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Reducing Hospital Capacity Needs for Seasonal Respiratory Infections: The Case of Switching to High-Dose Influenza Vaccine for Dutch Older Adults

  • Florian Zeevat
    Correspondence
    Correspondence: Florian Zeevat, MSc, Department of Health Sciences, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, Groningen 9713 AV, The Netherlands.
    Affiliations
    Department of Health Sciences, University Medical Center Groningen, University of Groningen, The Netherlands
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  • Jan C. Wilschut
    Affiliations
    Department of Medical Microbiology and Infection Prevention, University Medical Center Groningen, University of Groningen, The Netherlands
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  • Cornelis Boersma
    Affiliations
    Department of Health Sciences, University Medical Center Groningen, University of Groningen, The Netherlands

    Faculty of Management Sciences, Open University, Heerlen, The Netherlands

    Health-Ecore, Zeist, The Netherlands
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  • Maarten J. Postma
    Affiliations
    Department of Health Sciences, University Medical Center Groningen, University of Groningen, The Netherlands

    Department of Economics, Econometrics & Finance, Faculty of Economics & Business, University of Groningen, Groningen, The Netherlands
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Open AccessPublished:December 09, 2022DOI:https://doi.org/10.1016/j.jval.2022.11.020

      Abstract

      Objectives

      Influenza is responsible for considerable health and economic burden every year. Especially older adults are vulnerable for influenza infection and its complications due to immunosenescence and often-underlying medical conditions. Recently, the innovative quadrivalent high-dose influenza vaccine (QIV-HD) has become available in Europe. Through its enhanced immunogenicity, QIV-HD offers improved protection for older adults against respiratory as well as cardiovascular complications. We estimated the potential impact—specifically in terms of hospital admissions and related costs—of a hypothetical past switch from QIV-Standard dose (SD) to QIV-HD in The Netherlands.

      Methods

      Estimates of hospitalizations for the older adults vaccinated with QIV-SD were derived from the seasons 2010/2011-2017/2018. Subsequently, the number of respiratory infections and cardiovascular complications of influenza were estimated for the year 2019/2020 for both QIV-SD and QIV-HD. To calculate the overall corresponding savings, costs for hospital complications, derived from literature, were used.

      Results

      When QIV-HD would have been used instead of QIV-SD during the season 2019/2020, an additional 220 hospitalizations would have been averted among older adults of 60 years and older in the Netherlands. This corresponds to savings of €1 219 779 (uncertainty interval: 1 089 813-1 348 549), of which 69% is attributable to cardiovascular-related hospitalizations.

      Conclusions

      We demonstrate that a relevant improvement in influenza vaccination among older adults in The Netherlands can be achieved by switching from the current QIV-SD to QIV-HD. Not only comes a switch from QIV-SD to QIV-HD with a significant reduction in pressure on hospital capacity but also with notable cost savings.

      Keywords

      Optimal protection against influenza is more important than ever, because, with COVID-19 restrictions being lifted, severe seasonal influenza epidemics are to be expected. Indeed, immunity in the population has lacked regular boosting because of social distancing and other restrictions, resulting in increased risks for seasonal influenza epidemics.
      • Dhanasekaran V.
      • Sullivan S.
      • Edwards K.M.
      • et al.
      Human seasonal influenza under COVID-19 and the potential consequences of influenza lineage elimination.
      Such epidemics will come with additional pressure on hospital and intensive care unit capacity and corresponding societal costs, especially among adults 60 years and older (60+). For this risk group, the quadrivalent influenza vaccine (QIV) has been in use since 2019/2020 in The Netherlands. Nevertheless, the vaccine effectiveness of QIV remains suboptimal in elderly individuals. Notably, we demonstrated that even if the 60+ group in The Netherlands had been vaccinated with QIV during the 2010/2011 through 2017/2018 seasons, on an average, hundreds of influenza-associated respiratory disease hospitalizations would still have occurred among these senior individuals on an annual basis.
      • Zeevat F.
      • Crépey P.
      • Dolk F.C.K.
      • Postma A.J.
      • Breeveld-Dwarkasing V.N.A.
      • Postma M.J.
      Cost-effectiveness of quadrivalent versus trivalent influenza vaccination in the Dutch national influenza prevention program.
      Ergo, despite vaccination with QIV, there remains a considerable burden of influenza among older adults with a corresponding need for healthcare capacity. With ongoing developments in the area of influenza vaccines, further improvements in vaccination programs might therefore be considered. Potential improvements include, for example, a switch from the standard-dose (SD) to a high-dose (HD) vaccine formulation for the 60+ population. Current SD inactivated influenza vaccines contain 15 μg
      • Lunny C.
      • Antony J.
      • Rios P.
      • et al.
      Safety and effectiveness of dose-sparing strategies for intramuscular seasonal influenza vaccine: a rapid scoping review.
      of the hemagglutinin antigen per virus strain included in the vaccine. By contrast, the HD vaccine contains 60 μg

