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Original Research |

Examination of Links Between Herpes Zoster Incidence and Childhood Varicella Vaccination

Craig M. Hales, MD, MPH; Rafael Harpaz, MD, MPH; M. Riduan Joesoef, MD, PhD; and Stephanie R. Bialek, MD, MPH
[+] Article and Author Information

From the National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia.

Disclaimer: The findings and conclusions in this article are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

Acknowledgment: The authors thank Carla Winston, PhD; Barbara Bardenheier, PhD, MS; Chad Heilig, PhD; John Zhang, PhD; and Ronald Henry for their valuable technical assistance.

Potential Conflicts of Interest: None disclosed. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M13-1026.

Reproducible Research Statement: Study protocol: Not available. Statistical code: Available from Dr. Hales (e-mail, chales@cdc.gov). Data set: Not available.

Requests for Single Reprints: Craig M. Hales, MD, MPH, Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, 1600 Clifton Road NE, Mail Stop A-34, Atlanta, GA 30333; e-mail, chales@cdc.gov.

Current Author Addresses: Drs. Hales, Harpaz, Joesoef, and Bialek: Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, 1600 Clifton Road NE, Mail Stop A-34, Atlanta, GA 30333.

Author Contributions: Conception and design: C.M. Hales, R. Harpaz, R. Joesoef, S.R. Bialek.

Analysis and interpretation of the data: C.M. Hales, R. Harpaz, R. Joesoef, S.R. Bialek.

Drafting of the article: C.M. Hales, R. Harpaz.

Critical revision of the article for important intellectual content: C.M. Hales, R. Harpaz, R. Joesoef, S.R. Bialek.

Final approval of the article: C.M. Hales, R. Harpaz, R. Joesoef, S.R. Bialek.

Statistical expertise: C.M. Hales, R. Harpaz.

Administrative, technical, or logistic support: R. Joesoef.

Collection and assembly of data: C.M. Hales, R. Joesoef.

Ann Intern Med. 2013;159(11):739-745. doi:10.7326/0003-4819-159-11-201312030-00006
Text Size: A A A

Background: Introduction of a universal varicella vaccine program for U.S. children in 1996 sparked concern that less-frequent exposure to varicella would decrease external boosting of immunity to varicella zoster virus and thereby increase incidence of herpes zoster (HZ).

Objective: To determine whether the varicella vaccination program has influenced trends in HZ incidence in the U.S. population older than 65 years.

Design: Retrospective study of Medicare claims.

Setting: Medicare, 1992 through 2010.

Participants: 2 848 765 beneficiaries older than 65 years.

Measurements: Annual HZ incidence from 1992 through 2010; rate ratios (RRs) for HZ incidence by age, sex, and race or ethnicity; and state-level varicella vaccination coverage.

Results: 281 317 incident cases of HZ occurred. Age- and sex-standardized HZ incidence increased 39% from 10.0 per 1000 person-years in 1992 to 13.9 per 1000 person-years in 2010 with no evidence of a statistically significant change in the rate of increase after introduction of the varicella vaccination program. Before introduction of this program, HZ incidence was higher in women (RR, 1.21 [95% CI, 1.19 to 1.24]) than men and was lower in black persons (RR, 0.51 [CI, 0.48 to 0.53]) and Hispanic persons (RR, 0.76 [CI, 0.72 to 0.81]) than white persons. In a model adjusted for sex, age, and calendar year from 1997 to 2010, HZ incidence did not vary by state varicella vaccination coverage (RR, 0.9998 [CI, 0.9993 to 1.0003]).

Limitation: Uncertain level and consistency of health-seeking behavior and access and uncertain accuracy of disease coding.

Conclusion: Age-specific HZ incidence increased in the U.S. population older than 65 years even before implementation of the childhood varicella vaccination program. Introduction and widespread use of the vaccine did not seem to affect this increase. This information is reassuring for countries considering universal varicella vaccination.

Primary Funding Source: None.


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HZ incidence among Medicare beneficiaries older than 65 years, by age group, 1992–2010.

HZ = herpes zoster.

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Appendix Figure 1 Age- and sex-standardized HZ incidence among immunocompetent Medicare beneficiaries older than 65 years, 1992–2010.

