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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.

Asunto(s)

Herpesvirus Humano 1 , Queratitis Herpética , Macrófagos , Replicación Viral , Queratitis Herpética/inmunología , Queratitis Herpética/virología , Queratitis Herpética/terapia , Animales , Macrófagos/inmunología , Ratones , Herpesvirus Humano 1/inmunología , Córnea/virología , Córnea/inmunología , Inmunidad Innata , Línea Celular , Modelos Animales de Enfermedad , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Piroptosis , Ratones Endogámicos C57BL , Humanos , Femenino , Carga Viral

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Herpes simplex keratitis (HSK) is a blinding disease caused by herpes simplex virus type 1 (HSV-1) infection, and rapid eradication of the virus from the affected cornea is imperative. Nod-like receptors (NLRs) are intracellular innate immune sensors closely associated with cell death, inflammation and immune responses. In this study, we investigated the role of NLRP12 in the antiviral immunology in HSK and the underlying mechanisms. We found that NLRP12 expression was significantly decreased in HSV-1-infected human corneal epithelial cells (HCE-Ts) and HSK mouse corneas. Overexpression of NLRP12 significantly reduced viral replication in infected HCE-Ts and functioned through inflammasome-mediated pyroptosis and downstream IL-18-IFN-γ axis. In HSK mouse models, overexpression of NLRP12 reduced viral replication in the cornea and alleviated HSK symptoms. This resulted from enhanced antiviral immune responses including the activation of specific immune cells in both the cornea and the draining lymph nodes. Specifically, the NLRP12-IL-18-IFN-γ axis regulated the interaction between infected corneal epithelial cells and macrophages. In conclusion, our study identified a role of NLRP12 in mediating pyroptosis and regulating antiviral immune responses. This novel finding opens the possibilities of NLRP12 as a viable target in the therapeutic strategies for HSV-1 infection.

Asunto(s)

Herpesvirus Humano 1 , Interferón gamma , Interleucina-18 , Queratitis Herpética , Ratones Endogámicos C57BL , Piroptosis , Transducción de Señal , Animales , Queratitis Herpética/inmunología , Queratitis Herpética/virología , Humanos , Interleucina-18/metabolismo , Interleucina-18/inmunología , Interferón gamma/metabolismo , Interferón gamma/inmunología , Herpesvirus Humano 1/inmunología , Herpesvirus Humano 1/fisiología , Ratones , Córnea/virología , Córnea/inmunología , Córnea/patología , Femenino , Replicación Viral , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Modelos Animales de Enfermedad , Inflamasomas/metabolismo , Inflamasomas/inmunología , Inmunidad Innata

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Herpes simplex virus type 1 (HSV-1) infection of the eyes results in herpes simplex keratitis (HSK), which has led to vision loss and even blindness in patients. However, the rate of drug resistance in HSV is on the rise; therefore, new antiviral agents with sufficient safety profiles must be developed. At present, we assessed the anti-HSV-1 activity of 502 natural compounds and their ability to reduce the HSV-1-induced cytopathic effect. We chose harmol for further studies because it exhibited the highest antiviral activity. We found that harmol inhibited both HSV-1 F and HSV-1/153 (a clinical drug-resistant strain) replication, with an EC50 of 9.34 µM and 5.84 µM, respectively. Moreover, harmol reduced HSV-1 replication in corneal tissues and viral progeny production in tears, and also alleviated early corneal surface lesions related to HSK. For example, harmol treatment preserved corneal thickness and nerve density in HSK mice. Interestingly, harmol also showed a promising antiviral effect on HSV-1/153 induced HSK in mouse model. Furthermore, harmol combined with acyclovir (ACV) treatment showed a greater antiviral effect than either one alone in vitro. Therefore, harmol may be a promising therapeutic agent for managing HSK.