      Sanofi Pasteur Ltd. (2022) Product Monograph Including Patient Medication Information, FLUZONE® High-Dose Quadrivalent. https://elsevier.proofcentral.com/en-us/landing-page.html?token=42dee043eed2b438e607f51c64e30f. Accessed January 1, 2022.

      hemagglutinin per strain. HD influenza vaccine has been shown to be superior compared with SD in various studies,
      • DiazGranados C.A.
      • Dunning A.J.
      • Kimmel M.
      • et al.
      Efficacy of high-dose versus standard-dose influenza vaccine in older adults.
      • DiazGranados C.A.
      • Robertson C.A.
      • Talbot H.K.
      • Landolfi V.
      • Dunning A.J.
      • Greenberg D.P.
      Prevention of serious events in adults 65 years of age or older: A comparison between high-dose and standard-dose inactivated influenza vaccines.
      • Lee J.K.H.
      • Lam G.K.L.
      • Shin T.
      • Samson S.I.
      • Greenberg D.P.
      • Chit A.
      Efficacy and effectiveness of high-dose influenza vaccine in older adults by circulating strain and antigenic match: an updated systematic review and meta-analysis.
      with improved vaccine effectiveness and no increase in serious adverse events. QIV-HD is available for older adults in the United States since 2020, and its use has been recommended in countries such as Canada, Germany, Italy, and the United Kingdom.
      Summary of the National Advisory Committee on immunization (NACI) seasonal influenza vaccine statement for 2021-2022.
      • Grohskopf L.A.
      • Alyanak E.
      • Broder K.R.
      • et al.
      Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices – United States, 2020-21 influenza season.
      Resolution and scientific justification of the German Standing Committee on Vaccination (STIKO) for updating the influenza vaccination recommendation for adults ≥ 60 years of age. Robert Koch Institut.

      Cicchetti A, Rumi F, Basile M, et al. Report HTA del Vaccino Quadrivalente ad Alto Dosaggio (QIV-HD) EFLUELDA® per la Prevenzione dell’Influenza Stagionale e Delle Sue Complicanze Nella Popolazione Over 65. Italian Journal of Public Health. https://www.ijph.it/rails/active_storage/blobs/redirect/eyJfcmFpbHMiOnsibWVzc2FnZSI6IkJBaHBUUT09IiwiZXhwIjpudWxsLCJwdXIiOiJibG9iX2lkIn19-ad6117264e8178fec474b2fafffc57d1c35b3e57/QIJPH-2021_2%20-%2015%20Settembre.pdf?disposition=attachment. Accessed January 10, 2022.

