Herpes zoster in older adults in Ontario, 2002–2016: Investigating incidence and exploring equity

Sarah A. Buchan; Nick Daneman; Jun Wang; Sarah E. Wilson; Gary Garber; Anne E. Wormsbecker; Tony Antoniou; Shelley L. Deeks

doi:10.1371/journal.pone.0246086

Peer Review History

Original SubmissionSeptember 12, 2020
3 Dec 2020 Decision Letter - Graciela Andrei, Editor PONE-D-20-28759 Herpes zoster in older adults in Ontario, 2002-2016: investigating incidence and exploring equity PLOS ONE Dear Dr. Buchan, 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. Please submit your revised manuscript by Jan 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. 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We will update your Data Availability statement on your behalf to reflect the information you provide. 5. PLOS requires an ORCID iD for the corresponding author in Editorial Manager on papers submitted after December 6th, 2016. Please ensure that you have an ORCID iD and that it is validated in Editorial Manager. To do this, go to ‘Update my Information’ (in the upper left-hand corner of the main menu), and click on the Fetch/Validate link next to the ORCID field. This will take you to the ORCID site and allow you to create a new iD or authenticate a pre-existing iD in Editorial Manager. Please see the following video for instructions on linking an ORCID iD to your Editorial Manager account: https://www.youtube.com/watch?v=_xcclfuvtxQ [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: This retrospective study was meticulously designed. The limitations of it are those seen typically when relying on administrative databases. Bearing this in mind, the authors have made a robust effort to understand the epidemiology of HZ and PHN stratified by demographic, clinical and socio-economic status. The discussion of its limitations and how it might explain differences in incidences compared to previous literature is rational. The statistical methods used were simple and appropriate for the aim of the study. A mention of the statistical software used would make it complete. The style of the manuscript is technical and appropriate. If I had one comment to make stylistically, it would be to use subheadings in the 'Discussion' to highlight the differences by 'Demographic', 'Clinical' and 'Social' covariates. This would help to drive home some core messages such as 'Age does not equal frailty.'; 'Differences in SES may relate to cost and/or poor access' and 'Immunocompromise is a significant risk factor with implications for choice of vaccine.' Reviewer #2: In this paper the authors are reporting the incidence of Herpes Zoster and its complications in Ontario between 2002 and 2016 based on public health records and prescriptions for antiviral drugs commonly used for Herpes Zoster and PHN complications. Furthermore they want to relate the incidence to equity and access to available vaccines and therefore report the incidence within different percentiles of income in a period where the vaccine only was available at cost price and there was no publicly founded vaccine. This was all based on the assumption that the lower the income the lower the chance that the vaccine was taken. Unfortunately, they do not show any data to validate this assumption. It is said that due to the lack of HZ vaccine-specific billing codes, they could not identify whether an individual had received HZ vaccine. But in their definition they mention that they excluded people with a coincident vaccination fee code (G538, G539), so apparently there are vaccination fee codes that they could use to calculate the relation between vaccination and income, especially in the VZ era. Of course there could be confounder of the influenza vaccination but that can be corrected for by season or billing for the influenza vaccine. Since there are not very many other vaccines targeting the older population, this could give a good estimate of the assumed relationship between SES and vaccination rate for LZV. Next to that the data confirm the already known increased risk for Herpes Zoster in frail elderly compared to non-frail elderly, especially in the 65-69 group, immunocompromised patients such as patients using immune suppressive drugs such as patients with autoimmune diseases and transplant patients. To have a better idea of the impact of targeted Zoster vaccinations it would be nice to have also some estimates about the total size of possible targeted populations, such as immunocompromised patients, or frail elderly. Of course it is possible to calculate population size by combining table 2 incidences with total number of cases from table 1, but it is nice to provide those numbers. With those numbers and the described efficacy of the LZV vaccine to prevent HZ (from literature or from the data suggested above) it would be possible to estimate the cost-effectiveness to target specific candidates with high risk to HZ and its complications. Such additions would certainly improve the impact of the paper and better consolidate the conclusions that additional prevention efforts should be targeted toward adults who are immunocompromised, frail, and those living in lower income neighbourhoods. ****** 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: Yes:** Dr Alex Chaudhuri 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.0246086.r001
Revision 1
29 Dec 2020 Author Response 1. This retrospective study was meticulously designed. The limitations of it are those seen typically when relying on administrative databases. Bearing this in mind, the authors have made a robust effort to understand the epidemiology of HZ and PHN stratified by demographic, clinical and socio-economic status. The discussion of its limitations and how it might explain differences in incidences compared to previous literature is rational. The statistical methods used were simple and appropriate for the aim of the study. A mention of the statistical software used would make it complete. Thank you for these comments. 2. The style of the manuscript is technical and appropriate. If I had one comment to make stylistically, it would be to use subheadings in the 'Discussion' to highlight the differences by 'Demographic', 'Clinical' and 'Social' covariates. This would help to drive home some core messages such as 'Age does not equal frailty.'; 'Differences in SES may relate to cost and/or poor access' and 'Immunocompromise is a significant risk factor with implications for choice of vaccine.' We have included sub-headings in the Discussion section to address this comment (Page 16, line 227; page 17, line 256; page 19 line 296). Reviewer #2: In this paper the authors are reporting the incidence of Herpes Zoster and its complications in Ontario between 2002 and 2016 based on public health records and prescriptions for antiviral drugs commonly used for Herpes Zoster and PHN complications. Furthermore they want to relate the incidence to equity and access to available vaccines and therefore report the incidence within different percentiles of income in a period where the vaccine only was available at cost price and there was no publicly founded vaccine. This was all based on the assumption that the lower the income the lower the chance that the vaccine was taken. Unfortunately, they do not show any data to validate this assumption. 1. It is said that due to the lack of HZ vaccine-specific billing codes, they could not identify whether an individual had received HZ vaccine. But in their definition they mention that they excluded people with a coincident vaccination fee code (G538, G539), so apparently there are vaccination fee codes that they could use to calculate the relation between vaccination and income, especially in the VZ era. Of course there could be confounder of the influenza vaccination but that can be corrected for by season or billing for the influenza vaccine. Since there are not very many other vaccines targeting the older population, this could give a good estimate of the assumed relationship between SES and vaccination rate for LZV. In our study, we assessed changes in medically-attended herpes zoster visits using diagnostic codes in outpatient and hospital settings. Our primary outcome of interest was medically attended herpes zoster and one of our analyses included examining incidence before and after availability of vaccine through private purchase. As the reviewer indicates, there are no specific vaccine-billing codes for herpes zoster in Ontario; as such, we could not directly estimate vaccine uptake in our population. However, there are two generic (i.e., no specific vaccine indicated) vaccine fee codes (G538, G539) that are used for a variety of vaccines and in order to prevent outcome misclassification by reducing any chance that someone whose visit was due to a herpes zoster vaccine, and not for herpes zoster itself, we decided to remove any visit with a concurrent vaccination code. We did not use the generic vaccine code as a proxy for herpes zoster as other vaccines that are available to adults over 65 years of age were also captured using the generic code during the study period. This may include pneumococcal vaccine (also funded for adults ≥65 years in Ontario). Further, some practitioners may bill other vaccines such as influenza or tetanus and diphtheria booster [both publicly funded in the province] or travel vaccines using these generic codes. As such, we were unable to use these codes as a proxy for LZV. 2. Next to that the data confirm the already known increased risk for Herpes Zoster in frail elderly compared to non-frail elderly, especially in the 65-69 group, immunocompromised patients such as patients using immune suppressive drugs such as patients with autoimmune diseases and transplant patients. Our results provide further evidence about the risk of herpes zoster in immunocompromised patients and older adults; further, the use of frailty as an indicator beyond age alone is a more recent application and one for which quantitative data are not always available. We believe these results will be relevant to policy-makers and practitioners in the context of vaccine decision making. 3. To have a better idea of the impact of targeted Zoster vaccinations it would be nice to have also some estimates about the total size of possible targeted populations, such as immunocompromised patients, or frail elderly. Of course it is possible to calculate population size by combining table 2 incidences with total number of cases from table 1, but it is nice to provide those numbers. With those numbers and the described efficacy of the LZV vaccine to prevent HZ (from literature or from the data suggested above) it would be possible to estimate the cost-effectiveness to target specific candidates with high risk to HZ and its complications. Such additions would certainly improve the impact of the paper and better consolidate the conclusions that additional prevention efforts should be targeted toward adults who are immunocompromised, frail, and those living in lower income neighbourhoods. Thank you for this suggestion. We have now included the average annual population size for each characteristic included in Tables 1-4 in our supplementary material (S1 Table). Attachments Attachment Submitted filename: Response to reviewers_2020_12_29.docx https://doi.org/10.1371/journal.pone.0246086.r002
13 Jan 2021 Decision Letter - Graciela Andrei, Editor Herpes zoster in older adults in Ontario, 2002-2016: investigating incidence and exploring equity PONE-D-20-28759R1 Dear Dr. Buchan, 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, Graciela Andrei 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: 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 #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: Thank you for addressing the reviewers' comments. The paper reads more cogently with all the requisite information clearly presented. ****** 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: Yes:** Dr Alex Chaudhuri https://doi.org/10.1371/journal.pone.0246086.r003
Formally Accepted
2 Feb 2021 Acceptance Letter - Graciela Andrei, Editor PONE-D-20-28759R1 Herpes zoster in older adults in Ontario, 2002-2016: investigating incidence and exploring equity Dear Dr. Buchan: 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. Graciela Andrei Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0246086.r004

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