Superior limbic keratoconjunctivitis: Update on pathophysiology and management.

Superior limbic keratoconjunctivitis (SLK) is an under-recognized condition characterized by a final common pathologic presentation of superior conjunctival and limbal inflammation and staining. Existing literature attributes both microtrauma and local inflammation, frequently in the setting of tear film insufficiency, as the underlying mechanisms that lead to a self-perpetuating pathologic process dependent in on inflammatory cells and signaling. Effective treatments act by targeting inflammation and by mitigating mechanical stressors. This critical review discusses the latest in our understanding of the pathophysiology of SLK and how it guides our treatment strategies.

Eosinophilic Keratoconjunctivitis in Cats.

Eosinophilic keratitis is a disease of the feline ocular surface. It is characterized by conjunctivitis, white to pink raised plaques on the corneal and conjunctival surfaces, corneal vascularization, and variable ocular pain. Cytology is the diagnostic test of choice. Identification of eosinophils in a corneal cytology sample usually confirms the diagnosis, although lymphocytes, mast cells, and neutrophils are often present concurrently. Immunosuppressives are the mainstay of therapy, topically or systemically. The role of feline herpesvirus-1 in the pathogenesis of eosinophilic keratoconjunctivitis (EK) remains unclear. Eosinophilic conjunctivitis is a less common manifestation of EK and presents as severe conjunctivitis without corneal involvement.

Successful treatment of severe recalcitrant vernal keratoconjunctivitis and atopic dermatitis associated with elevated IgE levels with omalizumab.

We report the clinical case of an atopic patient with important manifestations impacting the quality of life at the cutaneous and ocular site. The condition resisted conventional treatments, and omalizumab had to be used to treat the disease successfully.

[Keratoconjunctivitis photoelectrica (arc eye)]. / Photokératoconjonctivite par coup d'arc.

Photokeratitis is a painful keratitis caused by exposure of insufficiently protected eyes to the ultraviolet (UV) rays. We talk about "arc eye" when photokeratitis is caused by UV rays emitted by electric arc during electric arc welding process. We here report the case of a 35-year old rider, with no previous medical-surgical history, who had looked at an electric arc for a few minutes while the doors of his building were welded. He had bilateral burning in his eyes associated with lacrimation, photophobia and blepharospasm. Clinical examination showed corrected visual acuity of 8/10 and 9/10, conjunctival hyperemia with punctate erosive keratitis limited to palpebral fissure after the use of fluorescein. Given patient's clinical picture, keratoconjunctivitis photoelectrica (arc eye) was diagnosed. Treatment was based on topical antibiotics, wetting agents as well as agents with healing properties. Outcome was marked by total disappearance of the signs with restoration of bilateral visual acuity (10/10). This study highlights the role of prevention using appropriate protection equipment.

Relapsing viral keratoconjunctivitis in COVID-19: a case report.

BACKGROUND: Since the outbreak of Coronavirus Disease 2019 (COVID-19) in December 2019, many studies have reported the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the conjunctival sac of patients infected with this virus, with several patients displaying symptoms of viral conjunctivitis. However, to our best knowledge, there is no in-depth report on the course of patients with COVID-19 complicated by relapsing viral conjunctivitis or keratoconjunctivitis. CASE PRESENTATION: A 53-year-old man confirmed with COVID-19 developed symptoms of viral conjunctivitis in the left eye approximately 10 days after the onset of COVID-19. The results of a nucleic acid test were positive for SARS-CoV-2 in the conjunctival sac of the left eye. The symptoms were relieved 6 days after treatment. However, the patient was subsequently diagnosed with viral keratoconjunctivitis in both eyes 5 days after the symptoms in the left eye were satisfactorily relieved. The disease progressed rapidly, with spot staining observed at the periphery of the corneal epithelium. Although SARS-CoV-2 could not be detected in conjunctival secretions, the levels of inflammatory factors, such as interleukin-6, were increased in both eyes. Both eyes were treated with glucocorticoids, and symptoms were controlled within 5 days. There was no recurrence. CONCLUSIONS: In this case report, the pathogenesis, clinical manifestations, treatment, and outcome of a case with COVID-19 complicated by relapsing viral keratoconjunctivitis is described, and the involvement of topical cytokine surge in the pathogenesis of COVID-19 as it relates to viral keratoconjunctivitis is reported.

