Evaluation of 80 virologically-confirmed cases of ocular herpes. Study of the correlation between the type of virus and the epidemiologic characteristics of the disease

80 strains were isolated from patients with herpetic ocular infection during the period May 1979 to May 1981: 17 patients with herpetic blepharitis, 40 patients with superficial keratitis and 23 with deep stromal keratitis or kerato-uveitis. Among 63 patients treated with antiviral agents, clinical resistance to the drug was observed in 17 cases. The strains were typed as HSV 1.1, 1.2 or 2.2 by seroneutralization and thermosensitivity in cellular cultures. No relationship between the viral types and the patient age, previous history of corticosteroid therapy and the response of ocular lesions to antiviral treatment were detected. It appeared that there was a relationship between the viral type and the clinical type of infection: 70% of herpetic blepharitis and 83% of superficial keratitis were due to HSV 1.1 while 71% of stromal keratitis were due to HSV 1.2. No HSV 2.2 was isolated. These results seem to support the hypothesis that genetic differences between herpetic virus strains may determine their virulence.     

Ocular herpes simplex virus infections: reduced sensitivity to acyclovir in primary disease.

Forty isolates of herpes simplex virus (HSV) obtained from ocular herpetic infections were assayed for their sensitivity to five antiviral agents. There were wide ranges of sensitivity to foscarnet, idoxuridine, and vidarabine, but the majority were sensitive to acyclovir and ganciclovir. Reduced sensitivity to acyclovir was seen in four isolates, all of which were from primary infections acquired in the community and without a previous history of treatment with antiviral drugs.     

Pathogenesis of herpes simplex keratitis: The host cell response and ocular surface sequelae to infection and inflammation

Herpes simplex virus type 1 (HSV) keratitis is a leading cause of infectious blindness. Clinical disease occurs variably throughout the cornea from epithelium to endothelium and recurrent HSV stromal keratitis is associated with corneal scarring and neovascularization. HSV keratitis can be associated with ocular pain and subsequent neutrophic keratopathy. Host cell interactions with HSV trigger an inflammatory cascade responsible not only for clearance of virus but also for progressive corneal opacification due to inflammatory cell infiltrate, angiogenesis, and corneal nerve loss. Current antiviral therapies target viral replication to decrease disease duration, severity and recurrence, but there are limitations to these agents. Therapies directed towards viral entry into cells, protein synthesis, inflammatory cytokines and vascular endothelial growth factor pathways in animal models represent promising new approaches to the treatment of recurrent HSV keratitis.     

Acyclovir--a promising antiviral agent: a review of the preclinical and clinical data in ocular herpes simplex management

Acyclovir (Aciclovir), previously known as acycloguanosine, has been found to be a potent and selective inhibitor of viruses of the herpes group. A clear therapeutic effect has been demonstrated in animals and in clinical studies, especially for herpes simplex virus (HSV) infection of the eye. Various reports indicate that acyclovir is as effective as or superior to other available antiviral agents with low host toxicity and mild side effects. The possibility of systemic use of this drug and the effect on HSV latency are encouraging, although more evaluation is needed. Acyclovir is a promising new antiviral agent for the topical treatment of HSV ocular infection.     

