In vivo CRISPR gene editing in patients with herpetic stromal keratitis.

In vivo CRISPR gene therapy holds large clinical potential, but the safety and efficacy remain largely unknown. Here, we injected a single dose of herpes simplex virus 1 (HSV-1)-targeting CRISPR formulation in the cornea of three patients with severe refractory herpetic stromal keratitis (HSK) during corneal transplantation. Our study is an investigator-initiated, open-label, single-arm, non-randomized interventional trial at a single center (NCT04560790). We found neither detectable CRISPR-induced off-target cleavages by GUIDE-seq nor systemic adverse events for 18 months on average in all three patients. The HSV-1 remained undetectable during the study. Our preliminary clinical results suggest that in vivo gene editing targeting the HSV-1 genome holds acceptable safety as a potential therapy for HSK.

[Recurrent herpetic erosion of the cornea: diagnosis, treatment and prevention of recurrences]. / gerpeticheskaya retsidiviruyushchaya eroziya rogovitsy: diagnostika, lechenie i preduprezhdenie retsidivov.

A group of patients was found to have a special form of recurrent corneal erosion caused by types I and II herpes virus. This form represents an independent form of ophthalmic herpes - herpetic recurrent erosion (HRE) of the cornea. The herpetic etiology of recurrent corneal erosion was confirmed by the immunofluorescence study of scraping from the conjunctiva, which revealed a high concentration of the herpes simplex virus antigen. Treatment of patients (171 patients, 182 eyes) with HRE included 2 consecutive stages: stage I - relief of acute symptoms of the disease with the help of conservative treatment (instillations of interferon inducers, autologous serum, corneal protectors, tear substitutes, use of therapeutic soft contact lenses); in some cases, phototherapeutic keratectomy was used in the absence of the effect of conservative therapy, as well as in the localization of the focus in the optical zone. Stage II involved anti-relapse therapy based on the use of a Russian-produced herpes vaccine in the intercurrent period. After vaccination, observation for 2 years or more showed that 81.3% of patients achieved clinical recovery (complete cessation of HRE recurrences), 15.8% had a decrease in the frequency and severity of relapses, while 2.9% of patients did not respond to the treatment.

IFN-λ Regulates Neutrophil Biology to Suppress Inflammation in Herpes Simplex Virus-1-Induced Corneal Immunopathology.

HSV-1 infection of the cornea causes a severe immunoinflammatory and vision-impairing condition called herpetic stromal keratitis (SK). The virus replication in corneal epithelium followed by neutrophil- and CD4+ T cell-mediated inflammation plays a dominant role in SK. Although previous studies demonstrate critical functions of type I IFNs (IFN-α/ß) in HSV-1 infection, the role of recently discovered IFN-λ (type III IFN), specifically at the corneal mucosa, is poorly defined. Our study using a mouse model of SK pathogenesis shows that HSV-1 infection induces a robust IFN-λ response compared with type I IFN production at the corneal mucosal surface. However, the normal progression of SK indicates that the endogenous IFN responses are insufficient to suppress HSV-1-induced corneal pathology. Therefore, we examined the therapeutic efficacy of exogenous rIFN-λ during SK progression. Our results show that rIFN-λ therapy suppressed inflammatory cell infiltration in the cornea and significantly reduced the SK pathologic condition. Early rIFN-λ treatment significantly reduced neutrophil and macrophage infiltration, and IL-6, IL-1ß, and CXCL-1 production in the cornea. Notably, the virucidal capacity of neutrophils and macrophages measured by reactive oxygen species generation was not affected. Similarly, ex vivo rIFN-λ treatment of HSV-1-stimulated bone marrow-derived neutrophils significantly promoted IFN-stimulated genes without affecting reactive oxygen species production. Collectively, our data demonstrate that exogenous topical rIFN-λ treatment during the development and progression of SK could represent a novel therapeutic approach to control HSV-1-induced inflammation and associated vision impairment.

[Chinese expert consensus on the diagnosis and treatment of herpes simplex keratitis (2023)].

As one of the common infectious corneal diseases, herpes simplex keratitis (HSK) has diverse clinical manifestations, is prone to recurrence, and can lead to blindness. In recent years, as new virus detection technologies, treatment drugs and surgical methods have emerged, there are more options for the diagnosis and treatment of HSK, but many problems still exist. In order to further standardize the clinical diagnosis and treatment of HSK and provide guidance and reference for clinical work, the Ocular Infection Group of Chinese Ophthalmologist Association has gathered relevant domestic experts, and reached this consensus on the diagnosis, treatment, and prevention of HSK through full discussion, on the basis of previous opinions, and in consideration of the latest research progress, relevant guidelines abroad and expert recommendations regarding the clinical care of patients with HSK.