Density and Morphology of Corneal Epithelial Dendritic Cells are Different in Allergy.

Purpose: The role of corneal epithelial dendritic cells (CEDC), a subtype of antigen presenting cells, in ocular allergy remains largely unknown. This cross-sectional study evaluated the density and morphology of CEDC in participants diagnosed with systemic allergy, to increase our understanding of the role of CEDC in ocular inflammation associated with systemic allergy.Materials and methods: A convenience sample of 50 participants was categorised into allergic and non-allergic groups (31 allergic and 19 non-allergic) based on the results of skin prick test (SPT). Ocular allergy symptoms, clinical ocular surface signs and serum IgE were assessed. In vivo confocal microscopy was performed on the right eye only. The number of CEDC in a 1mm2 region at both the central and mid-peripheral cornea was manually counted. CEDC morphology was graded on a 1 to 3 scale.Results: Ocular surface symptoms, signs (other than eyelid oedema), and serum IgE were significantly higher in the allergic (SPT+) group. CEDC density at the mid-peripheral cornea was significantly lower in the allergic group (p = .003). CEDC morphology grades were significantly higher in allergic participants in the central cornea (p = .02), with the highest grade morphology observed only in allergic participants. No associations were evident between CEDC density or morphology and ocular signs, symptoms or serum IgE.Conclusions: The study showed reduced CEDC density and cells with longer dendrites in allergic participants. The more mature CEDC morphology in the allergic group is suggestive of an inflammatory or immune response.

Genomic foundations of evolution and ocular pathogenesis in human adenovirus species D.

Human adenovirus commonly causes infections of respiratory, gastrointestinal, genitourinary, and ocular surface mucosae. Although most adenovirus eye infections are mild and self-limited, specific viruses within human adenovirus species D are associated with epidemic keratoconjunctivitis (EKC), a severe and highly contagious ocular surface infection, which can lead to chronic and/or recurrent, visually disabling keratitis. In this review, we discuss the links between adenovirus ontogeny, genomics, immune responses, and corneal pathogenesis, for those viruses that cause EKC.

Assessment of clinical signs associated with adenoviral epidemic keratoconjunctivitis cases in southern Japan between 2011 and 2014.

Adenoviral epidemic keratoconjunctivitis (EKC) is a major cause of ocular morbidity worldwide and specific antiviral therapies are not available. EKC is primarily caused by Human adenovirus D (HAdV-D) types 8, 37, 53, 54, 56 and 64. Considering the genomic variation in HAdV-D, we hypothesized that clinical signs could be differentiated by virus type. The hypothesis was retrospectively tested with clinical signs recorded from 250 patients with ocular infections visiting an ophthalmological clinic in southern Japan between 2011 and 2014. The results showed that conjunctival opacity, corneal epithelial disorders and pre-auricular lymphadenopathy, were more frequently associated with EKC than other ocular infections. Furthermore, HAdV types 8, 37 and 54, caused corneal complications and longer infections significantly more frequently than infections by types 53 and 56 (P < 0.05). Our descriptive results supported that symptoms severity vary with the infecting type, however, further research is needed to improve diagnosis of EKC.

Human adenovirus type 26 uses sialic acid-bearing glycans as a primary cell entry receptor.

