Repurposing FIB-4 index as a predictor of mortality in patients with hematological malignancies and COVID-19

Noorwati Sutandyo; Sri Agustini Kurniawati; Achmad Mulawarman Jayusman; Anisa Hana Syafiyah; Raymond Pranata; Arif Riswahyudi Hanafi

doi:10.1371/journal.pone.0257775

Peer Review History

Original SubmissionApril 7, 2021
21 Jun 2021 Decision Letter - Senthilnathan Palaniyandi, Editor PONE-D-21-11387 Repurposing FIB-4 Index as a Predictor of Mortality in Patients with Hematological Malignancies and COVID-19 PLOS ONE Dear Dr. Sutandyo, 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. We have revived the opinions of expert reviewers as agree with reviewers comments raised a few concerns about this study. We invite you to submit a revised version of the manuscript, please consider and address each of the comments raised by the reviewers. Please submit your revised manuscript by Aug 01 2021 11:59PM. 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The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Partly Reviewer #2: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: No ****** 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: Knowledge of COVID-19 pathogenesis in cancer patients is very limited but accumulating steadily. Any efforts in the direction are useful and extremely important. Data has to be examined carefully prior to any conclusions considering all the possibilities and probabilities within the scope of the study. Studies correlating FIB-4 index with COVID-19 infections in the context of fibrosis and type II diabetes milletus have already been published. In the current study authors propose a correlation between FIB-4 index and mortality in hematological malignancies. In addition to the caveats listed by the authors there are more questions that need to be addressed. 1.Is there correlation between COVID -19 negative or low load infection to heavy load of the infection in cancer patients. 2. Are there any insights in to possible treatment regimen so as to reduce the viral load and not aggravate cancer progression. 3. The sample size is limited. It would be interesting to observe data from multiple studies to be able to establish a correlation between FIB-4 index and mortality in hematological malignancies and COVID-19. Reviewer #2: The authors evaluated the prognostic value of FIB-4 in patients with various hematologic malignancies. FIB-4 is calculated by AST, ALT, platelet and age, and was originally developed for the assessment of chronic liver disease. There have been some previous publication highlighting the value of FIB-4 in patients with acute illness like COVID19. The hypothesis is FIB-4 is prognostic in this population. The analysis seems to be reasonable, though the clinically more important question “what is the impact of underlying hematologic malignancy in patients with COVID19” was not assessed in this study, as there is no COVID19 patient data without hematologic malignancy presented. The table 1 shows grouping of patients only by “survivor” and “non-survivor”. For this kind of analysis, sufficient follow up duration for all patients is important. The authors state the median follow up duration of 33 days but no range. If “mortality” is the endpoint, it is best to provide a specified time mortality (i.e. 30-day mortality etc) using Kaplan-Meyer estimate. The Table 2 is evaluated for “time to mortality”, which seems appropriate. Remission and relapse information are provided but majority were “neither”. It is not clear what exactly it means. If it indicates that the patient was undergoing the initial therapy for the primary malignancy, it should be clarified. The implication is significantly different if they were on treatment versus not. The research would be valuable if this study was focused on patients who were undergoing treatment for hematologic malignancy or those who experienced COVID during therapy or within 30 (or whatever number) days from the completion of treatment. Or, the complete opposite would be to focus on those who were in remission and not receiving treatment. In any case, such full analyses may not be necessarily feasible due to limited number of patients. The timing that FIB-4 was calculated based on the value at the time of admission. It is possible that the FIB-4 reflects the severity of the disease as it worsens, but not necessarily prognostic as one single parameter at diagnosis. It is worth mentioning the time from the onset of symptoms to admission (FIB-4 assessment) or time from diagnosis to admission (FIB-4 assessment). Or FIB-4 at the time of diagnosis, if available, would be also valuable. At last, but not least, FIB-4 formula was “borrowed” from other studies (originally from chronic liver scarring) but there is no rigorous evaluation of the formula itself in this context. Why ALT needs to be square rooted and placed in the denominator? The impact of age (e.g. 1 vs 10 vs 50) is appropriately reflected in this formula? Such discussion or consideration, or to state the limitation of the current study in this regard would strengthen the paper. ****** 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.0257775.r001
Revision 1