Age- and sex-standardized HZ incidence among immunocompetent Medicare beneficiaries older than 65 years, 1992–2010.

This immunocompetent subpopulation excluded beneficiaries with any International Classification of Diseases, Ninth Revision, Clinical Modification, code indicating a potentially immunocompromising condition or a condition that may be managed with immunosuppressive treatment (see Appendix Table for the list of codes). HZ = herpes zoster.

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Appendix Figure 2.

Age- and sex-standardized ratios of HZ incidence to the incidence of 10 selected conditions, 1995–2010.

The 10 conditions and associated International Classification of Diseases, Ninth Revision, Clinical Modification, codes were impacted cerumen (380.4), calculus of kidney and ureter (592.x), urinary tract infection (599.0), ingrowing nail (703.0), lipoma (214.x), sprains and strains of wrist and hand (842.xx), inflammation of eyelids (373.xx), epistaxis (784.7), hemorrhoids (455.x), and gout (274.0, 274.9). HZ = herpes zoster.

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Comments on Hales and colleagues’ examination of links between herpes zoster and chickenpox vaccination
Posted on December 7, 2013
Benson Ogunjimi, Philippe Beutels
Centre for Health Economics Research & Modeling Infectious Diseases (CHERMID), Vaccine & Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Antwerp, Belgium
Conflict of Interest: None Declared
Hales and colleagues found a 39% increase in herpes zoster (HZ) incidence in The US in 2010 versus 1992 (1). They concluded that the annual increase in HZ incidence could not have been caused by the implementation of chickenpox (CP) vaccination, but was already present before CP vaccination was introduced, in 1996.
Although the study was well performed, the validity of their final conclusion would benefit from further exploration of their interesting dataset.
First, the lack of a difference in HZ incidence pre and post introduction of CP vaccination could be caused by a transitional phase during which registration practices improve. This means that during the start-up phase of electronic registration of ICD codes, an artificial increase in incidence could be observed for some conditions (2). Therefore, it would be interesting to show and analyse the data in Appendix figure 2 from 1992 onwards, rather than from 1995.
Second, the efficacy of HZ vaccination decreases with age (3) and, as noted by the authors, mixing with children decreases with age in older age groups. In the current analysis it is possible that an actual effect of CP vaccine implementation in relatively younger age groups is missed due to the fact that all age groups > 65 years are joined together. The analysis would thus have benefitted from the addition of the variable "age group" to the interaction term between calendar year and implementation period.
Third, a major limitation is that the dataset only includes people > 65 years. Indeed, modeling studies over the time span observed here predict the highest increase in HZ to occur in those younger than 65 years (4, 5).
Fourth, the inter-state comparison of HZ incidence would benefit from using CP incidence data (both natural and breakthrough) or serial age-specific seroprevalence based force of infection estimates, instead of 1-dose vaccination coverage in < 36 month old children, especially since potentially influential catch-up vaccination in older children seems to have been ignored.
Finally, the authors don’t expect a substantial impact of HZ vaccination in > 60 year olds (2010 coverage: 14%), but this seems not to have been explored in the analyses, for instance in relation to HZ incidence in immunocompetent persons.
In conclusion several issues remain to be addressed before the data presented in this study can confirm that widespread CP vaccination has no influence on HZ incidence in unvaccinated groups in the US.

1. Hales CM, Harpaz R, Joesoef MR, Bialek SR. Examination of links between herpes zoster incidence and childhood varicella vaccination. Ann Intern Med. 2013;159(11):739-45.
2. Ogunjimi B, Van Damme P, Beutels P. Herpes Zoster Risk Reduction through Exposure to Chickenpox Patients: A Systematic Multidisciplinary Review. PLoS One. 2013;8(6):e66485.
3. Levin MJ, Oxman MN, Zhang JH, Johnson GR, Stanley H, Hayward AR, et al. Varicella-zoster virus-specific immune responses in elderly recipients of a herpes zoster vaccine. Journal of Infectious Diseases. 2008;197(6):825-35.
4. Karhunen M, Leino T, Salo H, Davidkin I, Kilpi T, Auranen K. Modelling the impact of varicella vaccination on varicella and zoster. Epidemiol Infect. 2010;138(4):469-81.
5. Bilcke J, van Hoek AJ, Beutels P. Childhood varicella-zoster virus vaccination in Belgium: cost-effective only in the long run or without exogenous boosting? Hum Vaccin Immunother. 2013;9(4):812-22.