Asunto(s)

Antivirales , Modelos Animales de Enfermedad , Herpesvirus Humano 1 , Queratitis Herpética , Replicación Viral , Animales , Antivirales/farmacología , Antivirales/uso terapéutico , Queratitis Herpética/tratamiento farmacológico , Queratitis Herpética/virología , Ratones , Herpesvirus Humano 1/efectos de los fármacos , Herpesvirus Humano 1/fisiología , Replicación Viral/efectos de los fármacos , Aciclovir/farmacología , Aciclovir/uso terapéutico , Córnea/virología , Córnea/efectos de los fármacos , Córnea/patología , Chlorocebus aethiops , Humanos , Femenino , Células Vero , Ratones Endogámicos BALB C

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The aim of our minireview is to provide a brief overview of the diagnosis, clinical aspects, treatment options, management, and current literature available regarding herpes simplex keratitis (HSK). This type of corneal viral infection is caused by the herpes simplex virus (HSV), which can affect several tissues, including the cornea. One significant aspect of HSK is its potential to cause recurrent episodes of inflammation and damage to the cornea. After the initial infection, the HSV can establish a latent infection in the trigeminal ganglion, a nerve cluster near the eye. The virus may remain dormant for extended periods. Periodic reactivation of the virus can occur, leading to recurrent episodes of HSK. Factors triggering reactivation include stress, illness, immunosuppression, or trauma. Recurrent episodes can manifest in different clinical patterns, ranging from mild epithelial involvement to more severe stromal or endothelial disease. The severity and frequency of recurrences vary among individuals. Severe cases of HSK, especially those involving the stroma and leading to scarring, can result in vision impairment or even blindness in extreme cases. The cornea's clarity is crucial for good vision, and scarring can compromise this, potentially leading to visual impairment. The management of HSK involves not only treating acute episodes but also implementing long-term strategies to prevent recurrences and attempt repairs of corneal nerve endings via neurotization. Antiviral medications, such as oral Acyclovir or topical Ganciclovir, may be prescribed for prophylaxis. The immune response to the virus can contribute to corneal damage. Inflammation, caused by the body's attempt to control the infection, may inadvertently harm the corneal tissues. Clinicians should be informed about triggers and advised on measures to minimize the risk of reactivation. In summary, the recurrent nature of HSK underscores the importance of both acute and long-term management strategies to preserve corneal health and maintain optimal visual function.

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INTRODUCTION: Herpes simplex keratitis stands as a prominent factor contributing to infectious blindness among developed nations. On a global scale, over 60% of the population tests positive for herpes simplex virus type-1 (HSV-1). Despite these statistics, there is currently no vaccine available for the virus. Moreover, the conventional nucleoside drugs prescribed to patients are proving ineffective in addressing issues related to drug resistance, recurrence, latency, and the escalating risk of vision loss. Hence, it is imperative to continually explore all potential avenues to restrict the virus. This review article centers on the present treatment methods for HSV-1 keratitis (HSK), highlighting the ongoing clinical trials. It delves into the emerging drugs, their mode-of-action and future therapeutics. AREAS COVERED: The review focuses on the significance of a variety of small molecules targeting HSV-1 lifecycle at multiple steps. Peer-reviewed articles and abstracts were searched in MEDLINE, PubMed, Embase, and clinical trial websites. EXPERT OPINION: The exploration of small molecules that target specific pathways within the herpes lifecycle holds the potential for substantial impact on the antiviral pharmaceutical market. Simultaneously, the pursuit of disease-specific biomarkers has the capacity to usher in a transformative era in diagnostics within the field.

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Antivirales , Desarrollo de Medicamentos , Herpesvirus Humano 1 , Queratitis Herpética , Humanos , Queratitis Herpética/tratamiento farmacológico , Queratitis Herpética/virología , Antivirales/farmacología , Antivirales/uso terapéutico , Herpesvirus Humano 1/efectos de los fármacos , Herpesvirus Humano 1/aislamiento & purificación , Animales , Farmacorresistencia Viral , Diseño de Fármacos

