PONE-D-24-22500Causes and risk factors for an acute kidney injury outbreak among children in The Gambia, June – September 2022: A case-cohort studyPLOS ONE

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Additional Editor Comments:

Thank you for submission of this manuscript:

Causes and risk factors for an acute kidney injury outbreak among children in The Gambia, June – September 2022: A case-cohort study (PONE-D-24-22500)

Although the topic is interesting, there are several issues that must be corrected before further processing of this manuscript can be done.

Abstract

1. No study objective written

Introduction

1. Add more data and update about death toll number, fatality rate, what kind of medications, what substances cause this issue (DEG/EG) (all available here: https://www.kidney-international.org/article/S0085-2538(22)01025-0/fulltext)

2. No citation from line 69-79, please add more

3. Reference 5 is missing

Methods

1. No need “” in STROBE

2. Add primary data collection in addition to “the national epidemiological surveillance system, line-list and preliminary epidemiological reports”

3. Update DHS data to 2019-2020 (https://dhsprogram.com/publications/publication-FR369-DHS-Final-Reports.cfm) and write the interpretation

4. Add definition of suspected, probable, and confirmed AKI cases in addition to general AKI definition

5. Add proper citation for SAS as analytical software

6. Any explanation about controls who may become cases (no AKI is the inclusion of control)

7. Please rewrite: All 82 confirmed cases were sought for inclusion in the study (contradictive since the authors stated that they cannot include every case due to financial constraints)

8. Eleven patients from suspected and probable cases? Please explain from many cases of this group

9. It is vague: probability sampling technique (there are many specific techniques, such as cluster sampling), please correct it

10. Add the Gambia income determination (quantitative threshold such as household annual income and income per capita is more suitable, not only about pipe – add reference only if there is no reference to the quantitative determination of income)

11. Looks like there is more than 3:1 control:cases (nearer to 4:1)

Result

1. It is inconsistent, where is the 82 confirmed cases as mentioned earlier?

2. Quranic education is not a form of formal education, consider to merge with no education

3. What is the threshold for younger child? Two Gambian children with a one-year difference seems not standard

Discussion

1. Add citation in the first paragraph

2. Is there any specific measure that already done by the government (in addition to withdrawing the drug) – to prevent similar event in the future

Figure

1. From where is figure 1? If from other sources, state the permission to publish, while if created by the authors, please add about software utilized to create it

Table 1&2

1. Do statistical analysis to compare characteristics between each group. Descriptive statistics are not enough – update in the methods

Table 1

1. The authors wrote that they include all 82 patient; however, the one mentioned in the table is only 63 – please explain about this difference

2. Is all data have abnormal data distribution? Because ratio is mentioned in median (IQR), please check

3. Add MUAC long form

4. Why is there many missing weight and height (>60?)

5. Remove Relation caregiver – child (mother), n (%)

6. Remove Education mother (High school), n (%) 321 90 (34.9) 19 (30.2)

7. Consider removing: Education head of family, n (%)

Funding

1. Add funding number

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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

Reviewer #3: Yes

Reviewer #4: Yes

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

Reviewer #1: No

Reviewer #2: I Don't Know

Reviewer #3: Yes

Reviewer #4: Yes

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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: No

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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

**********

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: Incidences like the one which happened in Gambia expose the perils of adulterated medicine and begs better regulatory oversight and control measures to prevent such incidences. Authors have done an epidemiological investigation to confirm the cause and contributory risk factors. I have following comments:

Material and methods need more clarity. Authors state that cases and controls were selected from the main cohort. Were all the cases of AKI in the region during the study period selected? Or was it studied in only the main cohort which as per the study is only 625 patients. How was the main cohort selected?

How did the authors ensure that all the cases of AKI were selected?

What was the study period? It needs to be mentioned.

What was the criteria for selecting sub cohort? Why was there a necessity to create a sub cohort?

The flowchart in figure 2 mentions that there were 11 patients who were unreachable and eliminated. Once again it mentions there were 5 more unreachable and number of suspected/probable cases have thus reduced to 6. This is confusing. Number of cases who were removed because of unreachable should be clubbed together only once.

AKI definition is not clear. There are clear cut definitions of AKI as per KDIGO. That should be mentioned.

