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Herpes Zoster Ophthalmicus Review and Prevention

Davis, Andrew R. M.D.; Sheppard, John M.D.

doi: 10.1097/ICL.0000000000000591
Review Article

Abstract: Varicella-zoster virus (VZV) is the etiologic agent of both chickenpox and Herpes zoster (HZ). In the United States, there are around one million cases of HZ per year. Ten percent of HZ cases are subtyped as herpes zoster ophthalmicus (HZO) specifically and involve the V1 distribution. Herpes zoster ophthalmicus is a significant cause of blindness in the United States. This article will provide a basic overview of VZV, HZ, and HZO with a focus on preventative measures in an effort to prevent blindness through improving clinician awareness and education. The differences in clinical effectiveness and duration of effectiveness of the live (Zostavax) and recombinant vaccines (Shingrix) are illustrated. There is now a trend toward using the recombinant vaccine as recommended by the Advisory Committee for Immunization Practices (ACIP) for healthy adults 50 or older.

Department of Ophthalmology, Eastern Virginia Medical School, Norfolk, VA.

Address correspondence to John Sheppard, M.D., Virginia Eye Consultants/Cincinnati Eye Institute, 241 Corporate Boulevard, Norfolk, VA 23502; e-mail:

J. Sheppard (Novartis, Bausch+Lomb, Allergan), The remaining author has no conflicts of interest to disclose.

Accepted January 12, 2019

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Varicella-zoster virus (VZV) is a part of the Herpesviridae family and therefore has similar characteristics as its family members. Varicella-zoster virus is enveloped, has double-stranded DNA, and establishes latency.1 The envelop of the virus is derived from host cells, and thus, it is sensitive to detergents. Seven specific glycoproteins have been identified (gB, gC, gE, gH, gI, gK, and gL) that serve as clinical markers for cell-mediated immunity (CMI) and humoral immunity to VZV. Several different genotypes have been identified and vary geographically. The main genotypes in the United States and Europe are B and C, whereas J, J2, and A1 are more common in Africa and Asia.2,3 The virus spreads by direct cell-to-cell contact and is spread through the respiratory tract. Initial viral particle replication is believed to begin in the nasopharynx as polymerase chain reaction samples of nasopharynx secretions have been found to be positive for VZV DNA in exposed persons. Viremia occurs through lymphatic spread of viral particles from the nasopharynx to circulating T lymphocytes. The virus arrives at the skin, and epithelial cells become infected with the virus leading to chickenpox (varicella).4,5

In primary VZV infection (i.e., chickenpox or varicella) lesions are generally noted to be in varying stages with simultaneous maculopapular, vesicular, and scab components. In herpes zoster (HZ), lesions are all typically in the same stage given the dermatologic infection is localized and originates from the surrounding nerves. Chickenpox is generally self-limited but can be devastating in immunocompromised hosts. After establishing a primary infection, VZV remains latent in sensory dorsal root ganglia and the trigeminal ganglion. Varicella-zoster virus is kept at bay in the sensory ganglia by the cell-mediated branch of the immune system. When cellular-mediated immunity is compromised by HIV infection, use of immunosuppressive agents, or certain malignancies and lymphoproliferative disorders, VZV is permitted to arise from its latent state and spread through sensory neurons by way of microtubules. Subsequently, epithelial cells become infected and the clinical entity known as HZ result.1,3,4,6,7

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The individual lifetime risk for HZ is estimated to be around 30%8 and is traditionally believed to be more common in older individuals due to decreased cellular-mediated immunity. Reactivation typically occurs unilaterally and along the thoracic or lumbar dermatomes. Patients often complain of neuralgia in the given dermatome before the onset of erythema that progresses to a maculopapular rash followed by progression to a vesicular rash. In contrast to chickenpox, HZ lesions are typically in the same stage.1 It is uncommon to have lesions of the rash at different stages. For example, vesicles with scabs would be abnormal in HZ. These lesions typically form over the course of 5 days and resolve after 10 to 15 days, but healing of the dermis can be prolonged for up to 1 month. Immunocompromised hosts can have lesions for longer and are at a greater risk for dissemination.1,3 Herpes zoster ophthalmicus (HZO) specifically affects the V1 distribution. As the V1 nerve innervates many ocular and periocular structures, a variety of clinical entities result. To understand these entities, one must review the anatomy of the V1 nerve.3,7,9,10

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After the acute onset of neuralgias, an erythematous rash develops. This is followed by a maculopapular rash and vesicles that form unilaterally in any, or all, of the branches of the V1 nerve. There are varying estimates of the number of patients with HZO who present with ocular involvement and essentially any of the ocular or periocular structures can be involved (see above anatomy review)3,11 (Fig. 1 and Table 1).

