Production of the Cytokine VEGF-A by CD4+ T and Myeloid Cells Disrupts the Corneal Nerve Landscape and Promotes Herpes Stromal Keratitis.

Herpes simplex virus type 1 (HSV-1)-infected corneas can develop a blinding immunoinflammatory condition called herpes stromal keratitis (HSK), which involves the loss of corneal sensitivity due to retraction of sensory nerves and subsequent hyperinnervation with sympathetic nerves. Increased concentrations of the cytokine VEGF-A in the cornea are associated with HSK severity. Here, we examined the impact of VEGF-A on neurologic changes that underly HSK using a mouse model of HSV-1 corneal infection. Both CD4+ T cells and myeloid cells produced pathogenic levels of VEGF-A within HSV-1-infected corneas, and CD4+ cell depletion promoted reinnervation of HSK corneas with sensory nerves. In vitro, VEGF-A from infected corneas repressed sensory nerve growth and promoted sympathetic nerve growth. Neutralizing VEGF-A in vivo using bevacizumab inhibited sympathetic innervation, promoted sensory nerve regeneration, and alleviated disease. Thus, VEGF-A can shape the sensory and sympathetic nerve landscape within the cornea, with implications for the treatment of blinding corneal disease.

[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.

New-Onset of Herpes Simplex Keratitis After Blepharoplasty, Case Series and Review of the Literature.

PURPOSE: To report 3 cases of new-onset herpes simplex keratitis (HSK) after uncomplicated extraocular plastic surgery and discuss potential risk factors. METHODS: This case series includes 3 patients who underwent uncomplicated blepharoplastic surgery. Within 2 weeks postoperatively, all patients reported ocular discomfort, and their ophthalmic examinations revealed corneal lesions suspicious of HSK. One case was confirmed as an active herpes infection, and the other 2 cases were clinically diagnosed with HSK. The patients were treated with oral acyclovir and followed up for up to 6 weeks. RESULTS: All patients demonstrated improvement without sequelae at follow-up visits from 5 days to 4 weeks after initiating acyclovir treatment. CONCLUSIONS: Risk factors for new-onset HSK after uncomplicated extraocular surgeries may be related to an immunocompromised state, postoperative administration of topical or periocular corticosteroids, or environmental factors such as psychological stress. Ophthalmologists, particularly plastic surgeons, should be vigilant for ocular discomfort following eyelid surgeries and consider the possibility of herpes infection. This report highlights the importance of recognizing and managing HSK in the context of extraocular plastic surgery.

Herpes simplex keratitis following Smart Pulse Technology assisted transepithelial photorefractive keratectomy: a case report.

BACKGROUND: Herpes simplex keratitis (HSK) is a rare and sight-threatening complication following refractive surgery. SmartSurfACE surgery is the result of combining transepithelial photorefractive keratectomy (trans-PRK) with Smart Pulse Technology (SPT) to diminish surface irregularities of the residual stromal bed after surgery with less pain, faster re-epithelialization, and better postoperative visual acuity. In this article, we report the first case of HSK following SmartSurf ACE without history of herpetic eye disease. CASE PRESENTATION: A 21-year-old woman underwent bilateral SmartSurfACE without history of clinical herpetic infection, active eye disease, or systemic disease. Mild superficial punctate keratitis occurred on the tenth postoperative day. The condition was not improved by ophthalmic drugs of anti-inflammation or epithelial healings. Dendritic corneal ulcer appeared within one month, which is the commonly recognized clinical manifestation of herpes simplex keratitis. The patient was managed with topical and systemic antiviral agents. After nine days of antiviral therapy, the lesion healed up, remaining mild stromal scarring in both eyes ultimately. CONCLUSION: Herpes simplex keratitis is a rare but sight-threatening complication following refractive surgery. For the ocular irritation symptoms of postoperative patients, we should consider the possibility of HSK and give timely treatment.

Fetal and neonatal abnormalities due to congenital herpes simplex virus infection: a literature review.