Laser in situ keratomileusis in patients with a history of ocular herpes

PURPOSE: To report the outcomes of laser in situ keratomileusis (LASIK) in patients with a history of ocular herpes simplex virus (HSV) or herpes zoster ophthalmicus (HZO). SETTING: Clínica Baviera, Instituto Oftalmológico Europeo, Madrid, Spain. METHODS: In this retrospective case series, the records of eyes with a history of ocular herpes that had LASIK from 2003 through 2005 were reviewed. The main outcome measure was postoperative recurrence of ocular herpes. RESULTS: Forty-nine eyes (48 patients) with a history of ocular herpes (HSV keratitis, 28 eyes; HSV eyelid lesions, 17 eyes; HZO, 4 eyes) were identified. All LASIK procedures were uneventful. Herpetic disease was inactive at the time of surgery in all eyes and for more than 1 year in 31 eyes. Perioperative antiviral systemic prophylaxis was used in 13 patients with a history of HSV keratitis. No eye developed reactivation of herpetic keratitis during the follow-up (range 1 to 28 months). CONCLUSIONS: Laser in situ keratomileusis was safe in patients with a history of ocular herpes; no recurrences occurred during the follow-up period. However, candidates should be selected with caution and surgery performed only in eyes in which the herpes has been inactive for 1 year before surgery, without stromal disease, and with regular topography and pachymetry maps and normal corneal sensitivity. The most reasonable clinical strategy is perioperative systemic antiviral prophylaxis.     

Drugs and recurrent ocular herpes

There are two types of ocular herpes simplex virus (HSV), type 1 and type 2, and infections can be primary or recurrent. This paper reviews characteristics of herpes infections, the prevalence of the disease, virus latency and reactivation, types of ocular involvement, and current concepts for the management of ocular HSV. Various exogenous factors associated with recurrent herpes of the eye are covered with an emphasis placed on corticosteroids, epinephrine, and medroxyprogesterone. Mechanisms of drug action, and reactivation/exacerbation of ocular herpes are discussed. Clinical guidelines for potential drug contraindications are discussed.     

Herpes simplex keratitis in patients with acquired immune deficiency syndrome

Acquired immune deficiency syndrome (AIDS) is associated with a wide spectrum of systemic and ocular infectious diseases. Little information is known about herpes simplex virus type 1 (HSV-1) keratoconjunctivitis in association with AIDS. The authors present six cases of recurrent HSV keratitis occurring in AIDS patients. Features of the herpetic keratitis in these patients included unilateral dendritic or geographic epithelial keratopathy; predilection for peripheral versus central corneal involvement; one to three recurrences per patient over a mean observation period of 17 months, with a median dendrite-free interval of 7 months; and a moderately prolonged clinical course with a median healing time of 3 weeks using topical antiviral therapy. Only one of six cases had stromal infiltrative involvement. These cases raise the question of whether the immunologic abnormalities associated with AIDS may affect the clinical characteristics and course of HSV keratitis.     

In vitro sensitivity to antiviral agents of herpes simplex viruses isolated from patients with herpetic keratitis

Thirty-five clinical isolates of herpes simplex virus type 1 (HSV-1) from 34 patients (35 eyes) with herpetic keratitis were examined in vitro for 5-iodo-2'-deoxyuridine (IDU) and acyclovir (ACV) sensitivity. In addition, the effect of clinical treatment with these two drugs in herpetic keratitis was also investigated. The viral effective dose50 (ED50) was defined as the concentration that inhibited the plaque count by 50% compared to the count of the no drug controls. The viral ED50 of IDU ranged from 0.073 to 0.77 micrograms/ml (0.33 +/- 0.16; Mean +/- SD) and that of ACV from 0.0032 to 0.33 micrograms/ml (0.13 +/- 0.11). No virus with markedly diminished sensitivity to IDU and ACV was found. These results suggest that all HSV-1 strains isolated from patients have good sensitivity in vitro to antiviral agents.     

Intentional reactivation of latent ocular herpes infection during BVDU therapy

Sixteen adult New Zealand white rabbits with previously confirmed herpes simplex virus type 1 (HSV-1) infections were stimulated by iontophoresis of 6-hydroxydopamine into the cornea and were followed-up by topical epinephrine treatment to confirm latency. A total of 224 ocular cultures were obtained, of which 73 were positive for HSV during the seven day cycle. Twenty-seven of the 32 eyes (84%) had at least one positive culture. Animals were randomly divided into two treatment groups. Upon repeat stimulation (Cycle 2), concurrent with oral and topical bromovinyl-deoxyuridine (BVDU) therapy, only 3/104 ocular cultures were HSV positive, while 24/112 ocular cultures from placebo-treated animals were positive. Anti-HSV serum titers were comparable before and after BVDU therapy and the HSV isolates from BVDU treated animals did not develop drug resistance (i.e., ED-50 values were approximately 0.1-0.2 ug/ml both before and after therapy). It was concluded that BVDU had a demonstrable therapeutic effect on the recovery of HSV-1 from ocular cultures during intentional reactivation, but the latent ganglionic infection was not eliminated.     

