Fluctuations in quality of life and immune responses during intravenous immunoglobulin infusion cycles

Jordan K. Abbott; Sanny K. Chan; Morgan MacBeth; James L. Crooks; Cathy Hancock; Vijaya Knight; Erwin W. Gelfand

doi:10.1371/journal.pone.0265852

Peer Review History

Original SubmissionOctober 15, 2021
2 Dec 2021 Decision Letter - Jagadeesh Bayry, Editor PONE-D-21-33136Fluctuations in quality of life and immune responses during intravenous immunoglobulin infusion cyclesPLOS ONE Dear Dr. Abbott, 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. ==============================Both the reviewers have commented that the article is of interest to the community. Additional data and interpretation are required. ============================== Please submit your revised manuscript by Jan 16 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. 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: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Jagadeesh Bayry, DVM, PhD, HDR Academic Editor PLOS ONE Journal Requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at 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. 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: Partly ******** 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: The paper is of some interest, however several aspects need to be clarified. QOL is the results of a number of factors, including psycological, behavioural and social factors. Moreover, the authors tested a number of cytokines that have a role in immunity, but their role on brain, i.e. on mood is less clear. The authors should determine whether the change in QOL is a true change (and not linked to a positive or negative reinforcement due to the administration of IVIg per se). It is likely that a depression questonnaire could be helpful. Also, the authors should consider how the administration of IVIg leads to the apparent feeling or freedom and safety thus allowing 8and leading into) a better QOL. Finally, all the immunologic changes are somehow expected, but how do they impact on patients moddo and functionality? any relationship with psychological behaviours? Reviewer #2: This is an interesting paper, but a bit more data and interpretation could help the reader assess the applicability and clinical significance of the conclusions to individual patients. The data and comments requested below should be available already, but should be added to the presentation. It is probably not feasible at this time, but it would have been informative to have weekly data points throughout each infusion-infusion cycle, rather than just comparing the pre-infusion and 7-day time points. Answers to a few questions would help the readers focus on the results: 1. Were pre-infusion meds such as NSAIDS, aspirin or steroids allowed, or used in any patients ? Were there any clinically significant infusion reactions and did these lead to results different from infusions with no reactions ? 2.Were any patients on continuous prophylactic or treatment antibiotics ? 3. Please add to table 1 data on the duration of IVIG treatment and/or number of infusions preceding enrollment for each subject. 4. The authors should clarify if their use of the term "VAS" score refers only to their 100 point "thermometer" and not to the 5 point boxed choices on the modified SF-12. 5. In fig 2B, the authors should indicate the number of values for each response category (1-4), indicate whether any subject ever reported a value of 5, and comment on the consistency of individual subjects' responses over the multiple intervals represented in the figure. To aid in interpreting the results, the authors should discuss whether there is any data on the clinical relevance of the change in Tregs from 2.28 % to 2.42% portrayed in Fig 3, and discuss the minimal clinically important difference in this measurement, as well as in the cytokine values in fig 4. Is there any data available on the range of results for normal controls in their laboratory ? In addition, different symbols or colors should be used for IVIG-naive vs experienced subjects. The authors should also discuss the degree of variability vs consistency in Treg responses in different infusion cycles in individual subjects (fig S3, and S4-S5) Fig 5 could also be split into two figures- one showing the IVIG-naive subjects and one showing the experienced subjects. The authors conclude that the changes in IL-25 they report may partially explain "the clinical efficacy of IVIG in allergic disease", citing the over-20 year-old reference #21 in regard to this "efficacy". What is the evidence that the decrement in IL-25 they report is clinically significant? Given the lack of substantiation of the efficacy of IVIG in most atopic diseases, and the facts that the FDA has not approved IVIG for any atopic disease, and that the AAAAI review of uses of IVIG does not recommend it for atopic disease, this conclusion appears to be an overstatement rather than a "take-home message" as it seems currently stated. The authors should probably substitute the latest AAAAI recommendations for IgG therapy (Perez et al JACI 2017) for the outdated reference 1 they now cite. ****** 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.0265852.r001
Revision 1
4 Feb 2022 Author Response note: response is also provided as a word document with formatting. 1/19/2022 To the Reviewers, Thank you for taking the time and attention to review our submitted manuscript. The comments were insightful, and by addressing your concerns, we feel that the quality of the manuscript has significantly improved. A point-by-point response to the concerns is listed below. We hope that you find that our responses adequately address your concerns and answer your questions. Sincerely, Jordan Abbott, MD, MA University of Colorado, School of Medicine Department of Pediatrics, Section of Allergy and Immunology Note for the Editor: CSL Inc. has granted permission to supply the deidentified dataset. It is included as an excel file labeled supplemental data. Reviewer #1: The paper is of some interest, however several aspects need to be clarified. QOL is the results of a number of factors, including psycological, behavioural and social factors. Moreover, the authors tested a number of cytokines that have a role in immunity, but their role on brain, i.e. on mood is less clear. The authors should determine whether the change in QOL is a true change (and not linked to a