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Background and Objectives: Herpes simplex keratitis (HSK) is the leading infectious cause of corneal damage and associated loss of visual acuity. Because of its frequent recurrence, it represents a major health problem; thus, timely and accurate diagnosis is the key to successful treatment. To enable this, we aimed to determine HSK patients' demographic and clinical features. Materials and Methods: This prospective study included 55 patients diagnosed with HSK between March 2019 and August 2022 at the Department of Ophthalmology, Clinical Hospital Rijeka. Results: We found that HSK is most prevalent in the elderly, with 72.73% of patients older than 60. The most common HSK types were dendritic (HSK-D; 43.64%) and stromal with epithelial ulceration (HSK-SEU 23.64%). HSK recurrences occurred in 65.45% of patients, with most having two to five recurrences (55.56%). Visual acuity at presentation (65.5%) and after treatment (50.9%) was mostly in the 20/50 range. The longest period until the disease symptoms were resolved was in the group with stromal HSK without epithelial ulceration (HSK-SnEU), for which symptoms lasted more than 11 weeks in 87.5% of patients. The overall incidence of HSK-related complications was high (85.45%), with 76.4% of patients having corneal scarring. The average time from symptom to treatment was 15.78 days. Interestingly, we observed a strong seasonality in the incidence of HSK, which was most prevalent in the colder months, with 63.6% of cases occurring between October and March. Conclusions: To the best of our knowledge, this is the first prospective study in Croatia, and one of the few in Europe, to describe the demographic and clinical features of HSK patients. We found that HSK is most common in the elderly population, with its dendritic form as a clinical presentation. We have shown that HSK is prone to recurrence and secondary complications, with a worryingly long time between symptom and treatment, indicating the need for diagnostic testing in routine practice.

Asunto(s)

Queratitis Herpética , Humanos , Queratitis Herpética/epidemiología , Queratitis Herpética/diagnóstico , Femenino , Masculino , Persona de Mediana Edad , Anciano , Estudios Prospectivos , Adulto , Agudeza Visual , Anciano de 80 o más Años , Recurrencia , Centros de Atención Terciaria/estadística & datos numéricos , Demografía

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BACKGROUND: Atopic conditions are known to be associated with viral and bacterial infections. The purpose of this study was to determine the relationship between the effects of atopic conditions on the severity and recurrence of ocular infections including herpes simplex virus (HSV). METHODS: This study was performed on 474 consecutive patients with infectious keratitis caused by bacteria, fungus, acanthamoeba, HSV, or varicella-zoster virus. The relationships between the atopic condition and specific infectious pathogens and HSV were determined using real-time PCR. RESULTS: Our findings showed that atopic dermatitis (AD) was significantly associated with the incidence of HSV keratitis (odds ratio (OR), 10.2; P = 0.000). Other associations with AD were observed only with bacteria in an adverse manner. HSV proliferation in the lesions of patients with HSV keratitis whose AD was associated with non-infectious atopic blepharitis were significantly greater by 145-folds (P = 0.000). The presence of asthma or allergic rhinitis also increased the HSV DNA copy numbers. A recurrence of HSV keratitis was observed in 70 patients (43.2 %), and mean time to recurrence was 1647 days. Cox proportional hazard model indicated that the epithelial type of HSV recurrence but not the stromal type was associated with atopic conditions especially with AD. The factors significantly associated with a recurrence was AD associated with non-infectious atopic blepharitis (HR: 6.11, P = 0.000) and asthma (HR: 3.03, P = 0.025). CONCLUSIONS: Atopic conditions, especially AD with atopic blepharitis, are significantly associated with the development, increased proliferation, and shorter time to a recurrence on HSV keratitis.

