Recurrent Herpes Simplex Research Articles

Therapeutic Use of Soluble Fas Ligand Ameliorates Acute and Recurrent Herpetic Stromal Keratitis in Mice.

The present study was designed to test the therapeutic value of soluble FasL (sFasL) in an acute model of herpetic stromal keratitis (HSK) and, more importantly, a recurrent model of HSK using BALB/c, BALB-lpr, and National Institutes of Health (NIH) mice. Mice were infected either acutely with the KOS strain of herpes simplex virus 1 (HSV-1) or latently with the McKrae strain of HSV-1. Acutely infected mice as well as ultraviolet-B (UV-B) reactivated mice (recurrent infection) were treated with sFasL, or soluble TNF-related apoptosis inducing ligand (sTRAIL), or BSA daily or 3 times/wk by using either a combination of subconjunctival injection and topical ointment, or with topical ointment alone. These mice then were evaluated for corneal opacity and neovascularization for 6 weeks. Following acute and recurrent HSV-1 infection, wild-type BALB/c mice treated with sFasL displayed significantly reduced incidence of corneal opacity and neovascularization compared to the control animals. However, BALB-lpr mice, which are deficient in Fas+ inflammatory cells, displayed no such differences in ocular disease, as expected. Latently infected NIH mice treated with sFasL displayed similar results. Flow cytometric analysis revealed that the corneal inflammatory infiltrate in those treated with sFasL was significantly less than in sTRAIL- or BSA-treated mice. Furthermore, corneas from sFasL-treated mice displayed relatively more cells undergoing apoptosis. This study provides evidence that sFasL treatment has potential therapeutic benefit in reducing inflammatory infiltrate and neovascularization in primary and recurrent forms of HSK, and that it does so by augmenting the restriction of Fas+ inflammatory cells mediated by membrane FasL.

Management and Prevention of Herpes Zoster Ocular Disease.

Herpes zoster (HZ) is caused by reactivation of latent varicella zoster virus (VZV) in people who have had chicken pox, usually resulting in a painful, unilateral, dermatomal, vesicular rash. Herpes zoster ophthalmicus occurs when the first division of cranial nerve V is involved. HZ is common, with approximately 1 million new cases per year in the United States, and occurs in 1 in 3 persons. Although the rate of HZ increases with age, over half of all cases occur under the age of 60 years. Complications of herpes zoster ophthalmicus include eye disease, postherpetic neuralgia (PHN), and strokes. VZV has also been found in temporal arteritis biopsies. There is growing evidence that HZ is followed by chronic active VZV infection contributing to these complications. In view of this, and the efficacy of suppressive antiviral treatment in reducing recurrent herpes simplex keratitis, a randomized controlled trial of suppressive valacyclovir to reduce new or worsening anterior segment disease and/or PHN is needed. The zoster vaccine (ZV) is safe and effective in reducing the burden of illness, severity of PHN, and incidence of HZ. It is Centers for Disease Control and Prevention recommended for persons aged 60 years and above without impaired cellular immunity, and Food and Drug Administration approved for those aged 50 and older. It is most effective in preventing HZ in recipients in their 50s. Because of underusage of the ZV, it has not impacted the epidemiology of the disease. Barriers to its use include cost, variable reimbursement, frozen storage, and lack of a strong recommendation by doctors.

Photobiomodulation in oral medicine: a review.

Photobiomodulation (PBM) or low-level laser therapy (LLLT) in dentistry is an evolving science, with an increasing number of controlled clinical studies exploring its potential as a treatment modality. The present study provides an outline of the biologic mechanism of PBM and summarizes the findings of clinical studies of PBM for specific applications in oral medicine. Controversies and drawbacks associated with PBM, which require further research, are also identified. Current literature reports the potential of PBM in various applications in oral medicine. Furthermore, well-documented research confirms its efficacy in certain conditions, such as oral mucositis, recurrent herpes simplex infection, and burning mouth syndrome. The absence of any reported adverse effects is an advantage over conventional therapeutic modalities. While PBM has proved to be effective for some specific applications, it is not a panacea. The paucity in standardized studies, coupled with ambiguity over the laser parameters, has limited its credibility as a therapeutic modality.