positive or negative reinforcement due to the administration of IVIg per se). It is likely that a depression questonnaire could be helpful. Also, the authors should consider how the administration of IVIg leads to the apparent feeling or freedom and safety thus allowing 8and leading into) a better QOL. Finally, all the immunologic changes are somehow expected, but how do they impact on patients moddo and functionality? any relationship with psychological behaviours? We appreciate the interest in the paper. It is clear that QOL encompasses a number of factors as identified by the reviewer. To assess QOL we utilized a validated instrument. This was not to imply there were no limitations to the approach but one that appeared effective in addressing our primary target, the “wear-off” effect. There are many reports of cytokine changes affecting behavior and mood through the CNS. We have modified the manuscript discussion section to address this issue and included a relevant reference. Mood questionnaires per se were not part of our approach as they appear more targeted to assessing depression and bipolar function. The SF-12 is a validated health-related quality-of-life questionnaire consisting of questions that measure health domains to assess both physical and mental health. As the majority of the patients were on long-standing, regular IVIG infusions , it is not clear how we could assess “apparent feeling or freedom and safety..leading to a better QOL." The revised paragraph is pasted here: This study aimed to identify associations between cytokine changes and variation in QOL through the IVIG cycle. Many of the cytokines monitored have been implicated in altering CNS function and mood, and as a result, may affect QOL determinations (19). Despite identifying quite large immediate cytokines changes, we did not find associations between these changes and the reported QOL improvements. There are multiple likely reasons for this. First, the non-naive group, which made up most of the study population, experienced lower magnitude and less significant cytokine level changes than the naive group, so there were less dramatic changes available for comparison. Second, the low number of enrolled subjects restricts the power of the study to identify subtle correlations missed here. Third, it is possible that timing of this relationship differs from that designed in the study in that additional analyte changes may be occurring between the infusion and day 7. Fourth, the relationship between cytokine fluctuations in the blood and alterations in the CSF is not entirely clear. It is conceivable that changes in the CNS such as blood-brain barrier alterations, increases or decreases in glymphatic flow, or changes in tissue cytokine levels may have minimal impact on serum levels, particularly when dramatic shifts in analyte levels seem to be simultaneously occurring in other parts of the body. Given the demonstrated role of LPS in altering CNS glymphatic function (20), the known role of low level chronic LPS exposure in CVID (21), and the ability of IVIG to reduce LPS levels in the blood, a corresponding change in CNS conditions may be expected in patients that suffer from chronic LPS exposure. Considering these aspects, it is difficult to rule out that cytokine changes directly or indirectly induced in the CNS do in fact correlate with the reported QOL changes. Innovative approaches to monitoring CNS physiology would be helpful to further understand these relationships. Reviewer #2: This is an interesting paper, but a bit more data and interpretation could help the reader assess the applicability and clinical significance of the conclusions to individual patients. The data and comments requested below should be available already, but should be added to the presentation. It is probably not feasible at this time, but it would have been informative to have weekly data points throughout each infusion-infusion cycle, rather than just comparing the pre-infusion and 7-day time points. Answers to a few questions would help the readers focus on the results: 1. Were pre-infusion meds such as NSAIDS, aspirin or steroids allowed, or used in any patients ? Were there any clinically significant infusion reactions and did these lead to results different from infusions with no reactions ? Preinfusion medications were administered in 8 of the subjects. Four received acetaminophen only. Two received acetaminophen and diphenhydramine. One received hydrocortisone 100mg, and one received both hydrocortisone 100mg and acetaminophen. There were no significant infusion reactions. Pretreatment did not significantly impact any of the significant findings including VAS, fatigue, general health, Treg percentage, or any of the cytokines changes from pre-infusion to either post-infusion or day 7. Three additional supplemental figures are now included that show the relationship between pretreatment on the specified outcomes: change in VAS pre-post and pre-day7, change in fatigue score pre-post and pre-day7, change in general health pre-post and pre-day7, Treg pre-post and pre-day7s, and change in cytokine levels pre-post and pre-day7. 2.Were any patients on continuous prophylactic or treatment antibiotics ? Information regarding antibiotic use was not collected for the group. The authors no longer have access to the patient's charts as the study is closed and they are no longer at the institution. Anecdotally, patients treated at this center at the time of the study were infrequently on prophylactic antibiotics. 3. Please add to table 1 data on the duration of IVIG treatment and/or number of infusions preceding enrollment for each subject. We appreciate this excellent suggestion, as it would be nice to determine if there is a correlation between duration of IVIG treatment and cytokine changes within the experienced IVIG user group. Unfortunately, the precise length of time that each subject was on IVIG prior to enrollment was not recorded or extracted from the medical record. Only whether the subject started IVIG during the trial was recorded. It is therefore not possible to add this information to the table or to perform an analysis of the relationship between duration of IVIG and cytokine changes in this group. 