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Recurrencia , Humanos , Femenino , Masculino , Adulto , Persona de Mediana Edad , Adolescente , Anciano , Dermatitis Atópica/epidemiología , Queratitis/microbiología , Queratitis/epidemiología , Adulto Joven , Queratitis Herpética , Niño , Simplexvirus , Incidencia , Preescolar , Anciano de 80 o más Años

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Herpes simplex keratitis (HSK) is a common blinding corneal disease caused by herpes simplex virus type 1 (HSV-1) infection. Antiviral drugs and corticosteroids haven't shown adequate therapeutic efficacy. During the early stage of HSV-1 infection, macrophages serve as the first line of defense. In particular, CD169+ macrophages play an important role in phagocytosis and antigen presentation. Therefore, we constructed GM-gD-lip, a ganglioside GM1 liposome vaccine encapsulating HSV-1 glycoprotein D and targeting CD169+ macrophages. After subconjunctival injection of the vaccine, we evaluated the survival rate and ocular surface lesions of the HSK mice, as well as the virus levels in the tear fluid, corneas, and trigeminal ganglia. We discovered that GM-gD-lip reduced HSV-1 viral load and alleviated the clinical severity of HSK. The GM-gD-lip also increased the number of corneal infiltrating macrophages, especially CD169+ macrophages, and polarized them toward M1. Furthermore, the number of dendritic cells (DCs) and CD8+ T cells in the ocular draining lymph nodes was significantly increased. These findings demonstrated that GM-gD-lip polarized CD169+ macrophages toward M1 to eliminate the virus while cross-presenting antigens to CD8+ T cells via DCs to activate adaptive immunity, ultimately attenuating the severity of HSK. The use of GM-gD-lip as an immunotherapeutic method for the treatment of HSK has significant implications.

Asunto(s)

Herpes Simple , Herpesvirus Humano 1 , Queratitis Herpética , Vacunas , Animales , Ratones , Liposomas , Linfocitos T CD8-positivos , Gangliósidos , Queratitis Herpética/tratamiento farmacológico , Herpesvirus Humano 1/fisiología , Córnea , Macrófagos , Glicoproteínas

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PURPOSE: To benchmark the epidemiologic features of pediatric ocular surface inflammatory diseases (POSID). DESIGN: Retrospective cohort study. PARTICIPANTS: Patients 18 years of age or younger with a medical claim for a diagnosis of POSID in the Optum Labs Data Warehouse between 2007 and 2020. METHODS: Patients with claims of blepharokeratoconjunctivitis (BKC), herpes simplex keratoconjunctivitis (HSK), or vernal keratoconjunctivitis (VKC) were included. Those with less than 6 months of follow-up before the initial diagnosis of POSID were excluded. Odds ratios (ORs) were derived from multivariable logistic regression analyses evaluating the associations between epidemiologic variables and POSID development. MAIN OUTCOME MEASURES: The primary outcome was the estimated prevalence of POSID. Prevalence of POSID subtypes and changes in prevalence over time were also evaluated. RESULTS: Two thousand one hundred sixty-eight patients with POSID were identified from 2018 through 2019, yielding an estimated prevalence of 3.32 per 10 000. The prevalence of POSID was higher among children between 5 and 10 years of age, male children, those of Asian descent, and those living in the Northeast and the West census regions of the United States. The prevalence (per 10 000) of BKC, HSK, and VKC in the same period were 0.59 (95% confidence interval [CI], 0.53-0.65), 0.74 (95% CI, 0.68-0.81), and 1.99 (95% CI, 1.88-2.10), respectively, and significant differences were found in terms of age, sex, racial, ethnic, and regional distributions among the diagnoses. Between 2008 through 2009 and 2018 through 2019, a significant increase in POSID was noted among Asians (from 6.26 [95% CI, 5.28-7.36] to 11.80 [95% CI, 10.40-13.34]) driven by changes in VKC. Multivariable analysis demonstrated that age older than 5 years (OR, 2.57-3.75; 95% CI, 2.17-4.34), male sex (OR, 1.38; 95% CI, 1.26-1.50), Asian descent (OR, 3.12; 95% CI, 2.70-3.60), and Black or African American descent (OR, 1.26; 95% CI, 1.02-1.55) were associated with POSID development. CONCLUSIONS: This study provides an estimated prevalence of POSID and its 3 common subtypes in the United States, with important epidemiologic differences among them. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