Risk factors influencing survival of acellular porcine corneal stroma in infectious keratitis: a prospective clinical study.

BACKGROUND: A worldwide lack of donor corneas demands the bioengineered corneas be developed as an alternative. The primary objective of the current study was to evaluate the efficacy of acellular porcine corneal stroma (APCS) transplantation in various types of infectious keratitis and identify risk factors that may increase APCS graft failure. METHODS: In this prospective interventional study, 39 patients with progressive infectious keratitis underwent therapeutic lamellar keratoplasty using APCS and were followed up for 12 months. Data collected for analysis included preoperative characteristics, visual acuity, graft survival and complications. Graft survival was evaluated by the Kaplan-Meier method and compared with the log-rank test. RESULTS: The percentage of eyes that had a visual acuity of 20/40 or better increased from 10.3% preoperatively to 51.2% at 12 months postoperatively. Twelve patients (30.8%) experienced graft failure within the follow-up period. The primary reasons given for graft failure was noninfectious graft melting (n = 5), and the other causes included recurrence of primary infection (n = 4) and extensive graft neovascularization (n = 3). No graft rejection was observed during the follow-up period. A higher relative risk (RR) of graft failure was associated with herpetic keratitis (RR = 8.0, P = 0.046) and graft size larger than 8 mm (RR = 6.5, P < 0.001). CONCLUSIONS: APCS transplantation is an alternative treatment option for eyes with medically unresponsive infectious keratitis. Despite the efficacy of therapeutic lamellar keratoplasty with APCS, to achieve a good prognosis, restriction of surgical indications, careful selection of patients and postoperative management must be emphasized. Trial registration Prospective Study of Deep Anterior Lamellar Keratoplasty Using Acellular Porcine Cornea, NCT03105466. Registered 31 August 2016, ClinicalTrails.gov.

Bolstering the Number and Function of HSV-1-Specific CD8+ Effector Memory T Cells and Tissue-Resident Memory T Cells in Latently Infected Trigeminal Ganglia Reduces Recurrent Ocular Herpes Infection and Disease.

HSV type 1 (HSV-1) is a prevalent human pathogen that infects >3.72 billion individuals worldwide and can cause potentially blinding recurrent corneal herpetic disease. HSV-1 establishes latency within sensory neurons of trigeminal ganglia (TG), and TG-resident CD8+ T cells play a critical role in preventing its reactivation. The repertoire, phenotype, and function of protective CD8+ T cells are unknown. Bolstering the apparent feeble numbers of CD8+ T cells in TG remains a challenge for immunotherapeutic strategies. In this study, a comprehensive panel of 467 HLA-A*0201-restricted CD8+ T cell epitopes was predicted from the entire HSV-1 genome. CD8+ T cell responses to these genome-wide epitopes were compared in HSV-1-seropositive symptomatic individuals (with a history of numerous episodes of recurrent herpetic disease) and asymptomatic (ASYMP) individuals (who are infected but never experienced any recurrent herpetic disease). Frequent polyfunctional HSV-specific IFN-γ+CD107a/b+CD44highCD62LlowCD8+ effector memory T cells were detected in ASYMP individuals and were primarily directed against three "ASYMP" epitopes. In contrast, symptomatic individuals have more monofunctional CD44highCD62LhighCD8+ central memory T cells. Furthermore, therapeutic immunization with an innovative prime/pull vaccine, based on priming with multiple ASYMP epitopes (prime) and neurotropic TG delivery of the T cell-attracting chemokine CXCL10 (pull), boosted the number and function of CD44highCD62LlowCD8+ effector memory T cells and CD103highCD8+ tissue-resident T cells in TG of latently infected HLA-A*0201-transgenic mice and reduced recurrent ocular herpes following UV-B-induced reactivation. These findings have profound implications in the development of T cell-based immunotherapeutic strategies to treat blinding recurrent herpes infection and disease.

[Deep anterior lamellar keratoplasty combined with antiviral therapy in the treatment of severe herpes necrotizing stromal keratitis].