FIG. 1

FIG. 1



Commonly, the periocular skin and eyelids become involved with vesicles, erythema, and edema. Patients tend to present with unilaterally marked swelling and vesicles of the forehead, scalp, and eyelids. Secondary bacterial cellulitis can result commonly from Gram-positive organisms and require systemic antibiotic treatment. Chronically, cicatricial changes to the eyelids may lead to trichiasis or lagophthalmos that is severe enough to require surgical correction. The puncta often become scarred, and pigmentary changes of the dermis are frequently present long after initial infection. Infrequently, pain without an eruptive phase may occur, and this is known as zoster sin herpete.3,12,13

Conjunctivitis presents with a papillary or follicular reaction with or without membranes and pseudomembranes. Conjunctival vesicles or petechial hemorrhages are frequent. In cases of severe conjunctival involvement, symblepharon formation occurs.3,12,13 Episcleritis may be evident early on in the disease course and can last up to several months. Scleritis may lead to thinning of the sclera and staphyloma formation.3,12,13

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Corneal Involvement

Herpes zoster ophthalmicus can involve any of the corneal layers. There are generally three phases to corneal involvement: acute (active viral infection), subacute (immunologic response to viral infection), and chronic (sequelae of viral infection). In response to active viral replication, patients typically present with a punctate epithelial keratitis (see clinical picture) with swollen epithelial cells. Pseudodendrites may form acutely and represent a conglomeration of punctate epithelial keratitis, they may also be seen chronically. Pseudodendrites are usually raised, edematous epithelial lesions that occur within a few days after HZO onset. They have blunt ends, and there is no loss of cornea epithelium as in HSV. Pseudodendrites only minimally stain with fluorescein or rose Bengal.3,12,13 (Figs 2 and 3).

FIG. 2

FIG. 2

FIG. 3

FIG. 3

Because of an immunologic response of the viral infection, anterior stromal infiltrates (also known as nummular keratitis) immediately under Bowman's layer can occur and typically present after 10 days. Anterior infiltrates occur deep to previous epithelial lesions.13 Endotheliitis is also believed to occur due to an immune reaction form viral invasion of endothelial cells and may present with diffuse or localized folds of Descemet's membrane, stromal and epithelial edema, and typically presents after 1 week. Disciform keratitis, although infrequent, manifests as multiple areas of corneal edema with minimal infiltration and intact overlying epithelium. This unique clinical finding is believed to be secondary to a viral infection in the endothelium or an immune reaction to viral particles in the stroma, and this is similar to HSV.3,12,13

Typically, uveitis presents as either a granulomatous or nongranulomatous iridocyclitis and vaso-occlusive iris atrophy occurs during acute infection.3,12,13 Trabeculitis may ensue resulting in a secondary glaucoma.

During the chronic phase, sequelae of infection manifest that often lead to chronic blindness. Corneal nerve damage leads to decreased corneal sensation and subsequent epithelial defects known as neurotrophic keratopathy. These sterile ulcerations regularly become secondarily infected. Interstitial keratitis seldomly becomes persistent and refractory leading to corneal neovascularization, opacification, and lipid deposition. Damage to the endothelial cells may lead to chronic corneal edema. Glaucoma habitually develops as a result of trabeculocyte damage or steroid use.3,12,13 It should be noted that acute VZV is oftentimes followed by recurrent and longstanding infection leading to iritis, and dendritiform epithelial keratitis.

