Herpes Zoster Eye Disease: New Ways to Combat an Old Foe?

Abstract

Herpes zoster (HZ), also known as “shingles,” is caused by reactivation of the varicella-zoster virus in individuals who have had chicken pox, and there are approximately 1.2 million new cases of HZ annually in the United States.1Suaya J.A. Chen S.Y. 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: ofu049Crossref PubMed Scopus (36) Google Scholar Although HZ typically results in a painful, unilateral, dermatomal, vesicular rash, zoster sine herpete (shingles without skin findings) has been reported. The demographics of individuals with HZ have been changing, and recently, new risk factors have been identified.2Liesegang T.J. Herpes zoster ophthalmicus natural history, risk factors, clinical presentation, and morbidity.Ophthalmology. 2008; 115: S3-S12Abstract Full Text Full Text PDF PubMed Scopus (271) Google Scholar For ophthalmologists, herpes zoster ophthalmicus (HZO) continues to put our patients at risk for vision loss. Efforts to combat vision loss from HZ require a multifaceted approach from vaccination to potential long-term suppressive therapy. Although classically thought of as a disease of the elderly or immunosuppressed, HZ is frequently seen in younger individuals, and greater than 90% of affected individuals are immunocompetent. The overall incidence of HZ is increasing: From the Olmstead County Study, the incidence of HZ has increased more than 4-fold from the time periods 1945–1960 to 1980–2007, which translates into 2.5% per year.3Kawai K. Yawn B.P. Wollan P. et al.Increasing incidence of herpes zoster over a 60-year period from a population-based study.Clin Infect Dis. 2016; 15: 221-226Google Scholar This increasing incidence also has been seen worldwide.3Kawai K. Yawn B.P. Wollan P. et al.Increasing incidence of herpes zoster over a 60-year period from a population-based study.Clin Infect Dis. 2016; 15: 221-226Google Scholar Furthermore, the age at onset of HZ has been decreasing.4Hernandez P.O. Javed S. Medoza N. et al.Family history and herpes zoster risk in the era of shingles vaccination.J Clin Virol. 2011; 52: 344-348Crossref PubMed Scopus (39) Google Scholar, 5Lin T.Y. Yang F.C. Lin C.L. et al.Herpes zoster infection increases the risk of peripheral arterial disease: a nationwide cohort study.Medicine. 2016; 95e4480Google Scholar The alarming findings of increasing incidence and decreasing age at presentation have similarly been seen for HZO.6Chan A.Y. Conrady C.D. Ding K. et al.Factors associated with age of onset of herpes zoster ophthalmicus.Cornea. 2015; 34: 535-540Crossref PubMed Scopus (18) Google Scholar, 7Davies E.C. Pavan-Langston D. Chodosh J. Herpes zoster ophthalmicus: declining age at presentation.Br J Ophthalmol. 2016; 100: 312-314Crossref PubMed Scopus (15) Google Scholar Although it has been suggested that varicella vaccination in childhood (which would reduce adult encounters with varicella that would result in a “boost” in immunity and postponement of HZ)8Hope-Simpson E. The nature of herpes zoster: a long-term study and a new hypothesis.Proc R Soc Med. 1965; 58: 9-20PubMed Google Scholar has resulted in these alarming trends, the increase in incidence of HZ actually began before childhood vaccination practices.9Leung J. Harpaz R. Molinari N.A. et al.Herpes zoster incidence among insured persons in the United States, 1993-2006: evaluation of impact of varicella vaccination.Clin Infect Dis. 2011; 52: 332-340Crossref PubMed Scopus (173) Google Scholar In addition, in Europe, where routine varicella vaccination is not widespread, similar increased rates of HZ are seen.3Kawai K. Yawn B.P. Wollan P. et al.Increasing incidence of herpes zoster over a 60-year period from a population-based study.Clin Infect Dis. 2016; 15: 221-226Google Scholar As ophthalmologists, we often think of HZ mostly just in the setting of HZO, but it is important to remember that HZ is a systemic disease. Varicella can reside in any ganglia, and therefore zoster complications can range from deafness (cranial nerve VIII) to paraparesis (vertebral ganglia) to motor neuropathy (any sensory ganglia).10Cohen J.I. Clinical practice: herpes zoster.N Engl J Med. 2013; 369: 255-263Crossref PubMed Scopus (411) Google Scholar Postherpetic neuralgia (PHN), which is pain beyond 3 months after onset of zoster, is the most common complication of HZ. Postherpetic neuralgia occurs in approximately 30% of patients with HZO with ocular involvement, particularly in older individuals,11Borkar D.S. Tham V.M. Esterberg E. et al.Incidence of herpes zoster ophthalmicus: results from the Pacific Ocular Inflammation Study.Ophthalmology. 