A Young Adult Male with Chronic Mucocutaneous Candidiasis (CMC) with Signal Transduction and Activator of Transcription 1 (STAT 1) Mutation and Progressive Multifocal Leukoencephalopathy (PML)

M O N D A Y 600 Variable Presentations of Gain of Function STAT1 Mutations within a Single Institution with Features Beyond Chronic Mucocutaneous Candidiasis Sheila M. Bina, MD, Jenni Y. Yoon, MD, Jennifer W. Leiding, MD; University of South Florida, St. Petersburg, FL. RATIONALE: Gain of function (GOF)mutations in signal transducer and activator of transcription 1 (STAT1) are a major cause of chronic mucocutaneous candidiasis (CMC). Susceptibility to viral, bacterial, fungal, and mycobacterial infections can also occur. In addition to infection susceptibility, patients with GOF-STAT1 mutations suffer from many other manifestations. METHODS: Retrospective chart reviews were performed on 5 patients with GOF-STAT1 mutations to identify specific infectious susceptibility and other immunologic manifestations. RESULTS: All 5 patients identified have mutations in the coiled-coiled or DNA binding domains of STAT1, all consistent with gain of function. Four patients have CMC, 1 has recurrent herpes simplex virus stomatitis, 1 had Mycobacterium fortuitummediastinal lymphadenitits, and 2 have recurrent sinopulmonary infections. One patient presented at 5 months of age with immunodysregulation-polyendocrinopathy-enteropathy-X-linked (IPEX) like manifestations including severe refractory diarrhea, diabetes, and failure to thrive. Successful matched unrelated bone marrow transplant was performed at 3 years of age. In addition to CMC, one patient had a giant hand granuloma caused by Trichopyton tonsurans. Other non-infectious manifestations include generalized seizures, autoimmune hemolytic anemia, recurrent thrombosis, and squamous cell carcinoma. CONCLUSIONS: In addition to CMC, these patients demonstrate broad infectious susceptibility and many other manifestations of GOF-STAT1 mutations including IPEX-like disease, vascular disease, autoimmunity, and malignancy.

Clinical efficacy of oral ganciclovir for prophylaxis and treatment of recurrent herpes simplex keratitis.

Background:Herpes simplex keratitis (HSK) caused by herpes simplex virus 1 (HSV-1), which has high recurrent rate and incidence of severe vision loss, is the leading cause of infectious blindness in the world. The aim was to explore the clinical efficacy of oral ganciclovir (GCV) in the prevention of recurrent HSK.Methods:A multicenter, prospective, randomized, single-blind, and controlled clinical trial was conducted from April 2010 to June 2013. One hundred seventy-three patients (173 eyes involved) who were diagnosed as recurrent HSK definitely, including stromal keratitis and corneal endotheliitis, were divided into three groups randomly: negative control (placebo) group was topically administered with 0.15% GCV ophthalmic gel, 4 times per day and 0.1% fluorometholone eye drops, 3 times per day until resolution of HSK; positive control acyclovir (ACV) group was topically adopted the same ophthalmic gel and eye drops and additionally received oral ACV 400 mg 5 times a day for 10 weeks and followed by 400 mg 2 times per day for 6 months; test GCV group was topically adopted the same treatment as negative control group and additionally received oral GCV 1000 mg 3 times per day for 8 weeks. The symptoms and signs were evaluated before and after the therapy 1st week, 2nd week and then followed up every 2 weeks until recovery. Furthermore, we followed up recurrence of HSK for every 3 months after recovery and then assessed the cure time, recurrent rate and adverse reactions.Results:One hundred and seventy-three patients were followed up 7–48 months (mean 32.1 ± 12.3 months), but 34 patients were failed to follow-up. The cure time was 12.1 ± 4.3, 11.9 ± 4.0 weeks in negative control (placebo) group and positive control ACV group respectively (P = 0.991), which was longer than that in test GCV group (8.6 ± 2.8 weeks) and there was a significant difference between test GCV group and negative control (placebo) group or positive control ACV group (P = 0.000). Furthermore, the recurrent rate was higher in negative control (placebo) group (47.3%) than that in positive control group ACV (26.7%) and test GCV group (17.2%), and there was a great significant difference among the three groups (P = 0.007), but there was no significant difference between positive control ACV group and test GCV group (P = 0.358). In addition, there was no obvious adverse reaction expect neutropenia (only one patient in test GCV group).Conclusion:Short-term oral GCV could cure recurrent HSK and endotheliitis, shorten the course, reduce recurrent rate of HSK and have confirmed safety.