Was any biochemical tests done? Like serum creatinine? If yes then please provide details

Please provide detailed table with logistic regression. What factors were adjusted for? There seems to be many confounders.

The tables need to be redone completely. Under AKI heading sum of so many columns is coming as 64 but the number mentioned is 63.

In Table 2 under the clinical characteristics the N value is varying everytime (eg. 319, 318,312…) rather than being constant at the number 321. The numbers are not adding up.

More number of patients who developed AKI had fever, vomiting. Was this before (as a part of disease process) or after giving the medicines?

Reviewer #2: This is a well written and relevant article. I would suggest a few modifications to the draft to make it useful to readers of the journal

Paragraph 1, line 3: Can include obstructive uropathy as other causes of AKI.

Line 4 - elaborate why burden of AKI is high in children in sub-saharan Africa

For secondary exposures - elaborate on concomitant drugs (antibiotics, antimalarial drugs),

toxins from animals and industrial toxins - which groups or products were analysed? Are they associated with AKI? Although the statistical analyses paragraph mentions natural and industrial toxins - no mention of it in results or analyses shared.

Did the authors attempt to examine the time between consumption of adulterated medicines and development of AKI? A similar interval between ingestion and onset of AKI in cases would be an important aspect to prove causation in all cases.

A breif description on the pathophysiology of AKI due to DEG in the discussion section would further improve the article.

Reviewer #3: The manuscript entitled “Causes and risk factors for an acute kidney injury outbreak among children in The Gambia, June – September 2022: A case-cohort study” discusses the consumption of diethylene glycol and ethylene glycol adulterated medicines manufactured by one pharmaceutical company, leading to acute kidney injury (AKI) in children eight years old or younger. Health providers and the public need to be sensitized about the dangers of adulterated medicines, and the government needs access to resources and expertise in pharmaceutical quality control.

Additionally, the definition of AKI should be corrected. It is not accurately defined as the serum creatinine level above normal. Instead, it would be best to use the pediatric AKI definitions such as p-RIFLE, AKIN, or KDIGO.

Reviewer #4: Overall: Bittaye et al report on a case-control study conducted in the Gambia in order to investigate an outbreak of AKI among young children in 2022. They found higher odds of developing AKI among children who had ingested adulterated medicines compared to children who did not.

The study addresses an important event. Concerns remain on how the authors dealt with recall bias especially that data was collected/ interviews were conducted months after the cases and that in the interim there had been countrywide sensitization of communities on the symptoms of illness and the suspected culprit medications? Perhaps a study limitation section could address this concern.

The authors also need to define better what a confirmed case is and what tests/criteria was used to conclude that AKI was of unknown etiology. Suggest the use of phrases “epidemiological” definition of AKI and “clinical” definition of AKI.

Introduction:

1. Line 66-67 “The primary causes of AKI include extrarenal pathology such as prerenal azotemia, specific kidney diseases such as acute interstitial nephritis or non-specific conditions such as nephrotoxicity”

- Generally, the term “primary cause” of AKI would imply conditions originating in the kidney. please us alternative phrase

- Post-renal causes also important cause in children

2. Line 67-68 “Drug induced nephrotoxicity is the third commonest cause of AKI.3”

Not in children. More common causes are infections such as sepsis, malaria, acute gastroenteritis, insect and snake bites, nephrotoxins such as haeme, congenital anomalies of the kidneys etc Kindly review papers below:

-Olowu WA, Niang A, Osafo C, et al. Outcomes of acute kidney injury in children and adults in 347 sub-Saharan Africa: a systematic review. The Lancet Global Health. 2016;4(4):e242-e250.

-Macedo E, Cerdá J, Hingorani S, Hou J, Bagga A, Burdmann EA, et al. Recognition and management of acute kidney injury in children: the ISN 0by25 Global Snapshot study. PLoS One. 2018; 13(5):e0196586. pmid:29715307

-Lameire N, Van Biesen W, Vanholder R. Epidemiology of acute kidney injury in children worldwide, including developing countries. Pediatr Nephrol. 2017; 32(8):1301–14. pmid:27307245

-Susantitaphong P, Cruz DN, Cerda J, Abulfaraj M, Alqahtani F, Koulouridis I, et al. World incidence of AKI: a meta-analysis. Clin J Am Soc Nephrol. 2013; 8(9):1482–93. pmid:23744003

3. line 69-71: “a pediatric nephrologist at Edward 70 Francis Small Teaching Hospital (ETSTH) – the only teaching hospital in The Gambia – observed an unusual increase in the number of cases of AKI among children from five months to seven years of age..”