Adenoviruses are clinically important agents. They cause respiratory distress, gastroenteritis, and epidemic keratoconjunctivitis. As non-enveloped, double-stranded DNA viruses, they are easily manipulated, making them popular vectors for therapeutic applications, including vaccines. Species D adenovirus type 26 (HAdV-D26) is both a cause of EKC and other diseases and a promising vaccine vector. HAdV-D26-derived vaccines are under investigation as protective platforms against HIV, Zika, and respiratory syncytial virus infections and are in phase 3 clinical trials for Ebola. We recently demonstrated that HAdV-D26 does not use CD46 or Desmoglein-2 as entry receptors, while the putative interaction with coxsackie and adenovirus receptor is low affinity and unlikely to represent the primary cell receptor. Here, we establish sialic acid as a primary entry receptor used by HAdV-D26. We demonstrate that removal of cell surface sialic acid inhibits HAdV-D26 infection, and provide a high-resolution crystal structure of HAdV-D26 fiber-knob in complex with sialic acid.

Human adenoviral type 54 keratoconjunctivitis accompanied by stellate keratitis and keratic precipitates: two cases.

BACKGROUND: Of the 10 patients with adenoviral type 54 keratoconjunctivitis examined at Nojima Hospital, 2 developed stellate keratitis and mutton-fat keratic precipitates (KPs) following acute symptoms. CASE PRESENTATION: We encountered 10 cases of epidemic keratoconjunctivitis from August to October 2017. All patients were adults with a mean age of 60.9 ± 10.0 years. The species D human adenovirus (HAdV)-54 was detected in the conjunctival scrapings of these patients. Fluorometholone instillation was administered during the first week for acute symptomatic relief. Case 1: A 64-year-old female was prescribed with fluorometholone instillation, which was discontinued after 1 week when her symptoms alleviated. One week after discontinuation of the instillation, she presented with blurred vision in her left eye with KPs and multiple stellate keratitis. The anterior chamber had no apparent cells. Her symptoms disappeared after 1 week of betamethasone instillation. Case 2: A 66-year-old female was prescribed with 0.1% fluorometholone instillation, which was discontinued within10 days. Three months after the appearance of initial symptoms, multiple subepithelial corneal infiltrates (MSI) appeared in her eyes. Stellate keratitis and dark-brown pigmentation were observed in the centres of MSI, with several cells in the anterior chamber. Betamethasone was prescribed, and MSI and stellate keratitis improved within 1 week. However, KPs were observed in the left eye. The instillation was continued for 3 more weeks until symptoms improved. CONCLUSIONS: MSI is an immune reaction that occurs after the disappearance of acute symptoms. Here, corneal findings and KPs were observed after improvement in eye redness and discontinuation of steroids. These symptoms were presumed to be secondary inflammation due to immune response to the adenoviral antigen. The clinical features of HAdV-54 keratoconjunctivitis on the ocular surface are initially moderate, but become active in the subacute to chronic phases. This may develop atypical findings, including stellate keratitis with KPs. Although early steroid administration can relieve acute symptoms, it may facilitate chronic corneal immunological reaction.

Management of advanced ocular surface disease in patients with severe atopic keratoconjunctivitis.

AIM & OBJECTIVE: Severe ocular surface disease, including limbal stem cell deficiency (LSCD) can occur as a consequence of severe atopic keratoconjunctivitis (AKC) that has been inadequately treated. Our goal was to describe the management and outcomes of severe ocular surface disease in AKC patients. METHODS: We performed a retrospective analysis of a case series of 13 eyes of 8 patients with advanced ocular surface disease associated with severe AKC. The clinical presentation, medical and surgical management, and visual and anatomic outcomes were analyzed. RESULTS: Five eyes were treated with medical interventions alone, which included topical or systemic immunomodulatory therapy (IMT) for all eyes. These eyes had a decline in mean visual acuity from LogMAR 0.96 to 2.04 between the initial and final visits related to recurrent epithelial defects or corneal ulceration. Eight eyes were treated with surgical approaches in addition to medical treatment. Initial surgical treatments included limbal stem cell transplantation (n = 5), Boston keratoprosthesis (n = 2), and superficial keratectomy (n = 1). Both eyes that underwent primary keratoprosthesis had severe post-operative complications and became no light perception. In the remainder of the surgically treated eyes, there was an improvement visual acuity from LogMAR 1.43 to 0.6 between the pre-operative and final post-operative visit. CONCLUSION: Visual rehabilitation in eyes severe ocular surface disease due to prolonged AKC is challenging. While some patients did experience improved vision, most eyes did not improve or experienced severe complications with vision loss. Early intervention with immunomodulatory therapy may prevent progression of the disease to advanced stages.