Normal laser-evoked cortical responses in patients with chronic hemibody pain.

Patients with widespread unilateral chronic pain associated with recurrent herpes simplex virus (HSV) infections show functional and/or structural changes in the insula, anterior cingulate cortex, frontal and prefrontal cortices, as well as the thalamus, suggesting central dysfunction of the pain system in these patients. Central pain has been associated with attenuated laser-evoked cortical responses. We aimed to clarify whether the observed deficient activation of these areas to acute nociceptive stimuli is due to a lesion at a lower level of pain processing pathways. We explored the functional integrity of the ascending nociceptive pathways by recording the cortical-evoked responses to noxious laser stimulation using magnetoencephalography and electroencephalography in eight patients (age 41-51 years, mean 46) with recurrent HSV infections and a history of chronic, spontaneous, widespread unilateral pain, and in nine age-matched healthy control subjects. The cortical-evoked fields of the HSV patients originating from the secondary somatosensory and posterior parietal cortices, as well as the evoked potentials recorded from the midline, did not differ from those of the control subjects, indicating functionally intact ascending nociceptive pathways. The present results show that our patients with chronic hemibody pain do not show signs of spinothalamic tract lesion. This indicates normal processing of sensory aspects of painful stimuli, while higher pain processing areas show altered activation. We conclude that normal laser-evoked magnetic fields (LEF) or laser-evoked potentials (LEP) may not exclude central pain condition.

Randomised controlled trial of topical kanuka honey for the treatment of cold sores

ObjectivesTo investigate the acceptability of topical medical grade kanuka honey for treatment of recurrent Herpes Simplex Labialis (HSL) and the feasibility of an individual crossover design. DesignAn open-label, single group, crossover randomised controlled trial. MethodsFifteen participants aged 16 years or older with a doctor's diagnosis of recurrent HSL were randomised to receive, according to a crossover design, either 5% acyclovir cream or medical grade kanuka honey for their next two episodes of HSL. Randomised treatments were applied to the lips five times per day from the first symptoms of developing the cold sore, until the lesion resolved. The primary outcome was the lesion healing time, defined as the time from development of first symptoms of the cold sore to return of normal skin. A key secondary outcome was acceptability of the honey treatment on visual analogue scale (VAS) (0=completely unacceptable to 100=completely acceptable). Kaplan–Meier survival plots, estimates of median healing times, and Cox Proportional Hazards with a random effect for participants to take into account the crossover design compared time to healing between treatments. Results5/15 (33%) participants provided no data for either intervention, one provided complete data for only the honey intervention, and one provided data only on acceptability of the honey intervention. The Kaplan–Meier estimates of median healing time were similar for honey and acyclovir, both nine days. The hazard ratio for time to healing was 0.57 (95% CI 0.19 to 1.72), p=0.32, favouring honey. The acceptability of honey was good, mean (SD) VAS 81.9 (24.2). ConclusionsTopical medical grade kanuka honey was highly acceptable to patients for the treatment of HSL. A large trial of kanuka honey in HSL may require an alternative recruitment site such as pharmacies, a parallel group rather than crossover design, and closer ongoing supervision of treatment and documentation of outcomes than used in our study.

Ganciclovir ophthalmic gel 0.15% for the treatment of acute herpetic keratitis: background, effectiveness, tolerability, safety, and future applications.

Eye disease due to herpes simplex virus (HSV) is a leading cause of ocular morbidity and the number one infectious cause of unilateral corneal blindness in the developed parts of the globe. Recurrent keratitis can result in progressive corneal scarring, thinning, and vascularization. Antiviral agents employed against HSV have primarily been nucleoside analogs. Early generation drugs included idoxuridine, iododesoxycytidine, vidarabine, and trifluridine. While effective, they tended to have low bioavailability and measurable local cellular toxicity due to their nonselective mode of action. Acyclovir 0.3% ointment is a more selective agent, and had become a first-line topical drug for acute HSV keratitis in Europe and other places outside of the US. Ganciclovir 0.15% gel is the most recently approved topical treatment for herpes keratitis. Compared to acyclovir 0.3% ointment, ganciclovir 0.15% gel has been shown to be better tolerated and no less effective in several Phase II and III trials. Additionally, topical ganciclovir does not cause adverse systemic side effects and is therapeutic at lower concentrations. Based on safety, efficacy, and tolerability, ganciclovir 0.15% gel should now be considered a front-line topical drug in the treatment of dendritic herpes simplex epithelial keratitis. Topics of future investigation regarding other potential uses for ganciclovir gel may include the prophylaxis of recurrent HSV epithelial keratitis, treatment of other forms of ocular disease caused by herpesviruses and adenovirus, and ganciclovir gel as an adjunct to antitumor therapy.

FEATURES OF CYTOKINE PRODUCTION IN PATIENTS WITH RECURRENT HERPETIC INFECTION

Cytokines play an important role in resistance to herpesvirus infections. Therefore, studies of cytokine profile are necessary in recurrent herpetic infection. However, functional studies of cytokine network upon remission of the disease yielded controversial results. In this paper, we provide some results concerning comprehensive evaluation of ex vivo cytokine production by whole blood leukocytes drawn from 15 patients observed during clinical remission of recurrent Herpes Simplex virus infection. We have found a decrease of IL-1β, IL-8 and IL-10 production, as well as imbalance of cytokine profile, with predominance of IFNγ and IL-8 synthesis over IL-10 production, along with increased IL-4 and IL-13 levels to IL-1β contents. Differently directed correlations between the content of activated lymphocytes (CD3+HLA-DR+ and CD3+CD4+CD25+), natural killers (СD3-СD16/56+), NKT-cells and cytokine production levels were found in the groups of patients and healthy individuals. These differences may be due to shifts in major cytokineproducing populations in herpesvirus infections.

HSV-1 and Alzheimer's disease: more than a hypothesis.

Among the multiple factors concurring to Alzheimer’s disease (AD) pathogenesis, greater attention should be devoted to the role played by infectious agents. Growing epidemiological and experimental evidence suggests that recurrent herpes simplex virus type-1 (HSV-1) infection is a risk factor for AD although the underlying molecular and functional mechanisms have not been fully elucidated yet. Here, we review literature suggesting the involvement of HSV-1 infection in AD also briefly mentioning possible pharmacological implications of these findings.

Possible Neonatal Herpes Simplex Virus (HSV) Acquired Postpartum from Maternal Oral HSV Reactivation after Neuraxial Morphine.

In this report, we describe a case of a neonatal oral herpes simplex virus (HSV) infection possibly acquired from a mother who had oral HSV reactivation in association with neuraxial morphine. Neuraxial morphine is commonly administered for postpartum analgesia after cesarean delivery. While there is evidence that neuraxial morphine increases the risks of oral HSV reactivation in parturients, there has been no report of neonatal HSV infection directly acquired from a mother who had HSV recurrence from neuraxial morphine.

