The determination of causality of drug induced liver injury in patients with COVID-19 clinical syndrome

Lina Mohammad Naseralallah; Bodoor Abdallah Aboujabal; Nejat Mohamed Geryo; Aisha Al Boinin; Fatima Al Hattab; Raza Akbar; Waseem Umer; Layla Abdul Jabbar; Mohammed I. Danjuma

doi:10.1371/journal.pone.0268705

Peer Review History

Original SubmissionSeptember 30, 2021
10 Feb 2022 Decision Letter - Evy Yunihastuti, Editor PONE-D-21-31507The determination of causality of drug induced liver injury in patients with COVID-19 clinical syndromePLOS ONE Dear Dr. danjuma, 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 Mar 26 2022 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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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 [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: No 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: At first the mission of this study was very good and interesting because until now the diagnosis of DILI has always been a problem and is often placed at the end after other possible diagnoses have been ruled out. But upon further reading of this study, it was frankly very confusing. There were inconsistencies in the method because it was first said to be a retrospective cohort but later said to be cross sectional. Moreover, if this was done retrospectively, it would be very difficult to screen out DILI cases based on the RUCAM scale, which has many question components.Of course, there will be a lot of recall bias if the incident has passed. The cross sectional method is not suitable for determining DILI cases. Moreover, when the initial case of COVID occurred, by looking at the increase in the transaminases enzyme, it was very difficult to determine from the start whether the case was DILI or not. Reviewer #2: The suggestions that we can give to the manuscript with the title "The determination of causality of drug induced liver injury in patients with COVID-19 clinical syndrome”, are : 1. The grammatical errors in the text were quite at large in number. Authors need to send the manuscript for proofreading and correction. 2. In my opinion, some of the information provided in the Introduction section are more suitable to be included in the Discussion instead. A lengthy introduction compared to the Discussion might give an impression that available studies in the literature on this matter is more than adequate in contributing the information without the need of the current study. 3. It is better if the authors can provide more updates or additional facts that can be obtained from this study compared to what already been published in the literature, and also presents data from others Asian countries, especially Southeast Asia, as comparison data. 4. As highlighted by the authors, study sample was very small, many patients were excluded. 5. I suggest that the authors display figures in a format that is easier to understand, especially table 4. 6. Reference : correct or cite in full reference numbers 7, 18, 19. ****** 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. Attachments Attachment Submitted filename: Manuscript Number PONE-D-21-31507.doc https://doi.org/10.1371/journal.pone.0268705.r001
Revision 1
17 Feb 2022 Author Response The editor-in-Chief 14/02/2022 Plos One Dear sir, The determination of causality of drug induced liver injury in patients with COVID-19 clinical syndrome Please find enclosed our response to reviewers’ comments. We believe that our response and changes made to the manuscript did enhance its scientific message and will be immensely useful to the readers of this journal Kind regards, Dr Mohammed I Danjuma On behalf of other co-authors Response to reviewer’s comment Comment from the Editor “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 In general, the response is reasonable. However, several points require further clarification:” Authors response Editors comment noted with thanks. We have carried out an exhaustive review of the manuscript styling consistent with PLOS ONE editorial policy as advised. Reviewers comment “At first the mission of this study was very good and interesting because until now the diagnosis of DILI has always been a problem and is often placed at the end after other possible diagnoses have been ruled out. But upon further reading of this study, it was frankly very confusing. There were inconsistencies in the method because it was first said to be a retrospective cohort but later said to be cross sectional. Moreover, if this was done retrospectively, it would be very difficult to screen out DILI cases based on the RUCAM scale, which has many question components. Of course, there will be a lot of recall bias if the incident has passed. The cross-sectional method is not suitable for determining DILI cases. Moreover, when the initial case of COVID occurred, by looking at the increase in the transaminases enzyme, it was very difficult to determine from the start whether the case was DILI or not” Authors response We have noted reviewers’ comment with thanks. We regret the oversight if there was an interchangeable mention of study design between “cross sectional” and “retrospective” in different sections of the manuscript. Our study design was retrospective and despite its obvious limitations (as ably highlighted by the reviewer), the changing pattern and clinical phenotypes of DILI across different clinical environment and patient settings, meant that a significant proportion of both the foundational and subsequent published work on it (with RUCAM as a causality determination tool) has been through a mixture of both prospective and retrospective study designs (1,2, 3, 4). We do recognize prospective design