OBJECTIVE: Herpes simplex virus (HSV) infection during pregnancy can cause severe neonatal infections. It is also a rare cause of congenital infections. We aimed to describe fetal and neonatal abnormalities of congenital HSV infection in order to define the features that are accessible to prenatal diagnosis during ultrasound screening and/or during a work-up for congenital malformations. METHODS: We analysed all cases of congenital HSV infection (CHI) described before and/or after birth and identified in Pubed and classified the findings as accessible or not to prenatal diagnosis. RESULTS: Thirty-six cases of congenital herpes infection were reported, of which 15 were described prenatally and 21 postnatally. The most frequently reported malformations accessible to prenatal diagnosis were cerebral anomalies. The most common abnormalities described after birth were skin lesions and keratitis, which are not considered amenable to prenatal ultrasound detection. CHI can due to either HSV1 or HSV2 infection, whether primary or non-primary infection, with or without the presence of maternal symptoms. CONCLUSION: Prenatal ultrasound abnormalities due to CHI are rare, varied and non-specific. There is no clear role for fetal ultrasound in the routine management of women with primary or non-primary HSV infection in pregnancy. However, in fetuses with ultrasound abnormalities suggestive of congenital infection, HSV should still be considered as a differential diagnosis after the more common in utero infections, such as cytomegalovirus, are excluded.

Immune- and Nonimmune-Compartment-Specific Interferon Responses Are Critical Determinants of Herpes Simplex Virus-Induced Generalized Infections and Acute Liver Failure.

The interferon (IFN) response to viral pathogens is critical for host survival. In humans and mouse models, defects in IFN responses can result in lethal herpes simplex virus 1 (HSV-1) infections, usually from encephalitis. Although rare, HSV-1 can also cause fulminant hepatic failure, which is often fatal. Although herpes simplex encephalitis has been extensively studied, HSV-1 generalized infections and subsequent acute liver failure are less well understood. We previously demonstrated that IFN-αßγR-/- mice are exquisitely susceptible to liver infection following corneal infection with HSV-1. In this study, we used bone marrow chimeras of IFN-αßγR-/- (AG129) and wild-type (WT; 129SvEv) mice to probe the underlying IFN-dependent mechanisms that control HSV-1 pathogenesis. After infection, WT mice with either IFN-αßγR-/- or WT marrow exhibited comparable survival, while IFN-αßγR-/- mice with WT marrow had a significant survival advantage over their counterparts with IFN-αßγR-/- marrow. Furthermore, using bioluminescent imaging to maximize data acquisition, we showed that the transfer of IFN-competent hematopoietic cells controlled HSV-1 replication and damage in the livers of IFN-αßγR-/- mice. Consistent with this, the inability of IFN-αßγR-/- immune cells to control liver infection in IFN-αßγR-/- mice manifested as profoundly elevated aspartate transaminase (AST) and alanine transaminase (ALT) levels, indicative of severe liver damage. In contrast, IFN-αßγR-/- mice receiving WT marrow exhibited only modest elevations of AST and ALT levels. These studies indicate that IFN responsiveness of the immune system is a major determinant of viral tropism and damage during visceral HSV infections. IMPORTANCE: Herpes simplex virus 1 (HSV-1) infection is an incurable viral infection with the most significant morbidity and mortality occurring in neonates and patients with compromised immune systems. Severe pathologies from HSV include the blindness-inducing herpetic stromal keratitis, highly debilitating and lethal herpes simplex encephalitis, and generalized infections that can lead to herpes simplex virus-induced acute liver failure. While immune compromise is a known factor, the precise mechanisms that lead to generalized HSV infections are unknown. In this study, we used and developed a mouse model system in combination with real-time bioluminescence imaging to demonstrate the relative importance of the immune and nonimmune compartments for containing viral spread and promoting host survival after corneal infection. Our results shed light on the pathogenesis of HSV infections that lead to generalized infection and acute liver failure.

Herpes simplex virus keratitis: an update of the pathogenesis and current treatment with oral and topical antiviral agents.

Ophthalmic herpes simplex viral keratitis is responsible for a range of ocular manifestations from superficial epithelial disease to stromal keratitis and endotheliitis. The Herpetic Eye Disease Study has guided the management of herpetic eye disease for almost twenty years, but newer medications such as valacyclovir are now available and are considered to have better bioavailability than acyclovir. In this review, we examine the existing evidence on the pathogenesis of different ophthalmic herpes simplex viral keratitis disease modalities and the role of oral and topically administered antiviral drugs in the treatment of herpes simplex viral keratitis.