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PURPOSE: Herpes simplex keratitis (HSK), caused by type 1 herpes simplex virus (HSV) reactivation, is a severe infectious disease that leads to vision loss. HSV can trigger metabolic reprogramming in the host cell and change the extracellular vesicles (EV) cargos; however, little is known about the EV metabolic signatures during ocular HSV infection. Here, we aimed to depict the EV-associated metabolic landscape in HSK patients' tears. METHODS: We collected 82 samples from 41 participants with unilateral HSK (contralateral unaffected tears were set as negative control), including subtype cohorts of 13 epithelial, 20 stromal, and 8 endothelial HSK. We isolated tear EVs via our previously established platform and conducted metabolic analysis using LC-MS/MS. The metabolic signatures for recognizing HSK and subtypes were assessed through differential analysis and machine learning algorithms. RESULTS: Hypopsia and increased extracellular CD63 levels were observed in affected eyes. We identified 339 metabolites based on sEVs isolated from tears. Differential analysis revealed alterations in energy and amino acid metabolism, as well as the infectious microenvironment. Furthermore, we observed dysregulated metabolite such as methyldopa, which is associated with inappropriate neovascularization and corneal sensation loss, contributing to the HSK severity particularly in the stromal subtype. Moreover, machine learning classification also suggested a set of EV metabolic signatures that have potential for pan-keratitis detection. CONCLUSIONS: Our findings demonstrate that tear EV metabolites can serve as valuable indicators for comprehending the underlying pathological mechanisms. This knowledge is expected to facilitate the development of liquid biopsy means and therapeutic target discovery.

Asunto(s)

Queratitis Herpética , Espectrometría de Masas en Tándem , Humanos , Cromatografía Liquida , Queratitis Herpética/diagnóstico , Córnea/metabolismo , Simplexvirus

RESUMEN

Purpose: To compare the surgical outcomes of combined penetrating keratoplasty (PK) and cataract surgery with those of sequential surgery (cataract surgery after PK) for herpes simplex keratitis (HSK). Methods: The medical records of consecutive patients diagnosed with HSK who underwent combined or sequential PK and cataract surgery in active and stable stages between June 2015 and June 2022 were reviewed retrospectively. Complications, graft survival, endothelial cell density (ECD), and final BCVA were compared and analyzed between both surgical methods in each stage. Results: A total of 171 eyes of 171 patients were enrolled, including active stage (69 combined, 46 sequential) and stable stage (34 combined, 22 sequential). The average follow up was 24.2 ± 15.8 months (range, 3 months - 48 months). The final BCVA had obvious improvement and the postoperative ECD was not different in combined and sequential groups of each stage. In sequential group of active stage, 66.7% of persistent epithelial defects and 50% of HSK recurrence occurred within 3 months after cataract surgery; nevertheless, compared to that in sequential group, capsular rupture (p = 0.021), persistent epithelial defects (p = 0.027), and HSK recurrence (p = 0.035) occurred more frequently in combined group, leading to a lower graft survival rate (p = 0.045); at the last visit, 46.4 and 67.4% of grafts remained clear in combined and sequential groups, respectively. By contrary, 82.4 and 50.0% of grafts remained clear in stable stages of combined and sequential groups at the last visit, respectively, and a higher graft survival rate was observed in combined group (p = 0.030). Conclusion: Although the postoperative ECD is not different between two surgical groups in each stage, sequential surgery in active stage of HSK seems to have advantages in less complications and higher graft survival rate, whereas combined surgery in stable stage has a better outcome than that in sequential surgery.