is more robust in DILI determination and less prone to confounding especially recall bias. That notwithstanding, peculiar circumstances especially in the setting of COVID-19 pandemic meant that the priority in the initial cycle of the pandemic for example was largely driven by the need to develop new therapeutics and prevention strategies with little or no focus on strategies to examine the effects of these therapeutics. Most of the data that recent studies on DILI are examining were the retrospectively collected repository data that accrued during the pandemic; and have since provided an excellent repository platform to both detect emerging “drug signals” but to also investigate various well validated pathways and algorithms which have been in clinical use (such as our study). But we do recognize the legion of retrospective study design limitations, and have acknowledged as much in the main manuscript (highlighted in yellow) Reviewer’s comment “The grammatical errors in the text were quite at large in number” Authors response Reviewer’s comment noted with thanks. We regret the oversight. We have exhaustively reviewed the manuscript and have made relevant corrections to spelling mistakes and grammatical errors as advised Reviewer’s comment “In my opinion, some of the information provided in the Introduction section are more suitable to be included in the Discussion instead. A lengthy introduction compared to the Discussion might give an impression that available studies in the literature on this matter is more than adequate in contributing the information without the need of the current study”. Authors response Reviewer’s comment noted with thanks. We regret the oversight. We have re-written the introduction section to reflect the current understanding of uncertainties that still exists in the adjudication of DILI in patients with COVID-19 clinical syndrome. Reviewer’s comment “it is better if the authors can provide more updates or additional facts that can be obtained from this study compared to what already been published in the literature, and also presents data from others Asian countries, especially Southeast Asia, as comparison data” Authors response We have noted reviewers’ comment. We have already cited several studies and authorities from Asia and different parts of the world to provide a comparative context to this current work (reference 6 and 9-12). Additionally, DILI adjudication with RUCAM scale in patients with COVI-19 is an emerging challenge and will explain the relatively few studies there are for a robust comparison with ours. Reviewer’s comment As highlighted by the authors, study sample was very small, many patients were excluded. Authors response We note reviewers’ comments with thanks. We did acknowledge that one of the limitations of our work is its relatively small sample size for which we have already recommended validation by a larger sample sized prospective patient cohort (highlighted in yellow). Reviewer’s comment I suggest that the authors display figures in a format that is easier to understand, especially table 4. Authors response Many thanks for the suggestion. We have additionally carried a pictorial representation of the data in table 4 in form of Bar chart Reviewer’s comment “Reference: correct or cite in full reference numbers 7, 18, 19.” Authors response We noted reviewers’ comment with thanks and regret the oversight regarding the highlighted references. We have amended those references as appropriate. References 1. Abid A, Subhani F, Kayani F, Awan S, Abid S. Drug induced liver injury is associated with high mortality-A study from a tertiary care hospital in Pakistan. PLoS One. 2020 Apr 10;15(4) 2. Chen F, Chen W, Chen J, et al. Clinical features and risk factors of COVID-19-associated liver injury and function: A retrospective analysis of 830 cases. Ann Hepatol. 2021; 21:100267 3. Danan G, Teschke R. Roussel Uclaf Causality Assessment Method for Drug-Induced Liver Injury: Present and Future. Front Pharmacol. 2019; 10:853. Published 2019 Jul 29. doi:10.3389/fphar.2019.00853 4. Cunningham M, Iafolla M, Kanjanapan Y, Cerocchi O, Butler M, Siu LL, et al. (2021) Evaluation of liver enzyme elevations and hepatotoxicity in patients treated with checkpoint inhibitor immunotherapy. PLoS ONE 16(6): e0253070 Attachments Attachment Submitted filename: Response to reviewers comments_PLOS ONE.docx https://doi.org/10.1371/journal.pone.0268705.r002
6 May 2022 Decision Letter - Evy Yunihastuti, Editor The determination of causality of drug induced liver injury in patients with COVID-19 clinical syndrome PONE-D-21-31507R1 Dear Dr. danjuma, 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, Evy Yunihastuti, MD 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 Reviewer #2: 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 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 responded appropriately. This study has a valuable and novelty idea. Some issues has been clarified clearly. Reviewer #2: Suggestions for displaying research data in an easy-to-understand display, as well as the need for further research in many centers with heterogeneous samples. ****** 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:** Chyntia Olivia Maurine Jasirwan, MD, PhD Reviewer #2: No https://doi.org/10.1371/journal.pone.0268705.r003
Formally Accepted
11 Aug 2022 Acceptance Letter - Evy Yunihastuti, Editor PONE-D-21-31507R1 The determination of causality of drug induced liver injury in patients with COVID-19 clinical syndrome Dear Dr. Danjuma: 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. Evy Yunihastuti Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0268705.r004

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