Iodine increases pulmonary type I interferon responses and decreases covid-19 disease severity: Results from an open label randomized clinical trial

René Traksel; Jasper Broen; Arjen van Henten; Marc Königs; Arjun Raj; Laura van Eyndhoven; Richard Verheesen

doi:10.1371/journal.pone.0341126

Peer Review History

Original SubmissionAugust 1, 2025
1 Aug 2025 Author Response Transfer Alert This paper was transferred from another journal. As a result, its full editorial history (including decision letters, peer reviews and author responses) may not be present. https://doi.org/10.1371/journal.pone.0341126.r001
8 Oct 2025 Decision Letter - Cheorl-Ho Kim, Editor Dear Dr. Broen, Please submit your revised manuscript by Nov 22 2025 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. 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'. 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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 . 2. Thank you for stating the following financial disclosure: “Maxima Medical Center Innovation Fund” Please state what role the funders took in the study. If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." If this statement is not correct you must amend it as needed. Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf. 3. Please update your submission to use the PLOS LaTeX template. The template and more information on our requirements for LaTeX submissions can be found at http://journals.plos.org/plosone/s/latex . 4. Thank you for stating the following in the Acknowledgments Section of your manuscript: “This study has been performed with financial aid of the Maxima Medical Center Innovation Fund for which we are grateful. “ We note that you have provided additional information within the Acknowledgements Section that is not currently declared in your Funding Statement. Please note that funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows: “Maxima Medical Center Innovation Fund” Please include your amended statements within your cover letter; we will change the online submission form on your behalf. 5. Please amend the manuscript submission data (via Edit Submission) to include authors R.A.M. Traksel MD, J.C.A. Broen MD, PhD , M.J. Henten MD , M.H.H Königs MD, PhD , A. Raj PhD , L.C. Van Eyndhoven PhD,, R.H. Verheesen. 6. We notice that your supplementary figures are included in the manuscript file. Please remove them and upload them with the file type 'Supporting Information'. Please ensure that each Supporting Information file has a legend listed in the manuscript after the references list. 7. If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. 8. 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): Thank you for your submission to Plos One. I have completed to review your manuscript, as you can read them. I am very pleased to inform that your manuscript will be reconsidered for publication in Plos One. One major revision comments are slightly critical but I think the criticisms can strengthen your manuscript if you would properly revise it. I would like to receive your revision within one month. Thank you Sincerely Cheorl-Ho Kim Editor [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? Reviewer #1: Partly 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 Reviewer #1: No Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes Reviewer #2: Yes ****** Reviewer #1: Major Revisions A. Thyroid Function & The Wolff-Chaikoff Effect: As a high-dose iodine intervention carries the risk of inducing transient hypothyroidism through the Wolff-Chaikoff effect, it would significantly improve the manuscript to include thyroid function test data. At a minimum, please discuss this known side effect and address the omission of thyroid monitoring as a limitation. B. Statistical Power: The study's sample size of 141 is smaller than the target of 200, making the study underpowered for its primary outcomes. The authors should explicitly acknowledge that the failure to find a significant effect on mortality or ICU transfer may be due to this limitation. C. Exploratory vs. Primary Outcomes: The manuscript highlights the positive finding for reduced ICU stay in the abstract and conclusion, but this was a secondary outcome. It is crucial to rephrase this to emphasize that the primary endpoints were not met, and the positive finding is exploratory and hypothesis-generating. D. Open-Label Design: The unblinded, open-label design introduces a risk of bias, particularly for any subjective or patient-reported outcomes. Acknowledging this limitation in the discussion will provide a more transparent and robust account of the study. Minor Revisions e. Please replace the term "lege artis" with a specific description of the standard of care provided to the control group. f. Clarify the patient enrollment process, specifically how patients who were too ill to consent were handled, to ensure