PONE-D-24-01611Acute febrile illness in Kenya: clinical characteristics and pathogens detected among patients hospitalized with fever, 2017-2019PLOS ONE

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Reviewers' comments:

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Comments to the Author

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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

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

Reviewer #1: Yes

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

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Reviewer #1: No

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Reviewer #1: 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: General Comments

This is an expansive and interesting study that delves into the pathogens associated with acute febrile illness, and particularly “undifferentiated fever” (i.e. excluding diarrheal disease and/or lower respiratory disease) across four different geographical settings in Kenya. It is limited by the number of pathogens tested for and the fact that only blood specimens were collected and tested. Further depth could also have been undertaken with respect to analysing risk factors, i.e. for more common infections (malaria) as well as perhaps by grouping similar pathogens. However, the limitations are in fact an important component, and do a good job of highlighting the challenges of conducting comprehensive AFI surveillance – there are just too many pathogens that are associated with fever, and too many biological specimens that would need to be collected and tested to look for them all! There are enormous opportunities in standardizing methodologies and approaches for AFI surveillance and characterization, and this paper adds nicely to that literature.

Specific Comments

- Lines 74-78: When a patient is “admitted”, does this refer to both in-patient and out-patient care? The implication from the language is in-patient only, in which case it would be helpful to describe why individuals presenting with fever who were deemed eligible for out-patient care were not considered eligible. Or is this because eligibility was determined by review of logs, and so most out-patients would have already left the hospital by the time the surveillance staff tried to locate them? This could be worth clarifying, as it would help to explain the quite high percentage of patients that the surveillance staff were not able to locate. It could also have implications for some of the findings presented later, particularly with respect to mortality.

- Line 131: Typically, “assent” refers to verbal agreement; do the authors mean to say that verbal assent was documented in writing? Or should this be changed to “written consent” being obtained?

- Line 140: Was the lack of blood collection in 30% of cases due to refusal by the patient or for other reasons?

- Line 140-150: Were there any cases that were excluded due to signs of obvious injury as the cause of the infection (often an exclusion factor in AFI studies – see for example https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9436081/), or other routine childhood infections not typically associated with transmissible pathogens (i.e. otitis)? The authors do note that a number of common and endemic viral causes of fever (i.e. enteroviruses, adenoviruses) were not considered here which is definitely a limitation, but there might be non-infectious causes that should be considered as well.

- Lines 161-170: I appreciate that most individual diseases were detected too infrequently for robust risk factor analysis, but presumably this could have been done for malaria? Likewise the authors could have considered grouping similar pathogens (i.e. arboviruses) to look for risk factors associated with pathogens with similar ecological drivers and transmission patterns.

- Line 195-196: Suggest highlighting Figure 4 and seasonal patterns more clearly in the results section, it’s a bit hidden here but is potentially important. I appreciate that the authors consider the data to be too sparse for specific pathogens to conduct seasonal analyses (see Line 281) but there are additional qualitative observations that could be made; also there are sufficient data on overall number of eligible patients over time that could potentially be used to look for seasonal trends, segregated by region, in number of AFI cases presenting to the hospitals.

- Line 227-229: This is an important point and one that perhaps could be highlighted further, particularly since quite a number of other studies focused on undifferentiated fever in malaria-endemic settings will exclude patients with a positive malaria RDT – despite the fact that sub-clinical malaria may abound and thus Plasmodium infection actually isn’t contributing to symptoms. Researchers working on AFI should be encouraged to include malaria-positive patients in their studies to ascertain if there might be co-infections causing AFI.

- Line 274: Blood culture can also potentially can be biased by prophylactic antibiotic usage; was treatment history or reported self-medication included on the intake questionnaire?

- Table 1: How was the questionnaire developed and validated? For animal exposure, contact with rodents (i.e. presence of rodents in the house; recent sightings of rodents) would seem to be an important variable to include; likewise perhaps having a separate category for other wildlife. How was “contact” with animals defined?

- Figure 2: This is a helpful chart to highlight the large proportion of cases in which no pathogen was detected, but not very helpful for visualizing the breakdown of identified pathogens/co-infections. Consider re-doing the chart to show only cases in which one or more pathogens were detected, to spread out the colors more evenly and allow readers better granularity of information. Figure 3 can remain as is to highlight the large proportion of cases with no pathogen detected (which is more interesting to see split across age groups, in any case).

- Supplemental tables: The supplemental materials do not seem to be available for review which is a shame, as I wanted to see what additional information was provided, especially Tables S1 and S2. In addition, the authors note assistance from the journal would be required to make underlying data available – one option would be to submit the manuscript, including underlying de-identified databases, to a pre-print server (i.e. https://www.medrxiv.org/) or online repository (i.e. https://osf.io/; also suitable for pre-prints).

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Reviewer #1: Yes: Claire Standley

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Acute febrile illness in Kenya: clinical characteristics and pathogens detected among patients hospitalized with fever, 2017-2019

PONE-D-24-01611R1

Dear Dr. Verani,

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.

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Kind regards,

Pierre Roques, Ph.D.

Academic Editor

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Additional Editor Comments (optional): I joint the reviewer about the question of survery of animals around the houses but also agreed that this is not mandatory in this article.

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

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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

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

Reviewer #1: 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: No

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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

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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: Many thanks for the detailed and considered responses to my comments - the manuscript will be an asset to the literature on AFI studies. While I support publication in its current form, if other reviewers or the editors request further edits, you could consider adding a sentence about opportunities for further exploration of animal contact (i.e. more robust consideration of household rodents and defining contact more precisely) in future studies, perhaps in the section related to limitations. But again, this is just a suggestion! I look forward to seeing the paper in print.

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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: Yes: Claire Standley

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