2013; 120: 451-456Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar and it is the most common cause of suicide due to pain in individuals older than 70 years of age. In the United States, the adjusted annual incremental total all-cause health care costs increases by more than $1800 for individuals with HZ compared with those without and by more than $7200 for those with PHN compared with those without.12Meyer J.L. Madhwani S. Rausch D. et al.Analysis of real-world health care costs among immunocompetent patients aged 50 years or older with herpes zoster in the United States.Hum Vaccin Immunother. 2017; 13: 1861-1872Google Scholar It is estimated that worldwide, HZ costs $1 billion, and with PHN, the costs increase to more than $2 billion.13Ultsch B. Köster I. Reinhold T. et al.Epidemiology and cost of herpes zoster and postherpetic neuralgia in Germany.Eur J Health Econ. 2013; 14: 1015-1026Crossref PubMed Scopus (60) Google Scholar, 14White R.R. Lehardt G. Singhal P.K. 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: 781-792Crossref PubMed Scopus (55) Google Scholar With approximately 1.2 million new cases of HZ in the United States annually, and 10% to 20% involving the first division of cranial nerve (CN) V,1Suaya J.A. Chen S.Y. 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: ofu049Crossref PubMed Scopus (36) Google Scholar there are between 120 000 and 240 000 new cases of HZO in the United States annually. Ocular complications from HZO include vesicular dermatitis, preseptal cellulitus, various types of keratitis, neurotrophic keratopathy, uveitis, glaucoma, retinitis, choroiditis, and optic neuritis. The rate of ocular involvement in the setting of HZO has been shown to be as high as 65%, with conjunctivitis being the most common finding (57%). However, vision-threatening findings such as keratitis can occur in up to 12%.15Szeto S.K.H. Chan T.C.Y. Wong R.L.M. et al.Prevalence of ocular manifestations and visual outcomes in patients with herpes zoster ophthalmicus.Cornea. 2017; 36: 338-342Google Scholar More concerning is that even with appropriate treatment, 25% of patients experience chronic or recurrent disease by 5 years out from HZO.16Tran K.D. Falcone M.M. Choi D.S. et al.Epidemiology of herpes zoster ophthalmicus.Ophthalmology. 2016; 123: 1469-1475Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar The overall rate of recurrent eye disease has been found to be as high as 51%,17Miserocchi E. Fogliato G. Bianchi I. et al.Clinical features of ocular herpetic infection in an Italian referral center.Cornea. 2014; 33: 565-570Crossref PubMed Scopus (38) Google Scholar and these recurrences and chronic disease can lead to significant visual morbidity. So what can we do? As outlined by the American Academy of Ophthalmology’s Policy Statement in this issue (see page 1813),18American Academy of OphthalmologyPolicy Statement. Recommendations for herpes zoster vaccine for patients 50 years of age and older.Ophthalmology. 2018; 125: 1813-1816Google Scholar the first line of defense is vaccination. The Zostavax (Merck, Kenilworth, NJ) vaccine was approved by the US Food and Drug Administration in 2006 for use in individuals aged 60 years or older to prevent shingles. This lower age limit was decreased to 50 years in 2011. Unfortunately, despite the Centers for Disease Control and Prevention (CDC) recommending this vaccine for routine use in individuals aged 60 years or more, the vaccination rates in the United States have been very low among immunocompetent individuals aged 60 years and older: 14% in 2010 and still only 31% in 2015.19Williams W.W. Lu P.J. O’Halloran A. et al.Surveillance of vaccination coverage among adult populations – United States, 2015.MMWR Surveill Summ. 2017; 66: 1-28Crossref PubMed Scopus (306) Google Scholar In addition, only an estimated <2% of individuals aged 50–59 years received this vaccine.20Zhang D. Johnson K. Newransky C. et al.Herpes zoster vaccine coverage in older adults in the U.S., 2007-2013.Am J Prev Med. 2017; 52: e17-e23Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar Because this is a live attenuated virus, individuals who are immunocompromised with diseases that affect cell-mediated immunity or those undergoing immunosuppressive treatment are not to have this vaccine. In addition, for those people on an antiviral chronically, it needs to be stopped 1 day before through 2 weeks after the vaccine is given. There have been several cases of reactivation of HZ keratitis or uveitis reported within 2 to 5 weeks of Zostavax vaccination,21Khalifa Y.M. Jacoby R.M. Margolis T.P. Exacerbation of zoster interstitial keratitis after zoster vaccination in an adult.Arch Ophthalmol. 