Recognition of a disulfiram ethanol reaction in the emergency department is not always straightforward

Kristof Segher; Liesbeth Huys; Tania Desmet; Evi Steen; Stefanie Chys; Walter Buylaert; Peter De Paepe

doi:10.1371/journal.pone.0243222

Peer Review History

Original SubmissionMay 13, 2020
7 Sep 2020 Decision Letter - Emily Chenette, Editor PONE-D-20-14245 Recognition of a disulfiram ethanol reaction in the emergency department is not always straightforward. PLOS ONE Dear Dr. Desmet, Thank you for submitting your manuscript to PLOS ONE; I apologise for the unusually delayed review timeframe. 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. Your manuscript has been assessed by two reviewers, whose comments are appended below. In addition to addressing the concerns that they have raised, please ensure that you clarify whether the records used in this study were anonymised and/or whether the IRB waived the requirement for informed consent. Furthermore, we note that one or more reviewers has recommended that you cite specific previously published works. As always, we recommend that you please review and evaluate the requested works to determine whether they are relevant and should be cited. It is not a requirement to cite these works. Please submit your revised manuscript by Oct 19 2020 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: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols We look forward to receiving your revised manuscript. 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If patients provided informed written consent to have data from their medical records used in research, please include this information. 3.We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. In your revised cover letter, please address the following prompts: a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent. b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. We will update your Data Availability statement on your behalf to reflect the information you provide. [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: I Don't Know ****** 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 is a clinically important piece of work that points to a relevant problem and investigates it in an interesting, intelligent way. Only some important literary quotations are still missing from my point of view: 1) Page 13, line 222: Disulfiram is also increasingly used for the following conditions: cocaine addiction, tumor diseases and pathological gambling. Please cite papers for each disease. This makes the examination all the more relevant. 2) Page 15, line 283: There are biochemical markers, which can improve and verify a hidden DSR, please cite this paper and discuss it: Urinary Ethylglucuronide Assessment in Patients Treated With Disulfiram: A Tool to Improve Verification of Abstention and Safety, Mutschler et al, Clin Neuropharmacol . Nov-Dec 2010;33(6):285-7. doi: 10.1097/WNF.0b013e3181fc9362. 3) Diskussion: I think it would be also interesting to short discuss this paper by Mutschler et al: Experienced Acetaldehyde Reaction Does Not Improve Treatment Response in Outpatients Treated With Supervised Disulfiram, Clin Neuropharmacol . Jul-Aug 2011;34(4):161-5. doi: 10.1097/WNF.0b013e3182216fd5. 4) It would be interesting to discuss the effect of the drug in more detail (biological effect, psychological effect). Furthermore pharmacogenetic aspects. Reviewer #2: This study provides a new perspective on the difulfiram-ethanol reaction (DER) and is useful to emergency room clinicians. Assuming the statistical analysis to be adequate and appropriate, the main body of the research seems to need no modification. However, a few peripheral points would benefit from clarification or expansion. 1. Describing the DER as an ‘aversive reaction’ tout court reinforces the widespread but incorrect notion that disulfiram (DSF) works by ‘aversion’ – i.e. the repeated coupling of drinking with an unpleasant response. In reality, most patients never deliberately test out DSF’s acataldehydaemic potential because the vicarious knowledge of that potential deters them from drinking while ALDH inhibition persists. The mechanism is deterrence, not aversion. 2. DSF and its active metabolite S-methyl N,Ndiethylthiolcarbamate sulfoxide do not have long half-lives and are usually undetectable after 48 hours. However, because it is an irreversible ‘suicide inhibitor’ of ALDH, ALDH inhibition persists until the body produces new ALDH in adequate quantities. This process is probably genetically determined and can be as short as a couple of days or as long as 10 days – occasionally more. 3. Carbon disulphide – another metabolite of DSF – may be easier to detect than DSF itself. It, too, persists for about two days after the last dose. 4. DSF dosage information was not systematically collected in the study but one patient is recorded as having 400mg daily. Although bioavailability can vary with the manufacturing process, a starting dose of 200-250-mg is usually appropriate, though some supervised DSF programmes use 400/400/5-600mg on Monday/Wednesday/Friday. Dosage will only need increasing if the patient risks drinking and gets no reaction or only a very mild one. 5. Although I have never had occasion to use fomepizole, I think it deserves a slightly longer discussion, including its mode of action. I also think there may be a case for using it in any severe case of suspected DER pending further investigations or confirmation. 