Herpes zoster is a serious health problem in the United States. Current estimates of new cases in the US are up to 1.2 million each year, about 20% of which are herpes zoster ophthalmicus (HZO).1 It is estimated that one in three people over their lifetime will have zoster. Although it is more common and severe in immunocompromised persons, the vast majority, or over 90%, of patients afflicted with zoster are not immunocompromised. While the incidence goes up significantly with age, starting in the 40s, the number of cases is highest in people in their 50s.2-3,4 In one Centers for Disease Control and Prevention (CDC) study, the mean age of onset was 52 years.5
Risk factors for the development of zoster include increased age, immunocompromised status, female gender, severe physical limitation,6 heart failure,7 traumatic brain injury,8 diabetes,1 acute kidney failure,9 and depression.10
Disease Complications and Costs
The complications and sequelae of herpes zoster can be severe and long term, even very rarely resulting in death.11 Thus, the costs caused by herpes zoster and it complications, including direct medical care costs from acute and chronic pain, eye complications, secondary infections and neuropathies, are estimated at $1 billion in direct medical costs,12 with indirect costs from lost work and work productivity adding to that total, especially in younger age groups such as those 50-59 years of age.13
Ocular complications of herpes zoster include infectious and inflammatory anterior and posterior segment disease, neurotrophic ocular surface disease and eyelid malposition and scar. Severe, irreversible vision loss may result from corneal opacification, glaucoma and retinal disease.14 Approximately 20% of individuals affected by HZO develop potentially serious ocular disease, such as keratitis, uveitis, glaucoma, or neurotrophic disease. The 10-year probability of developing severe visual loss (20/200 or worse), a serious eyelid malposition or chronic trichiasis varies between 2 and 9 percent depending upon the treatment of the disease. Early recommended treatment with systemic antiviral therapy may decrease the incidence or severity of serious sequelae, but the likelihood of preventing complications is reduced if therapy is delayed, usually considered to be after more than 3 days of initial symptoms15 or rash. Post-herpetic neuralgia is more likely in older patients, patients with more severe acute pain and rash, and in patients with ophthalmic involvement.16,17 Systemic complications of zoster include stroke, which is more common after HZO than HZ in other locations,18-21 temporal arteritis,22 and possibly heart attack23, 24 and depression.25
Evaluation of Current Evidence
Recent evidence appears to indicate that the age of onset of zoster is decreasing. Two studies reported a significant 5-year decrease in the mean age of onset of zoster from more than 60 years of age to less than 60 years of age.26,27 Both studies recommended vaccination age may need to be lowered to 50 years of age. The mean age of patients developing HZO-related ocular disease is 63 years.28
Effectiveness of Vaccinations and Recommendations of Other Organizations
A randomized controlled clinical trial demonstrated that the Zoster Vaccine Live (an attenuated live virus vaccine) decreased the incidence of zoster 51% and, the occurrence of postherpetic neuralgia by 66% in immunocompetent people age 60 years and older.29 The vaccine decreased the incidence of zoster more than 60% in people in their 60s, compared to less than 40% in people 70 years and older. However, the effect on disease severity was greater in older persons, resulting in similar reduction in disease burden across age groups.
On the basis of this study, the Zoster Vaccine Live was approved by the FDA in 2006 and recommended by the CDC in 2008 for immunocompetent people age 60 years and older. CDC also recommended zoster vaccine for people with chronic medical conditions, including those affecting humoral immunity, and people who anticipate becoming immunocompromised. In the US, the low rate of zoster vaccination is a public health problem. As of 2014 CDC data, only 28% of eligible people age 60 years and older have received it.30
In 2011, the FDA expanded their approval of the vaccine for immunocompetent people 50-59 years of age, after it was shown to decrease the incidence of zoster by 70% in this age group.31 One study found that the cost-benefit ratio was more than 3 times higher for vaccination at age 50 years compared to age 60 years. This contributed to the CDC decision to maintain their recommendation for immunization beginning at age 60 years.32 (Footnote 1) This report was based on assumptions that complications increase with age and the efficacy of the vaccine decreases over time. However, although post herpetic neuralgia increases with age, ocular, neurologic, and other non-pain complications do not.33 In addition, duration of vaccine efficacy in people age 60 years and older is inversely related to increasing age, not time since vaccination.34 No data is available on people age 50-59 years.