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BACKGROUND: Corneal neovascularization (CNV) is a symptom of herpes simplex keratitis (HSK), which can result in blindness. The corneal angiogenesis brought on by herpes simplex virus type 1 (HSV-1) is strongly affected by vascular endothelial growth factor A (VEGFA). The N6-methyladenosine (m6A) modification catalyzed by methyltransferase-like 3 (METTL3) is a crucial epigenetic regulatory process for angiogenic properties. However, the roles of METTL3 and m6A in HSK-induced CNV remain unknown. Here, we investigated these roles in vitro and in vivo. METHODS: A PCR array in HSV-1-infected human umbilical vein endothelial cells (HUVECs) was used to screen for METTL3 among the epitranscriptomic genes. Tube formation and scratch assays were conducted to investigate cell migration capacity. The global mRNA m6A abundance was evaluated using a dot blot assay. Gene expression was assessed by RT-qPCR, western blotting, and fluorescence immunostaining. In addition, bioinformatic analysis was conducted to identify the downstream molecules of METTL3 in HUVECs. METTL3 knockdown and STM2457 treatment clarified the specific underlying molecular mechanisms affecting HSV-1-induced angiogenesis in vitro. An acute HSK mouse model was established to examine the effects of METTL3 knockdown or inhibition using STM2457 on pathological angiogenic development in vivo. RESULTS: METTL3 was highly upregulated in HSV-1-infected HUVECs and led to increased m6A levels. METTL3 knockdown or inhibition by STM2457 further reduced m6A levels and VEGFA expression and impaired migration and tube formation capacity in HUVECs after HSV-1 infection. Mechanistically, METTL3 regulated LRP6 expression through post-transcriptional mRNA modification in an m6A-dependent manner, increasing its stability, upregulating VEGFA expression, and promoting angiogenesis in HSV-1-infected HUVECs. Furthermore, METTL3 knockdown or inhibition by STM2457 reduced CNV in vivo. CONCLUSION: Our findings revealed that METTL3 promotes pathological angiogenesis through canonical Wnt and VEGF signaling in vitro and in vivo, providing potential pharmacological targets for preventing the progression of CNV in HSK.

Asunto(s)

Neovascularización de la Córnea , Herpesvirus Humano 1 , Queratitis Herpética , Animales , Ratones , Humanos , Neovascularización de la Córnea/genética , Neovascularización de la Córnea/patología , Herpesvirus Humano 1/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Vía de Señalización Wnt , Queratitis Herpética/patología , Neovascularización Patológica , Células Endoteliales de la Vena Umbilical Humana/metabolismo , ARN Mensajero/genética , Metiltransferasas/genética , Metiltransferasas/metabolismo

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This article describes the case of a 21-year-old female habitual contact lens wearer who complained of left eye pain, redness, and decreased vision for one week. When a ring-shaped corneal infiltration indicative of an Acanthamoeba infection was discovered, standard anti-amoebic topical therapy with polyhexamethylene biguanide and chlorhexidine was commenced. However, her keratitis worsened. At the same time, corneal scraping revealed no pathogens. An anterior chamber examination revealed a loss of corneal sensation, and a positive herpes simplex virus (HSV) immunoglobulin G serology test indicated HSV keratitis. She was eventually treated with oral anti-viral medication and recovered completely. Her case was unusual, as she had a history of contact lens use, painful corneal ulceration, and the development of Acanthamoeba keratitis-like corneal ring infiltration. This case also reinforces the various manifestations of HSV keratitis, which lead to delayed diagnosis and treatment.

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PURPOSE: To evaluate the rates of Herpes Simplex Virus types 1 (HSV-1) and 2 (HSV-2) in ocular specimens. METHODS: Retrospective case series of all patients with a positive laboratory evaluation for ocular HSV performed at the Auckland District Health Board, Auckland, New Zealand between 1 January 2006 and 31 December 2017 were included in the study. RESULTS: A total of 423 specimens were positive for HSV-1 (99.3%, n = 419) or HSV-2 (0.7%; n = 4). The majority of positive tests were identified through DNA amplification (n = 352; 83%) testing while the remainder were obtained by viral culture (n = 71; 17%). Ocular disease caused by HSV-2 in this study included acute retinal necrosis (n = 2), keratitis (n = 1), and blepharitis (n = 1). CONCLUSIONS: HSV type 2 is a rare cause of ocular and peri-ocular infection but may cause severe, vision threatening disease.