6. The authors say that even small quantities of alcohol can cause a DER. ‘Small’ is a rather elastic but in reality, small amounts such as in sauces never cause a reaction, or only an extremely mild one, though patients who inadvertently swallow small amounts of an alcoholic sauce sometimes have a panic attack that can superficially resemble a DER. Some very recent papers have drawn attention to the fact that inadvertently inhaling alcohol in hand-sanitisers can cause a DER, probably because of a rapid but transient build-up of acetaldehyde in lung tissues that then passes directly and quickly to the heart and brain. While COVID persists, this may be worth mentioning. However, the total amount of alcohol inhaled – compared with the amount in even one glass of wine – is so small that severe DERs from this route seem very unlikely and alcohol absorption directly through the skin is negligible. ****** 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: Yes:** Colin Brewer [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.0243222.r001
Revision 1
12 Oct 2020 Author Response Dear Editor-in-chief, Dear Reviewers, First of all, we would like to thank you and the reviewers for the time spent on reviewing the manuscript and the thoughtful comments helping us improving the article. In the attached letter we would like to answer the comments and questions listed. Reviewer #1 1. Page 13, line 222: Disulfiram is also increasingly used for the following conditions: cocaine addiction, tumor diseases and pathological gambling. Please cite papers for each disease. This makes the examination all the more relevant. Other conditions in which disulfiram is used for (including references) have been added to the manuscript (line 229-231). 2. Page 15, line 283: There are biochemical markers, which can improve and verify a hidden DSR, please cite this paper and discuss it: Urinary Ethylglucuronide Assessment in Patients Treated With Disulfiram: A Tool to Improve Verification of Abstention and Safety, Mutschler et al, Clin Neuropharmacol . Nov-Dec 2010;33(6):285-7. doi: 10.1097/WNF.0b013e3181fc9362. The authors thank you for this contribution and have adapted the text accordingly (line 313- 316). 3. Diskussion: I think it would be also interesting to short discuss this paper by Mutschler et al: Experienced Acetaldehyde Reaction Does Not Improve Treatment Response in Outpatients Treated With Supervised Disulfiram, Clin Neuropharmacol . Jul-Aug 2011;34(4):161-5. doi: 10.1097/WNF.0b013e3182216fd5. The authors thank you for this addition and have incorporated this interesting observation in the manuscript (line 234-235 ; reference 47). 4. It would be interesting to discuss the effect of the drug in more detail (biological effect, psychological effect). Furthermore pharmacogenetic aspects. The authors agree with these comments. The manuscript has been adapted based on the suggestions provided. Although this is a very interesting comment, we feel that a discussion on the biological and psychological effects is beyond the scope of this paper. We would therefore suggest not including it. It is not clear to us to which specific pharmacogenetic aspects of disulfiram the reviewer is alluding. Reviewer #2 1. Describing the DER as an ‘aversive reaction’ tout court reinforces the widespread but incorrect notion that disulfiram (DSF) works by ‘aversion’ – i.e. the repeated coupling of drinking with an unpleasant response. In reality, most patients never deliberately test out DSF’s acataldehydaemic potential because the vicarious knowledge of that potential deters them from drinking while ALDH inhibition persists. The mechanism is deterrence, not aversion. The authors agree with these comments. The manuscript has been adapted and the term « aversive reaction » has been omitted throughout the entire manuscript. 2. DSF and its active metabolite S-methyl N,Ndiethylthiolcarbamate sulfoxide do not have long half-lives and are usually undetectable after 48 hours. However, because it is an irreversible ‘suicide inhibitor’ of ALDH, ALDH inhibition persists until the body produces new ALDH in adequate quantities. This process is probably genetically determined and can be as short as a couple of days or as long as 10 days – occasionally more. The authors thank you for this contribution and have adapted the text accordingly (line 62-66 & line 308-311). 3. Carbon disulphide – another metabolite of DSF – may be easier to detect than DSF itself. It, too, persists for about two days after the last dose. The authors thank you for this contribution and have adapted the text accordingly (line 352-353). 4. DSF dosage information was not systematically collected in the study but one patient is recorded as having 400mg daily. Although bioavailability can vary with the manufacturing process, a starting dose of 200-250-mg is usually appropriate, though some supervised DSF programmes use 400/400/5-600mg on Monday/Wednesday/Friday. Dosage will only need increasing if the patient risks drinking and gets no reaction or only a very mild one. The dosage of disulfiram was not systematically reported in this study. This fell beyond the scope of the study. The authors agree that a gradual increase of the dosage of disulfiram may be preferable. 