Disseminated disease due to non-tuberculous mycobacteria in HIV positive patients: A retrospective case control study

Nils Wetzstein; Ari Geil; Gerrit Kann; Annette Lehn; Gundolf Schüttfort; Johanna Kessel; Tobias M. Bingold; Claus P. Küpper-Tetzel; Annette Haberl; Christiana Graf; Maria J. G. T. Vehreschild; Christoph Stephan; Michael Hogardt; Thomas A. Wichelhaus; Timo Wolf

doi:10.1371/journal.pone.0254607

Peer Review History

Original SubmissionFebruary 1, 2021
17 May 2021 Decision Letter - Qigui Yu, Editor PONE-D-21-03465 Disseminated disease due to non-tuberculous mycobacteria in HIV positive patients is associated with earlier rehospitalisation but not with higher mortality: a retrospective case control study. PLOS ONE Dear Dr. Wetzstein, 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 28 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. 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In the ethics statement in the manuscript and in the online submission form, please provide additional information about the patient records used in your retrospective study, including: a) whether all data were fully anonymized before you accessed them; b) the date range (month and year) during which patients' medical records were accessed; c) the date range (month and year) during which patients whose medical records were selected for this study sought treatment. If the ethics committee waived the need for informed consent, or patients provided informed written consent to have data from their medical records used in research, please include this information. 2. Thank you for stating the following in the Competing Interests section: " Nils Wetzstein, Ari Geil, Gerrit Kann, Annette Lehn, Johanna Kessel, Tobias M. Bingold, Claus P. Küpper-Tetzel, Christiana Graf and Thomas A. Wichelhaus have nothing to disclose. Gundolf Schüttfort received funding from Gilead Sciences and speaker fees from ViiV Healthcare, Bristol Meyer Squibb, MSD and Hormosan for participation in Advisory Boards, Data Safety and Monitoring Boards and for preparation of educational materials and lecturing fees, all outside the submitted work. Annette Haberl received speaker fees from Gilead Sciences, Janssen-Cilag and MSD and also participated in MSD advisory boards. Support of congress participation was provided by Gilead Sciences and Janssen-Cilag. Maria JGT Vehreschild has received research grants from 3M, Astellas Pharma, Biontech, DaVolterra, Evonik, Gilead Sciences, Glycom, Immunic, MaaT Pharma, Merck/MSD, Organobalance, Seres Therapeutics, Takeda Pharmaceutical, has received speaker fees from Astellas Pharma, Basilea, Gilead Sciences, Merck/MSD, Organobalance, Pfizer and been a consultant to Alb Fils Kliniken GmbH, Arderypharm, Astellas Pharma, DaVolterra, Farmak International Holding GmbH, Ferring, Immunic AG, MaaT Pharma, Merck/MSD, SocraTec R&D GmbH, all outside the submitted work. Christoph Stephan has received research grants from Gilead Sciences, Janssen, MSD, ViiV-Healthcare and has received fees for scientific advice from Merck/MSD, and Theratechnologies, all outside the submitted work. Michael Hogardt received Honoraria for consulting (Chiesi GmbH), and lectures (Chiesi GmbH/Horizon Pharma/Thieme Publisher Group), all outside the submitted work. Timo Wolf received fees for lectures, consultancies and travel grants from: Gilead, Merck Sharp Dome, Janssen, all outside the submitted work." 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 respond by return email with your amended Competing Interests Statement and we will change the online submission form on your behalf. Please know it is PLOS ONE policy for corresponding authors to declare, on behalf of all authors, all potential competing interests for the purposes of transparency. 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This will take you to the ORCID site and allow you to create a new iD or authenticate a pre-existing iD in Editorial Manager. Please see the following video for instructions on linking an ORCID iD to your Editorial Manager account: https://www.youtube.com/watch?v=_xcclfuvtxQ 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): [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 ******** 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: Yes 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: This paper provides some interesting clinic finding of disseminated NTM disease occurring to HIV patients. The results are straightforward. I just had some minor concerns. 1). In figure 2, will there be any statistical significance across different groups? 2). In figure 3A, although P value is not significant, there are indeed some small difference of survival between control and disseminated NTM groups. Perhaps different statistic method(s) can be used? Or would it be possible to include more patient data? Reviewer #2: This study, by Wetzstein et al., looked to explore the effect of disseminated NTM disease on HIV patient prognosis. The main conclusions found were 1) Earlier rehospitalization and 2) longer duration of hospital stays. The manuscript should be looked over for grammatical errors/ wording prior to publication. For example, the sentence starting “thus” on lines 213-214. Barring this minor concern, the paper is well written and convincing of its’ conclusion. ****** 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. https://doi.org/10.1371/journal.pone.0254607.r001