      Advice on influenza vaccines for 2021/22. Joint Committee on Vaccination and Immunisation.
      Recently, the potential benefit of a switch from SD to HD to further reduce hospitalizations has been demonstrated in retrospective database analyses in the United States.
      • van Aalst R.
      • Russo E.M.
      • Neupane N.
      • et al.
      Economic assessment of a high-dose versus a standard-dose influenza vaccine in the US Veteran population: estimating the impact on hospitalization cost for cardio-respiratory disease.
      • van Aalst R.
      • Gravenstein S.
      • Mor V.
      • et al.
      Comparative effectiveness of high dose versus adjuvanted influenza vaccine: a retrospective cohort study
      • Young-Xu Y.
      • Van Aalst R.
      • Mahmud S.M.
      • et al.
      Relative vaccine effectiveness of high-dose versus standard-dose influenza vaccines among Veterans Health Administration patients.
      Here, we estimated the potential impact—specifically in terms of hospital admissions and related costs—of a switch from QIV-SD to QIV-HD in The Netherlands. Hospital capacity has emerged as a crucial factor in infectious disease control during the COVID-19 pandemic, justifying the focus of our study.
      The remaining burden of influenza in The Netherlands among the 60+ group can be estimated at approximately 61 500 influenza cases annually, over the period of 2010/2011-2017/2018 (with assumed QIV-SD coverage rates of 50% and 70% among 60- to 65-year-old people and 65+, respectively).
      • Zeevat F.
      • Crépey P.
      • Dolk F.C.K.
      • Postma A.J.
      • Breeveld-Dwarkasing V.N.A.
      • Postma M.J.
      Cost-effectiveness of quadrivalent versus trivalent influenza vaccination in the Dutch national influenza prevention program.
      This remaining burden is largely due to immunosenescence contributing to the modest vaccine effectiveness of QIV-SD in this specific group. As indicated above, QIV-HD, because of its 4 times higher dose of antigen than QIV-SD, induces a stronger immune response and therefore overcomes part of the immunosenescence effects and provides older adults with improved protection against influenza. Specifically, the HD vaccine has been shown to provide superior protection against cardiovascular complications of influenza and corresponding hospitalizations.
      • DiazGranados C.A.
      • Robertson C.A.
      • Talbot H.K.
      • Landolfi V.
      • Dunning A.J.
      • Greenberg D.P.
      Prevention of serious events in adults 65 years of age or older: A comparison between high-dose and standard-dose inactivated influenza vaccines.
      Cardiovascular complications have been found to occur from days up to months after the actual influenza infection.
      • Ruane L.
      • Buckley T.
      • Hoo S.Y.S.
      • et al.
      Triggering of acute myocardial infarction by respiratory infection.
      • Warren-Gash C.
      • Hayward A.C.
      • Hemingway H.
      • et al.
      Influenza infection and risk of acute myocardial infarction in England and Wales: a CALIBER self-controlled case series study.
      • Warren-Gash C.
      • Blackburn R.
      • Whitaker H.
      • McMenamin J.
      • Hayward A.C.
      Laboratory-confirmed respiratory infections as triggers for acute myocardial infarction and stroke: a self-controlled case series analysis of national linked datasets from Scotland.
      We estimated the number of hospitalizations in the 60+ population that could have been additionally avoided with the use of QIV-HD instead of QIV-SD in the season 2019/2020. In this season, QIV-SD was used for the first time and the epidemiology was not influenced yet by the COVID-19 restrictions, potentially enhancing representativeness for the coming years. The hospitalization estimates for the 60+ population vaccinated with QIV-SD over the period 2010-2018 by Zeevat et al
      • Zeevat F.
      • Crépey P.
      • Dolk F.C.K.
      • Postma A.J.
      • Breeveld-Dwarkasing V.N.A.
      • Postma M.J.
      Cost-effectiveness of quadrivalent versus trivalent influenza vaccination in the Dutch national influenza prevention program.
      were used as a starting point (Appendix Table 1 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2022.11.020), reflecting hospitalizations of both vaccinated and nonvaccinated individuals. Subsequently, we related the average number of hospitalizations and vaccination coverage rates over the period 2010-2018 to the vaccine effectiveness rates of QIV-SD with regard to respiratory, as well as cardiovascular complications of influenza and the most recent coverage rates for the 2019/2020 season as indicated in Appendix Table 2 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2022.11.020.
      • Zeevat F.
      • Crépey P.
      • Dolk F.C.K.
      • Postma A.J.
      • Breeveld-Dwarkasing V.N.A.
      • Postma M.J.
      Cost-effectiveness of quadrivalent versus trivalent influenza vaccination in the Dutch national influenza prevention program.
      ,