transparency regarding potential selection bias. g. The CONSORT flowchart indicates that some patients were excluded from the analysis. This appears to conflict with the statement that "We did not encounter missing data." Please reconcile this discrepancy. h. Please elaborate within Methods how Renal replacement therapy was calculated (0.00 vs. 0.01 in the intervention group as stated in Table 2). i. The statistical methods section would be clearer with a more detailed breakdown of which tests were applied to which specific variables. j. Confirm that all figures and tables are consistently formatted, with clear, descriptive legends. k. Ensure consistent use of terminology for the iodine intervention, either "potassium iodine tablets" or "Lugol's solution" throughout the manuscript. Reviewer #2: Iodine does not reduce mortality or ICU admissions; it may enhance antiviral immunity through increased type I interferon responses, contributing to shorter ICU stays in COVID-19 patients—the role of iodine in enhancing IFN-I mediated antiviral immunity. This article is of interest. The authors have new results, and they are well written. Therefore, this article is suitable for publication. ****** 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 https://doi.org/10.1371/journal.pone.0341126.r002
Revision 1
12 Dec 2025 Author Response Eindhoven, The Netherlands 8th of November Concerns: Revised version of manuscript PONE-D-25-32733 Dear editor, Dear Dr. Cheorl-Ho Kim, Thank you for considering the manuscript “Iodine increases type I interferon responses and decreases covid-19 disease severity: results from an open label randomized clinical trial” by Traksel et al. for publication in PLOS ONE after careful revision. Hereby we would like to provide the journal with the rebuttal letter in response to the issues raised by the reviewers. In addition to the revised manuscript, we added a revised manuscript with tracked changes as requested. We thank the editor for pointing towards a possibility to make all laboratory protocols available for the public. We are glad to inform the editor that all used laboratory and imaging analyses protocols have been published and are listed in the references. With kind regards, On behalf of all authors, Jasper Broen MD, PhD Rheumatologist and Clinical Pharmacologist Response to Reviewers Response to academic editor The academic editor considers the manuscript for publication after proper revision and mentions that the criticisms of the reviewers provide a possibility to further strengthen the manuscript. We would like to thank the editor for these kind words and hereby provide our thoughtful response to the raised issues and comments. 1. The academic editor requests to format the manuscript files in accordance with PLOS ONE’s style requirements. We have now adjusted the manuscripts files according to the provided PLOS ONE templates. 2. The academic editor asks to state the role of the “Maxima Medical Center Innovation Fund” and add a Role of Funder statement in the cover letter. We thank the academic editor for pointing this out and indeed stated: “The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.” We appreciate the effort provided by the editorial office to change the submission form for us. 3. The academic editor requests to update the submission by using the PLOS LaTeX template. We updated the submission as requested. 4. The editor mentions a discrepancy between the statements in the Acknowledgements section and the Funding Statement. We have now updated the submission as requested and would like to thank the editorial office for changing the online submission form on our behalf. 5. The editor requests to amend the manuscript submission data to include all authors stated on the manuscript. We have completed the manuscript submission data accordingly. 6. It is noticed that the supplementary figures are included in the manuscript file, these are directed to upload separately in a file type “supporting information”. We have now removed the supplementary files from the manuscript and uploaded the figures separately. 7. The editor advises to evaluate any specific citations suggested by the reviewers for relevancy before adding them to the manuscript. We thank the editor for this advice. We evaluated the suggestion made by reviewer 2 carefully. 8. The editor advises to review the references carefully and to mention changes in the tracked changes file. We have reviewed the references carefully and highlighted the changes in the manuscript. Response to peer reviewers comments. 1. Is the manuscript technically sound and do the data support the conclusions? Reviewer 1# Partly Reviewer 2# Yes We thank the reviewers for their time and comments, reviewer 1 further eludes on this verdict in 5.B.C.D. within the paragraph “Review Comments to the Author”. We added a more elaborate answer to these issues accordingly in this paragraph below. We would like to thank reviewer 2 for the positive answer. 