Deborah Pavan-Langston

Therapy of experimental herpes simplex encephalitis with aciclovir in mice.

This report is concerned with the capacities of aciclovir to protect mice challenged intracerebrally with multiple lethal doses of type 1 herpes simplex virus and to control multiplication of this virus in the brain. With treatment initiated 12 h after inoculation and continued for 4 consecutive days, aciclovir administered subcutaneously in daily doses ranging from 40 to 100 mg/kg led to 21-day survival rates of from 33 to 73% and reduced virus titers by 1 to ½ × 4 logs on postchallenge day 8. The therapeutic accomplishments of the 100-mg/kg doses of aciclovir were comparable to those of 1,000-mg/kg doses of vidarabine (9-β-d-arabinofuranosyladenine); however, as measured by impact on body weight, aciclovir was better tolerated than vidarabine at these similarly effective doses.

Long-term Oral Acyclovir Therapy: Effect on Recurrent Infectious Herpes Simplex Keratitis in Patients with and without Grafts

PURPOSE To evaluate the efficacy of long-term oral acyclovir therapy in reducing recurrences of dendritic or geographic herpes simplex keratitis (HSK). METHODS Thirteen patients with a history of frequently recurring HSK were followed before (mean, 27 months) and during long-term systemic acyclovir, and eight were followed after the acyclovir was discontinued. RESULTS Treatment ranged from 8.5 to 62 months (mean, 34 months). During treatment, the number of recurrences per month decreased from 0.15 to 0.03, and the average duration of relapses decreased from 12.6 to 7.8 days. Recurrences correlated with daily doses of oral acyclovir of 800 mg or less, intraocular surgery within 6 weeks of initiating treatment, and discontinuation of therapy against medical advice. CONCLUSION The results of this small study appear to demonstrate the efficacy of long-term oral acyclovir in prophylaxis of recurrent epithelial herpes simplex infection: therapeutic doses of oral acyclovir reduce both the rate and duration of recurrences of infectious herpetic keratitis. A multicenter, double-masked, placebo-controlled study is indicated.

Acyclic antimetabolite therapy of experimental herpes simplex keratitis.

In a masked controlled study we compared 3% acycloguanosine, 0.5% idoxuridine, and 3% vidarabine ointments in therapy of experimental herpes simplex virus keratitis in rabbits. The results of the acycloguanosine group were significantly better than the control groups and both other treatment groups, while producing none of the toxic side effects of increasing iritis, conjunctivitis or stromal keratitis, with continued drug application.

HSV-1-inducible proteins bind to NF-κB-like Sites in the HSV-1 genome

Several putative NF-kappa B-binding sites in the ICP0 and Vmw65 herpes simplex virus type-1 (HSV-1) genes have been identified. Oligonucleotides encoding some of these sites bind specifically to purified NF-kappa B protein and an NF-kappa B-like protein in nuclear extracts of phorbol ester- or cycloheximide-induced human embryonic lung (HEL) cells. HSV-1 infection of HEL cells induced a nuclear factor that binds specifically to kappa B sites in the ICP0 and Vmw65 gene regions and comigrates with complexes formed by purified NF-kappa B. The HSV-1-inducible nuclear factor bound to the authentic immunoglobulin (Ig) kappa B site. Transient expression of chloramphenicol acetyltransferase (CAT) plasmids containing two copies of the Ig kappa B site upstream of the c-fos promoter (kappa B2-CAT) showed activity in HEL cells. HSV-1 infection of kappa B2-CAT-transfected HEL cells, however, induced a dramatic increase in CAT activity; mutation in the NF-kappa B-binding site of kappa B2-CAT abolished the inducibility of CAT gene expression. Our results demonstrate that the HSV-1 ICP0 and Vmw65 gene regions contain binding sites for NF-kappa B, and that HSV-1-inducible proteins bind to NF-kappa B-like sites in the HSV-1 genome.

Pediatric herpes simplex of the anterior segment: characteristics, treatment, and outcomes.

PURPOSE To describe the clinical characteristics, treatment, and outcomes of herpes simplex virus (HSV) infections of the cornea and adnexae to raise awareness and to improve management of this important eye disease in children. DESIGN Retrospective case series. PARTICIPANTS Fifty-three patients (57 eyes) 16 years of age or younger with HSV keratitis (HSK), HSV blepharoconjunctivitis (HBC), or both in an academic cornea practice. METHODS The following data were collected: age at disease onset, putative trigger factors, coexisting systemic diseases, duration of symptoms and diagnoses given before presentation, visual acuity, slit-lamp examination findings, corneal sensation, dose and duration of medications used, drug side effects, and disease recurrence. MAIN OUTCOME MEASURES Presence of residual corneal scarring, visual acuity at the last visit, changes in corneal sensation, recurrence rate, and manifestations of HSK were assessed in patients receiving long-term prophylactic systemic acyclovir. RESULTS The median age at onset was 5 years. Mean follow-up was 3.6 years. Eighteen eyes had HBC only; 4 patients in this group had bilateral disease. Of 39 eyes with keratitis, 74% had stromal disease. Thirty percent of HSK cases were misdiagnosed before presentation. Seventy-nine percent of patients with keratitis had corneal scarring and 26% had vision of 20/40 or worse at the last visit. Eighty percent of patients had recurrent disease. Six of 16 patients (37%) receiving long-term oral acyclovir had recurrent HSV, at least one case of which followed a growth spurt that caused the baseline dosage of acyclovir to become subtherapeutic. CONCLUSIONS In a large series, pediatric HSK had a high rate of misdiagnosis, stromal involvement, recurrence, and vision loss. Oral acyclovir is effective, but the dosage must be adjusted as the child grows.

