Involvement of STAT4 in IgG subtype switching and ocular HSV-1 replication in mice.

PURPOSE: To assess the relative impact of elevated T-helper 2 (T(H)2)- and reduced T-Helper 1 (T(H)1)-dependent immune responses on ocular herpes simplex virus type 1 (HSV-1) infection. METHODS: Signal transducer and activator of transcription protein 4 knockout mice (BALB/c-STAT4(-/-)) and wild-type BALB/c control mice were immunized with avirulent HSV-1 strain KOS or were mock-immunized. Three weeks after the third immunization, neutralizing antibody titers were determined by plaque reduction assays. Following ocular infection with virulent HSV-1 strain McKrae, viral replication in the eye, blepharitis, corneal scarring (CS), survival, and immunoglobulin (Ig) isotypes in sera were determined. RESULTS: Vaccinated STAT4(-/-) and BALB/c mice contained significant and similar neutralizing antibody titers and were completely protected against HSV-1-induced death and CS. In contrast to vaccinated STAT4(-/-) mice, mock-vaccinated STAT4(-/-) mice had higher ocular HSV-1 titers than mock-vaccinated BALB/c mice on days 2-3 post-ocular infection. There were also significant differences in the levels of IgG2a, IgG2b, and IgG3 in the sera of STAT4(-/-) mice when compared to the control BALB/c mice. CONCLUSIONS: These results suggest that the absence of T(H)1 cytokine responses did alter protection against viral replication and IgG isotypes but not eye disease or survival.

[Ocular manifestations of measles in adults: About three cases]. / Manifestations oculaires de la rougeole chez l'adulte : à propos de trois cas.

Measles is a contagious viral infection that usually affects children. The disease is caused by morbillivirus, a virus of the family Paramyxoviridae. The clinical picture is characterized by four phases: incubation, invasion, eruption and desquamation. Ophthalmologic manifestations in measles are rare, dominated by conjunctivitis and keratitis. Corneal involvement is the main concern; it varies from simple superficial punctate keratitis to corneal perforation. We report three cases of acute keratitis in young adults during an epidemic. The epithelial involvement was peripheral, central or diffuse. The outcome was favorable under symptomatic topical treatment.

Macrophages are important determinants of acute ocular HSV-1 infection in immunized mice.

PURPOSE: To determine the effect of macrophage depletion on herpes simplex virus type (HAV)-1 replication in the eye and on the establishment of latency in trigeminal ganglia (TG) of immunized and ocularly infected mice. METHODS: BALB/c mice were immunized with five HSV-1 glycoprotein DNA genes or were sham immunized. The virulent HSV-1 strain KOS was used as a positive vaccine control. Immunized mice were depleted of their macrophages by dichloromethylene diphosphonate (Cl(2)MDP) injection. After ocular infection with the HSV-1 strain McKrae, virus replication in the eye, blepharitis, corneal scarring, and dermatitis were determined. Finally, the copy numbers of latency-associated transcript (LAT) and CD4(+) and CD8(+) T-cell transcripts in the TGs of surviving mice 30 days after infection were determined by RT-PCR. RESULTS: Depletion of macrophages in immunized mice increased HSV-1 replication in the eye of infected mice between days 1 and 5 after ocular infection. Depletion of macrophages did not alter the HSV-1-induced death or corneal scarring in immunized mice. Macrophage depletion, however, resulted in increased blepharitis in immunized mice. Finally, macrophage depletion had no effect on the establishment of latency in immunized mice, as the TGs from both depleted and mock-depleted mice were negative for the presence of the LAT transcript. CONCLUSIONS: In immunized mice during primary HSV-1 ocular infection, macrophages play an important role in vaccine efficacy against HSV-1 replication in the eye and blepharitis in infected mice. During the latent stage of HSV-1 infection, however, macrophage depletion failed to have any observable effect on HSV-1 latency in the TGs of infected mice.

Development of Herpes Simplex Virus Infectious Epithelial Keratitis During Oral Acyclovir Therapy and Response to Topical Antivirals.