Efficacy of valacyclovir vs acyclovir for the prevention of recurrent herpes simplex virus eye disease: a pilot study

PURPOSE: To compare the efficacy of one-year treatment with valacyclovir vs acyclovir in preventing recurrence of the herpes simplex virus (HSV) eye disease. DESIGN: Prospective, randomized, clinical trial pilot study. METHODS: Fifty-two immunocompetent patients with a history of recurrent ocular HSV disease were treated at the Ocular Immunology Service, San Raffaele Hospital, Milan, Italy. Twenty-six patients were randomized to the valacyclovir group (one 500 mg tablet daily), and 26 patients were randomized to the acyclovir group (one 400 mg tablet twice daily). The recurrence rate of ocular HSV disease during 12 months of treatment and drug-related side effects were monitored. RESULTS: Recurrence of any type of ocular HSV disease during the 12-month treatment period was 23.1% in the valacyclovir group, compared with 23.1% in the acyclovir group. No difference between the two groups was observed regarding the nature, frequency, or severity of adverse events. The most frequent adverse events were nausea and headache. CONCLUSIONS: One-year suppression therapy with oral valacyclovir (500 mg tablet daily) was shown to be as effective and as well tolerated as acyclovir (400 mg tablet twice daily) in reducing the rate of recurrent ocular HSV disease.     

Rapid diagnosis of ocular herpes simplex infections.

BACKGROUND--The Surecell herpes (HSV) test kit is a test for detecting the presence of herpes simplex viral antigen by means of a monoclonal antibody based immunoassay. The test has proved to be highly sensitive and specific in diagnosing genital, oral, and dermatological herpes infections. METHODS--In this study, samples from patients with ocular keratitis were evaluated by tissue cultures and the Surecell test. The eyes of New Zealand rabbits were then inoculated with HSV type 1 acute keratitis, acute Staphylococcus keratitis, and HSV type 1 postkeratitis (healed corneas). Tear film samples collected from each eye with a cotton swab were evaluated by routine culture (A-549 monolayers) and by the Surecell test with and without prior placement of the swab in Hank's medium. RESULTS--The Surecell system had a 70% sensitivity and a 100% specificity in the detection of HSV antigen in ocular infections, and was shown to be a quick, efficient, and accurate method of testing for HSV antigen in humans. CONCLUSION--These results from humans and rabbits indicate that the Surecell test, which requires no special equipment, can be a useful in office adjunct in the clinical diagnosis of ocular herpes simplex.     

Evidence-based treatment of herpes simplex virus keratitis: a systematic review

Herpes simplex virus (HSV) keratitis is a common cause of ocular and visual morbidity. In this article, we systematically review published randomized clinical trials (RCTs) for HSV epithelial and stromal keratitis in order to establish a rational evidence-based foundation for treatment of these disorders. Articles for review were identified in the MEDLINE database from January 1, 1966, to May 30, 2006. Our review criteria stipulated that each study be performed in prospective, randomized, and double-blinded fashion, that it be controlled, and that it rely on specific clinical criteria for diagnosis and outcome. Of articles thus identified in the English language press, 38 articles met our review criteria, 30 for HSV epithelial keratitis and 8 (comprising 7 RCTs) for HSV stromal keratitis. From these studies, we concluded that the best evidence from treatment trials on HSV epithelial keratitis supports the use of topical trifluridine and topical or oral acyclovir, and suggests a possible additional benefit for topical interferon. The best evidence from RCTs for HSV stromal keratitis supports the use of topical corticosteroids given together with a prophylactic antiviral to shorten the duration of active HSV stromal keratitis, and the use of long-term suppressive oral acyclovir therapy to reduce the incidence of recurrent HSV keratitis.     