Objective: To evaluate the efficacy of modified deep lamellar keratoplasty (DLKP) combined with antiviral medications for severe herpes necrotizing stromal keratitis. Methods: Retrospective case series study. Modified DLKP was performed in combination with antiviral medications in fifty patients (50 eyes) with severe necrotizing stromal keratitis, which was unresponsive to systemic and topical antiviral treatment for 1 week, at Shandong Eye Hospital. Before surgery, the operated eyes were examined using slit-lamp microscopy. The size of corneal ulceration and inflammatory infiltration and the depth of ulceration were observed in all of the patients. Corneal scraping and microbial culture and confocal laser scanning microscopy were used to exclude fungal, bacterial, Acanthamoeba, or other infections, and check the number of corneal endothelial cells. Anterior segment optical coherence tomography was used to examine the depth of infiltration, especially the thickness of the remaining cornea below the deepest ulceration. Antiviral drugs were used topically and systemically to control the infection and inflammation. Postoperatively, both antiviral drugs and low-dose corticosteroids were used. The ocular inflammation, corneal graft status and viral recurrence were monitored intraoperatively and postoperatively. Results: All of the fifty patients showed obvious inflammatory infiltration and stromal ulcers, and the corneal stroma in 23 patients (46%) remained less than 1/5 of the corneal thickness. Nine (18%) of the patients presented with descemetocele. The depth of infiltration ranged from 128 µm to 519 µm [mean, (265±84) µm]. The depth of corneal ulcers was deeper than 2/3 of the corneal thickness in 36 eyes (72%). The endothelial cells were visible in 26 eyes. The density of endothelial cells ranged from 1 275 cells/mm(2) to 2 994 cells/mm(2) [mean, (2 053±507) cells/mm(2)]. No fungal or bacterial infection was detected by corneal scraping. The microbial culture results were negative. All the inflammations in patients with severe herpes necrotizing stromal keratitis were under control by DLKP. No intraoperative corneal perforation occurred, and 6 eyes (12%) healed following amniotic membrane transplantation due to slow corneal epithelial healing. The infection was exacerbated two days following the surgery in two eyes (4%). These infections were controlled with enhanced antiviral medications in addition to the immediate withdrawal of corticosteroids. The corneal grafts returned to transparency at 1-2 weeks in 42 eyes (84%). Ten eyes (20%) exhibited recurrence due to medication withdrawal without the doctors' advice and a lack of regular visit during 2-year follow-up. Two patients (4%) developed stromal graft rejection for the same reasons. Conclusions: DLKP can achieve the results of ulcer healing for severe herpes necrotizing stromal keratitis. Combined antiviral therapy and close follow-up can reduce the viral recurrence. (Chin J Ophthalmol, 2018, 54: 97-104).

IL-2/anti-IL-2 antibody complex treatment inhibits the development but not the progression of herpetic stromal keratitis.

The IL-2/anti-IL-2 Ab immunocomplex has recently been shown to expand the naturally occurring pool of CD4(+)Foxp3(+) regulatory T cells (Tregs). In this study, we show that administration of the IL-2/anti-IL-2 Ab immunocomplex to C57BL/6 mice, prior to corneal HSV-1 infection, significantly increased the pool of Foxp3(+) Tregs when measured at early time points postinfection. Increased numbers of Foxp3(+) Tregs on days 2 and 4 postinfection resulted in a marked reduction in the development of severe herpetic stromal keratitis (HSK). When compared with corneas from the control group, corneas from the immunocomplex-treated group showed a significant reduction in the amount of infectious virus on day 2 but not on day 4 postinfection. Reduced viral load was associated with a 2-fold increase in NK cell numbers in corneas from the immunocomplex-treated group of mice. Moreover, a dramatic reduction in the influx of CD4 T cells in inflamed corneas was determined on days 7 and 16 postinfection in the immunocomplex-treated group of infected mice. Immunocomplex treatment given on days 5, 6, and 7 postinfection significantly increased Foxp3(+) Tregs in draining lymph nodes and in the spleen but failed to reduce the severity of HSK. In terms of the influx of CD4 T cells and granulocytes into inflamed corneas, no significant differences were noted between both groups of mice on day 16 postinfection. Our findings demonstrate that increasing Foxp3(+) Tregs early but not late postinfection in secondary lymphoid tissues is more efficacious in controlling the severity of HSK.

Antiviral treatment and other therapeutic interventions for herpes simplex virus epithelial keratitis.