- A little more detail on the usual numbers of AKI seen at the teaching hospital and how many were observed which caused the pediatric nephrologist to raise alarm ?

4. Line 76-78: “Nine samples of medicines taken by children with AKI and sent for toxicological tests were found to contain unacceptable levels of diethylene glycol and ethylene glycol”

Were these nine samples the actual ones retrieved from the AKI children or nine samples similar to ones (i.e. same brand, manufacturer) taken by the AKI children? Please clarify

5. line 74-75 “No toxic substances were detected in other pediatric medicinal products supplied 75 in The Gambia by other pharmaceutical companies.”

This sentence should come after line 78

6. Line 79-80: “Initial epidemiological investigations conducted by the MoH and US CDC were inconclusive as to the cause7”

- Some detail on why this report was inconclusive please?

- How does the current study address these reasons e.g the recall bias that was pointed out, the methods used in current study?

Methods:

1. Line 114-115: “or confirmed with serum creatinine above normal and of unknown etiology, diagnosed within the period June to September 2022.”

Please clarify the criteria for a “confirmed case”. i.e the level of increase above normal that would be considered as AKI.

“unknown etiology” – what tests were conducted on the cases to rule out the other AKI etiologies” ? I think a checklist of what was used to rule out usual causes would help.

2. Line 27 under sampling procedure:” All 82 confirmed cases were sought for inclusion in the study. We also sought to include eleven suspected or probable cases from WR1 and WR2.”

How were the cases identified? Examining hospital records? How many hospitals? Or was a national registry used.

3. Line 142 “The research team comprised surveillance officers that had interacted with the children previously.”

When previously? During the MOH/cdc study or when the outbreak was first identified?

Would this have been a risk for recall bias

Results:

1. Table 1 and 2, on which narration from line 187-201 is based, do not have p values to help show if the differences in the variables between the cases and controls were statistically significant

2. How many of the children were dialyzed?

3. Length of time between onset of anuria/oliguria and access to health facility

Discussion:

1. Line 228-229: “The temporal relationship between the importation of the suspected medicines into 229 the country, their consumption and development of AKI among the children is supportive of this hypothesis.”

This is being mentioned for the first time here. Needs to have a citation please or perhaps this should be expanded upon in the introduction section before being mentioned here.

2. Did dialysis access have any impact on the high mortality among the cases?

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Reviewer #1: Yes:  Pranaw Kumar Jha

Reviewer #2: Yes:  Sukanya Govindan

Reviewer #3: No

Reviewer #4: No

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PONE-D-24-22500R1Causes and risk factors for an acute kidney injury outbreak among children in The Gambia, June – September 2022: A case-cohort studyPLOS ONE

Dear Dr. Office,

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 Oct 31 2024 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,

Tungki Pratama Umar, M.D.

Academic Editor

PLOS ONE

Editor Comments :

Thank you for your effort to revise this manuscript following four reviewers and my comments. From the evaluation, most of the comments have been resolved, however, there are several concerns remained in this manuscript, both from the reviewers and I, which made a revise decision to be selected. Here are my comments, please also check all reviewers' comments.

- In the objective, add "in Gambia" since the risk factors is limited in this country

- After we collected primary data, add by what method (e.g. interview)

- Software used to generate Gambia map figure has not been written, also I think the authors deleted the caption (as shown by track changes). Or the authors plan to remove this figure?

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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: (No Response)

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

Reviewer #4: (No Response)

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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: Partly

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

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

Reviewer #1: No

Reviewer #2: I Don't Know

Reviewer #3: Yes

Reviewer #4: 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: No

**********

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

**********

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: Thanks for the rebuttal. I have following comments:

Also, authors should provide the p-value for baseline sociodemographic characteristics to show whether any of the baseline characteristics were different between the two groups.

Please mention what was the criteria for selecting factors for logistic regression analysis.

“In the identification of risk factors, by design, we do not look for the effect of an exposure on an outcome. Hence, there is nothing like adjusting for confounders.” The rebuttal is not right. The cause and effect relationship will be meaningful only if one adjusts for the baseline confounders which are very well present in the study. The groups developing AKI also had higher use of anti-inflammatory drugs, antibiotics, acetaminophen. How do we know that these were not the causes of the AKI rather than the suspected adulterated cough syrups. To say that the adulterated drug was the culprit authors should adjust for these factors in the study. Authors are not looking for just risk factors. They are putting a causal association with adulterated drug and hence it becomes important. “The acute kidney injury outbreak that occurred among children in The Gambia in the period June through September 2022 was causally associated with the ingestion of adulterated medicines.”

Reviewer #2: The revised version of the article addresses the queries posted by me and I suggest that the article be accepted for publication.

Reviewer #3: It would be interesting to explain the categorical variable "primary water source for drinking" to better understand the differences related to its score with 3 ordinal variables.

Reviewer #4: The manuscript reads very well.

Methods:

1. For the definition of controls: Were these all well children from the community from which the AKI cases originated or were some of them unwell with some other sickness at the time of the outbreak? Kindly clarify this in the definition of controls.

2. Line 129-130: “fever, vomiting, 130 diarrhea, cough, with history of syrup consumption or a child 8 years old”

This was used as one of the three definitions of a suspected AKI case.

This is too imprecise a definition for AKI since no renal specific symptoms are included in this definition. The mere fact that a child consumed syrup would be too imprecise to label them as suspected cases.

How many subjects were included because of this particular definition?

If subjects recruited on the basis of this definition did not have AKI, their inclusion could skew the results.

[ Additionally from table 1/2 some of the controls also had vomiting, diarrhoea, cough and had ingested adulterated medications suggesting that the presence of renal specific symptoms in the definition is important]

Discussion:

1. Line 272-274 “The alternative explanation of E. coli infection is unlikely because only 8% of cases presented with bloody 273 diarrhea which increases the risk of developing serious complications such as acute renal failure. Only two 274 samples tested positive for Shiga toxin-producing E. coli.”

It would be good to state if the clinical picture (low haemoglobin, low platelets, schistocytes) was present or not in any of the subjects if this data is available.

2. Dialysis was unavailable and this contributed to the high mortality rates.

Under recommendations, would be good to add a note that Africa needs heightened advocacy and provision of organ support services in general and paediatric dialysis facilities in particular.

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Reviewer #1: Yes:  PRANAW KUMAR JHA

Reviewer #2: Yes:  Sukanya Govindan

Reviewer #3: No

Reviewer #4: No

**********

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PONE-D-24-22500R2Causes and risk factors for an acute kidney injury outbreak among children in The Gambia, June – September 2022: A case-cohort studyPLOS ONE

Dear Dr. OKEIBUNOR,

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We look forward to receiving your revised manuscript.

Kind regards,

Tungki Pratama Umar, M.D.

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:

Thank you for your effort to revise this manuscript following three reviewers' comments. However, I noted that the response to the editor comments are inadequate (not listed). Thus, please recheck my comment as also mentioned earlier.

- After we collected primary data, add by what method (e.g. interview)

- Software used to generate Gambia map figure has not been written, also I think the authors deleted the caption (as shown by track changes). Or the authors plan to remove this figure?

[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 #3: All comments have been addressed

Reviewer #4: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

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Reviewer #1: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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

Reviewer #1: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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Reviewer #1: Yes

Reviewer #3: Yes

Reviewer #4: No

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Reviewer #1: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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6. Review Comments to the Author

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Reviewer #1: (No Response)

Reviewer #3: The manuscript is very interesting. I have the following comment: references 4 and 8 are the same. Please review the numbering of the corrected references in the article.

Reviewer #4: "Only 14 cases were assessed using the simple definition. However,

they were confirmed by a nephrologist to have had AKI using other clinical criteria."

Kindly provide a note in the manusript stating that the first definition was later ammended

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Reviewer #1: Yes:  Pranaw Kumar Jha

Reviewer #3: No

Reviewer #4: No

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Causes and risk factors for an acute kidney injury outbreak among children in The Gambia, June – September 2022: A case-cohort study

PONE-D-24-22500R3

Dear Dr. OKEIBUNOR,

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,

Tungki Pratama Umar, M.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: