Title: Estimation of the burden of varicella in Europe before the introduction of universal childhood immunization

Transcription

1 Author s response to reviews Title: Estimation of the burden of varicella in Europe before the introduction of universal childhood immunization Authors: Margarita Riera-Montes (margarita.riera@p-95.com) Kaatje Bollaerts (kaatje.bollaerts@p-95.com) Ulrich Heininger (ulrich.heininger@ukbb.ch) Niel Hens (niel.hens@uhasselt.be) Giovanni Gabutti (giovanni.gabutti@unife.it) Bayad Nozad (bayad.nozad@nhs.net) Angel Gil (angel.gil@urjc.es) Grazina Mirinaviciute (Grazina.Mirinaviciute@fhi.no) Elmira Flem (Elmira.Flem@fhi.no) Audrey Souverain (ASouverain.externe@spmsd.com) Thomas Verstraeten (thomas.verstraeten@p-95.com) Susanne Hartwig (SHartwig@spmsd.com) Version: 1 Date: 22 Mar 2017 Author s response to reviews: Dear Editor, On behalf of my fellow authors, I hereby re-submit the article entitled Estimation of the burden of varicella in Europe before the introduction of universal childhood immunization. The article has been revised according to the reviewers comments. You can find the detailed responses to all the comments in the grid below. I addition, we have made some minor editorial changes to grammar and revised the results sections for paper inclusion since we detected some inconsistencies between the text, tables and figure 1. All authors have approved the revised manuscript.

2 We look forward to your response. Sincerely, Margarita Riera, MD Author s reply to comments by Reviewer 1 In table 1 can you explain the differences between white and grey box? Can you add a legend to the table? Reply: The grey only indicated those cells with a number different from 0. We have removed the shading for clarity. Page 27 In table 3 for Italy is lacking the upper limit of 95%CI for the age group 40+. Could you please provided it or explain why it is lacking? Reply: It was a problem with the table formatting that was hiding the upper CI, now corrected. Page 30 Page 20: Please add a full stop in the second line to conclude the first sentence Reply: Corrected. Page 20 Author s reply to comments by Reviewer 2 General comment A principal concern I have with the systematic review within the manuscript is its similarity to another systematic review published by the ECDC in 2014 ( Is this paper part of the same work that generated that report? The authors should justify how this manuscript adds to the body of literature. Reply: We refer to the recent ECDC review in the background section as well as the review by Helmuth and specify that they were descriptive in nature while we aim to quantify the country specific burden of varicella. The other reviews did not do this. Major revisions

3 1.The first sentence in the 'Eligibility criteria' subsection of the methods should be revised as it's inconsistent with what was said in the background. It suggests that some countries have universal varicella immunization, but the background indicates that few countries have even implemented a general recommendation for the use of varicella vaccines. The ECDC report on varicella vaccination in the EU indicates that at least seven countries had programs in 2015, so these inconsistencies need to be sorted out in the text. Further to this, given that at least seven countries have immunisation programs, the effect of vaccination on seroprevalence studies included in the review needs to be addressed in the limitations, or described in the methods how it was dealt with in the analysis (e.g. studies done in countries with a vaccination program were excluded from the analysis if they were conducted after the introduction of the program). Reply: We have clarified in the eligibility criteria that criteria number 2 would apply only to those countries that have introduced universal varicella immunization. Therefore, all studies carried out after varicella vaccination introduction in those countries were excluded. See page 8. We have clarified in the background that 7 countries have introduced universal varicella vaccination. See page 5. 2.The full list of studies used for the analyses as shown in the supplementary data files does not appear to be included in the main references section of the manuscript. Full reference listing of these studies is required in the main body of the manuscript. Reply: References of studies included in the analysis have now been included in the main body in the results section. See page I am concerned about the fairly broad-brush equivalence of seroprevalence and incidence in the paper. Prevalence and incidence are different and distinct measures. In the fourth paragraph of the discussion the authors highlight the utility of using varicella serprevalence data to estimate incidence, but the way this is done varies between studies. In the three examples cited in the paragraph: Mossong et al used modelling to estimate age-specific force of infection, then applied this to estimate a crude age distribution of varicella cases; Ciofi degli Atti et al estimated agespecific lifetime cumulative incidence of varicella; and Munoz et al derived incidence by smoothed prevalence for each age group, with estimated variance of the estimated incidence was obtained by the delta method. Munoz et al also highlighted that the method they described may be applied to the study of incidence rates in relation to the prevalence of diseases if it is accepted that the infection produces permanent immunity; the risk of mortality is the same for infected and non-infected subjects and that the disease incidence and population remain constant in time. This variability in approaches to estimating incidence from seroprevalence data and the necessary assumptions need to be addressed by the authors in the discussion and the possible effect on the findings discussed. Thus, in the second sentence of the fourth paragraph of the discussion I think saying that the study "ensured" comparability across countries is not justified. 'Maximised' is a more appropriate word. Reply: We agree that methods used to derive incidence from seroprevalence data vary substantially across studies. Therefore, we opted to first collect all (publicly) available agespecific seroprevalence data. We then re-analysed all these data using the same approach across countries.