2010; 128: 1079Crossref Scopus (29) Google Scholar, 22Sham C.W. Levinson R.D. Uveitis exacerbation after varicella-zoster vaccination in an adult.Arch Ophthalmol. 2012; 130: 793-794Google Scholar, 23Hwang C.W. Steigleman W.A. Saucedo-Sanchez E. et al.Reactivation of herpes zoster keratitis in an adult after varicella zoster vaccination.Cornea. 2013; 32: 508-509Crossref PubMed Scopus (27) Google Scholar, 24Jastrzebski A. Brownstein S. Ziai S. et al.Reactivation of herpes zoster keratitis with corneal perforation after zoster vaccination.Cornea. 2017; 36: 740-742Crossref PubMed Scopus (22) Google Scholar including a case of HZ keratitis with corneal perforation,24Jastrzebski A. Brownstein S. Ziai S. et al.Reactivation of herpes zoster keratitis with corneal perforation after zoster vaccination.Cornea. 2017; 36: 740-742Crossref PubMed Scopus (22) Google Scholar and thus in the setting of HZO, vaccination should be followed by 4 to 6 weeks of careful monitoring. Perhaps these cases have given ophthalmologists pause when considering recommending the vaccine. However, all in all, this vaccine is efficacious because it reduces the burden of disease by 61% and the rate of PHN by 66%. Unfortunately, the efficacy has been shown to wane after 8 years to 4%.25Tseng H.F. Chi M. Smith N. et al.Declining effectiveness of herpes zoster vaccine in adults aged ≥60 years.J Infect Dis. 2012; 213: 1872-1875Google Scholar More recently, an adjuvanted HZ subunit vaccine, Shingrix (GlaxoSmithKline, Brentford, UK), was approved by the US Food and Drug Administration in October 2017 for immunocompetent individuals aged 50 years and older. Although this vaccine is not a live virus, the CDC has not specifically made recommendations for its use in immunocompromised individuals. However, it has been demonstrated to be 97% efficacious for all age groups 50 to 69 years,26Lal H. Cunningham A.L. Godeaux O. et al.Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults.N Engl J Med. 2015; 372: 2087-2096Crossref PubMed Scopus (810) Google Scholar and even 91% effective in those aged 70 years and older.27Cunningham A.L. Lal M. Kovac R. et al.Efficacy of the herpes zoster subunit vaccine in adults 70 years of age and older.N Engl J Med. 2016; 375: 1019-1032Crossref PubMed Scopus (588) Google Scholar The vaccine retains its efficacy at 88% at 4 years, and it is predicted to remain above baseline at 15 years. The vaccine is also 91% effective against PHN. The Advisory Committee on Immunization Practices (advises CDC on vaccine use) currently recommends adults who received Zostavax to be revaccinated with Shingrix.28Dooling K.L. Guo A. Patel M. et al.Recommendations of the Advisory Committee on Immunization practices for use of herpes zoster vaccines.MMWR Morb Mortal Wkly Rep. 2018; 67: 103-108Crossref PubMed Scopus (336) Google Scholar Despite needing 2 separate intramuscular injections 2 to 6 months apart, along with a 17% rate of grade 3 symptoms (those that prevented normal everyday activities),26Lal H. Cunningham A.L. Godeaux O. et al.Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults.N Engl J Med. 2015; 372: 2087-2096Crossref PubMed Scopus (810) Google Scholar Shingrix has been found to be cost-effective compared with Zostavax.29Prosser L.A. Economic evaluation of vaccination for prevention of herpes zoster and related complications [slides]. Presentation to the Advisory Committee on Immunization Practices, October 25, 2017, Atlanta, Georgia.https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2017-10/zoster-03-prosser.pdfGoogle Scholar To date, there has been 1 report of recurrent zoster eye disease (stromal keratitis) after vaccination with Shingrix.30Lehmann A. Matoba A. Reactivation of herpes zoster stromal keratitis after HZ/su adjuvanted herpes zoster subunit vaccine.Ophthalmology. 