Long-term follow-up of HIV-infected patients once diagnosed with acyclovir-resistant herpes simplex virus infection

Acyclovir-resistant herpes simplex virus (HSV) infection is common in immunocompromised patients, but the course of such infection is little known. We describe the long-term follow-up of HIV-infected patients diagnosed once with acyclovir-resistant HSV infections. We retrospectively studied all HIV-infected patients between 2000 and 2010 diagnosed with virologically confirmed acyclovir-resistant HSV infection. Patients' socio-demographic and immunovirological characteristics were described. Response to foscarnet or cidofovir and recurrences were reported. Among 5295 HIV-infected patients, 13 (0.2%) were once diagnosed with an acyclovir-resistant HSV infection. Twelve patients were men, nine patients were of African origin. All patients reported previous acyclovir exposure and median CD4 count was 183 cells/mm(3) Ten patients presented exclusively with cutaneous lesions. Initially, 11 patients were treated with foscarnet and two with cidofovir. The median follow-up was 67 months (6-145). All patients recurred, 10 presenting at least one acyclovir-resistant HSV recurrence. The median number of acyclovir-resistant HSV recurrences per patient was 2 (0 - 5). Regarding the first and second recurrences, 7/13 (54%) and 5/11 (45%) HSV clinical isolates exhibited resistance to acyclovir, respectively. Acyclovir-resistant HSV infection prevalence was low in our cohort. The rate of acyclovir-resistant HSV episodes averaged 50% during the two first recurrences.

The flavonoid from Polygonum perfoliatum L. inhibits herpes simplex virus 1 infection.

Herpes simplex virus 1 (HSV-1) is one of the most prevalent human pathogens in both industrialized and developing countries. This study was performed to analyze the antiviral activity of purified flavonoid from Polygonum perfoliatum L. against HSV-1 infection in vitro and in vivo. Flavonoid showed no inhibitory effect, when treated before virus infection, but it strongly inhibited viral replication and cell-to-cell spread which was vital for the virus's propagation. The therapeutic effect of the flavonoid in treating HSV-1 induced encephalitis was also investigated in mice. A dose-dependent increase of survival rate and mean survival time (MST) were observed in the flavonoid-treated mice. These results suggested that the flavonoid may be a viable therapeutic option for recurrent HSV-1 infection.

Immunological aspects of acute and recurrent herpes simplex keratitis.

Herpes simplex keratitis (HSK) belongs to the major causes of visual morbidity worldwide and available methods of treatment remain unsatisfactory. Primary infection occurs usually early in life and is often asymptomatic. Chronic visual impairment and visual loss are caused by corneal scaring, thinning, and vascularization connected with recurrent HSV infections. The pathogenesis of herpetic keratitis is complex and is still not fully understood. According to the current knowledge, corneal scarring and vascularization are the result of chronic inflammatory reaction against HSV antigens. In this review we discuss the role of innate and adaptive immunities in acute and recurrent HSV ocular infection and present the potential future targets for novel therapeutical options based on immune interventions.

A Case ofPhoma glomerataKeratitis Occurred in Recurrent Herpes Simplex Keratitis Cicatrix

Purpose: To report a case of Phoma glomerata keratitis occurring in recurrent herpes simplex keratitis cicatrix. Case summary: A 63-year-old male patient was admitted to our hospital with complaints of abrupt visual deterioration and ocular pain in his left eye. He was treated for recurrent herpes simplex keratitis in the same eye 12 years prior. Because central desmatocele was observed as a result of advanced corneal stromal melting, Gram staining, Potassium Hydroxide (KOH) mount, and culture were performed in corneal scrape specimens. On microbiological evaluation, a Phoma species was detected and Phoma glomerata was diagnosed using DNA sequencing method. Two consecutive amniotic membrane transplantations were performed with topical antifungal agents. The lesion was not improved when using topical amphotericin B and natamycin eyedrops, thus fluconazole eyedrops were used additionally. The corneal infection was resolved with central thick opacification. Conclusions: In the present case, herpetic keratitis was the main underlying causative factor because the patient had no past history of trauma. When diverse appearances of keratitis occur in herpes simplex keratitis patients, clinicians need to consider the concurrence of fungal infection, especially Phoma glomerata, a rare fungal organism. J Korean Ophthalmol Soc 2014;55(8):1229-1232