Adverse effects of low-dose systemic cyclosporine therapy in high-risk penetrating keratoplasty.

PURPOSE: The purpose of this study was to investigate the adverse effects of low-dose oral cyclosporine (CsA) therapy following high-risk corneal transplantation. METHODS: The medical records from 88 subjects who had undergone high-risk penetrating keratoplasties and had been administered oral CsA were retrospectively analyzed. High risk was defined as a history of graft rejection, three or more quadrants of vascularization, or the presence or history of intraocular inflammation. An initial CsA dose of 3-5 mg/kg per day was given for 3-7 days, followed by 2.5-3.5 mg/kg per day for approximately 1 month. The concentration of CsA was maintained at the target trough level of 120-150 ng/ml for at least 6 months or until serious complications developed. The relationship between the cumulative dose and duration of CsA administration and the adverse systemic effects, including the frequency of herpes keratitis, was evaluated. The incidence of herpes keratitis in the study subjects was compared with the incidence in 185 patients who had not received CsA therapy following penetrating keratoplasty. RESULTS: The mean survival time of the grafts was 33.6 months. Adverse effects occurred in 81.8 % of subjects. Hypertension, elevated liver enzyme levels, elevated serum creatinine level, and decreased absolute neutrophil count (ANC) were observed in 14.8, 6.8, 5.7, and 5.7 % of subjects, respectively. Simvastatin-induced rhabdomyolysis also developed in one case. Some patients exhibited minor complications, with gastrointestinal problems and hypertrichosis recorded in 5.7 and 3.4 % of subjects, respectively. Hypertension and hepatotoxicity most frequently occurred after 4 to 8 weeks of medication, while ANC decrease and nephrotoxicity generally developed after 24 weeks of treatment, with incidence related to the cumulative dose. Herpes keratitis occurred more frequently (31.8 %) in the CsA-treated subjects than in subjects that did not receive CsA therapy (p = 0.005). Most of the adverse effects were reversed after discontinuation of CsA therapy. CONCLUSION: The results of this study suggest that low-dose oral CsA therapy may induce various adverse effects, the most common of which are herpes keratitis and hypertension.

Herpesvirus entry mediator is a serotype specific determinant of pathogenesis in ocular herpes.

Infection with herpes simplex virus type 1 (HSV-1) and HSV-2 is initiated by viral glycoprotein D (gD) binding to a receptor on the host cell. Two receptors, herpesvirus entry mediator (HVEM) and nectin-1, mediate entry in murine models of HSV-1 and HSV-2. HVEM is dispensable for HSV-2 infection of the vagina and brain, but is required for WT pathogenesis of HSV-1 infection of the cornea. By challenging WT and HVEM KO mice with multiple strains of HSV-1 and HSV-2, we demonstrate that without HVEM, all HSV-1 strains tested do not replicate well in the cornea and infection does not result in severe symptoms, as observed in WT mice. In contrast, all HSV-2 strains tested had no requirement for HVEM to replicate to WT levels in the cornea and still cause severe disease. These findings imply that HSV-2 does not require HVEM to cause disease regardless of route of entry, but HVEM must be present for HSV-1 to cause full pathogenesis in the eye. These findings uncover a unique role for HVEM in mediating HSV-1 infection in an area innervated by the trigeminal ganglion and may explain why the presence of HVEM can lead to severe inflammation in the cornea. Thus, the dependence on HVEM is a dividing point between HSV-1 and HSV-2 that evolved to infect areas innervated by different sensory ganglia.

Herpetic keratouveitis mixed with bilateral Pseudomonas corneal ulcers in vitamin A deficiency.

A 56-year-old woman complained of blurred vision and pain in her right eye for several days. Slit lamp examination revealed a large epithelial defect and disciform stromal edema with ring infiltration in her right cornea. Unfortunately, hypopyon and purulent discharge subsequently developed in both eyes. Herpetic keratouveitis and a superimposed pseudomonas infection were diagnosed. A systemic review on the patient showed malnutrition due to her dietary preference and vegetarianism. After the infection was controlled, bilateral epithelial defects persisted for a long time. We performed amniotic membrane transplantation on both eyes and the clinical status improved with administration of vitamin and protein supplements. Although rare in Taiwan, vitamin A deficiency should be kept in mind when conjunctival and corneal xerosis occurred. Vitamin A supplements are suggested because of the increased susceptibility to infection in patients with this clinical status.

[The Chameleon of Herpetic Keratitis - Diagnosis and Therapy]. / Das Chamäleon der Keratitis herpetischer Genese - Diagnose und Therapie.

In Europe, herpes simplex virus type I (HSV) is a common cause of keratitis. The disease may be well treated if the ophthalmologtist is aware of the various types of clinical expressions of this typical unilateral chameleon, and treatment is adjusted accordingly. Types of expression include: (i) epithelial keratitis (dendritica/geographica), (ii) stromal keratitis (necrotising vs. non-necrotising = "interstitial keratitis"), (iii) endotheliitis (= "disciform keratitis"), (iv) so-called "metaherpetic keratitis" (= neurotrophic keratopathy), (v) (vascularised) corneal scars. In the acute phase, concomitant ocular hypertension should be treated predominantly without surgery (no prostaglandin analoga!). After keratoplasty and in cases of severe recurrences of herpetic keratitis, systemic aciclovir administration (2 × 400 mg/day) for at least one year is indispensable!

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.

[Lamellar minikeratoplasty for recurrent herpes keratitis in the late post-LASIK period].

The article presents a case report of sutureless lamellar minikeratoplasty for progressive corneal ulceration associated with herpes simplex infection in the late period after LASIK.

Herpes Simplex Keratitis as a Complication of Pterygium Surgery.

BACKGROUND Infectious keratitis after pterygium surgery is a rare but potentially devastating complication. The present study presents 5 cases of herpes simplex keratitis (HSK) after pterygium surgery. CASE REPORT This study was conducted in our clinic in a 5-year period from February 2017 to September 2021. The 5 patients were men, aged between 42 and 73 years, with no prior history of herpes simplex virus (HSV) infections. Symptoms appeared near 1 month (median 30 days, range 10 to 70 days) after primary pterygium surgery. Diagnosis was based on clinical symptoms and laboratory test results, such as tear HSV-sIgA, corneal tissue polymerase chain reaction, and next-generation sequencing of metagenomics. The epithelial (1/5) and stromal (4/5) subtypes of HSK were identified. The patients received topical ganciclovir gel, immunosuppressive eyedrops, and oral acyclovir tablets, along with additional surgical interventions if necessary. Three were healed with conservative therapy, 1 eye required amniotic membrane transplantation due to corneal melt, and 1 was perforated and followed by corneal grafting. Finally, a literature review of previous publications on HSK after ocular surgeries was conducted. CONCLUSIONS HSK is a rare but serious complication that can arise after uneventful pterygium surgery. It is worthy of attention that both epithelial and stromal forms can occur. Timely diagnosis and treatment are crucial to prevent unfavorable outcomes. Consequently, routine corneal fluorescein staining, tear sIgA examination, and corneal scraping for polymerase chain reaction or next-generation sequencing of metagenomics should be performed in any suspected cases.

Role of heparan sulfate in ocular diseases.

Heparan sulfate (HS), a ubiquitous and structurally diverse cell surface polysaccharide and extracellular matrix component, is a factor common to several major eye pathologies. Its multitude of functions and variable distribution among the different ocular tissues makes it an important contributor to a variety of disease states. Although HS facilitates the pathogenesis of many disorders, its role in each varies. Unique functions of HS have been particularly noted in viral and bacterial keratitis and age-related macular degeneration. Combined, these pathologies comprise a large portion of conditions leading to visual impairment worldwide. Given this prevalence of diseases facilitated by HS, it is prudent to take an in-depth look at this compound in the context of these pathologic states. While the initial part of the review will discuss the pathogenic aspects of HS, it is also important to consider the wider implications of such roles for HS. The remainder of the article will specifically address one such implication, the possibility for future use of novel HS-based therapeutics to combat these eye pathologies.