3 Jul 2021 Author Response Reviewer #1: Knowledge of COVID-19 pathogenesis in cancer patients is very limited but accumulating steadily. Any efforts in the direction are useful and extremely important. Data has to be examined carefully prior to any conclusions considering all the possibilities and probabilities within the scope of the study. Studies correlating FIB-4 index with COVID-19 infections in the context of fibrosis and type II diabetes milletus have already been published. In the current study authors propose a correlation between FIB-4 index and mortality in hematological malignancies. In addition to the caveats listed by the authors there are more questions that need to be addressed. Response: Thank you very much for reviewing our paper and providing constructive feedbacks for our article. 1.Is there correlation between COVID -19 negative or low load infection to heavy load of the infection in cancer patients. Response: Thank you very much for the question, we are sure that it will be an interesting analysis. Unfortunately, the data on patients’ viral load are unavailable. Thus we are unable to perform the analysis. 2. Are there any insights in to possible treatment regimen so as to reduce the viral load and not aggravate cancer progression. Response: Thank you very much for the question, in the Dharmais National Cancer hospital of Indonesia, we used 1. Avigan (Favipiravir) 2 x 1600 mg followed by 2 x 600 mg maintenance 2. Azithromycin 1 x 500 mg 3. Oseltamivir 2x75 mg 4. Vitamin D3 1x1000 IU 5. Vitamin C 2x500 mg 6. Zinc 1x20 mg 7. Betadine gargle 3x15 ml 8. Iodine nasal spray 3x1 Theoretically, we observe no potential mechanisms or drug-to-drug interaction that may aggravate cancer progression with the use of these medications. Although control group with other medications are required to sufficiently conclude. 3. The sample size is limited. It would be interesting to observe data from multiple studies to be able to establish a correlation between FIB-4 index and mortality in hematological malignancies and COVID-19. Response: Thank you very much for the suggestion, to the best of the authors’ knowledge, this is the first study evaluating the use of FIB-4 index as prognostication tool in patients with hematological malignancies with COVID-19. There are others in different type of population. Thus, this study serve as a basis for further investigation, it will be interesting if other studies in the future are conducted to confirm or debate the findings of the present study. We have added this in the limitation section. Reviewer #2: The authors evaluated the prognostic value of FIB-4 in patients with various hematologic malignancies. FIB-4 is calculated by AST, ALT, platelet and age, and was originally developed for the assessment of chronic liver disease. There have been some previous publication highlighting the value of FIB-4 in patients with acute illness like COVID19. The hypothesis is FIB-4 is prognostic in this population. The analysis seems to be reasonable, though the clinically more important question “what is the impact of underlying hematologic malignancy in patients with COVID19” was not assessed in this study, as there is no COVID19 patient data without hematologic malignancy presented. Response: Thank you very much for reviewing our paper and providing constructive feedbacks for our article. The table 1 shows grouping of patients only by “survivor” and “non-survivor”. For this kind of analysis, sufficient follow up duration for all patients is important. The authors state the median follow up duration of 33 days but no range. If “mortality” is the endpoint, it is best to provide a specified time mortality (i.e. 30-day mortality etc) using Kaplan-Meyer estimate. The Table 2 is evaluated for “time to mortality”, which seems appropriate. Response: Thank you very much for the suggestion, the patients were followed-up for 90 days and the Table 1 is for 3-months survival, we have added details in the methods and table. However, the event (mortality) occurred from one to 34 days. The Kaplan Meier estimate was for 90 days, however, the graph ended at the 34th day since all of the events occurred at or before the 34th day; we have revised the figure caption to add the details. Remission and relapse information are provided but majority were “neither”. It is not clear what exactly it means. If it indicates that the patient was undergoing the initial therapy for the primary malignancy, it should be clarified. The implication is significantly different if they were on treatment versus not. The research would be valuable if this study was focused on patients who were undergoing treatment for hematologic malignancy or those who experienced COVID during therapy or within 30 (or whatever number) days from the completion of treatment. Or, the complete opposite would be to focus on those who were in remission and not receiving treatment. In any case, such full analyses may not be necessarily feasible due to limited number of patients. Response: Thank you very much for the question, this study is conducted in patients undergoing chemotherapy for the primary malignancy. Thus all patients are currently receiving chemotherapy. We have added this to the methods section, we would like to apologize for the vague statement. The timing that FIB-4 was calculated based on the value at the time of admission. It is possible that the FIB-4 reflects the severity of the