      Cicchetti A, Rumi F, Basile M, et al. Report HTA del Vaccino Quadrivalente ad Alto Dosaggio (QIV-HD) EFLUELDA® per la Prevenzione dell’Influenza Stagionale e Delle Sue Complicanze Nella Popolazione Over 65. Italian Journal of Public Health. https://www.ijph.it/rails/active_storage/blobs/redirect/eyJfcmFpbHMiOnsibWVzc2FnZSI6IkJBaHBUUT09IiwiZXhwIjpudWxsLCJwdXIiOiJibG9iX2lkIn19-ad6117264e8178fec474b2fafffc57d1c35b3e57/QIJPH-2021_2%20-%2015%20Settembre.pdf?disposition=attachment. Accessed January 10, 2022.

      ,
      • Warren-Gash C.
      • Hayward A.C.
      • Hemingway H.
      • et al.
      Influenza infection and risk of acute myocardial infarction in England and Wales: a CALIBER self-controlled case series study.
      • Warren-Gash C.
      • Blackburn R.
      • Whitaker H.
      • McMenamin J.
      • Hayward A.C.
      Laboratory-confirmed respiratory infections as triggers for acute myocardial infarction and stroke: a self-controlled case series analysis of national linked datasets from Scotland.
      • Rose A.
      • Kissling E.
      • Emborg H.D.
      • et al.
      Interim 2019/20 influenza vaccine effectiveness: six European studies, September 2019 to January 2020.
      Also, in Appendix Table 3 in Supplementary Materials found at https://doi.org/10.1016/j.jval.2022.11.020, we provide the baseline costs for complications as used to estimate overall corresponding savings.
      • Zeevat F.
      • Crépey P.
      • Dolk F.C.K.
      • Postma A.J.
      • Breeveld-Dwarkasing V.N.A.
      • Postma M.J.
      Cost-effectiveness of quadrivalent versus trivalent influenza vaccination in the Dutch national influenza prevention program.
      ,
      • DiazGranados C.A.
      • Dunning A.J.
      • Kimmel M.
      • et al.
      Efficacy of high-dose versus standard-dose influenza vaccine in older adults.
      ,

      Statline - Consumentenprijzen; Prijsindex Centraal Bureau Voor de Statistiek (CBS). 2015=100. https://www.cbs.nl/nl-nl/cijfers/detail/83131NED. Accessed May 6, 2021.

