Predictive value of neutrophil to lymphocyte ratio for clinical outcomes in liver cirrhosis: A systematic review and meta-analysis

Jingjing Lin; Mengna Huang; Lina Shen

doi:10.1371/journal.pone.0335925

Peer Review History

Original SubmissionApril 14, 2025
2 Aug 2025 Decision Letter - Nilanka Perera, Editor Dear Dr. lin, 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. =================== 2. Discussion does not provide sufficient details and literature on the reasons how NLR could affect the mentioned outcomes. Please provide further literature on possible reasons for the observed higher mortality and other complications due to a high NLR. 3. Last sentence in the conclusion section is not clear. How would a RCT be designed to validate NLR values and outcomes? Please clarify. "To validate these observations and establish NLR as a robust prognostic indicator, large-scale multicenter randomized controlled 259 trials (RCTs) featuring extended follow-up durations and rigorous methodology are warranted" =================== Please submit your revised manuscript by Sep 16 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. 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. 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Please amend the manuscript submission data (via Edit Submission) to include authors Dr. Mengna Huang and Dr. Lina Shen. -->--> -->-->5. Please include your tables as part of your main manuscript and remove the individual files. Please note that supplementary tables (should remain/ be uploaded) as separate "supporting information" files.-->--> -->-->6. 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. ?> 7. 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. Reviewers' comments: Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? Reviewer #1: Yes Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: Yes Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #1: Yes 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: Comments: Methodology The sample size is adequate, and the sampling method is well-explained. The authors should please include the full search strings of the databases used in the appendix for reproducibility. Also, they should try and provide or show the table that has the complete search syntax as contained in the last sentence under ‘2.1 Literature Search Methodology’. Under Inclusion and Exclusion criteria, the authors excluded Neonatal or Pediatric studies. However, Pediatric sepsis studies made up two (2) out of eighteen (18) of the final analyzed studies for the paper. Please, let the authors clarify these two areas (line 6 under 2.2 Inclusion and exclusion criteria and line 5 under 3.1 Identification of relevant studies). Results The review adequately addressed the risk of bias and quality assessment with the appropriate tools being used (Newcastle-Ottawa Scale). This is good! A meta-analysis was used, but heterogeneity is high (I² =89%). The authors should consider providing a more in-depth exploration of sources of heterogeneity or revisiting whether the meta-analysis is appropriate. Discussion Limitation The authors’ effort to acknowledge the study’s limitations is appreciated, as this is a crucial aspect of transparent research reporting. The limitations section acknowledges moderate heterogeneity of the study, potential publication bias and the effects of pharmacotherapy on the NLR. I would recommend if the authors could add the possibilities of tackling these limitations and how these can guide future research on the prognostic relevance of NLR for liver cirrhosis. Minor Comments: -The authors should please clarify acronyms (PRISMA) at first mention (line 8 under subsection 2.2 Inclusion and exclusion criteria). -The authors should cite appropriately with adequate footnotes to all the pictures at the appendix. Reviewer #2: The authors have compiled a systematic review and meta-analysis on the predictive value of the neutrophil-to-lymphocyte ratio (NLR) for clinical outcomes in liver cirrhosis to be a valuable contribution to the literature, though it also has some notable limitations. The inclusion and exclusion criteria are fine and the authors managed to get adequate number of studies for the analysis. Authors have used a random effects approach due to the significant observed heterogeneity. However, random effect models were used for NLR vs ascites (P>0.05), NLR vs infected and non-infected cirrhotic patients (p>0.05) and NLR vs hepatic encephalopathy (p=0.34) as well. This can lead to misleading interpretations. Authors may want to change the model or justify their approach further. In addition to that, here is a couple of suggestions for the supporting materials. TableS1 Search strategy: This is not a typical table though it has been labelled as a table FigureS1 (a) Sensitivity analysis of hepatic encephalopathy incidence: x-axis labels needs to be improved ****** 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: Idowu Peter Shileayo Adebayo 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: Systematic Review Paper.docx https://doi.org/10.1371/journal.pone.0335925.r001
Revision 1
7 Sep 2025 Author Response Dear Editors and Reviewers: Thank you for your letter and for the reviewers’ comments concerning our manuscript entitled “Predictive value of neutrophil to lymphocyte ratio for the clinical outcomes of liver cirrhosis: a systematic review and meta-analysis” (ID:PONE-D-25-19873). Those comments are all valuable and very helpful for revising and improving our paper, as well as the important guiding significance to our researches. We have studied comments carefully and have made correction which we hope meet with approval. Revised portion are marked in red in the paper. The main corrections in the paper and the responds to the reviewer’s comments are as flowing: Responds to the editor’s comments: Editor #� 1.Comment. Language could be further improved for clarity. Please attend to revising the use of language throughout the manuscript. Response: Thank you for your detailed review of our paper. We sincerely thank you and the reviewers for taking the time to carefully review our work. After professional English editing, we have carefully handled the language issues mentioned in your feedback. 