Herpes simplex virus stromal keratitis is not titer-dependent and does not correlate with neurovirulence

We developed a murine model of ocular herpes simplex virus (HSV) disease which is particularly suited for testing stromal keratitis because most animals show some evidence of infection. Using this model, we characterized the ocular disease patterns caused by ten recent low-passage clinical isolates of HSV-1, as well as those caused by the established laboratory strains HSV-1 KOS and HSV-2 333. Viral strains were evaluated for their ability to cause stromal keratitis, blepharitis, vascularization of the cornea, and mortality. The model was not useful for scoring epithelial keratitis. The ocular disease caused by the recent isolates ranged from very mild disease to severe stromal keratitis. Some of the recent isolates caused disease as severe as the two laboratory strains. A comparison of the virulence characteristics expressed by various HSV strains indicated that the ability to cause stromal disease was correlated with vascularization of the cornea (correlation coefficient = 0.797, P less than 0.001) and was not correlated with the neurovirulence of the strains (correlation coefficient 0.045, P greater than 0.05). The severity of stromal keratitis was not dependent on the amount of inoculum over the range tested and a strain causing severe stromal keratitis caused severe ocular disease even when mixed with a nonstromal strain at ratios of 10:1, 100:1, and 1000:1.     

The severity of herpes simplex viral keratitis in mice does not reflect the severity of disease in humans.

Four herpes simplex type 1 virus (HSV) isolates were selected from patients with mild ocular disease and four from patients with severe ocular disease on the basis of the number of epithelial recurrences, presence or absence of stromal disease, visual acuity, and the need for corneal transplantation. The scarified right corneas of 20 BALB/c mice were inoculated with each low-passage HSV isolate (1.0 x 10(7) plaque-forming units/ml) and examined three times per week for 2 weeks for the presence and severity of epithelial and stromal disease. The eight individual virus isolates differed with respect to the incidence of dendritic disease (P less than 0.001), the severity of dendritic disease (P less than 0.001), the incidence of stromal disease (P = 0.002), and the severity of stromal disease (P = 0.001) they produced in the mouse. The severity of disease was compared for the two groups of viruses: (1) those that had caused mild disease in their human hosts and (2) those that had caused severe disease. There were no statistically significant differences in the severity or incidence (44 versus 43 animals, respectively) of dendritic disease or stromal disease (27 of 80 animals in each group) between the two groups. These data suggest that the naive BALB/c mouse model of acute HSV keratitis after topical ocular inoculation does not reflect clinically significant differences in the severity of human HSV keratitis that might be caused by variations in the virus genome.     

Efficacy of polyclonal antibodies for treatment of ocular herpes simplex infection.

PURPOSE: Herpes simplex virus (HSV) can cause corneal infections in humans and lead to permanent scarring, loss of vision, and blindness. Current treatment of epithelial HSV keratitis consists of using antiviral DNA analogs. In this study, we used in vitro and in vivo models to evaluate the efficacy of six polyclonal antibodies to HSV recombinant surface glycoprotein D in treating ocular epithelial HSV. METHODS: Confluent cultures of African Green monkey kidney fibroblasts (Vero cells) and normal 3-to 5-lb female New Zealand White rabbits were infected with HSV type 1, strain RE. In vitro virucidal and antiviral assays were performed, and the best of the compounds was chosen for the in vivo stage. Animals were carefully monitored until day 5 after HSV-1 inoculation, then arbitrarily divided into groups receiving, for 14 days, varying doses of: polyclonal antibodies four times a day, polyclonal antibodies three times a day, trifluorothymidine (current treatment of choice and the positive control) nine times a day, or 0.9% physiologic saline nine times a day. The animals were followed up in a masked fashion and carefully monitored for severity and resolution of the HSV infection by biomicroscopy (slit lamp) examination and viral cultures using standardized plaque assays. RESULTS: All six of the compounds tested were effective in vitro, but one compound in particular, SP-510-50, was superior. It was used for the in vivo testing and showed antiviral efficacy in a dose-dependent manner, and at dosing four times a day, it was of comparable efficacy to trifluorothymidine (nine times a day). CONCLUSIONS: We conclude that polyclonal antibodies to glycoprotein D appear to be effective antiviral agents in vitro and in vivo in a rabbit model of HSV-1 keratitis and show promise as a new antiviral treatment for ophthalmic use.     