English

INTRODUCTION: Vesicular lesions present in a zosteriform appearance are usually due to herpes zoster [varicella zoster virus], but uncommonly can denote zosteriform herpes simplex [herpes simplex virus]. Such lesions if recurrent that too in an immunocompetent host is unusual & worth reporting. CASE REPORT: We present a case that came to OPD with chief complaints of recurrent painless fluid filled eruptions over lower back. The frequency of recurrence was about once in 6-7 months & the lesions appeared sometimes on lower back & sometimes on lower abdomen. On performing tzank smear, syncytial cells were seen. Serologically, IgG antibodies for herpes simplex virus were found. CONCLUSION: Thus, it was a case of recurrent zosteriform herpes simplex presenting in contralateral dermatomes. We are reporting this case because of its unusual presentation & rarity.

Novel Composite Efficacy Measure To Demonstrate the Rationale and Efficacy of Combination Antiviral–Anti-Inflammatory Treatment for Recurrent Herpes Simplex Labialis

Historically, the primary target for research and treatment of recurrent herpes simplex labialis (HSL) has been limited to inhibiting herpes simplex virus (HSV) replication. Antiviral monotherapy, however, has proven only marginally effective in curtailing the duration and severity of recurrent lesions. Recently, the role of inflammation in the progression and resolution of recurrences has been identified as an additional target. This was evaluated in a randomized study comparing combination topical 5% acyclovir-1% hydrocortisone cream (AHC) with 5% acyclovir alone (AC; in the AHC vehicle) and the vehicle. The efficacy of each topical therapy was evaluated for cumulative lesion size--a novel composite efficacy endpoint incorporating episode duration, lesion area, and proportion of nonulcerative lesions. In that study, cumulative lesion area was significantly decreased with AHC compared with AC (25% decrease; P<0.05) and the vehicle (50% decrease; P<0.0001). As research continues in this arena, cumulative lesion area should be included as a measure of efficacy in clinical trials of recurrent HSL therapies.

Association Between Unprotected Ultraviolet Radiation Exposure and Recurrence of Ocular Herpes Simplex Virus

Studies have suggested that exposure to ultraviolet (UV) light may increase risk of herpes simplex virus (HSV) recurrence. Between 1993 and 1997, the Herpetic Eye Disease Study (HEDS) randomized 703 participants with ocular HSV to receipt of acyclovir or placebo for prevention of ocular HSV recurrence. Of these, 308 HEDS participants (48% female and 85% white; median age, 49 years) were included in a nested study of exposures thought to cause recurrence and were followed for up to 15 months. We matched weekly UV index values from the National Oceanic and Atmospheric Administration to each participant's study center and used marginal structural Cox models to account for time-varying psychological stress and contact lens use and selection bias from dropout. There were 44 recurrences of ocular HSV, yielding an incidence of 4.3 events per 1,000 person-weeks. Weighted hazard ratios comparing persons with ≥8 hours of time outdoors to those with less exposure were 0.84 (95% confidence interval (CI): 0.27, 2.63) and 3.10 (95% CI: 1.14, 8.48) for weeks with a UV index of <4 and ≥4, respectively (ratio of hazard ratios = 3.68, 95% CI: 0.43, 31.4). Though results were imprecise, when the UV index was higher (i.e., ≥4), spending 8 or more hours per week outdoors was associated with increased risk of ocular HSV recurrence.

The Scarlet H

The Scarlet H

Common and New Acyclovir Resistant Herpes Simplex Virus-1 Mutants Causing Bilateral Recurrent Herpetic Keratitis in an Immunocompetent Patient

We investigated thymidine kinase (tk) mutants isolated during multiple episodes of recurrent bilateral acyclovir resistant herpes simplex keratitis in an immunocompetent patient. From one eye, we found a single guanine insertion, previously shown to greatly reduce TK expression, and from the other, a previously unidentified substitution, which genetic experiments confirmed confers drug resistance. The substitution, although distant from substrate binding sites, reduced thymidine phosphorylation 10-20-fold, and acyclovir phosphorylation >100-fold. This phenotype should permit reactivation from latency to cause recurrent disease. The results may have implications for the prevalence and prevention of acyclovir resistance in patients with herpes simplex keratitis.