selected in the outpatient setting and IMCI nurses were trained at first-level health facilities, correct? This sentence is somewhat confusing and the setting of patient inclusion should be better specified.

3. Methods – Statistical analyses: Please be more specific on the analyses conducted, e.g. which tests were used for between-group comparisons? How was missing data handled? Were infants that were initially treated in the outpatient and later admitted to an inpatient facility excluded or counted as in- or outpatient treated cases?

4. Results: “A total of 18420 young infants 0-59 days old were assessed by IMCI-trained nurses at first-level health facilities at five study sites.” Again this may be misleading in terms of setting of patient screening (community vs first-level health facilities).

5. Results: How was the age and sex distribution of young infants with signs of PSBI? Did the authors collect any data on underlying comorbidity? E.g. add a demographics table.

6. Results: Did the distribution of signs of PSBI differ between <7, >= days old?

7. Results: „Of the 7129 young infants, fast breathing (in 7-59 days old)“. Another 18% had fast breathing (in <7d old) according to Fig. 2. I think it would be clearer to refer the proportions to the infants at risk, which means the <7, >=7 day olds or to report a combined proportion of fast breathing.

8. Results: „Compared to inpatient treatment, young infants who received outpatient treatment had a CFR 1.5 times lower for pneumonia (p = 0.74), 3.4 times lower for clinical severe infection or severe pneumonia (p < 0.0001) and 1.8 times higher for critical illness (p = 0.097).“ Were there any differences by study site, level of health facility, underlying comorbidity (if such data is available) or age group of infants (<7 days, >=7 days)? I think it would be important looking a bit deeper into this as this finding may have important implications for care.

9. Discussion: „This finding could be due to several reasons, such as delay in reaching the hospital after accepting referral advice, relatively sicker patients accepting referral advice, delay in getting appropriate treatment after reaching the hospital or inadequate quality of care, and development of nosocomial infections (23-25).“

9.a. Are there any other studies from LMIC with similar results?

9.b. Is there a way to adjust for severity of disease and comorbidities in the data? I think if the authors consider differences in disease severity as a possible explanation of their findings, it would be important to control for this confounder. Otherwise the results should be presented with more caution and this issue should be more prominently included in the discussion.

9.c. Where there any other signs detected by the trained nurses that can help to distinguish infants likely to benefit from hospital admissions vs. infants that may have better outcomes if treated in the outpatient setting?

10. Discussion: Fourth, infants categorized as having higher mortality risk signs, who are not as sick as critically ill, could benefit from a shorter stay in the hospital when they accept referral instead of the recommended seven days (8).

Based on which data was this conclusion made? Please underpin this hypothesis with data or references.

11. Can any conclusions on the definition of sepsis in LMIC be drawn from this data?

Reviewer #2: Abstract page 2:

1) The authors should avoid using abbreviations in the abstract (see Submission Guidelines of the Journal).

Introduction:

1) The authors state on page 4 row 1-6: “Neonatal mortality has decreased…for case fatality rate (CFR) of 9.8% (4).” Please try to supply the reader with more recent data about neonatal mortality, incidence of bacterial infections / sepsis and who they are defined!!! Some of the references are from 2009 and 2012.

2) There is discrepancy between the objective mentioned in the end of the introduction part of the manuscript (page 5 row 7-10) and the objective mentioned in the abstract in the background (page 2, row 3-4) part. The authors should give us consistent description of the “objective of the study”!!!

See the following information which should be integrated in your paper.

Neonatal Mortality ( Reference: data.unicef.org)

The first 28 days of life – the neonatal period – is the most vulnerable time for a child’s survival. Children face the highest risk of dying in their first month of life at an average global rate of 17 deaths per 1,000 live births in 2019, down by 52 per cent from 38 deaths per 1,000 in 1990.

In comparison, the probability of dying after the first month and before reaching age 1 was estimated at 11 deaths per 1,000 and the probability of dying after reaching age 1 and before reaching age 5 was estimated at 10 deaths per 1,000 in 2019.

Globally, 2.4 million children died in the first month of life in 2019 – approximately 6,700 neonatal deaths every day – with about a third of all neonatal deaths occurring within the first day after birth, and close to three-quarters occurring within the first week of life.

