Herpetic Keratitis Research Articles

The Role of T Cells in Herpes Stromal Keratitis.

The blinding inflammatory lesion stromal keratitis (SK), which occurs in some patients in response to ocular herpes simplex virus (HSV) infection, represents mainly an immune cell mediated inflammatory response to the virus infection. The principal orchestrators of the immunopathological lesions are T cells although additional events participate that include the extent of recruitment of non-lymphoid cells, the extent of neoangiogenesis, and the extent of damage to nerve function. This review focuses on evidence that the balance of the functional subsets of T cells has a major impact on lesion severity and duration. Accordingly, if proinflammatory Th1 and Th17 CD4 T cells, and perhaps in some cases CD8 T cells, predominate lesions occur earlier and are more severe. Lesions are diminished when cells with regulatory function predominate. Moreover, when regulatory cells acquire the property to produce Amphiregulin this may facilitate lesion resolution. An objective to controlling lesions is to learn how to manipulate the balance of T cells to favor the representation and function of regulatory T cells and their products over proinflammatory cells. In this review we emphasize how exploiting the differential metabolic requirements of immune cells could be a valuable approach to control SK.

Effectiveness of Seydana oil in combination treatment of herpetic endothelial keratitis

Purpose: to study the effectiveness of seydana (black cumin) oil in combined treatment of herpetic endothelial keratitis. Material and methods. The study included 68 patients (68 eyes) with herpetic endothelial keratitis, developed after cataract surgery. 35 men and 33 women aged 39 to 73 (58.3 ± 8.9) years were divided into two equal groups. The main group (34 patients, 34 eyes) received conventional treatment supplemented with black cumin oil, while the comparison group of 34 patients (34 eyes) received conventional treatment alone.Results. Cornea infiltration in the main group resorbed sooner than in the comparison group (18.43 ± 0.3 days and 23.2 ± 0.5 days respectively; p < 0.05). The treatment lasted shorter in the main group compared with the comparison group (22.1 ± 0.1 days vs. 25.2 ± 0.3 days; p < 0.05). Complete epithelialization was averagely noted on the 19th to the 21st day of treatment (respectively, 19.6 ± 0.9 and of 21.12 ± 0.6; p > 0.05). Visual acuity improved to achieve, respectively, 0.51 ± 0.24 and 0.44 ± 0.17 (p > 0.05).Conclusion. The patients who received seydana oil in addition to conventional treatment showed a significantly higher therapeutic effect in some parameters (resorption time of corneal infiltration and duration of treatment) than the comparison group.

Case Series: Pediatric Herpes Simplex Keratitis

Although the clinical appearance of pediatric ocular herpes simplex virus (HSV) is similar in children and adults, there is evidence that stromal disease and recurrences are more common in pediatric patients. Misdiagnosis of these patients is common, and patients can develop corneal scarring and amblyopia. This case series will review important clinical concepts on pediatric ocular HSV including differences in presentation and current treatment recommendations. Three pediatric patients with HSV keratitis are presented: a 6-year-old girl who was treated for unilateral disease over the course of 3 years, a 7-year-old boy who presented with bilateral disease, and a 3-year-old girl in whom the diagnosis was not apparent initially. All patients were successfully treated with oral acyclovir and topical steroids. One patient was also treated with topical antivirals. Pediatric HSV keratitis should be considered as a differential diagnosis in pediatric patients who present with keratitis. Accurate diagnosis of these patients is important so that amblyopia does not develop. Pediatric ocular HSV patients can be successfully treated with topical and/or oral medications, although their treatment duration may be 12 months or longer.

Unique Type I Interferon, Expansion/Survival Cytokines, and JAK/STAT Gene Signatures of Multifunctional Herpes Simplex Virus-Specific Effector Memory CD8+ TEM Cells Are Associated with Asymptomatic Herpes in Humans.

