• Cornea Society, Ocular Microbiology and Immunology Group and AAO Quality of Care Secretariat, Hoskins Center for Quality Eye Care

    Introduction

    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.

    Conclusion

    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.

    Footnotes

    1. 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.
    2. The ICER/QALY was $323,456 for vaccination at age 50 in reference 35.
    3. 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.

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    Approvals

    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