Definitions of indicators: Neonatal mortality rate:Probability of dying during the first 28 days of life, expressed per 1,000 live births. Infant mortality rate: Probability of dying between birth and exactly 1 year of age, expressed per 1,000 live births. Under-five mortality rate:Probability of dying between birth and exactly 5 years of age, expressed per 1,000 live births.

Methods:

1) The authors should explain why they defined outcome (“survival status”) on “day 15 after the initial assessment” and not in the end of the neonatal period day 28?

2) Page 6 row 18-21: “CFR, was defined at the…..alone or in combination” This description of CFR definition should be better placed in the Methods part of the manuscript but not in the section of “statistical analysis”.

Results:

1) The authors should decide how they want to present their results. It is unnecessary to present the same information in the text with a written description and a Figure which presents the same information. Therefore, I would suggest to omit Figure 1 from the manuscript.

2) The authors mentioned that 7086 children were included to the study. But on page 7, row 17; “Of the 7192 young infants….” Please clarify this discrepancy in the numbers of patients.

3) The authors should decide once again, how they want to present their results. It is unnecessary to present the same information in the text with a written description (page 7, row 21-23 and page 8, row 1-4) and a table (Table 1) which presents the same information. In this case I would suggest to leave Table 1 which supplies well-arranged information and only “refer the reader” to this table in the results part without presenting the same result in written way.

Discussion:

1) The authors state on page 9, row 1-2 that there was a higher CFR in outpatients compaired to inpatients with the same signs of critical illness this should be more in detail elaborated.

**********

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: No

Reviewer #2: 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.

PONE-D-20-17173R1

Clinical signs of possible serious infection and associated mortality among young infants presenting at first-level health facilities

PLOS ONE

Dear Dr. Nisar,

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 Jun 18 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,

Emma Sacks

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.

Additional Editor Comments (if provided):

Thank you for your careful revisions and an overall impactful analysis with important practice implications.

In addition to the final additional comments from one reviewer, can you also please address the following?

-Can you provide a bit more information about the distances, especially from first level facilities to hospitals? This might give more context about why families refuse referral and why the journey itself might be more dangerous for critically ill neonates. It might be important for understanding the differences between the 5 sites as well, which would be nice to include in the paper.

-I believe what you describe is actually a case fatality RATIO, not a rate (as it has no time component) ? But I leave it to your judgement

-Please be more specific about the exclusion criteria as related to "missing values" - was this any value, a certain indicator, a set of variables?

-In the ethical approval section, please list the IRBs at each site/country

-Unlike AFRNIEST, which is explained, SATT is not described (nor is the acronym spelled out). If references to SATT are included in the discussion, please give a bit more detail about the SATT trial.

-In the discussion, please include something about the potential of referral bias (or, why you believe there was none?). Could it be possible that nurses more strongly encourage referral of young infants who are more critically ill? These potential biases should also be alluded to in the limitations.

-Please add captions to figures (it looks like there are 2 figure 1s?)

-The paper would benefit from a careful read - there are a few sentences where the technical writing could be improved and abbreviations (such as "neonates up to 28 days were 6040" which is unclear or the contraction "we didn't" could be written out)

-In the future, please use line numbers to assist reviewers in providing feedback.

[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

**********

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

**********

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

Reviewer #1: 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

**********

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

**********

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: I thank the authors for considering my comments and this good revision. The additional analyses increase the value of the study and help to better understand the data. I have only minor comments:

Introduction: The focus of the study is on infants and neonates, thus I would suggesting adding also some epidemiological data on deaths due to infectious diseases/PSBI infection in infants to the first paragraph, which is now presenting data exclusively on neonates.

Methods: „Place of treatment was categorized into either hospitalized or outpatient.“ Place of treatment should be hospital not hospitalized from my point of view.

Table 4: Low body temperature – age 7-59 day, hospitalized treatment: 1/1 should be 100%?

**********

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

[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.

Clinical signs of possible serious infection and associated mortality among young infants presenting at first-level health facilities

PONE-D-20-17173R2

Dear Dr. Nisar,

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,

Emma Sacks

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Thank you for your thorough revisions. I believe the findings of this study are actually very important for guiding practice and policy, and I am enthusiastic to see it published. Thank you again for your patience during the review process.

Reviewers' comments: