PONE-D-20-29191

The association between nutritional status and TB treatment outcomes in Addis Ababa, Ethiopia: An ambi-directional cohort study

PLOS ONE

Dear Dr. Sahile,

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Frederick Quinn

Academic Editor

PLOS ONE

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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: Partly

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

Reviewer #1: I Don't Know

Reviewer #2: 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

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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

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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: Sahile Z and co-workers performed a retrospective and prospective cohort study of 456 TB patients in Addis Ababa, Ethiopia, comparing the TB treatment outcomes in persons with low BMI (<18.5 kg/m2) vs. those with BMI ≥ 18.5 kg/m2 at treatment initiation and after 2 months of treatment. Treatment outcomes were classified as “successful” – based on 1) negative AFB sputum smear at end of treatment + at least one other previous test or 2) completed treatment with resolution of symptoms. Unsuccessful outcome was defined as those with persistently positive AFB sputum smear at 5 months or later of TB treatment, died, or defaulted from treatment.

Comments:

1. How was the diagnosis of TB (pulmonary or extrapulmonary) made? Based on their aforementioned definition for “successful” and “unsuccessful” outcomes, it seems as if only AFB smear was done. If so, how was the diagnosis made for the smear-negative TB (which made up of ~26-27% of the TB subjects) and of the extrapulmonary TB (14-37% of the subjects)? How do they know that some of the acid-fast bacteria may be non-tuberculous mycobacteria. I think this should at least be mentioned as a limitation of the study.

2. The authors referred to the low BMI group as “exposed” and the normal/high BMI group as “unexposed.” What is the reasoning behind this? This seems unnecessary and actually makes the manuscript more difficult to understand. Indeed, in the last paragraph of the Results and first paragraph of the Discussion, they used the terms underweight and normal/overweight, which is less ambiguous than re-naming the groups to terms (exposed and unexposed) that are cryptic. Alternative, they could refer to the groups as low BMI or normal/high BMI rather than exposed and unexposed.

3. The comparisons in Table 1 between the underweight and normal/overweight patients need P values to determine significant differences (or lack thereof). While relatively smaller in numbers, the underweight group had higher number of prior relapsed TB and greater number who were infected with HIV, which could be confounders for worse treatment outcomes. We also know that failed prior therapy (relapsed) is likely associated with worse prognosis as it is a substrate for resistance to greater number of anti-TB drugs. Also, do you have data on number of prior treatments in the “relapsed” groups?

4. Similarly, the comparisons in Table 2 between the underweight and normal/overweight patients need P values to determine significant differences (or lack thereof). The number of HIV positive cases was ~1.7X greater in the underweight group vs the normal/overweight group and certainly could impact outcome. What % of those who are HIV positive were receiving anti-retroviral therapy as this may obviously impact outcome in several ways including improving host immunity and adverse interactions of anti-HIV drugs with anti-TB drugs.

5. In the abstract, the first sentence of Results section contradicts the first sentence of the Conclusion section. That is, I think the first sentence of the Conclusion should be “….underweight at baseline and after 2 months of treatment was a predictor for treatment failure” (rather than treatment success as it is written).

6. Are there data on the number of TB patients in each of the successful and unsuccessful treatment outcomes with MTB isolates that are rifampin resistant, MDR-TB, or XDR-TB? It seems likely that high levels of drug resistance may actually play a bigger role on whether the outcome is successful or unsuccessful. Along that line, were any patients diagnosed with Cepheid GeneXpert or another nucleic acid amplification test, which may confirm or refute the diagnosis of MDR-TB and thus one can compare patients with drug-susceptible TB with each other and those with MDR-TB with each other.

7. What was the general treatment regimen used and was it different between the underweight vs the normal/overweight groups? Those who were underweight were more likely to be smear-positive…was cavitary disease more common in this group since it may be a marker for more severe disease as well as greater bacterial burden.

8. In line 206, they noted “Among 106 pulmonary TB patients in the exposed group…” I am unclear where this “106” number is derived from. It is not in Table 2 I think.

9. In Table 3, since the UAOR for the weight change for 2 and 6 months after treatment, shouldn’t you have the data for the mean weight changes for the successful and unsuccessful treatment groups for these times after treatment was started? I think it would be important to show to the readers what directionality (weight gain, weight loss) the weight change was going.

10. In the first paragraph of the Discussion, the text goes back and forth unsuccessful and successful outcome. I think it would be less confusing to use one or the other whenever possible and not a combination of both. For example, one could say greater successful outcome vs. lower successful outcome, rather than greater successful outcome vs. higher unsuccessful outcome.

11. In the fifth paragraph of the Discussion, they noted “…we did not find any association between treatment outcome and weight at any time point….” which I do not understand. First of all, they examined BMI and not weight. Second, I thought they DID find an association between low BMI at baseline and at 2 months and lower successful outcomes. They also noted that “This is consistent with a Peru study that found baseline weight was not associated with treatment outcomes.” I don’t understand how this is consistent with the Peru study since low baseline BMI in their study was associated with lower treatment success; i.e., while I acknowledge the Peru study examined weight and the authors here examined BMI, it seems to me that their data, if anything, is NOT consistent with the Peru study.

12. In their Conclusion paragraph, the first sentence is ambiguous and needs more description of directionality; e.g., I think it is better phrased as “Low BMI at start of treatment was a proxy indicator for worse TB treatment outcomes while low BMI after 2 months of treatment was a strong predictor for unsuccessful treatment outcome.

Reviewer #2: • Sample size was based on reference 24 . It has been stated hat it is based on Indian study ‘Kindly check the reference

• Patients in the exposed group have larger number of smear positive cases . Has the correlation with outcomes seen in relation with smear positivity. Has it been considered in adjusted odds ratio.

• Death has been reported to occur in lesser days in unexposed group as compared to exposed group. What is the likely cause . Kindly discuss.

• Kindly check the table 2 . Kindly check outcome numbers for BMI at 2 months .

• Nutritional status has been compared with treatment outcome in various studies. What is the novelty of this study. While BMI is significantly associated with outcome, weight is not associated . kindly explain.

• What was the change in weight seen in 2 months and 6 months. kindly mention the numbers.

• Grammatical errors needs to be corrected.

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Reviewer #1: Yes: Edward Chan

Reviewer #2: No

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Attachments

Attachment

Submitted filename: Reviewer.docx

PONE-D-20-29191R1

Nutritional status and TB treatment outcomes in Addis Ababa, Ethiopia: An ambi-directional cohort study

PLOS ONE

Dear Dr. Sahile,

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. If you will need significantly more time 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,

Frederick Quinn

Academic Editor

PLOS ONE

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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: All comments have been addressed

Reviewer #2: (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: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: 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

**********

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

**********

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 done a nice job in addressing my previous comments. This is an important study to be added to risk factors for poor TB treatment outcomes.

Reviewer #2: Kindly mention the details of nutritional counselling and nutrition support and how were they provided

Kindly mention relation of nutritional support and nutritional counselling to BMI at 2 month and weight change

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Reviewer #1: Yes: Edward D. Chan

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.

Attachments

Attachment

Submitted filename: Reviewer.docx

Nutritional status and TB treatment outcomes in Addis Ababa, Ethiopia: An ambi-directional cohort study

PONE-D-20-29191R2

Dear Dr. Sahile,

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.

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Kind regards,

Frederick Quinn

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

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: The authors have written a very nice paper which will help clinicians care for patients with tuberculosis.

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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: No