2018; 125: 1682Abstract Full Text Full Text PDF Scopus (12) Google Scholar Given that both humoral and cell-mediated immune responses are expected to develop within 1 month of the first dose of Shingrix, this possibility certainly does exist. Therefore, as for zoster eye disease reactivation after Zostavax, ophthalmologists should be aware of this possibility for Shingrix. Even with the high efficacy rate of the new vaccine, however, we do know that it is not 100% effective, and we also know that vaccination rates are nowhere near 100%. As such, we will still see HZ and HZO, and the next line of defense is acute therapy during HZ, which has been well established as high-dose oral antiviral therapy for 1 week, given within 72 hours of onset of rash. This intervention has been shown to decrease the probability of subsequent visual loss and other adverse outcomes.31Severson E.A. Baratz K.H. Hodge D.O. et al.Herpes zoster ophthalmicus in Olmstead County, Minnesota. Have systemic antivirals made a difference?.Arch Ophthalmol. 2013; 121: 386-390Google Scholar Fortunately, as ophthalmologists, we most commonly see patients with HZO presenting from the primary care provider, and the patients are already receiving this treatment. For ophthalmologists, the problem starts when we have to get involved, because treatment for ocular findings is complex. For the cornea and anterior segment, it is a rather complex combination of antivirals and topical steroids. Although most episodes of disease can be treated, chronic and recurrent disease affects up to 25% of patients.16Tran K.D. Falcone M.M. Choi D.S. et al.Epidemiology of herpes zoster ophthalmicus.Ophthalmology. 2016; 123: 1469-1475Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar For stromal keratitis, which is the most visually significant problem for the cornea, a delicate balance of steroids is sometimes necessary, and even with it, patients can lose vision. Stromal keratitis is seen to be recurrent in 20% of eyes with HZO.17Miserocchi E. Fogliato G. Bianchi I. et al.Clinical features of ocular herpetic infection in an Italian referral center.Cornea. 2014; 33: 565-570Crossref PubMed Scopus (38) Google Scholar So how do we manage chronic or recurrent HZ disease in the eye? Unlike for herpes simplex virus (HSV) keratitis for which the Herpetic Eye Disease Study has demonstrated that long-term suppressive dosing with acyclovir 400 mg twice daily can reduce recurrences of HSV stromal keratitis by 45%,32Barron B.A. Gee L. Hauck W.W. et al.Herpetic Eye Disease Study. A controlled trial of oral acyclovir for herpes simplex stromal keratitis.Ophthalmology. 1994; 101: 1871-1882Abstract Full Text PDF PubMed Scopus (180) Google Scholar, 33Wilhelmus K.R. Beck R.W. Moke P.S. et al.Acyclovir for the prevention of recurrent herpes simplex virus eye disease.N Engl J Med. 1998; 339: 300-306Crossref PubMed Scopus (309) Google Scholar no such study has guided us for HZ keratitis, because varicella-zoster virus was thought to behave differently than HSV. However, more recent evidence suggests that clinical latency of HZ may not be a true period of latency and that subclinical viral transcription and translation may be occurring, held in check by an intact cell-mediated immune response.34Cohrs R.J. Mehta S.K. Schmid D.S. et al.Asymptomatic reactivation and shed of infectious varicella zoster virus in astronauts.J Med Virol. 2008; 80: 1116-1122Crossref PubMed Scopus (136) Google Scholar, 35Devlin M.E. Gilden D.H. Mahalingam R. et al.Peripheral blood mononuclear cells of the elderly contain varicella-zoster virus DNA.J Infect Dis. 1992; 165: 619-622Crossref PubMed Scopus (55) Google Scholar, 36Wilson A. Sharp M. Koropchak C.M. et al.Subclinical varicella-zoster virus viremia, herpes zoster, and T lymphocyte immunity to varicella-zoster viral antigens after bone marrow transplantation.J Infect Dis. 1992; 165: 119-126Crossref PubMed Scopus (159) Google Scholar When the immune system is disrupted, viral replication is favored, and disease recurrence is observed whereby active virus can be detected in recurrent epithelial dendriform lesions.37Pavan-Langston D. Yamamoto S. Dunkel E.C. Delayed herpes zoster pseudodendrites. Polymerase chain reaction detection of viral DNA and a role for antiviral therapy.Arch Ophthalmol. 1995; 113: 1381-1385Crossref PubMed Scopus (49) Google Scholar, 38Aggarwal S. Cavalcanti B.M. Pavan-Langston D. Treatment of pseudodendrites in herpes zoster ophthalmicus with topical ganciclovir 0.15% gel.Cornea. 2014; 33: 109-113Crossref PubMed Scopus (17) Google Scholar, 39Hu A.Y. Strauss E.C. Holland G.N. et al.Late varicella-zoster virus dendriform keratitis in patients with histories of herpes zoster ophthalmicus.Am J Ophthalmol. 