Asunto(s)

Herpes Simple , Herpesvirus Humano 1 , Queratitis Herpética , Humanos , Herpesvirus Humano 1/genética , Queratitis Herpética/diagnóstico , Queratitis Herpética/epidemiología , Estudios Retrospectivos , Ojo , Herpesvirus Humano 2/genética , Herpes Simple/diagnóstico , Herpes Simple/epidemiología

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PURPOSE: To report atypical clinical features and diagnosis of stromal herpes simplex keratitis (HSK) and to evaluate the diagnostic efficiency of tear HSV-sIgA in atypical HSK. STUDY DESIGN: Prospective observational study. METHODS: Records of keratitis' patients with tear herpes simplex virus (HSV)-sIgA test results acquired between May 2019 and November 2021 were evaluated retrospectively. Positive tear HSV-sIgA test was used to identify herpes simplex virus (HSV) infection. Patients with typical presentations and histories of HSV keratitis (HSK) were excluded. RESULTS: Eleven eyes of 11 patients initially diagnosed as keratitis caused by other etiology were confirmed as having HSV infection by positive results of tear HSV-sIgA. Clinical features of atypical stromal HSK were variable. Antiviral treatment was effective in all patients. CONCLUSION: The appearance of an atypical stromal HSK represents a diagnostic challenge. Tear HSV-sIgA test could help provide a quick diagnosis.

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Herpes Simple , Queratitis Herpética , Humanos , Estudios Retrospectivos , Queratitis Herpética/diagnóstico , Queratitis Herpética/tratamiento farmacológico , Simplexvirus , Sustancia Propia , Inmunoglobulina A Secretora

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Diseases like viral keratitis can harm corneal nerves, which are necessary for maintaining the health and functionality of the cornea. Recent research has shown that corneal nerve pathology affects the infected eye as well as the contralateral one, and that aberrant changes in sympathetic nerves can be seen, with the exception of sensory nerves that correspond to corneal sensation. However, apart from in vivo confocal microscopy and corneal sensation, there have been no additional prognostic indicators that allow clinicians to assess the severity of corneal nerve damage. While multiple functions of corneal nerves are mediated by neuropeptides, substance P, the first topical neuropeptide used in ocular clinical practice, was proved to regulate the process of viral infections, and it is involved in bilateral corneal pathologies through pro-inflammatory and neurotrophic functions in viral keratitis, so it may be used as a diagnostic biomarker or a therapeutic target. Therefore, this review summarized the changes and roles of corneal nerves as well as substance P in viral keratitis, which may serve as a reference for further study into associated mechanisms and clinical applications.

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Objective: To investigate the clinical characteristics and factors associated with herpes simplex virus keratitis. Methods: Patients with herpes simplex virus keratitis who came to our hospital from January 2018 to June 2022 were selected and divided into a good prognosis group and a poor prognosis group according to their prognosis. The clinical data of the two groups were compared, and univariate/multivariate logistic regression was used to analyze the factors influencing the poor prognosis of herpes simplex virus keratitis. Results: A one-way analysis of variance showed that, compared with the good prognosis group, the poor prognosis group had more elderly patients and a longer course of disease, and the difference was statistically significant (p < 0.05). There were significant differences in the types of patients between the two groups (p < 0.05). Univariate logistic regression analysis also showed that age (≥65 years) (OR: 1.557, 95%CI: 1.081-2.183, p < 0.05), course of disease (> 7 months) (OR: 1.303, 95%CI: 1.003-1.829, p < 0.05), epithelial type (OR: 2.321, 95%CI: 1.198-4.321, p < 0.05), and stromal type (OR: 2.536, 95%CI: 1.672-3.871, p < 0.05) were risk factors for poor prognosis. Multivariate logistic regression analysis showed that age (≥65 years) (OR: 1.656, 95%CI: 1.168-2.357, p < 0.05) and course of disease (> 7 months) (OR: 1.461, 95%CI: 1.031-2.001, p < 0.05) were independent risk factors for the prognosis of herpes simplex keratitis. Conclusion: The clinical symptoms of herpes simplex virus keratitis include corneal opacity, corneal posterior elastic layer folds, corneal infiltration, posterior corneal mass, corneal edema, and ocular pain. Age and course of disease are important factors in the prognosis of herpes simplex virus keratitis.