Revision 1
19 Jun 2021 Author Response Dear Editor, we are very thankful for the careful review of our paper, and the positive comments we received. We have revised the manuscript according to the suggestions and remarks made by the reviewers and hope that it will now be acceptable for publication. The review comprises this rebuttal letter, a marked-copy of our manuscript and an unmarked version. We responded to the Journal requirements as follows: Journal Requirements: 1. In the ethics statement in the manuscript and in the online submission form, please provide additional information about the patient records used in your retrospective study, including: a) whether all data were fully anonymized before you accessed them; b) the date range (month and year) during which patients' medical records were accessed; c) the date range (month and year) during which patients whose medical records were selected for this study sought treatment. If the ethics committee waived the need for informed consent, or patients provided informed written consent to have data from their medical records used in research, please include this information. We added the necessary information at the beginning of the Materials and Methods section: a) “Before further statistical analysis, all patient’s data were anonymised.” (line 80). b) “Medical records were accessed between October 2018 and December 2020.” (line 78-79). c) “For the period between 2006 and 2016, all patients treated at our centre with coded HIV infection (ICD codes B20-B24), coded NTM infection (ICD code A31) and positive microbiological results for NTM were identified and doubles excluded.” (line 74-78) As this is a retrospective study, informed consent was not necessary. This was added to lines 79-80. 2. Thank you for stating the following in the Competing Interests section: "Nils Wetzstein, Ari Geil, Gerrit Kann, Annette Lehn, Johanna Kessel, Tobias M. Bingold, Claus P. Küpper-Tetzel, Christiana Graf and Thomas A. Wichelhaus have nothing to disclose. Gundolf Schüttfort received funding from Gilead Sciences and speaker fees from ViiV Healthcare, Bristol Meyer Squibb, MSD and Hormosan for participation in Advisory Boards, Data Safety and Monitoring Boards and for preparation of educational materials and lecturing fees, all outside the submitted work. Annette Haberl received speaker fees from Gilead Sciences, Janssen-Cilag and MSD and also participated in MSD advisory boards. Support of congress participation was provided by Gilead Sciences and Janssen-Cilag. Maria JGT Vehreschild has received research grants from 3M, Astellas Pharma, Biontech, DaVolterra, Evonik, Gilead Sciences, Glycom, Immunic, MaaT Pharma, Merck/MSD, Organobalance, Seres Therapeutics, Takeda Pharmaceutical, has received speaker fees from Astellas Pharma, Basilea, Gilead Sciences, Merck/MSD, Organobalance, Pfizer and been a consultant to Alb Fils Kliniken GmbH, Arderypharm, Astellas Pharma, DaVolterra, Farmak International Holding GmbH, Ferring, Immunic AG, MaaT Pharma, Merck/MSD, SocraTec R&D GmbH, all outside the submitted work. Christoph Stephan has received research grants from Gilead Sciences, Janssen, MSD, ViiV-Healthcare and has received fees for scientific advice from Merck/MSD, and Theratechnologies, all outside the submitted work. Michael Hogardt received Honoraria for consulting (Chiesi GmbH), and lectures (Chiesi GmbH/Horizon Pharma/Thieme Publisher Group), all outside the submitted work. Timo Wolf received fees for lectures, consultancies and travel grants from: Gilead, Merck Sharp Dome, Janssen, all outside the submitted work." 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. We included the according statement in the competing interests section (line 369).. Please respond by return email with your amended Competing Interests Statement and we will change the online submission form on your behalf. This statement was also sent via email to the editorial office prior to this revision. Please know it is PLOS ONE policy for corresponding authors to declare, on behalf of all authors, all potential competing interests for the purposes of transparency. PLOS defines a competing interest as anything that interferes with, or could reasonably be perceived as interfering with, the full and objective presentation, peer review, editorial decision-making, or publication of research or non-research articles submitted to one of the journals. Competing interests can be financial or non-financial, professional, or personal. Competing interests can arise in relationship to an organization or another