Author's Response
Posted on January 28, 2014
Craig M. Hales, MD, MPH, Rafael Harpaz, MD, MPH, Stephanie R. Bialek, MD, MPH
Conflict of Interest: None Declared

We appreciate the interest in our study of herpes zoster (HZ) incidence before and after implementation of the universal childhood varicella vaccination program in the U.S.
Medicare claims, including those for HZ, have been available in an electronic format for research purposes as far back as 1980(1); therefore, initial increases in HZ incidence during the first few years of the study cannot be an artifact of a start-up phase of a new system for recording claims data.
Mixing with children decreases in older age groups; however, mixing patterns do not vary substantially by age among adults over 65 years of age (2). During 1992 - 2010 HZ incidence increased at a similar rate in all age groups and did not accelerate in any age group. To confirm this, we tested a 3-way interaction between calendar year, varicella vaccination implementation period, and age group in the Poisson model, as suggested by Dr. Ogunjimi, but it was not statistically significant.
Dr. Ogunjimi correctly notes that the findings in this study apply only to adults over 65 years of age and cannot exclude the possibility of an effect in younger age groups, as has been predicted by previous mathematical models. However, previous studies in the U.S.(3) and Canada(4) have not shown an acceleration in HZ incidence in adults <65 after implementation of childhood varicella vaccination programs.
Although few U.S. state health departments collected data on varicella incidence throughout the period of our study, Zhou et al.(5) used MarketScan databases to evaluate the effect of childhood varicella vaccination coverage, as reported by the National Immunization Survey, on varicella incidence during 1994 - 2002. They found that declines in varicella incidence were significantly greater and more rapid in 11 states with consistently high varicella vaccination coverage compared with those living in 19 states with consistently low coverage. Both we and Leung et al.(3), subsequently found that rates of HZ were no different in high and low varicella vaccination coverage states.
The HZ vaccine was introduced in 2006 with 1.9% uptake in 2007, increasing to only 14.4% in 2010; therefore, we expect the effect of the HZ vaccination, with 51% vaccine efficacy, on overall HZ incidence to be small. An additional analysis of years 1992 to 2006, excluding any influence of the HZ vaccination program, did not substantively alter the effect of varicella vaccination implementation period on HZ incidence.
In conclusion, we agree with Dr. Ogunjimi that it is impossible to confirm from our study that widespread varicella vaccination has no influence whatsoever on HZ incidence in certain individuals. However, while studies of the effect of exposure to varicella on individual risk for HZ have shown conflicting results, recent studies of the effect of declining childhood varicella incidence on adult HZ incidence provide reassurance that the varicella vaccination program has not resulted in population-level increases in HZ rates.

1. May DS, Kittner SJ. Use of Medicare claims data to estimate national trends in stroke incidence, 1985-1991. Stroke. 1994 Dec;25(12):2343-7. PubMed PMID: 7974571.
2. Mossong J, Hens N, Jit M, Beutels P, Auranen K, Mikolajczyk R, et al. Social contacts and mixing patterns relevant to the spread of infectious diseases. PLoS medicine. 2008 Mar 25;5(3):e74. PubMed PMID: 18366252. Pubmed Central PMCID: 2270306. Epub 2008/03/28. eng.
3. Leung J, Harpaz R, Molinari NA, Jumaan A, Zhou F. Herpes zoster incidence among insured persons in the United States, 1993-2006: evaluation of impact of varicella vaccination. Clin Infect Dis. 2011 Feb 1;52(3):332-40. PubMed PMID: 21217180.
4. Russell ML, Dover DC, Simmonds KA, Svenson LW. Shingles in Alberta: Before and after publicly funded varicella vaccination. Vaccine. 2013 Oct 4. PubMed PMID: 24099868.
5. Zhou F, Harpaz R, Jumaan AO, Winston CA, Shefer A. Impact of varicella vaccination on health care utilization. JAMA. 2005 Aug 17;294(7):797-802. PubMed PMID: 16106004. Epub 2005/08/18. eng.

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