BACKGROUND: Eye disease due to herpes simplex virus (HSV) commonly presents as epithelial keratitis which, though usually self-limiting, may persist or progress without treatment. OBJECTIVES: To compare the relative effectiveness of antiviral agents, interferon, and corneal debridement in the treatment of HSV epithelial keratitis. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2014, Issue 12), PubMed (January 1946 to 31 December 2014), EMBASE (January 1980 to 31 December 2014), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to 31 December 2014), System for Information on Grey Literature in Europe (OpenGrey) (January 1995 to 31 December 2014), BIOSIS (January 1926 to 5 May 2014), Scopus (January 1966 to 31 December 2014), Japan Science and Technology Institute (J-Global) (January 1975 to 31 December 2014), China National Knowledge Infrastructure (CNKI) (January 1979 to 31 December 2014), British Library's Electronic Table of Contents (Zetoc) (January 1993 to 7 May 2014). We looked for trials listed on the the metaRegister of Controlled Trials (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov), the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en), Chinese Clinical Trial Registry, the U.S. Food and Drug Administration (FDA) (www.fda.gov/), National Institute for Health and Clinical Excellence (NICE) (www. EVIDENCE: nhs.uk) and the European Medicines Agency (EMA) (www.ema.europa.eu/ema/) as of 31 December 2014. There were no language or date restrictions in the search for trials. We also culled literature digests and conference proceedings as of 15 April 2014. There were no language or date restrictions in the search for trials. SELECTION CRITERIA: Randomised and quasi-randomised trials of HSV dendritic or geographic epithelial keratitis were included that reported the proportion of eyes healed at one week, two weeks, or both after enrolment. DATA COLLECTION AND ANALYSIS: We tabulated data on study characteristics, risk of bias, and outcomes and used direct comparisons to estimate a risk ratio (RR) and, when feasible, a hazard ratio (HR) with a 95% confidence interval (CI). Heterogeneity was assessed by an inconsistency index. A multiple treatment comparison meta-analysis consolidated direct and indirect comparisons of relative healing at 14 days. MAIN RESULTS: One hundred thirty-seven studies involving 8333 eyes met the inclusion criteria. Placebo-controlled studies were heterogeneous in comparison with idoxuridine (RR 1.74; 95% CI 1.03 to 2.91) and few in number for vidarabine (RR 1.81; 95% CI 1.09 to 3.01), interferon (RR 1.32; 95% CI 1.06 to 1.64), and debridement. Vidarabine (RR 1.13; 95% CI 1.02 to 1.25), trifluridine (RR 1.30; 95% CI 1.18 to 1.43), acyclovir (RR 1.23; 95% CI 1.14 to 1.34), and brivudine (RR 1.34; 95% CI 1.18 to 1.51) were more effective than idoxuridine. Trifluridine (RR 1.17; 95% CI 1.03 to 1.32) and acyclovir (RR 1.11; 95% CI 1.03 to 1.19) were more effective than vidarabine. No significant differences in healing emerged among trifluridine, acyclovir, brivudine, and foscarnet although few studies compared brivudine or foscarnet with other antivirals. Any potential advantage of ganciclovir compared to acyclovir was mitigated by study heterogeneity and possible publication bias. Only one study evaluated the joint use of two topical antivirals. In a limited number of studies, oral acyclovir (RR 0.92; 95% CI 0.79 to 1.07) or the combination of oral acyclovir with a topical antiviral (RR 1.36; 95% CI 0.68 to 2.74) appeared as effective as a single topical antiviral agent. Compared to topical antiviral monotherapy, the combination of an antiviral with either interferon or debridement had inconsistent effects on expediting healing and improving outcome. AUTHORS' CONCLUSIONS: Placebo-controlled studies of HSV epithelial keratitis are limited to superseded interventions. Trifluridine and acyclovir are more effective than idoxuridine or vidarabine and similar in therapeutic effectiveness. Brivudine and foscarnet do not substantially differ in effectiveness from trifluridine or acyclovir. Ganciclovir is at least as effective as acyclovir. The addition of interferon to a nucleoside antiviral agent and the combination of debridement with antiviral treatment need to be further assessed to substantiate any possible advantage in healing.

Late reactivation of herpes zoster keratitis results in band keratopathy.