[Ophthalmic drug films in the therapy of experimental herpetic keratoconjunctivitis.]

INTRODUCTION: The complexity of the treatment of herpetic keratoconjunctivitis is due to the severity of the disease, complications, the transition to chronic relapsing forms and the insufficient effectiveness of the drugs used, which leads to a steady increase in the number of patients. The aim of the study was to evaluate the therapeutic efficacy of the eye drug films «GlazAvir¼ in the experimental model of acute herpetic eye infection in rabbits. RESEARCH OBJECTIVES: to study the specific activity of «GlazAvir¼ and compare the long-term indicators of the level of manifestation of individual clinical signs of keratoconjunctivitis. MATERIAL AND METHODS: In the work we used rabbits of the Chinchilla breed, the herpes simplex virus type 1 and the eye drug films «GlazAvir¼. A model of ophthalmic herpetic infection was formed by infection of rabbits with virus-containing material of a pre-scarified eye cornea against the background of local anesthesia. Аnimals were treated with the drug «GlazAvir¼ - 1 application per day for 7 days. Animals were observed daily for 15 days, then every 3 days until the 25th day of observation. The effectiveness of the drug was evaluated at the peak of the development of the pathological process. RESULTS AND DISCUSSION: There was a decrease in mortality from 50 to 20%, and an increase in average life expectancy by 27.87%, compared with the control in animals treated with «GlazAvir¼. It was noted after activation of herpetic keratoconjunctivitis on the 2nd - 5th day, at the peak of the disease (6-9th day) a statistically significant decrease in the activity of the pathological process (p<0.05) by rabbits treated with the «GlazAvir¼ ophthalmic drug films. The tendency to normalization by the rabbits treated with the «GlazAvir¼ preparation was observed until the 14th day. CONCLUSION: The data obtained indicate the pronounced effectiveness of the «GlazAvir¼ preparation in the treatment of experimental herpesvirus keratoconjunctivitis.

High Inflammatory Infiltrate Correlates With Poor Symptomatic Improvement After Surgical Treatment for Superior Limbic Keratoconjunctivitis.

PURPOSE: Superior limbic keratoconjunctivitis (SLK) is a chronic and recurrent condition of unknown etiology. It is often managed conservatively, but there is a high rate of success with surgical management for severe or recalcitrant cases. The purpose of this article is to describe and analyze clinicopathological features of patients with SLK who underwent surgical treatment and their association with the clinical outcome. METHODS: A total of 22 eyes from 18 patients who underwent surgical SLK management were retrospectively analyzed. Clinicopathological data were collected including details of follow-up and patient satisfaction (n = 15). Moreover, 12 cases had specimens available for review of histopathologic findings and COX-2 expression analysis by immunohistochemistry. RESULTS: From a clinical perspective, 66.7% of the SLK eyes had nonmechanical factors contributing to SLK, and 66.7% of eyes demonstrated significant symptomatic improvement after surgery. Histopathological analysis of all the lesions showed acanthosis and goblet cell loss. Unexpectedly, in 93% of the eyes, dilated lymphatic vessels were found. Furthermore, a high inflammatory infiltrate correlated with minimal symptomatic improvements (P = 0.013). Moreover, COX-2 expression was higher in patients with SLK than in a normal conjunctiva (P = 0.001). CONCLUSIONS: In this study, the most common systemic association with SLK was the patient's autoimmune status. Histopathological evaluation revealed that high inflammatory infiltration in the biopsy might be predictive of minimal symptomatic improvement with surgical management. Finally, the higher COX-2 expression in patients with SLK compared with that in individuals with a normal conjunctiva supports the use of anti-COX-2 drugs as a possible therapeutic target.

Expression of IL-33 in ocular surface epithelium induces atopic keratoconjunctivitis with activation of group 2 innate lymphoid cells in mice.