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Posterior Segment Manifestations

Making our way to the posterior segment, HZO has been shown to cause optic neuritis, and there are several case reports of optic neuritis after varicella vaccination in immunocompromised patients.14,15 In addition, VZV every so often involves the retina. In fact, the herpes viruses are the leading cause of acute retinal necrosis (ARN). This syndrome is characterized by a retinitis of yellow-white deep appearing lesions that start in the peripheral fundus and become contiguous around the periphery as they progress toward the posterior pole. Vasculitis, vitritis, and optic neuropathies are common components of ARN. The macula is usually not involved. As the peripheral lesions resolve, retinal breaks may occur and rhegmatogenous retinal detachments ensue. Variants of ARN with only patches of peripheral retinal whitening have been reported.16 Progressive outer retinal necrosis (PORN) occurs because of VZV and is more common in immunocompromised patients. Comparable with ARN, the retinitis in PORN starts with areas of retinal whitening that merge. However, the posterior pole usually becomes involved earlier. There is usually is not vitritis in PORN, and the vessels are only minimally involved in PORN as compared with ARN.3,5,14

The CNS becomes involved in certain instances leading to a meningoencephalitis, encephalitis, and strokes.1 Ocular motor palsies can affect the third, fourth, or sixth nerves resultant from a vasculitis that occurs in the orbital apex.15 Postherpetic neuralgia is a significant sequelae of HZO or HZ that preferentially affects the elderly and immunocompromised. Patients often experience recurrent pain in the affected area significant enough to reduce their overall quality of life and is described as a shooting, sharp pain. Postherpetic neuralgia frequently lasts for months and interferes with activities of daily living.17

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Varicella Vaccination

After the introduction of the varicella vaccine in the United States in 1995, the incidence of varicella reduced somewhere between 76 and 87% between 1995 and 2000.16 The vaccine itself consists of a live, attenuated virus from the Oka strain of VZV isolated in Japan. Currently, the Center for Disease Control (CDC) recommends two doses of the chickenpox vaccine for healthy children. In addition, adults without evidence of immune compromise, women who are healthy at prenatal/postnatal time points, and HIV-infected children and adults with adequate T-cell immunity if they do not have evidence of immunity to VZV18 based on lack of antibodies are recommended to be vaccinated. Although the vaccine has shown marked efficacy in reducing chickenpox, the Oka-attenuated virus still establishes latency and has the potential to cause HZ. However, the incidence of HZ secondary to the varicella vaccine (Oka strain of VZV) is substantially lower in children receiving chemotherapy for leukemia compared with children receiving chemotherapy who had wild-type VZV infections. In addition, there is concern that widespread varicella vaccination will lead to a reduction in wild-type virus exposure, and as a result, this reduction in wild-type virus exposure could potentially decrease an individual's immunity to latent wild-type infections and theoretically cause a higher incidence of wild-type VZV reactivation and subsequent HZ.18,19

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Herpes Zoster Vaccination: Live Vaccine (Zostavax, ZVL)

Most of the adults in the United States currently have been exposed to VZV,1 and this does not need to be confirmed serologically. As patients age, they will be more likely to have compromised CMI and reactivation of HZ. As such, HZ vaccination is indicated to prevent HZ and its complications.

The live HZ vaccine (Zostavax, ZVL) is a lyophilized formulation of a live, attenuated VZV strain and is the same strain used in varicella vaccines although at a much higher dose (14×) to stimulate cellular immunity. The vaccine is given as a 0.65-mL subcutaneous injection in the deltoid region and is a one-time vaccination.20

The Advisory Committee for Immunization Practices (ACIP) previously recommended the ZVL as the gold standard for people 60 or older whether they reported a previous history of varicella unless a contraindication existed. Now, the ACIP recommends the live vaccine for patients older than 60 only if a patient is allergic to the recombinant vaccine (Shingrix, RZV).21 In 2011, the FDA approved the ZVL for individuals 50 to 59 years of age. An extensive review in 2013 by the ACIP was undertaken regarding whether the vaccination should be recommended for this age group, but they concluded not to expand the indication given there were limited data on long-term protection provided by the HZ vaccine22

Generally, there are three groups of people in which ZVL is contraindicated: pregnant women, patients with an anaphylactic allergy to any of the vaccine's components, and those who are immunocompromised. AIDS patients with a CD4 <200 per cubic millimeter or less than 15% total lymphocytes, those who are on immunosuppressant therapy including high-dose steroids, those with hematologic or lymphatic malignancies, those who have evidence of impaired cellular immunity, those undergoing hematopoietic stem cell transplantation, and those receiving a recombinant human immune mediator or immunomodulator (especially anti-TNF factors such as adalimumab, infliximab, and etanercept) should not receive the vaccine.23