person. Please follow this link to our website for more details on competing interests: http://journals.plos.org/plosone/s/competing-interests 3. PLOS requires an ORCID iD for the corresponding author in Editorial Manager on papers submitted after December 6th, 2016. Please ensure that you have an ORCID iD and that it is validated in Editorial Manager. To do this, go to ‘Update my Information’ (in the upper left-hand corner of the main menu), and click on the Fetch/Validate link next to the ORCID field. This will take you to the ORCID site and allow you to create a new iD or authenticate a pre-existing iD in Editorial Manager. Please see the following video for instructions on linking an ORCID iD to your Editorial Manager account: https://www.youtube.com/watch?v=_xcclfuvtxQ The ORCID account of the corresponding author, Nils Wetzstein, was linked to the editorial manager with the following iD: 0000-0002-5589-4668. 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. The reference list was checked to be complete and correct. Finally, please see attached our remarks to the reviewers’ comments: Reviewers' comments: Reviewer #1: This paper provides some interesting clinic finding of disseminated NTM disease occurring to HIV patients. The results are straightforward. I just had some minor concerns. Thank you for your encouraging comments! 1). In figure 2, will there be any statistical significance across different groups? After matching, there was no statistical difference between the case and the control group as stated in lines 123-124 (p=0.33). CD4 cell counts were significantly higher in the control group before matching (p<0.0001).For clarification, we added these p values to figure 2. 2). In figure 3A, although P value is not significant, there are indeed some small difference of survival between control and disseminated NTM groups. Perhaps different statistic method(s) can be used? Or would it be possible to include more patient data? You are absolutely right. Mortality was slightly elevated in patients with disseminated NTM disease in comparison to controls (29.1 % vs. 18.3 %, p=0.24, lines 166-168). We cannot use another statistical method as the log-rank test is recommended in this situation. Of course, case numbers could be a problem. Unfortunately, we were not able to include enough controls with low CD4 cell counts. This is one of the limitations of our study as outlined in lines 237-239. Reviewer #2: This study, by Wetzstein et al., looked to explore the effect of disseminated NTM disease on HIV patient prognosis. The main conclusions found were 1) Earlier rehospitalization and 2) longer duration of hospital stays. The manuscript should be looked over for grammatical errors/ wording prior to publication. We checked the manuscript for grammatical errors and wording to the best of our knowledge. All changes are marked in the version with track changes of the revised manuscript. You can find them in lines 32, 53, 54, 60, 62, 81, 157, 197-198, 205, 209-210, 21, 214-216, 232, 234-235 and 245-246. In addition, we decided to shorten the title in order to make it more concise. It now reads: “Disseminated disease due to non-tuberculous mycobacteria in HIV positive patients: a retrospective case control study.” If any another linguistic adjustments are necessary, we will be happy to provide them. For example, the sentence starting “thus” on lines 213-214. We changed this sentence as well (now in lines 214-216): “Interestingly, blood cultures for mycobacterial culture were taken significantly more often in the case group, so that there might be unrecognized cases of disseminated NTM disease in the control group and the statistical effects shown in our study would be slightly underestimated.” Barring this minor concern, the paper is well written and convincing of its’ conclusion. If any additional information is required, we are happy to be of assistance. Best regards, on behalf of the team of authors, Nils Wetzstein https://doi.org/10.1371/journal.pone.0254607.r002
30 Jun 2021 Decision Letter - Qigui Yu, Editor Disseminated disease due to non-tuberculous mycobacteria in HIV positive patients: a retrospective case control study. PONE-D-21-03465R1 Dear Dr. Wetzstein, 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, Qigui Yu, M.D./Ph.D Academic Editor PLOS ONE Additional Editor Comments (optional): minor comments from one reviewer need to be addressed. Reviewers' comments: https://doi.org/10.1371/journal.pone.0254607.r003
Formally Accepted
2 Jul 2021 Acceptance Letter - Qigui Yu, Editor PONE-D-21-03465R1 Disseminated disease due to non-tuberculous mycobacteria in HIV positive patients: a retrospective case control study. Dear Dr. Wetzstein: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. 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. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Qigui Yu Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0254607.r004

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