2.Comment. Discussion does not provide sufficient details and literature on the reasons how NLR could affect the mentioned outcomes. Please provide further literature on possible reasons for the observed higher mortality and other complications due to a high NLR. Response: Thank you for your valuable comments. We have supplemented the discussion section with a mechanistic explanation and literature support on the impact of NLR on the prognosis of cirrhosis. The specific contents include: 1) excessive neutrophil activation directly damages liver cells through the release of reactive oxygen species and pro-inflammatory factors; 2) Lymphopenia leads to impaired immune function and increases the risk of infection. These additions provide a more comprehensive understanding of the pathophysiological mechanisms by which high NLR leads to poor prognosis. Thanks again for your guidance. 3.Comment. Last sentence in the conclusion section is not clear. How would a RCT be designed to validate NLR values and outcomes? Please clarify. Response: Thanks to the editor for the suggestion. 'Large-scale randomized controlled trial (RCT)' in the original text is a clerical error. Since NLR is an objective indicator rather than an intervention, a large-scale multicenter prospective cohort study should be conducted to further verify its clinical value by standardizing and dynamically monitoring the association between NLR and prognosis. We have made changes to the conclusion section, thank you for your guidance. Reviewer #1: 1.Comment. Methodology The sample size is adequate, and the sampling method is well-explained. The authors should please include the full search strings of the databases used in the appendix for reproducibility. Also, they should try and provide or show the table that has the complete search syntax as contained in the last sentence under ‘2.1 Literature Search Methodology’. Response: Thank you for your affirmation and suggestions on our research methodology. We have supplemented the full database search strategy (including detailed query queries from PubMed, Web of Science, Cochrane Library, and Embase) in the appendices of the paper as requested, and presented a full search syntax table in Table 1. These modifications will ensure reproducibility of the study. See Table 1 for details. Thank you again for your valuable advice. 2.Comment. Under Inclusion and Exclusion criteria, the authors excluded Neonatal or Pediatric studies. However, Pediatric sepsis studies made up two (2) out of eighteen (18) of the final analyzed studies for the paper. Please, let the authors clarify these two areas (line 6 under 2.2 Inclusion and exclusion criteria and line 5 under 3.1 Identification of relevant studies). Response: Thank you for your careful review and for pointing out the inconsistencies in this wording. You are absolutely right, the "pediatric sepsis studies" we mentioned in the exclusion criteria is indeed a clerical error. We have made changes to the original text. These modifications ensure consistency in the wording of the full-text exclusion criteria that we did exclude all studies of childhood cirrhosis (including neonatal and paediatric patients). Thank you for helping us improve the accuracy of our papers, which makes our research methodology description more rigorous. 3.Comment.Results The review adequately addressed the risk of bias and quality assessment with the appropriate tools being used (Newcastle-Ottawa Scale). This is good! A meta-analysis was used, but heterogeneity is high (I² =89%). The authors should consider providing a more in-depth exploration of sources of heterogeneity or revisiting whether the meta-analysis is appropriate. Response: Thank you for your affirmation and suggestions for our research. We have analysed the high heterogeneity (I²=89%) and added possible sources of heterogeneity in the discussion section, including: first, significant differences in NLR cutoff values used across studies (e.g., >3 vs. ≤3) directly affect the consistency of prognostic criteria; second, differences in study design (prospective vs. retrospective) and population characteristics (age, etiology) may lead to heterogeneous expression of immune-inflammatory responses; additionally, varying follow-up times (short-term vs. long-term prognosis) further increased outcome variability. These heterogeneities may impair the accuracy of NLR prediction potency. To reduce heterogeneous in future studies, we recommended: (1) determining optimal NLR cutoff values for etiology and staging specificity through multicenter studies; (2) adopting standardized study designs (e.g., unified prospective cohorts); (3) conducting mechanistic studies to elucidate the association between dynamic changes in NLR and immune-inflammatory pathways, thereby improving the clinical applicability and comparability of this market. At the same time, we verified the robustness of the results through sensitivity analysis and subgroup analysis, and confirmed that the random-effects model is still a suitable analytical method for this study. These additions are detailed in the revised version. Thank you for your valuable suggestions for improving the methodological quality of this study. 4.Comment.Limitation The authors’ effort to acknowledge the study’s limitations is appreciated, as this is a crucial aspect of transparent research reporting. The limitations section acknowledges moderate heterogeneity of the study, potential publication bias and the effects of pharmacotherapy on the NLR. I would recommend if the authors could add the possibilities of tackling these limitations and how these can guide future research on the prognostic relevance of NLR for liver cirrhosis. Response: Thank you for your attention and suggestions about the limitations of our research. In response to your comments, we have added the following in the Limitation Discussion section: 1) recommend standardized NLR cut-offs for future studies (e.g., multicenter studies to determine optimal thresholds for different stages of cirrhosis); 2) It is recommended to pre-register the study protocol on platforms such as PROSPERO to reduce publication bias; 3) Emphasize the need to record the patient's medication (such as antibiotics, immunomodulatory agents). These supplements provide specific directional suggestions for future research and help to more accurately evaluate the clinical value of NLR in the prognosis of liver cirrhosis. Thank you again for your valuable suggestions, which significantly enhance the academic quality of our papers. 