[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.

Herpetic Eye Disease Following the SARS-CoV-2 Vaccinations.

PURPOSE: To describe herpetic ocular infections following SARS-CoV-2 vaccinations. METHODS: A retrospective study of herpetic ocular infections after BNT162b2mRNA vaccination and a literature review. RESULTS: A cohort of five patients: three varicella zoster virus (VZV) and two herpes simplex virus (HSV) cases, as well as 19 literature cases: 9 cases of VZV and 10 cases of HSV post BNT162b2mRNA, AZD1222, mRNA-1273, and CoronaVac vaccinations. All cases presented within 28 days post vaccination. Most VZV and HSV cases (15/19) reported in the literature presented post first vaccine dose, while in our cohort 2 VZV cases presented post second dose and both HSV cases and one VZV case post third dose. The most common presentations were HZO with ocular involvement and HSV keratitis. All eyes had complete resolution; however, one had retinal detachment and three corneal scars. CONCLUSION: Herpetic ocular infections may develop shortly after SARS-CoV-2 vaccinations. Overall, the outcome is good.

Recurrent herpetic stromal keratitis in mice: a model for studying human HSK.

Herpes simplex virus 1 (HSV-1) infection of the cornea leads to a potentially blinding disease, termed herpetic stromal keratitis (HSK) that is characterized by lesions of an immunoinflammatory nature. In spite of the fact that HSK typically presents as a recurrent disease due to reactivation of virus which latently infects the trigeminal ganglia, most murine studies of HSK have employed a primary and not recurrent model of the disease. This report documents the several recurrent models of HSK that have been developed and how data generated from these models differs in some important aspects from data generated following primary infection of the cornea. Chief among these differences is the fact that recurrent HSK takes place in the context of an animal that has a preexisting anti-HSV immune response, while primary HSK occurs in an animal that is developing such a response. We will document both differences and similarities that derive from this fundamental difference in these models with an eye towards possible vaccines and therapies that demonstrate promise in treating HSK.

Stromal and endothelial herpes simplex virus keratitis reactivation in the convalescent period of COVID-19 - A case report.

A 73-year-old lady presented with a white spot and redness in the left eye for 1 month and had been treated elsewhere as a case of fungal keratitis. She had severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection 2 months before. Her past ocular history and examination gave a probable diagnosis of herpetic stromal and endothelial keratitis. She responded to oral acyclovir and topical steroid, leading to resolution of stromal edema and inflammation. Anterior chamber fluid polymerase chain reaction (PCR) confirmed pathogen herpes simplex virus (HSV)-1. HSV ocular reactivation after coronavirus disease 2019 (COVID-19) has been reported currently. The present report will add knowledge about this potential opportunistic ophthalmic infection during the recovery phase of COVID-19 disease.

Reactivation of Herpes Simplex Keratitis on a Corneal Graft Following SARS-CoV-2 mRNA Vaccination.

Background: Ocular herpes simplex is usually caused by herpes simplex virus type 1 (HSV-1) and less commonly by the type 2 virus (HSV-2). Ocular manifestations of HSV include blepharitis, conjunctivitis, lacrimal system obstruction, corneal involvement, and uveitis. Corneal involvement is one of the causes of loss of vision and can be epithelial herpetic keratitis or stromal herpetic keratitis. Objective: A significant population has a colonization of herpes viruses. Under certain circumstances, these viruses can reactivate with a significant ocular morbidity. Globally, COVID-19 vaccines are recommended; however, the vaccine safety data are limited. Case report: Herein, we reported a case of herpetic keratitis reactivation that occurred 2 days after receiving SARS-CoV-2 mRNA vaccine. The patient is a 50-year-old man who underwent penetrating keratoplasty (PKP) in 2020 for corneal opacity caused by a previous herpes simplex keratitis in 2013. Herpetic keratitis was treated successfully with topical antiviral acyclovir along with topical moxifloxacin and artificial tears. After treatment, prophylactic oral acyclovir was started. Conclusion: Both ophthalmologist and patients should be aware of this phenomenon. Long-term prophylactic antiviral treatment may be recommended for those patients.