5. Although I have never had occasion to use fomepizole, I think it deserves a slightly longer discussion, including its mode of action. I also think there may be a case for using it in any severe case of suspected DER pending further investigations or confirmation. The authors agree with these comments. The manuscript has been adapted based on the suggestions provided (line 328-329). 6. The authors say that even small quantities of alcohol can cause a DER. ‘Small’ is a rather elastic but in reality, small amounts such as in sauces never cause a reaction, or only an extremely mild one, though patients who inadvertently swallow small amounts of an alcoholic sauce sometimes have a panic attack that can superficially resemble a DER. Some very recent papers have drawn attention to the fact that inadvertently inhaling alcohol in hand-sanitisers can cause a DER, probably because of a rapid but transient build-up of acetaldehyde in lung tissues that then passes directly and quickly to the heart and brain. While COVID persists, this may be worth mentioning. However, the total amount of alcohol inhaled – compared with the amount in even one glass of wine – is so small that severe DERs from this route seem very unlikely and alcohol absorption directly through the skin is negligible. The authors thank you for this addition and have incorporated this interesting observation in the manuscript (line 66-70). Kindest regards, Dr. Tania Desmet Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0243222.r002
27 Oct 2020 Decision Letter - Steve Lin, Editor PONE-D-20-14245R1 Recognition of a disulfiram ethanol reaction in the emergency department is not always straightforward. PLOS ONE Dear Dr. Desmet, Thank you for submitting your manuscript to PLOS ONE. Thank you for submitting the revised manuscript. There were minor revisions recommended by one of our reviewers. Before we can accept this manuscript for publication, we ask you to consider addressing the reviewer's comments. Please submit your revised manuscript by November 26, 2020. 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: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols We look forward to receiving your revised manuscript. Kind regards, Steve Lin Academic Editor PLOS ONE [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 #2: (No Response) ******** 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: I Don't Know ****** 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: I suggest the publication of this clinically important paper. .............................................................................................................................................................. Reviewer #2: I am sorry if I seem difficult to satisfy but despite your agreement that the term 'aversive' is inappropriate, it still appears in Line 67, Please replace it with 'unpleasant'. Similarly, you have again claimed a long half-life for disulfiram, despite accepting that it is the effect on ALDH that is prolonged, not the half-life. Please correct this. ****** 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 Reviewer #2: Yes:** Dr Colin Brewer [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.0243222.r003
Revision 2
2 Nov 2020 Author Response Dear Editor-in-chief, Dear Reviewers, First of all, we would like to thank you and the reviewers for the time spent on reviewing the manuscript and the thoughtful comments helping us improving the article. In the attached letter we would like to answer the comments and questions listed. Reviewer #2 1. I am sorry if I seem difficult to satisfy but despite your agreement that the term 'aversive' is inappropriate, it still appears in Line 67, Please replace it with 'unpleasant'. The authors thank you for this contribution and have adapted the text accordingly (line 67). 2. Similarly, you have again claimed a long half-life for disulfiram, despite accepting that it is the effect on ALDH that is prolonged, not the half-life. Please correct this. The authors thank you for this contribution and have adapted the text accordingly (line 258- 259). Kindest regards, Dr. Tania Desmet Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0243222.r004
18 Nov 2020 Decision Letter - Steve Lin, Editor Recognition of a disulfiram ethanol reaction in the emergency department is not always straightforward. PONE-D-20-14245R2 Dear Dr. Desmet, 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, Steve Lin Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0243222.r005
Formally Accepted
23 Nov 2020 Acceptance Letter - Steve Lin, Editor PONE-D-20-14245R2 Recognition of a disulfiram ethanol reaction in the emergency department is not always straightforward Dear Dr. Desmet: 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. Steve Lin Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0243222.r006

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