In a transgenic mouse line hK14mIL33tg, with the expression of interleukin-33 (IL-33) driven by a keratin 14 promoter, keratoconjunctivitis developed spontaneously between 18 and 22 weeks of age under specific-pathogen-free conditions. These mice showed blepharitis and corneal impairments, and the histology revealed epithelial thickening in the conjunctiva and the cornea with infiltration of eosinophils, mast cells and basophils. IL-5, IL-13 and CCL11 were abundant in lacrimal fluid in the mice, and the gene expressions of IL-4, IL-5, IL-13, IL-33, Prg2 and Mmcp8 were significantly increased in the cornea. Furthermore, group 2 innate lymphoid cells (ILC2) producing IL-5 and IL-13 were markedly increased in the cornea. These phenotypes closely resemble human atopic keratoconjunctivitis (AKC). The characteristic ocular phenotype in these mice strongly suggests that IL-33 is crucial for the development of AKC. The mouse line may be useful as a novel model for research and development of therapeutic strategies for AKC.

Cervid herpesvirus 2 and not Moraxella bovoculi caused keratoconjunctivitis in experimentally inoculated semi-domesticated Eurasian tundra reindeer.

BACKGROUND: Infectious keratoconjunctivitis (IKC) is a transmissible disease in semi-domesticated Eurasian reindeer (Rangifer tarandus tarandus). It is regarded as multifactorial and a single causative pathogen has not yet been identified. From clinical outbreaks we have previously identified Cervid herpesvirus 2 (CvHV2) and Moraxella bovoculi as candidates for experimental investigations. Eighteen reindeer were inoculated in the right eye with CvHV2 (n = 5), M. bovoculi (n = 5), CvHV2 and M. bovoculi (n = 5) or sterile saline water (n = 3; controls). RESULTS: All animals inoculated with CvHv2, alone or in combination with M. bovoculi, showed raised body temperature, increased lacrimation, conjunctivitis, excretion of pus and periorbital oedema; clinical signs that increased in severity from day 2 post inoculation (p.i.) and throughout the experiment, until euthanasia 5-7 days p.i. Examination after euthanasia revealed corneal oedema, and three animals displayed a corneal ulcer. CvHV2 could be identified in swab samples from both the inoculated eye and the control eye from most animals and time points, indicating a viral spread from the inoculation site. CONCLUSIONS: This study showed that CvHV2 alone and in combination with M. bovoculi was able to cause the characteristic clinical signs of IKC in reindeer, whereas inoculation of M. bovoculi alone, originally isolated from a reindeer with IKC, did not produce clinical signs. Previous studies have suggested that herding procedures, animal stress and subsequent reactivation of latent CvHV2 infection in older animals is a plausible mechanism for IKC outbreaks among reindeer calves and young animals in reindeer herds. However, further studies are needed to fully understand the infection biology and epidemiology associated with IKC in reindeer.

Keratoconjunctivitis in a group of Icelandic horses with suspected γ-herpesvirus involvement.

REASONS FOR PERFORMING STUDY: The role of equid γ-herpesviruses on ocular surface diseases has been disputed, because the diagnosis is usually based on clinical symptoms and detection of viral DNA from samples obtained from live animals. OBJECTIVES: To describe the clinical course, results of polymerase chain reaction (PCR) analysis, in situ hybridisation, cell culture and pathohistological findings of select cases in a presumed outbreak of herpesvirus infection in a group of 15 Icelandic horses. STUDY DESIGN: Case series. METHODS: Pooled ocular and nasal swabs and peripheral blood mononuclear cells of horses diagnosed clinically with herpesvirus-associated keratoconjunctivitis were analysed for presence of equine herpesviruses (EHV)-2 and EHV-5 nucleic acid using real-time PCR. Necropsy specimens from one horse, subjected to euthanasia due to deterioration of clinical symptoms were examined histopathologically, and analysed for presence of EHV-2 and EHV-5 nucleic acid using real-time PCR. In situ hybridisation and cell culture of select samples were performed. RESULTS: All horses with symptoms of severe keratoconjunctivitis were positive for presence of either EHV-2 and/or EHV-5 nucleic acid using real-time PCR. Assessment of necropsy specimens of the most severely affected case, revealed presence of EHV-2 and/or EHV-5 nucleic acid in several ocular and extraocular anatomical locations. The remaining horses responded favourably to symptomatic treatment. CONCLUSIONS: This case series illustrates a severe outbreak of keratoconjunctivitis in a group of Icelandic horses, with suspected γ-herpesvirus involvement. For the first time equid γ-herpesviruses were detected in intraocular anatomical locations.

