Other Viral Diseases

Scott M. Whitcup

Key concepts

•Herpes simplex virus (HSV) is a common cause of inflammatory eye disease.

•Keratitis and anterior uveitis are frequent manifestations of HSV disease; secondary glaucoma is an important cause of vision loss.

•A number of randomized controlled trials help guide therapy for HSV ocular disease. Topical antiviral therapy is indicated for HSV keratitis. Although oral aciclovir did not improve outcome in patients with active epithelial keratitis receiving topical antiviral therapy, it did reduce recurrence and progression of HSV disease and appears to be beneficial for patients with HSV-associated uveitis.

•Varicella causes two distinct forms of disease: primary infection with varicella (chickenpox) and herpes zoster disease. Uveitis most commonly occurs with herpes zoster infection.

•Treatment with oral antiviral therapy appears to improve outcome in patients with herpes zoster infection.

•Viral infections associated with a transient mild uveitis during the acute stages of infection include measles (rubeola), mumps, influenza, dengue fever, Epstein– Barr virus (EBV), and human T-lymphotropic virus type I (HTLV-1).

Viruses are important causes of human disease and play a pathogenic role in a number of inflammatory eye diseases. Viruses were first identified in the late 1800s. The specific viral etiology of diseases such as foot-and-mouth disease and yellow fever soon followed. Viruses were first classified as a distinct group based on their small size. We now know that viral genomes are composed of either RNA or DNA, and can encode several to hundreds of proteins based on their size. By learning more about how viruses attach, infect, and replicate in cells has allowed new thera­ peutic approaches to fighting viral infection. Importantly, better detection of viruses has allowed us to determine a viral etiology for diseases previously thought to be idio­ pathic. For example, high-throughput sequencing of RNA obtained from the livers and kidneys of a cluster of patients with fatal transplant-associated diseases allowed the identification of a new arenavirus as the cause of the outbreak.1

Herpes simplex virus kerititis and keratouveitis

Although many viruses can induce intraocular inflamma­ tion, herpes simplex keratitis is probably the most common ocular disease associated with uveitis. Patients with stromal keratitis often have a concurrent anterior uveitis.1 Although in some patients this uveitis develops during the initial onset of epithelial disease, most patients have uveitis with stromal involvement. Recurrent episodes are common and can se­ verely damage the eye. Anterior uveitis may also occur in patients with a history of previous epithelial herpetic in­ fection without currently active corneal disease. Herpetic keratouveitis manifests as a red, photophobic, and often very painful eye with decreased vision.2 Secondary glaucoma frequently accompanies severe inflammatory episodes and can lead to vision loss.

Pathogenesis

It is difficult to know how much of the ocular inflammation is due to direct viral infection, an immune response against the virus, or induced autoimmunity as a result of molecular mimicry. Each may play a role and vary between patients. A similar disease to herpes stromal keratitis can be induced in experimental animals by infecting them with HSV type 1.3,4 A herpes protein, UL6, has been identified as a viral protein resembling corneal progein. Interestingly, both tolerance and autoimmunity can be induced in the same model, depending on host susceptibility to keratitis (Fig. 13-1).5

Diagnosis

The diagnosis of herpes simplex keratouveitis is most easily made in patients with a known history of herpes simplex keratitis confirmed by typical dendritic epithelial defects (Fig. 13-2) or stromal disease confirmed by culture data. The disease should also be suspected in patients with a signifi­ cant corneal opacity accompanied by synechiae and anterior chamber cells. Keratic precipitates in the area of corneal disease, hypopyon, and hyphema may be seen in some patients. In some patients the corneal disease may obscure the examination of the anterior chamber. Bacterial keratitis must be ruled out, as well as the possibility of secondary bacterial infection. The use of PCR is starting to help in identifying HSV as the causative agent in patients with uveitis of unknown etiology.6

It remains unclear whether the uveitis associated with herpes simplex keratitis is a secondary inflammatory response

CD4+

Cornea

T-cell antigen receptor

Keratitis (autoimmunity)

Herpes simplex virus type 1

Figure 13-1.  Experimentally induced herpes keratitis. Keratitis can be induced in mice by infecting them with herpes simplex virus type 1. Molecular mimicry may mediate both tolerance and autoimmunity in this animal model.39,40 Mice that are resistant to keratitis after they have been infected with herpes simplex virus type 1 appear to be tolerant of the corneal protein because of similarities between a peptide sequence expressed in corneal cells and a sequence found within an IgG2a-antibody variant that is unique to these animals. UL6, a protein expressed in herpes simplex virus type 1, is also similar to the corneal protein. In susceptible mice, this molecular mimicry is thought to be involved in the development of keratitis (Albert LJ, Inman RD. Molecular mimicry and autoimmunity. N Engl J Med 1999;341:2068–74.)