disease as it worsens, but not necessarily prognostic as one single parameter at diagnosis. It is worth mentioning the time from the onset of symptoms to admission (FIB-4 assessment) or time from diagnosis to admission (FIB-4 assessment). Or FIB-4 at the time of diagnosis, if available, would be also valuable. Response: Thank you very much for the suggestion, all patients in this study are patients undergoing chemotherapy for hematological malignancies. COVID-19 screening test using RT-PCR of nasopharyngeal samples are performed prior to hospitalization for chemotherapy, thus, the time from diagnosis to admission is within a few hours. We have added this to the methods section. As for the onset of symptoms to admission, we cannot provide adequate/clear documentation because many of symptoms overlap with those of malignancies and many patients display no COVID-19 related symptoms (24 patients). At last, but not least, FIB-4 formula was “borrowed” from other studies (originally from chronic liver scarring) but there is no rigorous evaluation of the formula itself in this context. Why ALT needs to be square rooted and placed in the denominator? The impact of age (e.g. 1 vs 10 vs 50) is appropriately reflected in this formula? Such discussion or consideration, or to state the limitation of the current study in this regard would strengthen the paper. Response: Thank you very much for the suggestion. Unfortunately, the reasoning for the formula is because one of the authors (Pranata R) published a paper on the use of FIB-4 Index in patients with COVID-19 (meta-analysis), many of the included studies are conducted in patients without liver diseases. Thus this is a simple repurposing of a widely used scoring method (so it can be directly used without creating an additional model to an already congested pool of prediction models), which include several important variables in patients with hematological malignancies. It turns out to be a good prediction model. Thus the model is not based on meticulous formula derived from rigorous evaluation, we have added this to the limitation section. https://doi.org/10.1371/journal.pone.0257775.r002
2 Sep 2021 Decision Letter - Senthilnathan Palaniyandi, Editor PONE-D-21-11387R1 Repurposing FIB-4 Index as a Predictor of Mortality in Patients with Hematological Malignancies and COVID-19 PLOS ONE Dear Dr. Sutandyo, 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. We have received the opinions of expert reviewer and we invite you to submit a revised version of the manuscript. Please submit your revised manuscript by Oct 17 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. 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. 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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 #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 #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? 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 #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 #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 #2: The authors addressed points that were raised by the reviewers adequately. The only minor point is, in Page 8, "Consecutive sampling of adults who were tested positive for COVID19 while undergoing chemotherapy for hematological malignancy" would be a better description of the population analyzed. ****** 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 #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. 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Revision 2
4 Sep 2021 Author Response Reviewer #2: The authors addressed points that were raised by the reviewers adequately. The only minor point is, in Page 8, "Consecutive sampling of adults who were tested positive for COVID19 while undergoing chemotherapy for hematological malignancy" would be a better description of the population analyzed. Response: Thank you very much for the suggestion, we have revised accordingly. Attachments Attachment Submitted filename: Response to Reviewer 2.docx https://doi.org/10.1371/journal.pone.0257775.r004
10 Sep 2021 Decision Letter - Senthilnathan Palaniyandi, Editor Repurposing FIB-4 Index as a Predictor of Mortality in Patients with Hematological Malignancies and COVID-19 PONE-D-21-11387R2 Dear Dr. Sutandyo, 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, Senthilnathan Palaniyandi, Ph.D 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 #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 #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? 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 #2: No ****** 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 #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 #2: All points have been addressed. ****** 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 #2: No https://doi.org/10.1371/journal.pone.0257775.r005
Formally Accepted
14 Sep 2021 Acceptance Letter - Senthilnathan Palaniyandi, Editor PONE-D-21-11387R2 Repurposing FIB-4 Index as a Predictor of Mortality in Patients with Hematological Malignancies and COVID-19 Dear Dr. Sutandyo: 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. Senthilnathan Palaniyandi Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0257775.r006

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