PURPOSE: To report an unusual case of a late-stage reactivation of immune stromal keratitis associated with herpes zoster ophthalmicus (HZO), occurring without any apparent predisposing factors, more than 4 years after an acute zoster dermatomal rash. Significant corneal hypoesthesia and a central band keratopathy developed within 6 months of the late-stage reactivation. The clinical case management, issues associated with management, and management options are discussed, including the use of standardized, regulatory approved, antibacterial medical honey. CASE REPORT: An 83-year-old woman presented for routine review with a reactivation of right anterior stromal keratitis and mild anterior uveitis, occurring more than 4 years after an acute HZO dermatomal rash and an associated initial episode of anterior stromal keratitis. Corneal sensation became markedly impaired, and over the subsequent 6 months, a right central band keratopathy developed despite oral antiviral and topical steroid therapy. Visual acuity with pinhole was reduced to 20/100 in the affected eye and moderate irritation and epiphora were experienced. The patient declined the surgical intervention options of chelation, lamellar keratectomy, and phototherapeutic keratectomy to treat the band keratopathy. Longer-term management has involved preservative-free artificial tears, eyelid hygiene, standardized antibacterial medical honey, topical nonpreserved steroid, and UV-protective wraparound sunglasses. The clinical condition has improved over 14 months with this ocular surface management regimen, and visual acuity of 20/30 is currently achieved in a comfortable eye. CONCLUSIONS: The chronic and recurrent nature of HZO can be associated with significant corneal morbidity, even many years after the initial zoster episode. Long-term review and management of patients with a history of herpes zoster stromal keratitis are indicated following the initial corneal involvement. Standardized antibacterial medical honey can be considered in the management of the chronic ocular surface disease associated with HZO and warrants further evaluation in clinical trials.

Overexpression of NLRP12 enhances macrophage immune response and alleviates herpes simplex keratitis.

Introduction: Herpes simplex keratitis (HSK) is a blinding disease caused by corneal infection of Herpes simplex virus type 1 (HSV-1). Effective clearance of HSV-1 from the infected cornea is crucial for HSK management. Macrophages play an important part in the innate immune defense against viral infections. This study investigates the immunomodulatory role of NLRP12 in macrophage immune response during HSV-1 infection. Methods: NLRP12 expression post-infection was assessed in various macrophage cell lines. Overexpression of NLRP12 was achieved by lentiviral transfection, and its effect on HSV-1 replication and immune responses were examined. Mechanistic insights into the role of NLRP12 were explored using immunofluorescence and Western Blot. For in vivo studies, ocular adoptive transfer of NLRP12-overexpressing bone marrow derived macrophages (BMDMs) was performed. HSV-1 viral loads, HSK symptoms, and macrophage-mediated immune responses were investigated. Results: A significant decrease in NLRP12 expression post-infection was observed in various macrophage cell lines. Overexpression of NLRP12 in macrophages reduced HSV-1 replication. Mechanistically, overexpression of NLRP12 triggered early and robust pyroptosis in response to HSV-1 infection, inducing interleukin (IL)-18 production and activating downstream antiviral responses through the JAK-STAT signaling pathway. In vivo, ocular adoptive transfer of NLRP12-overexpressing BMDMs to mouse corneas alleviated HSK damage and reduced HSV-1 viral loads. NLRP12-overexpressing BMDMs improved antiviral responses in the cornea and promoted the maturation of corneal-infiltrating macrophages and dendritic cells. Additionally, NLRP12-overexpressing BMDMs amplified the adaptive immune response in the submandibular draining lymph nodes. Discussion: These findings highlight the role of NLRP12 in macrophage-mediated immune response against HSV-1 infection and suggest its potential for possible immunotherapy for HSK.

Herpes simplex and herpes zoster eye disease: presentation and management at a city hospital for the underserved in the United States.

OBJECTIVE: To further define the spectrum of clinical disease and treatment among patients with herpes zoster ophthalmicus (HZO) and ocular herpes simplex viral (HSV) infection presenting at a large city hospital for the underserved in the United States. METHODS: Retrospective review of medical records of 64 patients (40 HZO and 24 ocular HSV infection) presenting to the Bellevue Hospital Emergency Department for the management of herpetic eye disease for which an ophthalmologic consultation was obtained from January 1, 2006, to December 31, 2011. RESULTS: The mean age of patients with HZO was 51 ± 15 years (n=40) versus 33 ± 16 years for patients with ocular HSV infection (n=24; P<0.0001). Overall, 73% of patients with HZO were aged <60 years (n=29 of 40), of whom, 90% (26 of 29) were immunocompetent. The most common decade of onset of HZO was 50 to 59 years (11 of 40, 28%). Four patients with HZO were immunocompromised (n=4 of 40; 10%), with 3 aged <60 years attributable to human immunodeficiency virus (n=3 of 29, 10%). The study included 12 patients eligible to receive the herpes zoster vaccine. None of these patients had a history of vaccination. Of the 24 patients with ocular HSV infection, corneal stromal disease was present in 7 patients and infectious epithelial keratitis in 10 patients. No patients were treated with long-term oral antiviral prophylaxis. CONCLUSIONS: Acute HZO was seen more commonly than ocular HSV infection. Patients with HZO were significantly older than those with ocular HSV infection. Available prevention modalities, such as the vaccine against herpes zoster and long-term oral antiviral therapy to reduce ocular HSV infection recurrence, were underused.