Another cost-effectiveness analysis of the zoster vaccine for age 50 years also reported similar results, but the conclusions were based on the following faulty assumptions and limitations: 1) the incidence of zoster would plateau after 2010 or 2015; 2) vaccine efficacy would wane at the same rate regardless of age of vaccination; 3) productivity loss among affected individuals would increase with age; 4) inadequate data on non-pain complications; and 5) the inclusion of severe vaccine reactions. (Footnote 2) However, studies from other countries indicate that the cost benefit ratio is similar for vaccination of patients in the 50-59 and 60-69 year old age groups.35,36 (Footnote 3) Cost-effectiveness analyses have focused on the impact of postherpetic neuralgia, and have not included the impact of zoster due to ocular and other non- pain complications.
A promising new adjuvanted herpes zoster subunit vaccine has been reported to be highly effective in adults age 50 years and older, but will probably not be approved and recommended in the USA for two years or longer.37 Delaying vaccination until approval of that vaccine could result in significant morbidity and long term sequelae of many potentially preventable cases of zoster.
Given the highest vaccine efficacy in the age group 50-59 years, the decreasing age of disease onset, the greatest number of cases in the 50-59 year old age group and the risk of significant ocular and systemic morbidity, the current evidence supports the use of the zoster vaccine in immunocompetent people age 50 years and older. FDA labeling confirms the efficacy of the vaccine in this population. Vaccination at an earlier age would reduce the burden of morbidity, loss of work productivity and sequelae due to the occurrence of zoster seen in this working age population. Ophthalmologists should advise their eligible patients age 50 years and older to obtain this vaccination, and should work with family physicians, internists, and other medical doctors to enhance zoster vaccination rates of immunocompetent patients in this age group, even if insurance coverage for those under age 60 years is variable.
- The Incremental Cost Effectiveness Ratio (ICER) per Quality Adjusted Life Year (QALY) was $287,000 for vaccination age 50 compared to $86,000 for age 60. ICER is used in cost-effective analyses of health care interventions. It is the difference in cost between 2 possible interventions divided by the difference in effect. It is the average added cost of one additional unit of effect.
- The ICER/QALY was $323,456 for vaccination at age 50 in reference 35.
- The ICER/QALY was ~$19,000 for age 50-59, compared to ~$16,000 age 60-69 for direct medical costs in reference 3, and ~40,000 euros for age 50 years and above, compared to ~39,000 euros age 60 and above in reference 36.
- Suaya JA, Chen SY, Li Q, et al. Incidence of herpes zoster and persistent post-zoster pain in adults with or without diabetes in the United States. Open Forum Infect Dis 2014;1:ofu049.
- Yawn BP, Gilden D. The global epidemiology of herpes zoster. Neurology 2013;81:928-30.
- Ghaznawi N, Virdi A, Dayan A, et al. Herpes zoster ophthalmicus: comparison of disease in patients 60 years and older versus younger than 60 years. Ophthalmology 2011;118:2242-50.
- Insinga RP, Itzler RF, Pellissier JM, et al. The incidence of herpes zoster in a United States administrative database. J Gen Intern Med 2005;20:748-53.
- Hernandez PO, Javed S, Mendoza N, et al. Family history and herpes zoster risk in the era of shingles vaccination. J Clin Virol 2011;52:344-8.
- Liu B, Heywood AE, Reekie J, et al. Risk factors for herpes zoster in a large cohort of unvaccinated older adults: a prospective cohort study. Epidemiol Infect 2015;143:2871-81.
- Wu PH, Lin YT, Lin CY, et al. A nationwide population-based cohort study to identify the correlation between heart failure and the subsequent risk of herpes zoster. BMC Infect Dis 2015;15:17.
- Tung YC, Tu HP, Tsai WC, et al. Increased Incidence of Herpes Zoster and Postherpetic Neuralgia in Adult Patients following Traumatic Brain Injury: A Nationwide Population-Based Study in Taiwan. PLoS One 2015;10:e0129043.
- Yang WS, Hu FC, Chen MK, et al. High Risk of Herpes Zoster among Patients with Advance Acute Kidney Injury--A Population-Based Study. Sci Rep 2015;5:13747.
- Liao CH, Chang CS, Muo CH, Kao CH. High prevalence of herpes zoster in patients with depression. J Clin Psychiatry 2015;76:e1099-104.
- Bricout H, Haugh M, Olatunde O, Prieto RG. Herpes zoster-associated mortality in Europe: a systematic review. BMC Public Health 2015;15:466.
- White RR, Lenhart G, Singhal PK, et al. Incremental 1-year medical resource utilization and costs for patients with herpes zoster from a set of US health plans. Pharmacoeconomics 2009;27:781-92.
- Gater A, Uhart M, McCool R, Preaud E. The humanistic, economic and societal burden of herpes zoster in Europe: a critical review. BMC Public Health 2015;15:193.