PURPOSE: To describe 3 cases of herpes simplex virus (HSV) vesicular blepharitis that progressed to infectious epithelial keratitis despite treatment with oral acyclovir, but responded to topical antiviral therapy. METHODS: Retrospective review of a small case series. RESULTS: One adult and 2 children presented with unilateral HSV vesicular blepharitis without evidence of corneal involvement. Each patient was placed on a therapeutic dose of oral acyclovir. While taking oral antiviral therapy, the patients developed HSV infectious epithelial keratitis, which was treated with trifluridine 1% solution 9 times daily in the adult and ganciclovir 0.15% ophthalmic gel 5 times daily in the 2 children. All 3 cases showed resolution of epithelial keratitis within 3 to 10 days after initiation of topical antiviral treatment while oral acyclovir was continued. CONCLUSIONS: Oral antiviral therapy alone may not adequately prevent progression of infectious ocular HSV blepharoconjunctivitis. Topical antiviral therapy appeared to enable resolution of HSV epithelial keratitis that arose during oral acyclovir treatment.

Conjunctival geographic ulcer: an overlooked sign of herpes simplex virus infection.

Herpes simplex virus (HSV) ocular infection causes significant visual burden worldwide. Despite the fact that dendritic or geographic corneal ulcers are typical findings in HSV epithelial keratitis, conjunctival ulcer as a sign of HSV infection has rarely been reported. Although easily overlooked, this important sign could be enhanced by fluorescein staining. We report two cases of conjunctival geographic ulcers proven to be HSV infection by viral isolation and polymerase chain reaction (PCR). One patient had bilateral disease and blepharitis, and the other had unilateral involvement without skin lesions. With timely diagnosis and proper management, excellent visual outcome can be expected.

Improved protection from primary ocular HSV-1 infection and establishment of latency using multigenic DNA vaccines.

PURPOSE: To compare the effectiveness of immunization with "naked" DNA corresponding to the genes encoding five HSV-1 glycoproteins, gB, gC, gD, gE, and gI (5gP DNA), with immunization with the five glycoproteins (5gP protein). Also, to compare immunization of 5gP protein in Montanide ISA 720 (SEPPIC, Paris, France), an adjuvant recently approved for use in humans, with immunization of 5gP protein in Freund's adjuvant. METHODS: BALB/c mice were vaccinated with 5gP DNA or 5gP protein emulsified in ISA 720 or Freund's adjuvant. Neutralizing antibody titers were determined by plaque-reduction assays. IL-2, -4, and -12 and IFN-gamma levels were determined by ELISA after in vitro stimulation of spleen cells. After ocular challenge with 2 x 10(5) plaque-forming units [pfu] per eye of HSV-1 strain McKrae, virus replication in the eye, survival, blepharitis, corneal scarring, and latency were determined. RESULTS: Neutralizing antibody titers (approximately 1:800-1:1200), corneal scarring (trace) and survival (100%) were similar for all vaccine groups, including 5gP DNA. Compared with the other vaccine groups, the 5gP DNA group had less ocular virus replication, as judged both by maximum virus titer and time of viral clearance. ISA 720 appeared more effective than Freund's against ocular virus replication and eye disease. The 5gP DNA-vaccinated mice had less blepharitis and latency than any other group and had the highest levels of IL-12 and IFN-gamma. All vaccine groups had similar levels of IL-2. CONCLUSIONS: The 5gP DNA vaccine appeared to be more effective than the corresponding protein subunit vaccine, regardless of adjuvant. Emulsification of the 5gP protein in ISA 720 appeared to be more effective than emulsification in Freund's adjuvant.

Reduced severity of HSV-1-induced corneal scarring in IL-12-deficient mice.

Evidence suggests that in BALB/c mice infected with HSV-1, increased corneal scarring correlated with the presence of IL-12p40 mRNA in the cornea. To determine if this observed correlation reflected function, we have utilized mice with a homologous disruption of the gene encoding either the IL-12p35 subunit or the IL-12p40 subunit of IL-12. The severity of corneal scarring following ocular infection with HSV-1 was reduced significantly in nai;ve IL-12p35- and IL-12p40-deficient mice compared with nai;ve BALB/c mice, with the corneal scarring being low grade in the IL-12p35-deficient mice and completely absent in the IL-12p40-deficient mice. The reduction in the corneal scarring could not be attributed to a reduction in the HSV-1 titers in the eyes, which were not significantly different from the BALB/c mice, or to differences in the production of T(H)1 responses (IL-2 and IFN-gamma production) by the infected mice. Taken together, these results suggest the importance of IL-12 in the induction of corneal scarring in HSV-1-infected mice.

Long-term acyclovir use to prevent recurrent ocular herpes simplex virus infection.