Bacteriology and antibiotic therapy in congenital nasolacrimal duct obstruction

AIMS: To determine the current bacteriology of mucopurulent discharge in congenital nasolacrimal duct obstruction (CNDO), the in vitro response to different antibiotics and clinical effectiveness of the antibiotics used to relieve babies from mucopurulent discharge. METHODS: A clinical study evaluated the effectiveness of local antibiotic agents clinically and in vitro. 50 samples were obtained from the lacrimal sac in 47 young children with CNDO. The patients' mean age was 21.45 +/- 17.09 months. The cultures were incubated and the infectious agents isolated. Sensitivity testing was performed in each case, testing 10 different local antibiotics. A control group of 10 babies expected for cataract surgery was constituted. RESULTS: Cultures were positive for bacteria from 72.64% of the samples. 73 isolates were recovered from the 50 samples. The bacterial species most frequently cultured was Streptococcus pneumoniae, representing 35.4% of the isolates, followed by Haemophilus influencae (19.6%). The sensitivity testing revealed ofloxacin and tetracycline to be the most effective drugs as monotherapy. Clinically the combination of bacitracin and neomycin, primarily used in half of the patients as initial therapy, was successful in curing the dacryocystitis in 82.5% of all patients. CONCLUSION: Chronic dacryocystitis due to CNDO is associated with an equal proportion of Gram positive and negative bacteria, which can be treated with a high effectiveness by a combination drug of bacitracin and neomycin.     

Screening of Ocular Enterobacteriaceae Isolates for Presence of Chromosomal Blandm-1 and ESBL Genes: A 2-Year Study at a Tertiary Eye Care Center

Purpose. Since, to our knowledge, there are no reports on the prevalence of the blaNDM-1 gene among ocular isolates of Enterobacteriaceae, and only limited information on the prevalence of extended spectrum beta-lactamases (ESBLs) among ocular bacterial isolates are available, our study was undertaken. Methods. A prospective study was done on 74 Enterobacteriaceae isolates from patients presenting with clinical suspicion of bacterial ocular infections during a period from January 2010-December 2011. All isolates were subjected to detection of ESBLs by double disc synergy and screened for the presence of CTX-M -I, II, III, and IV groups, and OXA, TEM, SHV, blaNDM-1 genes by PCR. Results. Of 74 ocular Enterobacteriaceae isolates 57 (77%) were ESBL producers tested by the double disc diffusion test. PCR-based DNA sequencing of these 57 ocular isolates showed the presence of CTX-M-15 (14.0%), blaOXA-1 (5.2%), blaSHV-1 (8.7%), and blaTEM-1 (7.0%) types. The blaNDM-1 was absent among these ocular isolates. The most widely disseminated ESBL gene among ocular isolates was CTX-M-15. Phenotypic and genotypic results showed 100% correlation. Conclusions. To our knowledge, this is the first extensive study performed to genotype ESBL-producing ocular Enterobacteriaceae isolates. The isolation of ESBL-producing Enterobacteriaceae organisms predominantly from conjunctival specimens indicates community-acquired infections/colonization by these bacteria in the conjunctiva of the patients, and cases are not related to hospital-acquired infections because of the short stay of ophthalmic patients in the hospitals. A shift in the resistance rates of ceftazidime from 37.5% to 79.7% over the years proves the increase in drug resistance among ocular clinical isolates.     