      • Soekhlal R.R.
      • Burgers L.T.
      • Redekop W.K.
      • Tan S.S.
      Treatment costs of acute myocardial infarction in the Netherlands.
      • Stevanovic J.
      • Denee L.
      • Koenders J.M.
      • Postma M.J.
      Incidence description and costs of acute heart failure in the Netherlands.
      • Buisman L.R.
      • Tan S.S.
      • Nederkoorn P.J.
      • Koudstaal P.J.
      • Redekop W.K.
      Hospital costs of ischemic stroke and TIA in the Netherlands.
      Uncertainty intervals for hospitalizations averted and corresponding cost savings were taken into the analysis using 95% confidence intervals on the vaccine effectiveness estimates for the 2019/2020 season.
      • van Aalst R.
      • Russo E.M.
      • Neupane N.
      • et al.
      Economic assessment of a high-dose versus a standard-dose influenza vaccine in the US Veteran population: estimating the impact on hospitalization cost for cardio-respiratory disease.
      ,
      2019 opnieuw een lichte stijging van het aantal griepvaccinaties [Dutch]. NIVEL.
      ,
      • van Aalst R.
      • Russo E.
      • Neupane N.
      • et al.
      Comparing the impact of high-dose versus standard dose influenza vaccines on hospitalization cost for cardiovascular and respiratory diseases: economic assessment in the US Veteran population during 5 respiratory seasons using an instrumental variable method.
      Using the average hospitalization data during the seasons 2010/2011-2017/2018 as baseline, it follows that in a scenario in which during the season 2019/2020 QIV-HD would have been used instead of QIV-SD, 220 hospitalizations among the 60+ group would have been additionally averted (Table 1
      • Zeevat F.
      • Crépey P.
      • Dolk F.C.K.
      • Postma A.J.
      • Breeveld-Dwarkasing V.N.A.
      • Postma M.J.
      Cost-effectiveness of quadrivalent versus trivalent influenza vaccination in the Dutch national influenza prevention program.
      ,
      • Rose A.
      • Kissling E.
      • Emborg H.D.
      • et al.
      Interim 2019/20 influenza vaccine effectiveness: six European studies, September 2019 to January 2020.
      ,
      2019 opnieuw een lichte stijging van het aantal griepvaccinaties [Dutch]. NIVEL.
      ). Of these averted hospitalizations, 150 were cardiovascular-related hospitalizations using the assumption that there is a 1:1.89 ratio between respiratory and cardiovascular-related hospitalizations caused by influenza for vaccinating with QIV-HD and 1:1.92 with QIV-SD.
      • van Aalst R.
      • Russo E.
      • Neupane N.
      • et al.
      Comparing the impact of high-dose versus standard dose influenza vaccines on hospitalization cost for cardiovascular and respiratory diseases: economic assessment in the US Veteran population during 5 respiratory seasons using an instrumental variable method.
      These additional hospitalizations, which could have been avoided by the use of the HD vaccine, represent a total expenditure of €1 219 779 (uncertainty interval: 1 089 813-1 348 549) of which €841 531 (ie, 69% of the total costs) is attributable to the aversion to cardiovascular-related hospitalizations.
      Table 1Estimated remaining hospitalizations after vaccination of senior Dutch citizens with QIV-SD or QIV-HD, showing hospitalizations additionally averted by QIV-HD (including the uncertainty interval), during the 2019/2020 influenza season, taking the estimated average level of influenza-related respiratory hospitalizations with the use of QIV-SD during the 2010/2011 through 2017/2018 seasons
      • Zeevat F.
      • Crépey P.
      • Dolk F.C.K.
      • Postma A.J.
      • Breeveld-Dwarkasing V.N.A.
      • Postma M.J.
      Cost-effectiveness of quadrivalent versus trivalent influenza vaccination in the Dutch national influenza prevention program.
      and 2019/2020 vaccine coverage rates as the baseline.
      • Rose A.
      • Kissling E.
      • Emborg H.D.
      • et al.
      Interim 2019/20 influenza vaccine effectiveness: six European studies, September 2019 to January 2020.
      ,
      2019 opnieuw een lichte stijging van het aantal griepvaccinaties [Dutch]. NIVEL.
      Age category in yearsComplicationQIV-HDQIV-SDDifference
      60-64Respiratory30345
      Cardiovascular566610
      All8610115
      65+Respiratory40547166
      Cardiovascular765905140
      All11701375205
      Total (60+)All12561476220 (197-244)
      HD indicates high dose; QIV, quadrivalent influenza vaccine; SD, standard dose.
      As exemplified by the COVID-19 pandemic, outbreaks of respiratory infections pose a significant pressure on hospital capacity in The Netherlands, as well as elsewhere. Nevertheless, this pressure is by no means restricted to the current COVID-19 crisis. For example, influenza regularly poses strains on hospital capacity during annual winter epidemics. In addition, increased influenza-related cardiovascular events may put an even higher pressure on hospital capacity. For the coming years, it is to be anticipated that epidemics of respiratory infections, influenza, and coronavirus alike will coincide during winter seasons.