A large proportion of the world population harbors herpes simplex virus 1 (HSV-1), a major cause of infectious corneal blindness. HSV-specific CD8+ T cells protect from herpesvirus infection and disease. However, the genomic, phenotypic, and functional characteristics of CD8+ T cells associated with the protection seen in asymptomatic (ASYMP) individuals, who, despite being infected, never experienced any recurrent herpetic disease, remains to be fully elucidated. In this investigation, we compared the phenotype, function, and level of expression of a comprehensive panel of 579 immune genes of memory CD8+ T cells, sharing the same HSV-1 epitope specificities, and freshly isolated peripheral blood from well-characterized cohorts of protected ASYMP and nonprotected symptomatic (SYMP) individuals, with a history of numerous episodes of recurrent herpetic disease, using the high-throughput digital NanoString nCounter system and flow cytometry. Interestingly, our results demonstrated that memory CD8+ T cells from ASYMP individuals expressed a unique set of genes involved in expansion and survival, type I interferon (IFN-I), and JAK/STAT pathways. Frequent multifunctional HSV-specific effector memory CD62Llow CD44high CD8+ TEM cells were detected in ASYMP individuals compared to more of monofunctional central memory CD62Lhigh CD44high CD8+ TCM cells in SYMP individuals. Shedding light on the genotype, phenotype, and function of antiviral CD8+ T cells from "naturally protected" ASYMP individuals will help design future T-cell-based ocular herpes immunotherapeutic vaccines.IMPORTANCE A staggering number of the world population harbors herpes simplex virus 1 (HSV-1) potentially leading to blinding recurrent herpetic disease. While the majority are asymptomatic (ASYMP) individuals who never experienced any recurrent herpetic disease, symptomatic (SYMP) individuals have a history of numerous episodes of recurrent ocular herpetic disease. This study elucidates the phenotype, the effector function, and the gene signatures of memory CD8+ T-cell populations associated with protection seen in ASYMP individuals. Frequent multifunctional HSV-specific effector memory CD8+ TEM cells were detected in ASYMP individuals. In contrast, nonprotected SYMP individuals had more central memory CD8+ TCM cells. The memory CD8+ TEM cells from ASYMP individuals expressed unique gene signatures characterized by higher levels of type I interferon (IFN), expansion and expansion/survival cytokines, and JAK/STAT pathways. Future studies on the genotype, phenotype, and function of antiviral CD8+ T cells from "naturally protected" ASYMP individuals will help in the potential design of T-cell-based ocular herpes vaccines.

Presumed Herpes simplex virus reactivation following LASIK mimicking diffuse lamellar keratitis

We report a rare presentation of herpetic stromal keratitis reactivation in a 43-yearold patient who underwent LASIK previously and presented with complaints of photophobia, pain, and redness. On examination, mild congestion was noted with deep-seated, ring-like infiltrate under the LASIK flap with some amount of scarring that was initially confused with diffuse lamellar keratitis. A detailed repeated history led to diagnosing herpetic keratitis reactivation that with timely treatment of antivirals and steroids helped us to achieve a good anatomic and visual outcome for the patient.

The efficacy of 0.1% tacrolimus ophthalmic suspension in the treatment of severe atopic keratoconjunctivitis

BackgroundSevere atopic keratoconjunctivitis (AKC) is a relatively rare disease, and some cases are refractory to conventional steroid treatment. ObjectiveTo examine the efficacy of 0.1% tacrolimus ophthalmic suspension in treating severe AKC during a 1-year follow-up. MethodsThis was a single-center, retrospective clinical study. Sixty eyes from 30 patients with severe AKC who were treated with 0.1% tacrolimus ophthalmic suspension 4 times per day, were included. The mean age of the patients was 21.5 ± 13.7 years. The severity of objective signs was observed at baseline (before treatment), at 2 weeks, and at 1, 2, 3, 6, and 12 months after treatment initiation. Ten objective signs of palpebral conjunctiva, bulbar conjunctiva, limbus, and cornea were assessed using 4 grades (0 = normal; 1+ = mild; 2+ = moderate; 3+ = severe). Safety was assessed based on the incidence and the severity of adverse events. ResultsThe total score of the 10 clinical signs significantly decreased from baseline 2 weeks after initiating tacrolimus eye drop treatment, except at 2 months. The mean total score of clinical signs was 13.6 ± 6.6 at the beginning of treatment, and decreased to 5.4 ± 4.8 12 months after initiation. Treatment was gradually tapered, with increasing intervals between applications. Additional medications were required to provide relief in 18 patients during follow-up. No patient discontinued treatment due to adverse drug effects. Herpes keratitis was observed in 3 cases during follow-up. However, these cases were completely controlled. ConclusionThe 0.1% tacrolimus ophthalmic suspension is effective for the treatment of severe AKC refractory to standard conventional treatments throughout a full year.

Prospective study of the sensitivity of the Wood’s lamp for common eye abnormalities

ObjectiveThe Wood’s lamp, a handheld instrument that uses long-wave ultraviolet (UV) light with magnification of 2–3 times, is commonly used by non-ophthalmologists for examining patients with eye complaints. The goal...

Evaluation of the antiviral potential of the soluble forms of glycoprotein D receptors on ocular herpes caused by HSV-1 and HSV-2 infections in a transgenic mouse model.

Ocular herpes, caused by herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) infections, remains an important corneal disease, which may result in loss of vision. Because the frequency of acyclovir resistance in HSV has increased, novel antiviral agents are needed for therapeutic approaches to ocular herpes. Several studies have demonstrated that fusion proteins containing entire ectodomain of HSV glycoprotein D receptors, including herpesvirus entry mediator A (HVEM), nectin-1 and nectin-2, and the Fc portion of human IgG (HVEMIg, nectin-1Ig, and nectin-2Ig, respectively), can exert antiviral effects in vitro and in vivo. Here, to evaluate the antiviral potential of HVEMIg, nectin-1Ig, and nectin-2Ig against ocular infections with HSV, transgenic mice expressing these fusion proteins were ocularly inoculated with HSV-1 and HSV-2. Transgenic mouse lines expressing HVEMIg and nectin-1Ig showed marked resistance to ocular herpes; on the other hand, mouse lines expressing nectin-2Ig did not. Furthermore, to investigate the therapeutic effects of nectin-1Ig, which can neutralize HSVs in vitro against ocular disease, transgenic mouse serum containing nectin-1Ig was dropped into the eyes of wild-type mice after HSV infection. Reduction of severe symptoms could be observed in mice treated with nectin-1Ig serum. These results warrant further study of soluble HVEM and nectin-1 products as preventive and therapeutic agents against ocular herpes caused by HSV-1 and HSV-2 infections, especially nectin-1Ig as a new eye drop.

The Effectiveness of Ganciclovir Comparing with Combination Therapy of Oxytetracycline HCI and Polymyxin B Sulfate in Herpetic Epithelial Keratitis

Introduction: Herpes simplex virus is a common keratitis agent. There are two different types of virus, type 1 and 2. Type 1 shows three main clinical pictures in cornea: epithelial herpetic keratitis, stromal keratitis, disciform keratitis. The aim of this study is to reduce the duration of herpetic keratitis treatment and eliminate the risk of complications. Material and Methods: Between January 2017 and January 2018, 29 patients with herpetic keratitis were included in the study. In the first group, the herpetic membrane was removed by a single shot on the herpetic lesion with the yag laser. Then, topically oxytetracycline hydrochloride+polymyxin B sulfate was applied. The second group was treated with topical antiviral therapy (Ganciclovir). After treatment, daily follow-up of patients, vision, tonus, fundus diameters and recovery times were noted and the data were compared statistically. Results: In group I and group II, the age of the patients did not differ significantly (p> 0.05). In group I and group II, the gender distribution of the patients did not differ significantly (p>0.05). In Group I and Group II, the degree of vision did not differ significantly (p>0.05). In group I and group II, the examination findings were not significant (p>0.05). In group I and group II, recovery time was significantly different (p

Evaluation of multiplex real-time polymerase chain reaction for the detection of herpes simplex virus-1 and 2 and varicella-zoster virus in corneal cells from normal subjects and patients with keratitis in India

Purpose:To determine the presence of herpes simplex virus and varicella zoster virus (HSV 1 and 2, VZV) in the cornea of normal subjects by multiplex real time quantitative (qPCR) assay and evaluate its utility in the diagnosis of viral keratitis.Methods:Corneal epithelial cells from 33 eyes of 22 patients undergoing photorefractive keratectomy surgery (controls) and 50 corneal scrapings from 50 patients with suspected HSV keratitis were analyzed for the presence of HSV1 by conventional PCR and for presence of HSV1 and 2 and/or VZV by multiplex real-time PCR. Corneal scrapings of patients were also tested for HSV1 antigen by immunofluorescence assay (IFA). The results were compared and clinical records reviewed.Results:HSV1 and VZV DNA were detected in 8/33 controls (mean-14.3 ± 7.96, range: 3-29.1 copies/mL) and 2/33 controls (mean-10.7 ± 10.9, range 3-18.5 copies/ml) respectively. HSV2 was not detected in any of the controls. Copy numbers above the mean + 1SD of controls were considered significant for viral load in patient samples. Significantly higher number of corneal scrapings (39/50, 78%) from patients were positive for HSV1 (1.2 × 106 copies/mL ± 3.7 × 106 copies/mL) by real time qPCR compared to IFA (11/48, 23%, P value 0.0001) and conventional PCR (20/50, 40%, P value 0.0002). Double infection with HSV-1 (1.5 × 107 copies/ml) and HSV-2 (3.57 × 104 copies/ml) in one case and VZV infection (1.03 × 102 copies/ml) in another was also detected by the multiplex real-time PCR.Conclusion:Multiplex real-time PCR reliably detects HSV1 and 2 and VZV DNA and is ideal for the diagnosis of HSV and VZV keratitis in an ocular microbiology laboratory.

Blockade of IL-27 signaling ameliorates herpes stromal keratitis with upregulated CD4+ Foxp3+ regulatory T cells influx in mice.

Purpose:The purpose of this study was to investigate the production of IL-27 p28 and EBI3 in the ocular inflammatory sites, and the role of IL-27 signaling in a model of HSV-1 induced herpetic stromal keratitis (HSK).Methods:The BALB/c mice were injected intraperitoneally (24 h before infection) with anti-IL-27 antibody or IgG antibody as control, infected with HSV-1 via corneal scarification, and then injected intraperitoneally with anti-IL-27 antibody or IgG antibody at 1, 3, and 5 days postinfection. Slit lamp and histopathology were used to assess disease outcome. The levels of IL-27 p28 and EBI3 in corneas were determined by western blotting and immunofluorescence. Furthermore, viral titers were determined, and immune cell infiltrates were collected and analyzed by flow cytometry.Results:We found that the levels of IL-27 p28 and EBI3 in corneas were elevated significantly at the peak of HSK, and both of them were expressed simultaneously in the epithelium, stroma, and endothelium of corneas. In the group of anti-IL-27 treatment, the severity of the corneal lesion and CD4+ T cells infiltration were significantly decreased, and the percentage of CD4+ Foxp3+ Tregs was upregulated markedly in the spleen, DLNs and cornea of HSK mice compared to IgG treatment.Conclusion:These results provided evidence that IL-27 as a pathogenic pro-inflammatory cytokine controlled CD4+ Foxp3+ Tregs production in HSK, which ultimately resulted in promoting the progression of HSK and poor prognosis.

Abordagem desafiante de uma úlcera de córnea neurotrófica e por exposição

ABSTRACT This study aims to describe a challenging clinical case of a patient with a neurotrophic and exposure corneal ulcer. A 75-year-old male patient, with history of right eye (RE) limbic stem-cell insuficiency due to complications of recurrent herpetic keratitis, underwent successful limbic stem-cell transplantation in 2008. In 2010, an uneventful penetrating keratoplasty was performed. After a cataract phacoemulsification surgery with intraocular lens implantation done in 2011, best corrected visual acuity was 20/20, and remained stable until 2015. In July 2015, the patient developed right facial nerve palsy and two months later, presented with an extensive central corneal ulcer, with a significant thinning of central stroma, without infection signs, but with an imminent risk of perforation. Treatment with topical ofloxacin and intensive ocular lubrification was started in association with permanent ocular oclusion. Due to lack of any clinical improvement, treatment with RGTA [Poli (carboximetilglucose) sulfate, dextrano T40] (Cacicol®, Thea) was started. After two weeks of treatment, a complete reepithelization and partial stromal filling was observed. Continued monitoring and treatment with artificial tears was maintained, with no recurrence observed. There is an unmet need for a medical therapy that could help corneal neurotrophic ulcers to heal. The presented clinical case shows that the approach of targeting extracellular matrix can be effective in the reepithelialization of neurotrophic and exposure corneal ulcer that do not respond to conventional treatments.