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer 1# Yes Reviewer 2# Yes We thank the reviewers for their positive feedback. 3. Have the authors made all data underlying the findings in their manuscript fully available? Reviewer #1: No Reviewer #2: Yes We thank reviewer #2 for the positive feedback and provided an explanation on how to get access to the full data. We like to point out that the requested data points behind means, medians and variance measures for the positive findings are already directly appreciable from the manuscript figures. 4. Is the manuscript presented in an intelligible fashion and written in standard English? Reviewer 1# Yes Reviewer 2# Yes We thank both reviewers for their positive feedback 5. Review comments to the author. Review comments to the author Reviewer #1: Major Revisions A. The reviewer advises to include thyroid function test data since a high-dose iodine intervention carries the risk of inducing transient hypothyroidism by the Wolff-Chaikoff effect. Or if not available, asks us to at least discuss this effect and address this as a limitation. We thank the invitation of the reviewer to further elude on the Wolff-Chaikoff effect. We would like to state that this effect is mainly described in persons with a far higher daily iodine intake than used in our trial and in patients with pre-existing thyroid conditions1. Since we excluded patients with thyroid diseases and the transient effect on TSH, T4 and T3 was not observed in multiple studies that included over 1000 individuals receiving a high dose of potassium iodine, we do not think this is a substantial bias or limitation in our study1,2. TSH and FT4 levels were not routinely checked after administration of the potassium iodine as part of the study protocol, however in clinical care setting at the ICU these values were tested in 30% of the patients and no signs of hypothyroidism were present. As suggested by the reviewer, we have now added this to the discussion. 1. Markou K, Georgopoulos N, Kyriazopoulou V, Vagenakis AG. Iodine-Induced hypothyroidism. Thyroid. 2001 May;11(5):501-10. doi: 10.1089/105072501300176462. PMID: 11396709. 2. Nauman J, Wolff J. Iodide prophylaxis in Poland after the Chernobyl reactor accident: benefits and risks. Am J Med. 1993 May;94(5):524-532. doi: 10.1016/0002-9343(93)90089-8. PMID: 8498398. B. The reviewer mentions that the sample size is smaller than the target size and the failure to find a significant effect on mortality or ICU transfer might be due to this limitation. The reviewer requests to explicitly acknowledge this in the manuscript. We agree with the reviewer and added to the discussion: “Notably, due to the pandemic coming to an end we were not able to reach the target size, which might have played a role in failure to find a significant effect on mortality or ICU transfer.” C. The reviewer asks to emphasize that the primary endpoints were not met and the secondary finding is exploratory and hypothesis-generating. The discussion included the following sentences: “Our primary hypothesis was that oral iodine reduces mortality and reduces transfers to the intensive care unit. Our study does not corroborate this hypothesis.” We changed this to “Our study does not corroborate this hypothesis and primary endpoints were not met.” Furthermore the discussion already included: “Next to the two primary endpoints mortality and ICU admission, we performed an exploratory analysis on the data gathered..” “Of note, cautious interpretation is warranted because the study was not designed for investigating this endpoint and the number of patients included in this sub analysis is limited. These findings of course warrant replication.” We hope this addresses the concerns of the reviewer sufficiently. D: The reviewer asks us to acknowledge the limitations of an unblinded, open label design in the discussion. This limitation has been addressed in the current discussion, it reads “The open label design has potential biases, however, the endpoints chosen, and outcomes collected by the researchers are highly objective outcomes e.g. survival, need to transfer to ICU and days on ICU and we do not believe the design had a significant biasing effect on the outcome.” Minor revisions E: The reviewer asks to replace the term lege artis with a specific description of the standard of care provided to the control group. We followed the advice of the reviewer and have now replaced the term with a more specific description. We would like to add that the issue of changing treatment throughout the pandemic is tackled with the block randomization procedure. F. The reviewer asks us to clarify how patients that were too ill to consent were handled to ensure transparency regarding potential selection bias. All patients were included at the ward and were able to