The shingles prevention study (SPS) was a multicenter randomized control study that enrolled 38,546 adults 60 years or older to receive the Oka/Merck VZV vaccine (zoster vaccine) or a placebo. The main outcome measures were incidence and severity of HZ and PHN, and the burden of illness caused by HZ. The patients were followed for a median of 3.12 years, and the vaccine was shown to reduce the burden of illness of HZ by 61.1%, the incidence of HZ by 51.1% (P<0.001), and the incidence of PHN by 66.5% (P<0.001).20

The short-term persistence substudy followed 7,320 of the vaccinated patients and 6,950 of placebo patients from the SPS through 4 years after vaccination. The burden of illness was reduced 50.1%, the incidence of PHN was reduced 61%, and the incidence of HZ was reduced 39.9%.22

The long-term persistence study enrolled 6,867 SPS vaccine recipient patients and followed them yearly from year 7 after vaccination to year 11 after vaccination. The burden of illness was reduced 37.3%, the incidence of PHN was reduced 35.4%, and the incidence of HZ was reduced a meager 21.1%. The vaccine efficacies in the STPS and LTPS studies waned with time, and the overall efficacy of the vaccination came into question.6 If a patient is vaccinated at 60 years of age (as the ACIP recommended previously), by the age of 71 when patients are generally believed to be more susceptible, the vaccine has likely lost most of its effect (given the results of the LTPS). This leaves older patients vulnerable to HZ. As boosters were not ever recommended, the overall effectiveness of the zoster vaccine in our aging baby-boomer population was debatable. There is therefore a need for a vaccine with a prolonged efficacy.

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Herpes Zoster Vaccination–Recombinant Vaccine (Shingrix, RZV)

Recent work has been underway to create a recombinant varicella vaccine containing VZV glycoprotein E using the ASO1B adjuvant system. The recombinant vaccine is given as two intramuscular injections 2 to 6 months apart, and both injections are required for efficacy.24 A recent multicenter, randomized, placebocontrolled study with 15,411 participants and a mean follow-up duration of 3.2 years showed the subunit vaccine efficacy was between 96.6% and 97.9% for all age groups (50–59, 60–69, >70). Around 11% of patients developed grade 3 systemic or localized solicited adverse events,24–26 however.

The subunit vaccine showed so much promise that the ACIP and CDC now recommends the subunit vaccine for healthy patients 50 and older, and they no longer recommend the live zoster vaccine as first-line therapy.8,15,27 The subunit vaccine might prove to be more effective in aging adults. In fact, a recent study confirmed that in adults age 60 or older, 9 years after receiving the subunit vaccine, humoral, and cellular immunity remained above prevaccination levels in all age groups. Schwarz et al.28 predicted immune responses would remain above baseline for 15 years.

The efficacy and long-term persistence of the new vaccine begs the question, should we also vaccinate patients with the recombinant vaccine if they already received ZLV? Grupping et al.26 studied this particular question and in 430 patients previously vaccinated with Zostavax, and Shingrix proved safe and effective.

The ACIP recommends the subunit vaccine for healthy patients 50 years and older, regardless if they have received the ZLV. The RZV is now the preferred vaccine and the use of ZLV should be reserved for patients 60 or older who are allergic to Shingrix. It has been theorized that the new recombinant vaccine will also prove safe for immunocompromised individuals. As of now, data regarding the safety profile of the RZV in immunocompromised individuals have not been analyzed for the ACIP to provide a recommendation. Safety data will need to be analyzed to determine whether the new recombinant vaccine is safe for immunocompromised patients. Of note, there has been a report of HZ stromal keratitis reactivation after use of the RZV.29 As of now, long-term data are needed to better understand uncommon complications of the new immunologic adjuvant used in the RZV and to draw further conclusions regarding its safety. Table 2, ACIP recommendations.



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Herpes zoster ophthalmicus is a serious and slight threatening illness. Widespread vaccination efforts are pivotal in preventing varicella and subsequent HZ. Primary care providers and ophthalmologist should serve on the front line in the effort to eradicate HZ-related blindness through vaccination. The recombinant vaccine is a great improvement in our vaccination strategy as it potentially provides longer lasting immunity against HZ and is now the preferred vaccine for adults 50 years and older.

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Herpes zoster; Varicella zoster virus; Herpetic uveitis; Herpetic keratitis; Vaccination

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