Commentary: Targeting herpetic keratitis by immunomodulation of IL-27 signaling.

Commentary: Targeting herpetic keratitis by immunomodulation of IL-27 signaling.

Healing of resistant corneal neurotrophic ulcers using a matrix regenerating agent

To assess the success rate of a matrix regenerating agent (RGTA) in the treatment of chronic corneal ulcers resistant to conventional treatments. Uncontrolled prospective observational study in patients with corneal neurotrophic ulcer (Stage 2 or 3 of the Mackie classification), unresponsive to standard medical or surgical treatments and managed with RGTA as an adjunctive treatment. Corneal ulcers were evaluated using slit-lamp examination and optical coherence tomography after 2 weeks, 1 month, 2 months and 3 months. Success was defined as complete corneal healing. RGTA was administered to 20 patients (20 eyes) with chronic corneal ulcers of various causes, including keratoplasty (7 eyes, 35.0%), herpetic keratitis (5 eyes, 25.0%) and intracorneal ring (3 eyes, 15.0%). Total corneal healing was observed in 13/20 patients (65.0%) within 1 to 3 months. RGTA was discontinued due to partial healing/ulcer stagnation in 6 patients (30.0%), and aggravation of the ulcer in 1 patient (5.0%). Relapses were reported in 4 patients (20.0%) several months after cessation of RGTA treatment. No adverse reactions were noted. In the event of failure of conventional treatments, RGTA may be an alternative medical treatment for patients with chronic corneal ulcers, avoiding the need to resort to surgical treatment.

Blockade of LAG-3 Immune Checkpoint Combined With Therapeutic Vaccination Restore the Function of Tissue-Resident Anti-viral CD8+ T Cells and Protect Against Recurrent Ocular Herpes Simplex Infection and Disease.

Recurrent viral diseases often occur after the viruses evade the hosts' immune system, by inducing exhaustion of antiviral T cells. In the present study, we found that functionally exhausted herpes simplex virus type 1 (HSV-1) -specific CD8+ T cells, with elevated expression of lymphocyte activation gene-3 (LAG-3), an immune checkpoint receptor that promotes T cell exhaustion, were frequent in symptomatic (SYMP) patients with a history of numerous episodes of recurrent corneal herpetic disease. Similarly, following UV-B induced virus reactivation from latency the symptomatic wild-type (WT) B6 mice that developed increase virus shedding and severe recurrent corneal herpetic disease had more exhausted HSV-specific LAG-3+CD8+ T cells in both trigeminal ganglia (TG) and cornea. Moreover, a therapeutic blockade of LAG-3 immune checkpoint with antagonist antibodies combined with a therapeutic immunization with gB498−505 peptide immunodominant epitope of latently infected B6 mice significantly restored the quality and quantity of functional HSV-1 gB498−505 specific CD8+ T cells in both TG and cornea and protected against UV-B induced recurrent corneal herpes infection and disease. In contrast to dysfunctional HSV-specific CD8+ T cells from WT B6 mice, more functional HSV-specific CD8+ T cells were detected in LAG-3−/− deficient mice and were associated with less UV-B induced recurrent corneal herpetic disease. Thus, the LAG-3 pathway plays a fundamental role in ocular herpes T cell immunopathology and provides an important immune checkpoint target that can synergizes with T cell-based therapeutic vaccines against symptomatic recurrent ocular herpes.

HERPETIC BLEFAROCERATOCONJUNCYVITIS. CLINICAL CASES

Purpose. Remind practitioners of the clinical picture of herpetic blepharoconjunctivitis, the clinical features of the three forms of herpetic conjunctivitis and its difference from adenoviral conjunctivitis. Material and methods. In the description of clinical cases it is shown that the rash of vesicles of herpes on the skin of the eyelids with blepharoconjunctivitis, allows to identify the etiology of the pathological process and choose the correct treatment strategy. Examines modern approaches to the treatment of herpes skin rashes and prophylactic measures for the eyes. It emphasizes the high risk of corneal damage and the development of herpetic keratitis during primary ofothalmus herpes, as well as the need for systemic and local antiherpetic therapy. Discussion. It is important to note that the alertness of the pediatric ophthalmologist in terms of detecting herpes blepharkeratoconjunctivitis, as the debut of a herpetic eye infection, is reduced. Laboratory confirmation is not always possible, which probably leads to the underdiagnosis of this disease. Conclusion. Inadequately selected therapy contributes to the further course of recurrent herpetic keratitis already in the adult patient’s age.

