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Though much research is happening in the diagnosis and treatment of viral eye infections, much of it might not be readily apparent to clinicians, explains Todd P. Margolis, MD, PhD.
Reviewed by Todd P. Margolis, MD, PhD
Though much is occurring in the diagnosis and treatment of viral eye infections, much of it may be under the radar for ophthalmologists. Variability in disease presentation and host immunity--relatively recent observations--are important factors, according to Todd P. Margolis, MD, PhD.
Ophthalmologists are perhaps not as aware of these diseases as they should be, and because of this, they can go unrecognized in the clinic, explained Dr. Margolis, the Alan A. and Edith L. Wolff Distinguished Professor and chairman, Department of Ophthalmology and Visual Science, Washington University, St. Louis.
Varicella zoster virus (VZV)
The incidence and prevalence of chronic and recurrent ocular VZV are unknown, and evaluating referral patients in practice makes it hard to ascertain the actual demographics, Dr. Margolis noted.
“Mucous plaque keratopathy--an infectious epithelial keratitis--is found in up to 13% of patients with ocular zoster and can occur years after the initial disease,” he said. “Recurrent iritis and uveitis have been documented in 7.4%, and recurrent keratitis is diagnosed in 6.9%.”
The percentage of ocular zoster patients with such complications may be higher, he noted.
“Physicians should keep in mind that more antiviral drugs and fewer corticosteroids are needed, in my experience,” Dr. Margolis said. “Patients are referred because of inflammation and are taking more steroids because physicians overlook the infectious component. When I decrease corticosteroids and increase antiviral drugs, patients tend to improve.”
Zoster sine herpete
The degree of skin eruption varies from easily missed lesions to extensive skin eruptions based on the affected structures.
When all the branches of the first division of the fifth cranial nerve are involved, very extensive involvement of the skin and eyes may develop. However, if only a single twig of the nasociliary branch of the first division of the trigeminal nerve is involved, there may be ocular involvement (cornea and/or iritis) in the absence of skin eruption (zoster sine herpete), Dr. Margolis noted.
A recent observation is VZV might cause temporal arteritis. A 2015 study (Neurology. 2015; published online before print Feb. 18, 2015) showed 40% of patients with giant cell arteritis (GCA) had VZV identified by polymerase chain reaction, and if many tissue samples were obtained and stained, 74% of patients had VZV antigen in skip areas, Dr. Margolis noted.
“These results suggest, but do not prove, that VZV causes temporal arteritis,” he said. Another study (JAMA Neurol. 2015;72:1281-1287) showed VZV antigen in 64% of patients negative for GCA. Similar findings were published (Ophthalmology. 2015;122:2142-2145) for patients with anterior ischemic optic neuritis suspected of having temporal arteritis but with negative biopsies; 5 of 7 patients were positive for VZV.
Herpes zoster vaccine (HZV)
Zoster vaccine live (Zostavax, Merck) has been available for more than a decade, but most eligible people have not been vaccinated, Dr. Margolis said.
Though the vaccine is not perfect, results have decreased disease incidence and severity. The incidence of zoster has decreased by 51%, and the incidence of post-herpetic neuralgia has decreased by 67%. However, the vaccine probably needs to be repeated after 10 years because of reduced efficacy over time.
A second vaccine, a gE subunit vaccine in a novel adjuvant (HZ/su, GlaxoSmithKline), is causing excitement because of its increased efficacy compared with the first vaccine. While the vaccine has not yet received FDA approval and is currently unavailable, a phase III study (N Engl J Med. 2015;372:2087-2096) reported the vaccine had 97.2% efficacy in preventing shingles and was as effective in patients aged more than 70 years compared with the shingles vaccine in current use in which patients aged more than 70 years did not benefit as much as younger patients.
This virus is highly prevalent in humans and is on the ocular surface. The virus reactivates in the blood during sepsis and organ transplantation. Not much is known about this virus, and its exact role in the pathogenesis of diseases is unknown.
However, in underscoring the virus’ importance, Dr. Margolis recounted the results of a study in Nepal conducted by his laboratory in which 30 of 32 vitreous taps from patients with seasonal hyperacute panuveitis were positive for TTV. Another study carried out by Russell Van Gelder, MD, found that sterile taps from patients with endophthalmitis were positive in 7 of 7 patients for TTV.
Fuchs’ heterochromic cyclitis (FHC)
With this virus, 20% to 100% of patients with FHC are positive for intraocular antibodies to rubella, according to Dr. Margolis.
“This suggests a localized immune response,” he said. Furthermore, 8% to 17% of these patients are positive for rubella RNA.
Interestingly, FHC develops less often in patients who were vaccinated for rubella, indicating that rubella may cause FHC, he noted.
However, some investigators have identified that 8% to 42% of those with FHC have cytomegalovirus (CMV) DNA in the anterior chamber, suggesting that both CMV and rubella may be causative agents of FHC.
CMV iritis in immune-competent patients is real. Physicians have probably seen it and misdiagnosed it, according to Dr. Margolis.
CMV iritis is characterized by unilaterality, masquerades as FHC or Possner-Schlossman syndrome, small corrals of keratoprecipitates, elevated IOP, or iris atrophy, and may be present with/without endothelitis with corneal edema. CMV DNA can be present in the aqueous. The virus responds to ganciclovir and valganciclovir, but not to acyclovir.
Over an 8-year span from 2007 to 2015, Dr. Margolis saw 9 men and 6 women (7 Asian, 8 Caucasians) with CMV iritis. Six of 10 patients who underwent vitreous taps were positive for CMV by polymerase chain-reaction assay. Valganciclovir was effective, whereas topical ganciclovir was not. IOP elevations, corneal edema, and anterior chamber reaction were achieved in a mean of 28 days with treatment. When medication was decreased, the CMV recurred in 9 of 10 patients; some were treated for up to 6 years.
Clinical variability, host immunity
The clinical features and outcomes seen with viral disease vary greatly among patients with the same microbe, and what causes this is the most important unresolved question in the infectious disease arena. Investigators point to various factors, such as the viral strain, latency site, or host immunity. Dr. Margolis favors the latter.
He discussed the epidemiology of herpes simplex virus (HSV)-1 ARN, a rare disease that occurs in 1 or 2 people per 5 million annually, despite that 80% of individuals have HSV in them. HSV-1 ARN is not an isolated entity. Affected patients also have a high incidence of a second eye disease and central nervous system involvement in addition to chronic iritis and late relapses.
“These patients are prone to central HSV infection but not peripheral (skin) disease,” he noted.
In a look-back investigation, Dr. Margolis and his colleagues found that of 7 patients with ARN, all also had encephalitis, which raises the question about a genetic component.
When considering immune risk factors for HSV, age and atopy are risks for ocular HSV; the C21orf91 genotype is a risk factor for labial HSV, and the TLR2 polymorphisms are risks for HSV encephalitis.
“Are these same polymorphisms in these genes responsible for patients who develop HSV-1 ARN?” he asked. This is not isolated to HSV-1 ARN but is apparent in other infectious diseases.
“We now understand that highly specific allelic polymorphisms predispose a limited number of individuals to diseases caused by viruses that otherwise only rarely cause overt disease,” he said. “A virus present in all of us may cause disease only in those unfortunate enough to have a specific genetic make-up.”
He added that research is showing a number of single gene variants can convey susceptibility or resistance to various pathogens.
Todd P. Margolis, MD, PhD
Dr. Margolis has no financial interest in the subject matter.