Recombination of the epsilon determinant and corneal tropism: Human adenovirus species D types 15, 29, 56, and 69.

Viruses within human adenovirus species D (HAdV-D) infect epithelia at essentially every mucosal site. Hypervariable loops 1 and 2 of the hexon capsid protein contain epitopes that together form the epsilon determinant for serum neutralization. We report our analyses comparing HAdV-D15, 29, 56, and the recently identified type 69, each with highly similar hexons and the same serum neutralization profile, but otherwise disparate genomes. Of these, only HAdV-D type 56 is associated with epidemic keratoconjunctivitis (EKC), a severe infection of ocular surface epithelium and underlying corneal stroma. In the mouse adenovirus keratitis model, all four viruses induced inflammation. However, HAdV-D56 entry into human corneal epithelial cells and fibroblasts in vitro dramatically exceeded that of the other three viruses. We conclude that the hexon epsilon determinant is not a prime contributor to corneal tropism.

Involvement of corneal lymphangiogenesis in a mouse model of allergic eye disease.

PURPOSE: The contribution of lymphangiogenesis (LA) to allergy has received considerable attention and therapeutic inhibition of this process via targeting VEGF has been considered. Likewise, certain inflammatory settings affecting the ocular mucosa can trigger pathogenic LA in the naturally avascular cornea. Chronic inflammation in allergic eye disease (AED) impacts the conjunctiva and cornea, leading to sight threatening conditions. However, whether corneal LA is involved is completely unknown. We addressed this using a validated mouse model of AED. METHODS: Allergic eye disease was induced by ovalbumin (OVA) immunization and chronic OVA exposure. Confocal microscopy of LYVE-1-stained cornea allowed evaluation of corneal LA, and qRT-PCR was used to evaluate expression of VEGF-C, -D, and -R3 in these mice. Administration of VEGF receptor (R) inhibitor was incorporated to inhibit corneal LA in AED. Immune responses were evaluated by in vitro OVA recall responses of T cells, and IgE levels in the serum. RESULTS: Confocal microscopy of LYVE-1-stained cornea revealed the distinct presence of corneal LA in AED, and corroborated by increased corneal expression of VEGF-C, -D, and -R3. Importantly, prevention of corneal LA in AED via VEGFR inhibition was associated with decreased T helper two responses and IgE production. Furthermore, VEGFR inhibition led a significant reduction in clinical signs of AED. CONCLUSIONS: Collectively, these data reveal that there is a distinct involvement of corneal LA in AED. Furthermore, VEGFR inhibition prevents corneal LA and consequent immune responses in AED.

A comprehensive review on vernal keratoconjunctivitis with emphasis on proteomics.

Allergic conjunctivitis presents as a spectrum of different clinical entities, such as perennial allergic conjunctivitis, seasonal allergic conjunctivitis, atopic keratoconjunctivitis and vernal keratoconjunctivitis. Vernal keratoconjunctivitis (VKC) is a disorder that is often associated with allergens and is seen during the spring season. Herein, we focused on vernal keratoconjunctivitis (VKC) and reviewed its epidemiology, clinical presentations, ocular associations, available treatment options, and the progressive understanding of its histopathological features; we have also systematically elaborated on the various studies on proteomics. Initial theories of a solely IgE-mediated mechanism have been replaced by those considering IgE and non-IgE mechanisms. Developments in basic and clinical research will open novel diagnostic approaches for the early detection and cure of the disease.