      • Nichols G.L.
      • Gillingham E.L.
      • Macintyre H.L.
      • et al.
      Coronavirus seasonality, respiratory infections and weather.
      Therefore, maximal control of these seasonal epidemics is crucial to avoid hospital capacity overload. Optimization of influenza vaccination represents one measure to achieve such maximal control. In the present study, we demonstrate that a relevant improvement in influenza vaccination among older adults in The Netherlands can be achieved by switching from the current QIV-SD to QIV-HD. Indeed, based on the 2019/2020 influenza season, we estimate that such a switch could avert an additional 220 cardio-respiratory hospitalizations annually, corresponding to almost €1.22 million in terms of cost savings in hospitals. This demonstrates that not only can a significant reduction in pressure on hospital capacity be achieved but also that a switch from QIV-SD to QIV-HD comes with notable cost savings as well. The significance of our results is further illustrated by comparing the 71 respiratory hospitalizations avoided in this analysis with previously published results,
      • Zeevat F.
      • Crépey P.
      • Dolk F.C.K.
      • Postma A.J.
      • Breeveld-Dwarkasing V.N.A.
      • Postma M.J.
      Cost-effectiveness of quadrivalent versus trivalent influenza vaccination in the Dutch national influenza prevention program.
      where it was estimated that switching from trivalent influenza vaccine to QIV (ie, SD) could result in 84 avoided respiratory-related hospitalizations. These published results were based on a slightly broader population of those aged 60+, as well as high-risk individuals < 60 years. Notably, these earlier findings gave rise to the switch from trivalent influenza vaccine to QIV (ie, SD) in The Netherlands.
      As indicated above, a major share of the benefits of the switch from QIV-SD to QIV-HD come from cardiovascular-related hospital admissions (68% of hospitalizations avoided). This logically derives from our assumption that for every respiratory hospitalization, almost 2 cardiovascular hospitalizations occur.
      • van Aalst R.
      • Russo E.
      • Neupane N.
      • et al.
      Comparing the impact of high-dose versus standard dose influenza vaccines on hospitalization cost for cardiovascular and respiratory diseases: economic assessment in the US Veteran population during 5 respiratory seasons using an instrumental variable method.
      In general, it can be concluded that including cardiovascular-related hospitalizations in a cost-effectiveness analysis may have a major impact on the favorability of the result compared with when respiratory-related hospitalizations alone are included.
      Against the perspective of a potential resurge of influenza, now that COVID-19 control measures are relaxed after 2 years of lockdowns and social distancing and in view of the recurrent pressure on hospital capacity within the broader context of winter peaks in respiratory infections, including not only influenza but also coronavirus, respiratory syncytial virus, and pneumococcal infections, further improvement in the Dutch influenza vaccination program by a switch to QIV-HD appears not only timely but also urgent.

      Article and Author Information

      Author Contributions: Concept and design: Zeevat, Wilschut, Boersma, Postma
      Acquisition of data: Zeevat
      Analysis and interpretation of data: Zeevat, Boersma, Postma
      Drafting of the manuscript: Zeevat, Wilschut, Boersma, Postma
      Critical revision of the paper for important intellectual content: Zeevat, Boersma, Postma
      Statistical analysis: Zeevat
      Supervision: Wilschut, Boersma, Postma
      Conflict of Interest Disclosures: Drs Boersma and Postma reported receiving grants and personal fees from various medical and pharmaceutical industries, all outside the submitted work. Dr Boersma holds stocks in Health-Ecore. Dr Postma holds stocks in Health-Ecore and Pharmacoeconomics Advice Groningen (PAG Ltd) and is an advisor to Asc Academics, all pharmacoeconomic consultancy companies. Dr. Postma is an editor for Value in Health and had no role in the peer-review process of this article. No other disclosures were reported.
      Funding/Support: This study was supported by EU IMI project on Vaccines and Infectious Diseases in the Ageing Population project (VITAL, awarded to Drs Zeevat, Boersma, and Postma). The VITAL project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement number 806776. The Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation program, and EPPIA-members.
      Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

      Supplemental Material

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