OBJECTIVE: To evaluate the effectiveness of more than 12 months of oral acyclovir therapy in reducing recurrences of ocular herpes simplex virus. METHODS: We retrospectively compared ocular herpes simplex virus recurrence in 2 groups of patients. In group 1, patients used oral acyclovir for at least 12 months and then discontinued the treatment. In group 2, patients received the treatment for at least 18 months. We compared recurrences when both groups were using acyclovir (period 1) and when only group 2 was receiving the drug (period 2). Statistical analysis was performed with the t test, chi2 test, and Kaplan-Meier method. RESULTS: Group 1 had 18 patients and a mean +/- SD follow-up of 45.2 +/- 22.2 months. Group 2 had 22 patients and a mean +/- SD follow-up of 42.4 +/- 30.2 months. Six patients (33%) in group 1 and 4 patients (18%) in group 2 had recurrence in period 1 (P =.3). In period 2, 14 patients (78%) in group 1 and 8 patients (36%) in group 2 had recurrence (P =.01). Mean +/- SD recurrence-free survival in period 2 was 15.3 +/- 5.5 months in group 1 and 37.3 +/- 6.3 months in group 2 (P =.001). CONCLUSIONS: Long-term oral acyclovir use seems to remain effective in decreasing the number of ocular herpes simplex virus recurrences beyond 12 months.

Predictors of recurrent herpes simplex virus keratitis. Herpetic Eye Disease Study Group.

PURPOSE: Determinants of the natural history of recurrent herpes simplex virus (HSV) keratitis have not been consistently established. We assessed how previous HSV eye disease affects the risk of recurrent HSV keratitis and evaluated whether demographic and other variables play any predictive role. METHODS: Three hundred forty-six patients in the placebo group of the Herpetic Eye Disease Study's Acyclovir Prevention Trial who had experienced an episode of HSV eye disease in the previous year were followed up for 18 months. Recurrences were categorized according to the type of involvement. Relative rates of recurrence were compared for categories of demographic variables, types and number of previous ocular HSV episodes, previous nonocular HSV infection, and month of the year. RESULTS: Fifty-eight (18%) of the 346 patients developed epithelial keratitis and 59 (18%) developed stromal keratitis during the 18 months of follow-up. Previous epithelial keratitis did not significantly affect the risk of epithelial keratitis (p = 0.84). In contrast, previous stromal keratitis increased the risk of stromal keratitis 10-fold (p < 0.001), and the risk was strongly related to the number of previous episodes (p < 0.001). Age, gender, ethnicity, and nonocular herpes were not significantly associated with recurrences, and no seasonal effects were observed. CONCLUSION: Among patients who experienced active ocular HSV disease in the previous year, a history of epithelial keratitis was not a risk factor for recurrent epithelial keratitis. In contrast, previous, especially multiple, episodes of stromal keratitis markedly increased the probability of subsequent stromal keratitis.

Herpes simplex blepharoconjunctivitis presenting as complete acquired ankyloblepharon.

PURPOSE: A 90-year-old woman was referred to us with a 1-month history of progressively worsening blepharoconjunctivitis. She had a complete acquired ankyloblepharon of the right lids, which resulted in the appearance of a right upper lid abscess on computed tomography. METHODS: Blepharotomy with separation and debridement of the lid margins was performed. RESULTS: Cultures were positive only for herpes simplex virus, type II. CONCLUSIONS: Herpes simplex blepharoconjunctivitis may take many clinical forms. Our patient's severe manifestations led to the clinical and radiologic appearance of preseptal cellulitis with a right upper lid abscess.

The effect of viral inoculum level and host age on disease incidence, disease severity, and mortality in a murine model of ocular HSV-1 infection.

It has been previously shown that the strain of virus, immune competence of the host, and innate resistance of the host have an effect on the severity of ocular disease induced by topical infection with herpes simplex virus type 1 (HSV-1). This study has expanded on earlier work by examining the effect of virus inoculum and host age on mortality, incidence of ocular disease, and severity of ocular disease. BALB/c mice were infected with inocula ranging from 2 x 10(3) to 1 x 10(6) pfu of HSV-1 strain CJ394. The most significant effect of variation in the inoculum was on the percent of mice developing disease. Increasing the inoculum resulted in significantly increased disease incidence, but at 5 x 10(3) pfu/mouse or higher, there was little difference in disease severity in those animals exhibiting symptoms. Decreasing host age also resulted in a significant increase in the incidence of ocular disease, but the dependence of disease severity on host age varied with the symptom being scored. In animals exhibiting disease, the peak severity of stromal keratitis and vascularization of the cornea were unaffected by host age. However, the severity of blepharitis was significantly reduced in older mice. Increasing host age also resulted in increased resistance to encephalitis. Three to four-week old mice were very susceptible to encephalitis (100% mortality), while only 20% of 4-5 week old mice died by day 15 post-infection. Mice older than 5 weeks were completely resistant to lethal encephalitis after corneal infection.