Клинический случай комбинированного лечения рецидивирующего стромального герпетического кератита с изъязвлением

Клинический случай комбинированного лечения рецидивирующего стромального герпетического кератита с изъязвлением

Epithelial defects after penetrating keratoplasty in infectious keratitis: An analysis of characteristics and risk factors.

To investigate the clinical characteristics, treatment, risk factors of occurrence and graft transparency of corneal epithelial defects after penetrating keratoplasty in patients with infectious keratitis. 594 patients (594 eyes) with infectious keratitis treated by penetrating keratoplasty at Shandong Eye Institute were reviewed retrospectively between January 2008 and January 2018. We investigated the demographic data, diameter and sources of graft, onset time, location, scope, time of healing and treatment of epithelial defects, as well as other postoperative complications and graft clarity. 114 of the 594 grafts (19.2%) that developed epithelial defects were included in the epithelial defects group, while the other 480 patients were classified in the non-defect group. The mean age of patients with epithelial defects was statistically greater than that of patients without epithelial defects (P = 0.006). The epithelial defects group accounted for a larger proportion of male patients (P<0.001). The proportion of patients with a graft diameter >9mm in the epithelial defect group (29.8%) was more than that in the non-defects group (16.3%) (P = 0.001). The incidence of epithelial defects significantly differed among the pathogenic causes of infectious keratitis (P = 0.002). The incidence of graft infection (21.1%, 9.2%, respectively, P<0.001) and graft dysfunction (7.9%, 2.5%, respectively, P = 0.012) in the epithelial defect group was higher than in the non-defects group. Multivariate logistic regression revealed that male sex (P = 0.001), age ≥ 60 years (P = 0.024), graft diameter >9mm (P = 0.001), bacterial (P = 0.039) and herpes simplex keratitis (P = 0.008), rheumatism (P = 0.031) and cancer treated with chemo- or radiotherapy (P = 0.032) were independent risk factors for epithelial defects. Graft clarity after epithelial defects were significantly differed between fungal and viral infections (P<0.001). We found that being an elderly male patient, a graft diameter >9 mm, bacterial and viral keratitis and systemic diseases (including rheumatism and cancer treated with chemo- or radiotherapy) were independent risk factors for postoperative epithelial defects.

Clinical Spectrum of Herpes Simplex Keratitis in Patients Attending various Health Institutions in North India

Clinical Spectrum of Herpes Simplex Keratitis in Patients Attending various Health Institutions in North India

"For your eyes only": ophthalmic complications following lung transplantation.

Ophthalmic complications in the lung transplant population are a little-known entity. It includes a spectrum of diseases ranging from infections such as cytomegalovirus (CMV) retinitis, herpetic keratitis, Pseudallescheria boydii to non-infectious complications such as posterior subcapsular cataracts (PSCs), cyclosporine retinopathy, and post-transplant lymphoproliferative disorder (PTLD). These diseases can be attributed to high levels of immunosuppression, advanced age, and drug-specific side effects. Underlying comorbidities such as diabetes mellitus may also play a role in the pathogenesis. Patients can present with varied symptoms such as blurry vision, floaters or eye pain. Prompt diagnosis often requires a high index of suspicion. With increasing numbers of transplants being performed worldwide, it is imperative for the pulmonologist and transplant physician to recognize these often subtle symptoms. Any visual symptom should trigger an ophthalmological evaluation in order to manage these complications; some of which pose the risk of systemic dissemination and significant morbidity. The following article provides an in-depth review of the common presenting symptoms, treatments and recent advances related to common ophthalmic complications following lung transplantation. While this article focuses on the lung transplant sub-population, the authors would like to point out that some of these complications are shared by other solid-organ transplants as well, by virtue of their shared immunosuppressive therapies.