[Contact lens-related keratitis]. / A kontaktlencse-viselés következtében kialakuló keratitisekrol.

Nowadays, keratitis, corneal infection due to wearing contact lens means an increasingly serious problem. Neglected cases may lead to corneal damage that can cause blindness in cases of otherwise healthy eyes. Early diagnosis based on the clinical picture and the typical patient history is an important way of prevention. Prophylaxis is substantial to avoid bacterial and viral infection that is highly essential in this group of diseases. Teaching contact lens wearers the proper contact lens care, storage, sterility, and hygiene regulations is of great importance. In case of corneal inflammation early accurate diagnosis supported by microbiological culture from contact lenses, storage boxes or cornea is very useful. Thereafter, targeted drug therapy or in therapy-resistant cases surgical treatment may even be necessary in order to sustain suitable visual acuity.

Amniotic membrane traps and induces apoptosis of inflammatory cells in ocular surface chemical burn.

PURPOSE: Severe chemical burns can cause necrosis of ocular surface tissues following the infiltration of inflammatory cells. It has been shown that amniotic membrane transplantation (AMT) is an effective treatment for severe chemical burns, but the phenotypes of cells that infiltrate the amniotic membrane and the clinical significance of these cellular infiltrations have not previously been reported. The present work studies the inflammation cell traps and apoptosis inducing roles of the amniotic membrane after AMT in patients with acute chemical burns. METHODS: A total of 30 patients with acute alkaline burns were classified as having either moderate or severe burns. In all participants, AMT was performed within one week of his/her injury. After 7-9 days, the transplanted amniotic membranes were removed. Histopathological and immunohistochemical techniques were used for the examination and detection of infiltrating cells, and tests for the expression of CD (cluster of differentiation)15, CD68, CD3, CD20, CD57, CD31, CD147, and CD95 (Fas) were performed. A TUNEL (TdT-mediated dUTP nick end labeling) assay was used to confirm apoptosis of the infiltrating cells. Three patients with herpes simplex-induced keratitis who had undergone AMT to treat persistent epithelium defects were used as a control group. Amniotic membrane before transplantation was used as another control. RESULTS: After amniotic membrane transplantation, the number of infiltrating cells in patients with severe burns was significantly higher than in patients with moderate burns or in control patients (p<0.05). Among the severe burns patients, CD15 and CD68 were widely expressed in the infiltrating cells, and CD3, CD20, and CD57 were only found in a small number of cells. Occasionally, CD31-positive cells were found in the amniotic membranes. More cells that were CD147, Fas, and TUNEL positive were found in patients with severe burns than in patients with moderate burns or in control patients. CONCLUSIONS: Neutrophils and macrophages were the main cells that had infiltrated into the amniotic membrane during the acute phase of healing from a chemical burns. AMT can trap different inflammatory cells and induce apoptosis of inflammatory cells in acute ocular chemical burns.

Targeting herpes simplex virus with CRISPR-Cas9 cures herpetic stromal keratitis in mice.

Herpes simplex virus type 1 (HSV-1) is a leading cause of infectious blindness. Current treatments for HSV-1 do not eliminate the virus from the site of infection or latent reservoirs in the trigeminal ganglia. Here, we target HSV-1 genomes directly using mRNA-carrying lentiviral particles that simultaneously deliver SpCas9 mRNA and viral-gene-targeting guide RNAs (designated HSV-1-erasing lentiviral particles, termed HELP). We show that HELP efficiently blocks HSV-1 replication and the occurrence of herpetic stromal keratitis (HSK) in three different infection models. HELP was capable of eliminating the viral reservoir via retrograde transport from corneas to trigeminal ganglia. Additionally, HELP inhibited viral replication in human-derived corneas without causing off-target effects, as determined by whole-genome sequencing. These results support the potential clinical utility of HELP for treating refractory HSK.

Antiviral treatment and other therapeutic interventions for herpes simplex virus epithelial keratitis.