provide consent themselves, this is pointed out in the “Methods” section. G. The reviewer mentions that some patients were excluded from the analysis based on the flow-chart and mentions that this is in conflict with the statement “we did not encounter missing data”. We do not believe this is in conflict, patients that were lost to follow-up or did not fulfil the full dosing scheme were excluded from analysis as is appreciable from the flow-chart. There were no missing data in the groups ultimately analysed for the primary outcomes. In the results section the reason for excluding patients in the analyses is stated. H. The reviewer asks us to elaborate within the Methods how Renal replacement therapy was calculated. Table 2 states the proportion of patients that had a certain outcome. Of the 67 patients that received iodine treatment, one patient received renal replacement therapy. This fraction is 0.0149 which was rounded to two decimals in table formatting and leads to a proportion of 0.01. Of course the statistics have been performed on the unrounded numbers. If we provide this information in the methods section for this variable, we need to do this for all variables and we do not believe this level of detail adds to the readability level of the Methods section. To provide more clarity on the matter, we added in the legend that numbers are rounded in two decimals behind the comma. I. The reviewer asks to provide a breakdown of which tests were applied to which specific variables. For continuous variables (e.g. days of admission, age) we used t-tests and linear regression and for non-continuous variables such as sex, mortality we used chi-square tests or Fisher exact tests where appropriate. We added this to the Methods section. J. The reviewer asks to confirm that all figures and tables are consistently formatted with clear, descriptive legends. All figure and tables were formatted following the Latex template. K. The reviewer asks to be consistent in the use of terminology for the iodine intervention and either use potassium iodine or Lugols solution throughout the manuscript. We have clarified the definition of Lugol solution by adding the following information to the revised manuscript: “To investigate whether iodine modulates antiviral immunity, we pretreated cells with Lugol’s solution, a ready-to-use aqueous solution containing 0.7% potassium iodide and 0.35% iodine dissolved in water (Sigma-Aldrich, 32922). We treated the cells at a concentration range of 0.01%-1% (v/v) Lugol’s solution in culture medium, which corresponds to a iodine concentration of 0.35-35µg/mL.” Reviewer #2 1. The reviewer mentions that our article is of interest, contains new results and is well written and provides the advice to publish it. We would like to thank the reviewer for this positive feedback and the recommendation for publication. Attachments Attachment Submitted filename: Rebuttal PLOS ONE 19112025_def.docx https://doi.org/10.1371/journal.pone.0341126.r003
4 Jan 2026 Decision Letter - Cheorl-Ho Kim, Editor Iodine increases pulmonary type I interferon responses and decreases covid-19 disease severity: results from an open label randomized clinical trial. PONE-D-25-32733R1 Dear Dr. Brien, 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 will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. For questions related to billing, please contact billing support . 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, Cheorl-Ho Kim, Ph.D. Academic Editor PLOS One Additional Editor Comments (optional): Dear Dr Broen, I would like to express my deep appreciation for your submission and revision as well as for your patience in waiting for our review and editorial process. I am confident that the careful dealing with manuscripts is the most important point to document the scientific findings, even not in leading journals like nature and science as a medium. That is the reason what I have had a long time to decide the final direction. Your present revision is now acceptable in the present form. Congratulations on your study. Thank you again Sincerely Cheorl-Ho Kim PhD Editor Professor Dept Biological Sciences Sungkyunkwan University Korea Reviewers' comments: Reviewer's Responses to Questions Comments to the Author Reviewer #1: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions??> Reviewer #1: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: N/A ****** 4. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #1: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes ****** Reviewer #1: None. The authors address all of my comments (including the Major and Minor comments) and at this point I've got no further comments. ****** 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: Dr Yaniv. S. Ovadia RD PhD ******** https://doi.org/10.1371/journal.pone.0341126.r004
Formally Accepted
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