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This article presents a retrospective analysis of the research findings by professor A.A. Kasparov, who developed and implemented a novel approach to treating ocular herpes. The treatment system is fundamentally different from the conventional chemotherapeutic approach and revolves around non-specific immunotherapy using an endogenous interferon inducer - a biosynthetic complex of polyriboadenylic and polyribouridylic acids, known as Poludan. This approach also incorporates personalized cell therapy based on Poludan, along with herpes vaccine aimed at preventing recurrence. The regenerative and antiviral properties of this approach have proven successful in treating other corneal conditions such as adenovirus infections, early postoperative bullous keratopathy, as well as in stimulation of epithelialization after refractive surgeries (photorefractive keratectomy, phototherapeutic keratectomy).

Asunto(s)

Enfermedades de la Córnea , Queratitis Herpética , Queratectomía Fotorrefractiva , Polirribonucleótidos , Humanos , Interferones/uso terapéutico , Estudios Retrospectivos , Queratitis Herpética/tratamiento farmacológico , Enfermedades de la Córnea/etiología , Enfermedades de la Córnea/terapia , Láseres de Excímeros

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Objective (Aim): The article is a case report of a very rare case of bilateral herpes simplex virus infection associated with bilateral necrotizing scleritis with scleral melt in an elderly north Indian female of lower middle socioeconomic status. Methods: A 65-year-old female presented to our clinic with a wide variety of presentations ranging initially from neurotropic corneal ulcer to necrotizing scleritis with scleral melt for 2 years. The patient records were evaluated and computed. A PubMed literature search on herpes scleritis was conducted and reviewed. Results: A keen sense of judgment, timely management, and patient counseling are crucial for a rapid and favorable outcome. Conclusions: Bilateral necrotizing scleritis with scleral melt can be a rare atypical presentation of herpes simplex keratitis. In such atypical cases, diagnosis may be challenging. Associated clinical findings, history of herpes keratitis, which may be recurrent, and response to antiviral drugs, may give clues towards the diagnosis in such atypical cases. In addition to this, surgical intervention should not be delayed if it seems inevitable. Abbreviations: RE = right eye, LE = left eye, BCL = bandage contact lens, KP = keratic precipitate, mm = millimeter, mg = milligram.

Asunto(s)

Úlcera de la Córnea , Herpes Simple , Enfermedades de la Esclerótica , Escleritis , Humanos , Femenino , Anciano , Escleritis/diagnóstico , Enfermedades de la Esclerótica/diagnóstico , Herpes Simple/diagnóstico , Herpes Simple/tratamiento farmacológico , Antivirales/uso terapéutico , Úlcera de la Córnea/complicaciones

RESUMEN

Herpes simplex keratitis (HSK) is a severe, infectious corneal disease caused by herpes simplex virus type 1 (HSV-1) infection. The increasing prevalence of acyclovir resistance, the side effects of hormonal drugs, and the ease of recurrence after surgery have made it crucial to develop new methods of treating HSK. HSV-1 evades the host immune response through various mechanisms. Therefore, we explored the role of the immunogenic cell death inducer PKHB1 peptide in HSK. After subconjunctival injection of PKHB1 peptide, we observed the ocular surface lesions and survival of HSK mice and detected the virus levels in tear fluid, corneas, and trigeminal ganglions. We found that PKHB1 peptide reduced HSV-1 levels in the eye and alleviated the severity of HSK. Moreover, it increased the number of corneal infiltrating antigen-presenting cells (APCs), such as macrophages and dendritic cells, and CD8+ T cells in ocular draining lymph nodes. We further observed that PKHB1 peptide promoted the exposure of calreticulin, as well as the release of ATP and high-mobility group box 1 in HSV-1-infected cells in vitro. Our findings suggested that PKHB1 peptide promoted the recruitment and maturation of APCs by inducing the release of large amounts of damage-associated molecular patterns from infected cells. APCs then phagocytized antigenic materials and translocated to the lymph nodes, triggering a cytotoxic T lymphocyte-dependent immune response that ultimately alleviated HSK.