A novel gammaherpesvirus in a large flying fox (Pteropus vampyrus) with blepharitis.

A novel gammaherpesvirus was identified in a large flying fox (Pteropus vampyrus) with conjunctivitis, blepharitis, and meibomianitis by nested polymerase chain reaction and sequencing. Polymerase chain reaction amplification and sequencing of 472 base pairs of the DNA-dependent DNA polymerase gene were used to identify a novel herpesvirus. Bayesian and maximum likelihood phylogenetic analyses indicated that the virus is a member of the genus Percavirus in the subfamily Gammaherpesvirinae. Additional research is needed regarding the association of this virus with conjunctivitis and other ocular pathology. This virus may be useful as a biomarker of stress and may be a useful model of virus recrudescence in Pteropus spp.

Hepatitis C virus induces abnormalities in surface and intraocular pressure: a comparative study.

OBJECTIVES: Various ocular lesions are associated with hepatitis C virus (HCV). Few studies have focused on untreated patients. This study aims to describe ocular lesions in untreated HCV-infected patients without ophthalmic symptoms by means of a comprehensive ophthalmologic examination. MATERIALS AND METHODS: Ninety-five consecutive naive HCV chronically infected patients and 54 controls (blood donors) were enrolled in a prospective, cross-sectional, single-center study. The following variables were analyzed: age, sex, HCV viral load and genotype, liver fibrosis, visual acuity, biomicroscopy of the anterior segment, lacrimal function (tear break-up time) and Schirmer's tests), posterior segment examination, and intraocular pressure. RESULTS: HCV-infected patients presented an almost four times higher risk of lacrimal function involvement by tear break-up time [odds ratio (OR)=3.76; 95% confidence interval (CI) 1.75-8.04, P=0.001] and Schirmer's test (OR=4.17; 95% CI 1.83-9.50, P=0.001) than the controls. The chances of palpebral biomicroscopic lesions (blepharitis) were also higher (OR=3.21; 95% CI 1.49-6.94, P=0.003). Mean tonometry was higher in HCV patients (right eye 14.4±2.3 vs. 12.2±1.5, P<0.001 and left eye 14.5±2.3 vs. 12.0±1.4, P<0.001). CONCLUSION: Naive HCV patients even with no ophthalmic complaints presented a greater prevalence of lacrimal function abnormalities and a higher frequency of blepharitis compared with the control group. As never formerly described, intraocular pressure in HCV patients was higher than that in controls.

Incidence, recurrence, and outcomes of herpes simplex virus eye disease in Olmsted County, Minnesota, 1976-2007: the effect of oral antiviral prophylaxis.

OBJECTIVES: To provide an estimate of the incidence of herpes simplex virus (HSV) eye disease in a community-based cohort, and to investigate the effect of prophylactic oral antiviral therapy on HSV recurrences and outcomes. METHODS: All Olmsted County, Minnesota, residents diagnosed with ocular HSV from 1976 through 2007 were retrospectively reviewed. The frequency of recurrences and adverse outcomes, such as vision loss or need for surgery, were compared between untreated patients and those treated prophylactically with oral antiviral medication. RESULTS: Three hundred ninety-four patients with ocular HSV were identified, yielding an annual incidence of 11.8 per 100,000 people (95% confidence interval [CI], 10.6-13.0). No trends in incidence or adverse outcomes were identified during the 32-year period. Oral antiviral therapy was prescribed in 175 patients. Patients were 9.4 times more likely (95% CI, 5.0-17.9) to have a recurrence of epithelial keratitis, 8.4 times more likely (95% CI, 5.2-13.7) to have a recurrence of stromal keratitis, and 34.5 times more likely (95% CI, 10.8-111.1) to have a recurrence of blepharitis or conjunctivitis if not being treated prophylactically at the time of the recurrence. Twenty patients experienced adverse outcomes, and 17 (85%) were not being treated with oral antiviral medications immediately preceding the adverse event. CONCLUSIONS: Oral antiviral prophylaxis was associated with a decreased risk of recurrence of epithelial keratitis, stromal keratitis, conjunctivitis, and blepharitis due to HSV. Patients with adverse outcomes due to ocular HSV were usually not being treated with oral antiviral prophylaxis.