4 Specifically, we estimated age-specific seroprevalence profiles using the catalytic model with a piecewise constant force of infection. Based on these estimated profiles, we derived the annual varicella incidence for age groups of interest. When doing so, we assumed lifelong immunity, time homogeneity and non-differential mortality.this systematic review of seroprevalence data and re-analyses are reported elsewhere. In the current paper, we now give more details on page I am also concerned that the results of the validation exercise do not convincingly validate the approach to estimate incidence in those countries without published estimates. I think this warrants a more qualified approach to interpretation of the findings in the discussion, perhaps with more emphasis on the findings from studies, versus those that have been extrapolated from the model. Reply: The aim of the study was to estimate the overall burden of varicella in Europe. In order to do this, we used the data available in the literature for those countries that had it, and used the model approach for countries with no or incomplete data, which is the main difference of this study with respect to previous reviews. We acknowledge in the discussion the limitations of the model. Minor revisions 1. Second paragraph of background: for completeness of describing the clinical course of VZV infection, the authors should also mention the latency phase and reactivation of virus as herpes zoster/shingles. Reply: Added to the background in page Second paragraph of background: fourth and fifth sentences are contradictory. The 4th sentence says that varicella is not a mandatory reportable disease in the EU, but fifth sentence says that some existing data are based on mandatory reporting. Reply: Sentence corrected to reflect that the mandatory notification and/or sentinel surveillance systems that exist are at the national level. See page Second paragraph of background: the authors have listed the aspects by which varicella surveillance systems differ. Does this also include case definitions? Reply: Yes, has been added.see page Third paragraph of background: the text from "To this end, we first " can be deleted as they describe methods and discussion/conclusions. Reply: Deleted. See page 6.

5 5. First paragraph of methods: the search has not been sufficiently described for someone to be able to repeat it. Firstly, was the PubMed search limited to articles published in English? If restricted to articles in English, this needs to be addressed in the limitations in the discussion. If not, explain how translated versions (or necessary data from these papers or reports) were obtained. Secondly, how the expressions 'AND' and 'OR' were used with the search terms needs to be defined. Thirdly, was there a lower date limit on articles retrieved? This needs to be stated so readers know how recent the data are. Further to this point, even though the dates of the studies are listed in the supplementary data tables, I think it would be helpful for readers if the surveillance period of review studies was included as a column in table 1. Reply: Full search terms and lower date limit added in page 7 as well as the specification that all languages were included and how translated versions were obtained (page 8). 6. The last sentence of the 'Data extraction' subsection of the methods makes a categorisation of studies to have a lower risk of bias by virtue of whether they have a prospective design or not. However, I don't accept that a study's quality or bias is necessarily lower just because it is retrospective. For example, a retrospective review of hospital records, conducted properly, can be relatively free of bias. Reply: While that may be true for some studies, in general it would be expected that there is a better control of bias with a prospective study. 7. In the 'Incidence estimation for countries without data' subsection of the methods: when the model failed to predict incidence and the authors extrapolated minimum and maximum observed estimates with in the same age group from countries with data, which 'countries' with data were used for the extrapolation? Was it all of them, or did the authors attempt to only use countries that were well matched on the country-level predictor variables shown to be associated with varicella transmissibility and health care use. Reply: Countries with data for each outcome used are listed in Table 2. Legend has been modified to indicate that those were the studies used for incidence estimation to avoid confusion and reference to table 2 has been inserted in the relevant sections. See pages 16 and The data tables presented in the manuscript are large and complex, and as a result it is difficult to compare estimates between countries. An easier way to compare them could be to present age specific rate ratios, using the 0-4 years age group as the referent rate (i.e. RR=1.0). This would be helpful in more clearly showing any differences in age distributions of varicella incidence between countries. Reply: The objective was to estimate country-specific incidence to build the overall burden of Europe and not focus on the differences between countries which is why no ratios are presented although we agree that ratios would facilitate the comparison across ages. 9. The first paragraph of the discussion compares the study data to data from EUVAC.NET, and presents a table, but seems more suited to the results section. A description of what

6 EUVAC.NET is should also be included (in the methods, if these comparison data are to form part of the results). Reply: It has now been included in methods and results. See pages 13 and 20. Discretionary revisions 1. Second paragraph of background: suggest that the first sentence states the formulations for the varicella vaccines currently licensed in Europe (e.g. monovalent, quadrivalent MMRV, etc.) Reply: We consider that it would not add to the article since the focus is disease burden not the vaccine. 2. I understand why data from mandatory notification systems were excluded from the analysis, given their propensity to under-report, but wonder if the authors considered comparing estimates of incidence from mandatory reporting with the scientifically robust studies included in the review to quantitate the magnitude of under-reporting (notification fraction) by the mandatory reporting systems. Reply: Data from EUVAC.NET is from mandatory notification systems for the most part. Unfortunately, we did not have robust data for most of the countries reporting data, only for Italy, Poland, Slovakia, Slovenia and Spain where the proportion of cases reported of all estimated was between 8% (Italy) and 51% (Slovenia).