BACKGROUND: Eye disease due to herpes simplex virus (HSV) commonly presents as epithelial keratitis. OBJECTIVES: To compare the relative effectiveness of antiviral agents, interferon, and corneal débridement in the treatment of acute HSV epithelial keratitis. SEARCH STRATEGY: We searched CENTRAL (The Cochrane Library 2010, Issue 4), MEDLINE (January 1950 to October 2010), EMBASE (January 1980 to October 2010), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to October 2010), Zetoc (British Library's Electronic Table of Contents), System for Information on Grey Literature in Europe (openSIGLE), Biosciences Information Service (BIOSIS), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov), Japan Information Center of Science and Technology (JICST-EPlus), and China Academic Journals database (CAJ) via China National Knowledge Infrastructure (CNKI) with citations confirmed using China/Asia On Demand (COAD). There were no language or date restrictions in the search for trials. All databases except CNKI and COAD were last searched on 27 October 2010, CNKI and COAD were searched on 1 April 2010. We also searched literature digests, conference proceedings and reference lists. SELECTION CRITERIA: Of 152 eligible studies,106 comparative treatment trials involving 5872 eyes with dendritic or geographic epithelial keratitis were analysed for corneal healing over two weeks. DATA COLLECTION AND ANALYSIS: Interventions were compared at 14 days after trial enrolment by calculating a risk ratio (RR) that was adjusted with indirect RR, assessed by an inconsistency index (I(2) ) and supplemented by a seven-day RR and a hazard ratio (HR). MAIN RESULTS: Idoxuridine, though uncertainly better in healing outcome than control because of few trials with 14-day follow up, allowed earlier corneal re-epithelialisation. Vidarabine resulted in a significantly better outcome than placebo in one trial (RR 1.96; 95% CI 1.10 to 3.49). Compared to idoxuridine, in combined direct and indirect analyses, vidarabine (RR 1.11; 95% CI 1.03 to 1.19), trifluridine (RR 1.31; 95% CI 1.20 to 1.42), acyclovir (RR 1.23; 95% CI 1.16 to 1.31), brivudine (RR 1.38; 95% CI 1.18 to 1.61), and ganciclovir (RR 1.40; 95% CI 1.25 to 1.57) were significantly more effective. Trifluridine (RR 1.12; 95% CI 1.04 to 1.21) and acyclovir (RR 1.11; 95% CI 1.05 to 1.19) appeared more effective than vidarabine. No significant differences were found in comparisons between acyclovir, trifluridine and brivudine. The comparison of ganciclovir to acyclovir was limited by heterogeneity and possible publication bias. The joint use of two topical antivirals (RR 1.00; 95% CI 0.89 to 1.12) and the use of oral acyclovir alone (RR 0.92; 95% CI 0.79 to 1.07) or combined with a topical antiviral (RR 1.08; 95% CI 0.99 to 1.17) appeared as effective as topical antiviral therapy. Compared to antiviral monotherapy, the combination of an antiviral with interferon (RR 1.03; 95% CI 0.99 to 1.07) or with débridement (RR 1.04; 95% CI 0.95 to 1.14) did not yield significantly better outcomes but may have accelerated healing. The corneal epithelial healing outcome was improved when antiviral therapy was added to débridement (RR 1.21; 95% CI 1.04 to 1.42). AUTHORS' CONCLUSIONS: Trifluridine and acyclovir are more effective than idoxuridine or vidarabine, and similar in therapeutic effectiveness. Brivudine and ganciclovir are at least as effective as acyclovir. While not improving outcome, the combination of interferon and an antiviral agent may speed healing. The effectiveness of corneal epithelial débridement is improved by an antiviral agent.

[Diagnostic and therapeutic aspects of herpes virus associated uveitis]. / Diagnostik und Therapie der Herpesvirus-assoziierten Uveitis.

According to the World Health Organization, 60- 95 % of the population worldwide is infected by viruses of the herpes viridae family. Excellent adaptation of the organisms and host-related factors are probably predisposing for this global distribution. Herpes virus infections are probably the most common infectious cause of blindness in the Western world. Besides the well known manifestations of keratitis and anterior uveitis caused by HSV and VZV, new aspects have been discovered, in particular, in CMV-related disorders. Molecular biological methods have been instrumental to explore and discover herpes virus associated disorders and have provided new insights. Whereas keratitis and anterior uveitis are the most common clinical manifestations, more severe disorders such as posterior uveitis, panuveitis and acute retina necrosis syndrome have all been attributed to herpes virus infections. Since the therapeutic intervention greatly varies in these acute situations, identification of the causative agent is essential. Serology is rarely helpful, whereas analyses of aqueous humor or vitreous samples provide clues for the etiology. Aqueous humor antibody testing and PCR have demonstrated excellent diagnostic power with high sensitivity and high specificity. This review is intended to provide an overview on the diagnosis and differential diagnosis of this important disorder.

[Recurrent herpetic corneal erosion: diagnosis and treatment].