- He Y, de Melo Franco R, Kron-Gray MM, et al. Outcomes of cataract surgery in eyes with previous herpes zoster ophthalmicus. J Cataract Refract Surg 2015;41:771-7.
- Severson EA, Baratz KH, Hodge DO, Burke JP. Herpes zoster ophthalmicus in olmsted county, Minnesota: have systemic antivirals made a difference? Arch Ophthalmol 2003;121:386-90.
- Kawai K, Rampakakis E, Tsai TF, et al. Predictors of postherpetic neuralgia in patients with herpes zoster: a pooled analysis of prospective cohort studies from North and Latin America and Asia. Int J Infect Dis 2015;34:126-31.
- Forbes HJ, Thomas SL, Smeeth L, et al. A systematic review and meta-analysis of risk factors for postherpetic neuralgia. Pain 2016;157:30-54.
- Sundstrom K, Weibull CE, Soderberg-Lofdal K, et al. Incidence of herpes zoster and associated events including stroke-a population-based cohort study. BMC Infect Dis 2015;15:488.
- Langan SM, Minassian C, Smeeth L, Thomas SL. Risk of stroke following herpes zoster: a self-controlled case-series study. Clin Infect Dis 2014;58:1497-503.
- Nagel MA, Gilden D. The relationship between herpes zoster and stroke. Curr Neurol Neurosci Rep 2015;15:16.
- Yawn BP, Wollan PC, Nagel MA, Gilden D. Risk of Stroke and Myocardial Infarction After Herpes Zoster in Older Adults in a US Community Population. Mayo Clin Proc 2016;91:33-44.
- Gilden D, Nagel M. Varicella Zoster Virus in Temporal Arteries of Patients With Giant Cell Arteritis. J Infect Dis 2015;212 Suppl 1:S37-9.
- Breuer J, Pacou M, Gauthier A, Brown MM. Herpes zoster as a risk factor for stroke and TIA: a retrospective cohort study in the UK. Neurology 2014;82:206-12.
- Wu PY, Lin CL, Sung FC, et al. Increased risk of cardiovascular events in patients with herpes zoster: a population-based study. J Med Virol 2014;86:772-7.
- Chen MH, Wei HT, Su TP, et al. Risk of depressive disorder among patients with herpes zoster: a nationwide population-based prospective study. Psychosom Med 2014;76:285-91.
- Chan AY, Conrady CD, Ding K, et al. Factors associated with age of onset of herpes zoster ophthalmicus. Cornea 2015;34:535-40.
- Davies EC, Pavan-Langston D, Chodosh J. Herpes zoster ophthalmicus: declining age at presentation. Br J Ophthalmol 2015.
- Yawn BP, Wollan PC, St Sauver JL, Butterfield LC. Herpes zoster eye complications: rates and trends. Mayo Clin Proc 2013;88:562-70.
- Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 2005;352:2271-84.
- Williams WW, Lu PJ, O'Halloran A, et al. Surveillance of Vaccination Coverage Among Adult Populations - United States, 2014. MMWR Surveill Summ 2016;65:1-36.
- Schmader KE, Levin MJ, Gnann JW, Jr., et al. Efficacy, safety, and tolerability of herpes zoster vaccine in persons aged 50-59 years. Clin Infect Dis 2012;54:922-8.
- Hales CM, Harpaz R, Ortega-Sanchez I, Bialek SR. Update on recommendations for use of herpes zoster vaccine. MMWR Morb Mortal Wkly Rep 2014;63:729-31.
- Yawn BP, Saddier P, Wollan PC, et al. A population-based study of the incidence and complication rates of herpes zoster before zoster vaccine introduction. Mayo Clin Proc 2007;82:1341-9.
- Li X, Zhang JH, Betts RF, et al. Modeling the durability of ZOSTAVAX(R) vaccine efficacy in people >/=60 years of age. Vaccine 2015;33:1499-505.
- Moore L, Remy V, Martin M, et al. A health economic model for evaluating a vaccine for the prevention of herpes zoster and post-herpetic neuralgia in the UK. Cost Eff Resour Alloc 2010;8:7.
- Preaud E, Uhart M, Bohm K, et al. Cost-effectiveness analysis of a vaccination program for the prevention of herpes zoster and post-herpetic neuralgia in adults aged 50 and over in Germany. Hum Vaccin Immunother 2015;11:884-96.
- Lal H, Cunningham AL, Godeaux O, et al. Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. N Engl J Med 2015;372:2087-96.
Approved by Cornea Society Executive Committee, February 2016
Approved by Ocular Microbiology and Immunology Group Board, June 2016
Approved by American Academy of Ophthalmology Board of Trustees, June 2016