Extraneuronal herpetic latency: animal and human corneal studies.

Abstract HSV DNA has been previously detected by both in situ and dot blot hybridization in neuronal tissues latently infected with herpes simplex virus (HSV), but not in extraneuronal tissues. The present study, using dot blot hybridization with a cloned full‐length HSV DNA probe and subtractive hybridization assays for detecting HSV RNA, reveals both the presence and activity of the HSV genome in 100% of HSV latently infected rabbit corneas tested. Studies on human herpetic corneas taken at keratoplasty using slot blot hybridization with a cloned full‐lenght HSV DNA probe demonstrated positive binding (hybridization) to the probe in 50% of samples tested but no binding to normal human control DNA. These studies confirm earlier, less sensitive virus recovery assays and implicate the cornea as an extraneuronal site of HSV latency and reactivation.

Superinfections in Herpes Simplex Keratitis

We reviewed 15 cases of culture-proven corneal superinfections in 15 patients (eight men and seven women ranging in age from 41 to 86 years) with recurrent herpes simplex keratitis. The factors that appeared to increase the risk of superinfection were the presence of an epithelial defect (found in all 15 cases), a history of recurrent herpetic keratouveitis (found in ten cases), and the use of topical corticosteroids (found in 13 cases). Eight of the 15 patients were taking antibiotics at the time the superinfections were diagnosed, indicating that topical antibiotics do not provide sufficient protection. Gram-negative rods were found in six cases (Proteus mirabilis, Pseudomonas aeruginosa, Serratia marcescens, Klebsiella oxytoca, Enterobacter cloacae, and Achromobacter sp.). Gram-positive organisms, often in association with another infecting agent, were found in six cases (Staphylococcus epidermidis, three cases; S. aureus, two cases; and Streptococcus sp., two cases). Fungal superinfections were found in three cases (Cephalosporium acremonium, Candida albicans, and Aspergillus fumigatus, one case each). Mycobacterium cheloni was found in two cases.

Aciclovir and Corneal Wound Healing

Masked controlled rabbit studies were done to determine the toxic effects on corneal wound healing of the antiviral drugs 3% aciclovir and 0.5% idoxuridine ointment in therapeutically effective concentrations. Aciclovir had no significant detrimental effect in comparison to controls on the quality of regenerating epithelium or the re-epithelialization of epithelial wounds. Idoxuridine treatment caused significant toxic changes in the regenerating epithelium clinically and histologically with a significant delay in epithelial wound healing in comparison to control or aciclovir treated eyes. Aciclovir had no significant effect on the collagen content of stromal wounds as measured by hydroxyproline levels. Idoxuridine caused a reduction in collagen content not significantly different from controls but significantly lower than aciclovir.

Rapid detection of herpes simplex virus (HSV) antigen in human ocular infections

The new HERPCHEK (Dupont, No. Billerica, MA) enzyme immunosorbent assay (EIA) was used in a double-blind clinical study for rapid and specific detection of ocular herpes simplex virus (HSV) infection. This 4-hour assay can be used to demonstrate conclusively the presence of HSV antigen without culture and thereby rapidly differentiate between HSV and other clinically similar ocular infectious diseases. Ocular samples were collected from 180 individuals including 30 patients with acute HSV, 90 with latent HSV (ie, currently asymptomatic but with a positive history), 11 with acute or latent varicella zoster virus, 30 with nonherpetic infections (due to adenovirus, Acanthamoeba or bacteria), and 19 normal controls. A clinical diagnosis was made by one of us (DPL) and duplicate tear-film samples obtained by swabbing the conjunctival cul-de-sac and cornea. Coded samples were tested by routine viral culture on Vero cell monolayers and also were run independently in the HERPCHEK test. During active HSV infection, the HERPCHEK correlated 100% with clinical diagnosis, and virus culture correlated 90% with clinical diagnosis. In all latent HSV ocular infections, other nonherpetic ocular infections and normal samples, both the HERPCHEK and culture assays were negative.

Ocular viral infections

The most important viral organisms involving the eye are the DNA viruses herpes simplex, varicella-zoster, cytomegalovirus, adenovirus, and vaccinia virus. All of these agents except CMV may cause acute epithelial infection, sterile trophic ulceration due to basement membrane damage, deep corneal stromal immune reaction, and iritis. Although there are three excellent antiviral drugs commercially available, only HSV and vaccinia virus are highly sensitive to therapy with these antimetabolites; varicella-zoster virus and CMV are equivocally responsive and adenovirus has not been shown to be susceptible to these agents. In selected situations, topical or systemic corticosteroids are useful for managing any associated immune reactions in the eyes, but patients on these drugs should be monitored carefully both for superinfections and for interference with tissue healing that might ultimately threaten the integrity of the globe.