5.Comment.Minor Comments: -The authors should please clarify acronyms (PRISMA) at first mention (line 8 under subsection 2.2 Inclusion and exclusion criteria). -The authors should cite appropriately with adequate footnotes to all the pictures at the appendix. Response: Thank you for the correction, we have added the full name to the first reference to PRISMA in subsection 2.2: "This study strictly follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines [29]". Thank you for correcting the appendix specifications. We have thoroughly checked all the images and tables in the appendix to ensure that each image has a complete citation note and necessary captions, and that the citation source is accredited in the appropriate place in the body. These changes further improve the standardization and readability of the paper. Please refer to the appendix for specific modifications. Thank you for helping us refine the details of the paper. 6.Comment. Authors have used a random effects approach due to the significant observed heterogeneity. However, random effect models were used for NLR vs ascites (P>0.05), NLR vs infected and non-infected cirrhotic patients (p>0.05) and NLR vs hepatic encephalopathy (p=0.34) as well. This can lead to misleading interpretations. Authors may want to change the model or justify their approach further. Response: Thank you for your important suggestions on statistical methods. We understand your concern about the application of the random-effects model and have further added in the revised draft that although the heterogeneity test P-value of some subgroup analyses (NLR vs. ascites, infection, and hepatic encephalopathy) > 0.05, we uniformly use the random-effects model based on the following considerations: (1) clinical heterogeneity between studies (e.g., population characteristics, etiologies); (2) The pre-scheme requires a unified model to ensure methodological consistency; (3) When the number of studies is small (e.g., < 5 items), the random-effects model is more conservative and reliable�Cited References: [1] Kanters S. Fixed- and Random-Effects Models. Methods Mol Biol. 2022;2345:41-65. doi: 10.1007/978-1-0716-1566-9_3. PMID: 34550583; [2] Barili F, Parolari A, Kappetein PA, Freemantle N. Statistical Primer: heterogeneity, random- or fixed-effects model analyses? Interact Cardiovasc Thorac Surg. 2018 Sep 1;27(3):317-321. doi: 10.1093/icvts/ivy163. PMID: 29868857). As a validation, we have supplemented the sensitivity analysis results showing that the effect size direction is consistent with the main analysis, supporting the robustness of the conclusions. 7.Comment.TableS1 Search strategy: This is not a typical table though it has been labelled as a table FigureS1 (a) Sensitivity analysis of hepatic encephalopathy incidence: x-axis labels needs to be improved Response: Thank you for your valuable suggestions on the Table S1 format. We have completely revised the form in accordance with the requirements of academic norms, and now use a tabular format to present a complete search strategy, with a clearer structure and more complete content. For specific changes, please refer to Table 1 in the revised draft. Your suggestions have significantly improved the normative nature of our research, thank you again. Thank you for your attention to the details of the chart. The issue with the display of the X-axis label in Figure S1(a) is due to a Stata software layout limitation. To ensure a clear presentation of the data, we have added the complete original data next to the chart and detailed it in the captions. This approach not only preserves the standardization of the software-generated graphics, but also allows the reader to accurately obtain all the necessary information. We will continue to optimize the presentation of the charts, and thank you for your valuable feedback. We tried our best to improve the manuscript and made some changes in the manuscript. These changes will not influence the content and framework of the paper. And here we did not list the changes but marked in red in revised paper. We appreciate for Editors/Reviewers’ warm work earnestly, and hope that the correction will meet with approval. Once again, thank you very much for your comments and suggestions. Attachments Attachment Submitted filename: response.docx https://doi.org/10.1371/journal.pone.0335925.r002
19 Oct 2025 Decision Letter - Nilanka Perera, Editor <p>Predictive value of Neutrophil to lymphocyte ratio for clinical outcomes in liver cirrhosis: a systematic review and meta-analysis PONE-D-25-19873R1 Dear Dr. lin, 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, Nilanka Perera, MD, PhD Academic Editor PLOS ONE ********** https://doi.org/10.1371/journal.pone.0335925.r003
Formally Accepted
Acceptance Letter - Nilanka Perera, Editor PONE-D-25-19873R1 PLOS ONE Dear Dr. Lin, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days to review your paper and let you know the next and final steps. Lastly, 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. You will receive an invoice from PLOS for your publication fee after your manuscript has reached the completed accept phase. If you receive an email requesting payment before acceptance or for any other service, this may be a phishing scheme. Learn how to identify phishing emails and protect your accounts at https://explore.plos.org/phishing. If we can help with anything else, please email us at customercare@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. Nilanka Perera Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0335925.r004

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