2010; 149: 214-220Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar Perhaps this is why a 2012 survey suggested that 56% of cornea specialists believe that prolonged oral antiviral prophylaxis could reduce recurrent signs of HZO. In addition, 28% believe that recurrence of HZO could be reduced even after the period of acyclovir administration,40Sy A. McLeod S.D. Cohen E.J. et al.Practice pattern and opinions in the management of recurrent or chronic herpes zoster ophthalmicus.Cornea. 2012; 31: 786-790Crossref PubMed Scopus (27) Google Scholar possibly because they were extrapolating results from the Herpetic Eye Disease Study. A more recent retrospective study using low-dose suppressive valacyclovir at 500 mg daily or acyclovir 400 mg twice daily did find that this dose reduced recurrent episodes of inflammation by 35% in patients with HZ and 39% in patients with HSV, suggesting that suppressive dosing may indeed help prevent recurrences in HZ as in HSV.17Miserocchi E. Fogliato G. Bianchi I. et al.Clinical features of ocular herpetic infection in an Italian referral center.Cornea. 2014; 33: 565-570Crossref PubMed Scopus (38) Google Scholar But short of this study, there is little evidence in the literature to confirm that we can prevent HZ keratitis in this fashion. With the goal to answer these questions, the Zoster Eye Disease Study was conceived.41Cohen E.J. Kessler J. Persistent dilemmas in zoster eye disease.Br J Ophthalmol. 2016; 100: 56-61Google Scholar The Zoster Eye Disease Study is a multicenter, randomized, placebo-controlled clinical trial to determine whether prolonged suppressive valacyclovir treatment reduces complications of HZO, including eye disease and PHN. The primary end point is delay in time to first occurrence by 12 months of new or worsening dendritiform epithelial keratitis, stromal keratitis, endothelial keratitis, and iritis (www.clincialtrials.gov). Secondary end points include the treatment effect on primary end point 6 months after treatment, as well as to test the hypothesis that suppressive valacyclovir treatment reduces the incidence, severity, and duration of PHN compared with placebo at 12 and 18 months. It is hoped that at the conclusion of this large trial, we will have good evidence on how to treat HZ eye disease. Herpes zoster continues to be a disease of incredible burden throughout the world. Although morbidity is often viewed from the systemic point of view, visual morbidity and quality of life from PHN are important considerations. With a new vaccine available, we have a stronger frontline defense against HZ eye disease, as long as we can encourage people to get it. Although ophthalmologists often view recommending vaccinations as the job of the primary care provider, given the incredible toll that HZ can take on the eye, we must take responsibility for protecting our patients and recommending this preventative measure. As recommended by the CDC, and as reinforced by the American Academy of Ophthalmology policy statement,18American Academy of OphthalmologyPolicy Statement. Recommendations for herpes zoster vaccine for patients 50 years of age and older.Ophthalmology. 2018; 125: 1813-1816Google Scholar with a decreasing age at presentation, all immunocompetent individuals 50 years of age and older should receive Shingrix. This includes those who have already had HZ because it can certainly happen again, although these individuals are somewhat protected immediately for some period of time after an episode because their immune system is primed. Second-line defense of treatment of acute HZ is well established, but third-line defense to prevent chronic disease is still under investigation. However, overall, the future seems brighter for our multipronged approach to deal with this old foe. Policy Statement: Recommendations for Herpes Zoster Vaccine for Patients 50 Years of Age and OlderOphthalmologyVol. 125Issue 11PreviewHerpes zoster is a serious health problem in the United States. Current estimates of new cases in the United States are up to 1.2 million annually, approximately 20% of which are herpes zoster ophthalmicus (HZO).1 It is estimated that 1 in 3 people will have herpes zoster in their lifetime. Although it is more common and severe in immunocompromised persons, the vast majority (>90%) of patients with herpes zoster are not immunocompromised. Although the incidence of herpes zoster goes up significantly with age, starting at 40 years, the number of cases is highest in people 50 to 59 years of age. Full-Text PDF