In vivo antiviral efficacy of a dipeptide acyclovir prodrug,val-val-acyclovir,against HSV-1 epithelial and stromal keratitis in the rabbit eye model

PURPOSE: A dipeptide prodrug of the antiviral nucleoside acyclovir (ACV), val-val-ACV (VVACV), was evaluated in vivo as a potential drug candidate for improving antiviral efficacy against herpetic epithelial and stromal keratitis. METHODS: The effect of 1% VVACV on epithelial keratitis induced by inoculation of HSV-1 strain McKrae (25 microL of 10(5) plaque-forming units [PFU]) in the scarified rabbit cornea and stromal keratitis induced by intrastromal injection of HSV-1 strain RE (10 microL of 10(5) PFU) was compared with that of 1% trifluorothymidine (TFT) and balanced salt solution as the vehicle control. Both eyes of 10 rabbits were used in each treatment group. Lesions were evaluated by slit lamp examinations over a 2-week period after infection. Aqueous humor samples and corneas were analyzed for drug concentrations at the end of each experiment. Cytotoxicity of VVACV in comparison with val-acyclovir (VACV), ACV, and TFT was evaluated in cellular proliferation assays. RESULTS: The dipeptide prodrug VVACV demonstrated excellent activity against HSV-1 in the rabbit epithelial and stromal keratitis models: 1% VVACV was as effective as 1% TFT. The prodrug was also less cytotoxic than TFT, which is the only effective drug currently licensed and routinely used for topical treatment of ocular herpes infections in the United States. CONCLUSIONS: The less cytotoxic and highly water-soluble prodrug VVACV, which showed excellent in vivo activity against HSV-1 in rabbit epithelial and stromal keratitis, is a promising drug candidate for treatment of ocular HSV infections.     

Antiviral activity and ocular kinetics of antisense oligonucleotides designed to inhibit CMV replication

PURPOSE: To compare the antiviral activity and ocular distribution of first- and second-generation antisense oligonucleotides intended for the treatment of cytomegalovirus (CMV) retinitis. METHODS: The antiviral activity of ISIS 13312 and ISIS 2922 (Isis Pharmaceuticals, Inc., Carlsbad, CA) against 10 clinical CMV isolates was compared with a plaque-reduction assay. The ocular pharmacokinetics were compared after intravitreal injection in rabbits (36-90 microg) and monkeys (125-500 microg). Vitreous and/or retina were collected after single and multiple injections to characterize ocular distribution, clearance, and accumulation. Oligonucleotide concentrations were measured by capillary gel electrophoresis and immunohistochemical techniques. RESULTS: ISIS 13312 and ISIS 2922 demonstrated comparable antiviral activity that was consistent among the 10 clinical isolates examined (50% inhibitory concentration [IC(50)], <1 microM). Activity was independent of the resistance of CMV isolates to DNA polymerase inhibitors. After intravitreal injection, the kinetics of ISIS 2922 and ISIS 13312 were characterized by clearance from vitreous and distribution to the retina; however, ISIS 2922 was cleared more quickly from the retina than ISIS 13312. The half-life of ISIS 13312 in the monkey retina was approximately 2 months. Retinal concentrations of ISIS 13312 were dose dependent, with approximately a twofold increase in concentration after once-monthly doses compared with single-dose concentrations. Immunohistochemical analysis indicated that both oligonucleotides were efficiently distributed to numerous ocular tissues, including retina, ciliary body, and optic nerve. CONCLUSIONS: ISIS 13312 possesses antiviral activity and pharmacokinetic properties that favor its use as a therapeutic agent in treatment of CMV retinitis. The half-life of ISIS 13312 in retina is longer than that of ISIS 2922, potentially allowing for less frequent administration.