Figure 13-2.  Typical dendritic epithelial defect caused by herpes simplex virus. (Courtesy of Sue Lightman, MD.)

to the corneal disease or whether it is induced by invasion of virus into the anterior uvea. Nevertheless, herpes simplex virus (HSV) has been isolated from the aqueous humor in some patients with the disorder.2 In experimentally induced herpes simplex uveitis the combination of sensitized T lymphocytes, herpes-specific antibody, and herpes simplex

Herpes simplex virus kerititis and keratouveitis

antigen is required to produce inflammation.7 In addition, topical ciclosporin A was shown to effectively reduce stromal haze and inflammation in experimental herpes simplex kera­ titis.8 If this situation applies to human disease, therapy that inhibits the cellular arm of the immune system could control the inflammation but enhance viral replication.

Experts differ on whether environmental factors can pre­ cipitate disease. Psychological stress has been cited as a potential trigger for recurrences of HSV ocular disease. However, when recall bias is controlled, a recent study failed to find an association between psychological stress and disease recurrence.9

Treatment

Herpetic eye disease is a disorder where numerous rand­ omized clinical trials help guide clinicians on how to best care for patients. Herpes simplex keratitis is treated with topical antiviral therapy such as trifluridine solution (Virop­ tic) every 2 hours or vidarabine ointment (Vira A) every 3 hours. Cycloplegic agents are also employed to reduce pain and prevent synechiae. In addition, topical corticosteroids should be used in patients with associated uveitis, but their use is sometimes delayed until the corneal epithelial disease resolves. In a recent controlled trial of topical corticosteroids for herpes simplex stromal keratitis, Wilhelmus and col­ leagues10 showed that prednisolone phosphate was signifi­ cantly better than placebo in reducing persistence or progression of stromal keratitis, as well as the time to resolu­ tion of uveitis. In this study both groups received topical trifluridine. Although some episodes may resolve without therapy, inflammation may lead to severe ocular damage.

Oral aciclovir does not appear to be beneficial for patients with HSV epithelial keratitis treated with topical antiviral agents. In an initial study, Barron and colleagues for the Herpetic Eye Disease Study Group11 reported no statistically or clinically significant beneficial effect of oral aciclovir in treating the stromal keratitis caused by HSV in patients receiving concomitant topical corticosteroids and triflurid­ ine. The Herpetic Eye Disease Study Group also conducted a well-controlled, randomized clinical trial of oral aciclovir for the prevention of stromal keratitis or iritis in patients with herpes simplex virus epithelial keratitis.12 Patients with HSV epithelial keratitis of 1 week or less duration were treated with topical trifluridine and then randomly assigned to receive a 3-week course of oral aciclovir 400 mg five times a day or placebo. The study showed that stromal keratitis or iritis developed in 17 of the 153 patients (11%) treated with aciclovir and in 14 of the 134 patients (10%) treated with placebo. In a second clinical trial the effect of oral aciclovir therapy for recurrences of HSV eye disease was investigated in 703 immunocompetent patients.8 In this study the cumu­ lative probability of a recurrence of any type of ocular HSV disease was 19% in the patients receiving aciclovir and 32% in patients receiving placebo. A benefit was seen for preven­ tion of both epithelial and stromal keratitis.9 There were only three patients with iritis; therefore the effect of treat­ ment on uveitis could not be determined in this study. However, in another trial, The Herpetic Eye Disease Study Group assessed the benefit of adding oral aciclovir to a regimen of a topical corticosteroid and trifluridine for the treatment of HSV-associated iridocyclitis.10 Patients with

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