4. The authors should clarify if their use of the term "VAS" score refers only to their 100 point "thermometer" and not to the 5 point boxed choices on the modified SF-12. The visual analogue scale (VAS) score refers to the “thermometer.” This fact has been clarified in the text describing the questionnaires. “The VAS is a single question where subjects rate their health on a scale of 0 to 100.” 5. In fig 2B, the authors should indicate the number of values for each response category (1-4), indicate whether any subject ever reported a value of 5, and comment on the consistency of individual subjects' responses over the multiple intervals represented in the figure. Thank you for this helpful suggestion. We looked more deeply into the trends of responses to this question and found that reporting worse health over the past week was more common on infusion day than on day 7. We added additional text to the result section indicating as such. We also now provide a new supplemental figure (fig S2C) that shows the reported score for each individual over the course of the study. To directly answer your questions, no subject responded with a 5 for the weekly health question, and the numbers of each response were as follows: “1” = 6, “2” = 21, “3” = 62, “4” = 12, “NA” = 5. These numbers were added to figure 2B. To aid in interpreting the results, the authors should discuss whether there is any data on the clinical relevance of the change in Tregs from 2.28 % to 2.42% portrayed in Fig 3, and discuss the minimal clinically important difference in this measurement, as well as in the cytokine values in fig 4. Is there any data available on the range of results for normal controls in their laboratory? The median Treg% increased as described, but some individuals experienced much larger changes and others experienced no change or a decrease. The most we can say regarding these changes within the context of this study is that the observed changes in Treg percentage did not correlate with an improvement in VAS or SF-12 responses; and moreover, the changes are not apparently the result of the observed cytokine changes. Therefore, the increase in Treg percentages dis not appear associated with clinical benefit. The reference range for Treg in the healthy local population is 1.8 to 8.3% of CD4+ T cells. There is no reference range available for the cytokine measurements, as the assay was performed solely on a research basis for this study. The clinical significance of the detected cytokine changes is not clear as they did not correlate with any measured clinical outcome. This conclusion may reflect the fact that the largest group of recipients were on an established regimen of infusions. In addition, different symbols or colors should be used for IVIG-naive vs experienced subjects. In the original figure 4, circles denote the IVIG-naive subjects and triangles denote the IVIG-experienced subjects. Red was used to denote statistically significant results. The authors should also discuss the degree of variability vs consistency in Treg responses in different infusion cycles in individual subjects (fig S3, and S4-S5) There was substantial variability among individuals from cycle to cycle. Five subjects experienced an increase in Tregs every cycle, 8 experienced an increase on 2 cycles, and 5 experienced an increase during only 1 cycle. No subjects failed to experience a Treg increase during at least 1 cycle. This information was added to the section describing the Treg results. Fig 5 could also be split into two figures- one showing the IVIG-naive subjects and one showing the experienced subjects. Thank you for this suggestion. The figure has now been separated into 2 figures. It is clear from the figure containing the naïve-subject trends that they have uniform cytokine responses, and we agree that it is better to present the figures in this way. The authors conclude that the changes in IL-25 they report may partially explain "the clinical efficacy of IVIG in allergic disease", citing the over-20 year-old reference #21 in regard to this "efficacy". What is the evidence that the decrement in IL-25 they report is clinically significant? Given the lack of substantiation of the efficacy of IVIG in most atopic diseases, and the facts that the FDA has not approved IVIG for any atopic disease, and that the AAAAI review of uses of IVIG does not recommend it for atopic disease, this conclusion appears to be an overstatement rather than a "take-home message" as it seems currently stated. The authors should probably substitute the latest AAAAI recommendations for IgG therapy (Perez et al JACI 2017) for the outdated reference 1 they now cite. We acknowledge the controversial nature of this statement and have deleted it and the reference. Attachments Attachment Submitted filename: rebuttal letter 20220119.docx https://doi.org/10.1371/journal.pone.0265852.r002
9 Mar 2022 Decision Letter - Jagadeesh Bayry, Editor Fluctuations in quality of life and immune responses during intravenous immunoglobulin infusion cycles PONE-D-21-33136R1 Dear Dr. Abbott, 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, Jagadeesh Bayry, DVM, PhD, HDR Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed ******** 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 ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: No ****** 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 ****** 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 ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The authors properly responded to all raised comments and the paper is now suitable for publication ****** 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 https://doi.org/10.1371/journal.pone.0265852.r003
Formally Accepted
14 Mar 2022 Acceptance Letter - Jagadeesh Bayry, Editor PONE-D-21-33136R1 Fluctuations in quality of life and immune responses during intravenous immunoglobulin infusion cycles Dear Dr. Abbott: 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. Jagadeesh Bayry Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0265852.r004

Open letter on the publication of peer review reports

PLOS recognizes the benefits of transparency in the peer review process. Therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. Reviewers remain anonymous, unless they choose to reveal their names.

We encourage other journals to join us in this initiative. We hope that our action inspires the community, including researchers, research funders, and research institutions, to recognize the benefits of published peer review reports for all parts of the research system.

Learn more at ASAPbio .