Recurrent corneal erosion (CE) is a common anterior eye disease, which usually occurs after injury, substantially limits a patient's ability to work, and is intractable. The authors single out an individual form of CE herpetic CE (HCE) on the basis of immunofluorescence assay of a conjunctival scrape, which shows the high concentration of herpes simplex virus antigen in 53% of CE cases. Confocal microscopy revealed epithelocyte polymorphism and basement membrane defects. The treatment of patients with HCE involved 2 steps: 1) relief of acute signs of the disease via drug therapy, rapid local autocyte cinotherapy (RLACCT), or phototherapeutic keratectomy (PTK) and 2) prevention of recurrences. For this the authors developed a method based on the systemic use of a new composition of the intradermal herpes vaccine Vitaherpavac in combination with the subcutaneous interferon inducer Poludan. RLACCT was found to be the most effective medical treatment for CE and PTK was the most effective surgical one. Vaccination with the concurrent subcutaneous injection of Poludan is an effective method in preventing recurrent HCE. During a follow-up of 2 years or more, 81% of the patients achieved clinical resolution; there was a decrease in recurrence rates and severity in 15.1% and no effect in 3.8%.

Development, Implementation, and Evaluation of Treatment Guidelines for Herpes Simplex Keratitis in Sydney, Australia.

PURPOSE: To develop and measure the uptake of a local guideline for herpes simplex keratitis (HSK) and to standardize initial antiviral therapy in Australia. METHODS: The Registered Nurses' Association of Ontario Toolkit: "Implementation of Best Practice Guidelines" was used to develop, implement, and evaluate the guideline at Sydney Eye Hospital. An implementation team was established to reach consensus on antiviral therapy guidelines through review of available evidence, identifying stakeholders, facilitators and barriers, creating strategies for implementation, and developing a sustainability plan. An audit of all adult HSK cases during a 6-month postguideline implementation period was conducted, and the results were compared with a preimplementation audit. A web-based survey was created to assess clinician awareness, usage, and level of knowledge of the guideline. RESULTS: Clinicians, pharmacists, and administrative staff were identified as stakeholders. Changing clinician's behavior was the major barrier to implementation. Implementation strategies included printed and online materials and lectures to clinicians. A postimplementation audit included 85 patients, and 95 clinicians received a web-based survey. The dose of the prescribed antiviral medication was in alignment with the local guideline in 80% (51/64) of the patients compared with 73% (163/223) before implementation (P = 0.331). Stromal HSK with ulceration and keratouveitis were excluded because there were no recommendations before implementation. Over 70% of clinicians (30/41) were aware of the guideline and accessed them through educational resources. CONCLUSIONS: Guidelines for the management of HSK may improve standardization of initial antiviral therapy in HSK. In practice, most clinicians were aware of and adhered to the local guideline.

[Therapeutic effect of acupoint injection as adjuvant treatment on dry eyes of convalescent herpes simplex keratitis].

OBJECTIVE: To evaluate the clinical effect of acupoint injection of houttuynia cordata as the accessory treatment on dry eyes of convalescent herpes simplex keratitis (HSK). METHODS: A total of 60 patients with dry eyes of convalescent HSK were randomized into an observation group and a control group, 30 cases in each one. In the control group, the artificial tears and anti-inflammatory drugs were combined in treatment. In the observation group, on the base of the treatment as the control group, the acupoint injection of houttuynia cordata at Neiqiuhou (Extra) was combined, 3 mL each time, once a day. After consecutive 3 injections, the injection was adjusted to be once every two days, consecutively for 3 times. The treatment for 6 times was as one course and one course of treatment was required. Separately, before treatment and in 7, 15 and 30 days after treatment, the changes of the scores of visual analogue scale (VAS), theresults of SchirmerⅠtest (SⅠT), the tear break-up time (BUT) and the score of corneal fluorescein staining (CFS) were observed and analyzed in the patients of the two groups. RESULTS: In 7, 15 and 30 days after treatment, VAS scores and CFS scores were all reduced as compared with those before treatment in the patients of the two groups (P<0.05), and the scores of VAS and CFS in the observation group were lower than those in the control group (P<0.05). In 7, 15 and 30 days after treatment, the values of SⅠT and BUT were all increased as compared with those before treatment in the patients of the two groups (P<0.05), and the values in the observation group were higher than the control group in 15 and 30 days after treatment (P<0.05). CONCLUSION: Acupoint injection of houttuynia cordata promotes corneal epithelial recovery, reduces the discomfort symptoms as well as increases tear secretion and the stability of tear film in dry eyes of convalescent herpes simplex keratitis.