Applications of topical immunomodulators enhance clinical signs of vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC): a meta-analysis.

PURPOSE: This meta-analysis aimed to review the safety and efficacy of topical cyclosporine A (CsA) and topical tacrolimus in allergic eye disease. METHODS: A systematic search identified thirteen studies and a total of 445 patients for inclusion, making this the largest meta-analysis published on the subject. The current review was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). RESULTS: Thirteen randomized control trials were included in the meta-analysis. Eleven studies used CsA as the treatment, and two used Tacrolimus. In total, 445 participants were included, of whom 76.6% were male. The mean age of participants across the included studies was 14 years. All studies reported clinical signs as evaluated by an examining clinician. Signs were usually assessed by anatomical region, with the most common regions being the conjunctiva and the cornea, and the most common signs assessed were hyperemia and papillae. Three studies accounted for more than 50% of the meta-analysis's weight. Effect size (d) ranged from - 2.37 to - 0.03, negative values favoring immunomodulators. Fixed Effect Meta-Analysis returned an SMD of - 0.81 (95% CI [- 0.98, - 0.65]). However, there was significant heterogeneity (I2 = 61%, Qw = 30.76) in the outcome measure (P = 0.0021); therefore, a random-effect meta-analysis was also completed in which the pooled SMD was - 0.98 (95% CI [- 1.26, - 0.69], τ2 = 0.16). CONCLUSIONS: This study affirms the current scientific community's stance that immunomodulators effectively treat clinical signs, including blepharitis, conjunctival hyperemia, edema, papillae, and corneal damage in severe ocular allergic disease.

Definition and Diagnostic Criteria for Pediatric Blepharokeratoconjunctivitis.

Importance: Pediatric blepharokeratoconjunctivitis (PBKC) is a chronic, sight-threatening inflammatory ocular surface disease. Due to the lack of unified terminology and diagnostic criteria, nonspecific symptoms and signs, and the challenge of differentiation from similar ocular surface disorders, PBKC may be frequently unrecognized or diagnosed late. Objective: To establish a consensus on the nomenclature, definition, and diagnostic criteria of PBKC. Design, Setting, and Participants: This quality improvement study used expert panel and agreement applying the non-RAND modified Delphi method and open discussions to identify unified nomenclature, definition, and definitive diagnostic criteria for PBKC. The study was conducted between September 1, 2021, and August 14, 2022. Consensus activities were carried out through electronic surveys via email and online virtual meetings. Results: Of 16 expert international panelists (pediatric ophthalmologists or cornea and external diseases specialists) chosen by specific inclusion criteria, including their contribution to scientific leadership and research in PBKC, 14 (87.5%) participated in the consensus. The name proposed was "pediatric blepharokeratoconjunctivitis," and the agreed-on definition was "Pediatric blepharokeratoconjunctivitis is a frequently underdiagnosed, sight-threatening, chronic, and recurrent inflammatory eyelid margin disease associated with ocular surface involvement affecting children and adolescents. Its clinical spectrum includes chronic blepharitis, meibomitis, conjunctivitis, and corneal involvement ranging from superficial punctate keratitis to corneal infiltrates with vascularization and scarring." The diagnostic criteria included 1 or more suggestive symptoms accompanied by clinical signs from 3 anatomical regions: the eyelid margin, conjunctiva, and cornea. For PBKC suspect, the same criteria were included except for corneal involvement. Conclusions and Relevance: The agreements on the name, definition, and proposed diagnostic criteria of PBKC may help ophthalmologists avoid diagnostic confusion and recognize the disease early to establish adequate therapy and avoid sight-threatening complications. The diagnostic criteria rely on published evidence, analysis of simulated clinical cases, and the expert panel's clinical experience, requiring further validation with real patient data analysis.

Pediatric Phlyctenular Keratoconjunctivitis at a Tertiary Care Center in the United States.

PURPOSE: The aim of this study was to evaluate characteristics and outcomes of pediatric phlyctenulosis at a tertiary care center in the United States. METHODS: A retrospective cohort study of phlyctenulosis diagnosis in patients younger than 18 years was conducted. Demographics, presenting features, treatment regimens, and outcomes were analyzed. RESULTS: Seventy patients (95 eyes) with phlyctenulosis were identified. Fifty-four patients (77.1%) were Hispanic, which was greater than the center's proportion of pediatric patients identifying as Hispanic (53.8%, P < 0.0001). Common comorbidities included adjacent external/lid disease (82.9%), allergic/atopic disease (18.6%), and viral infections (8.6%). Nine patients had tuberculosis testing which was negative in all cases. Five patients had vitamin A testing which revealed deficiency in 1 patient. Treatment regimens were diverse and included varying combinations of topical and systemic medications. Complications included corneal scarring (27.4%), corneal neovascularization (40.0%), amblyopia (16.8%), corneal perforation (3.2%), and severe limbal stem-cell deficiency (1.1%). 26.3% of affected eyes had final visual acuity worse than 20/40. Differences in rates of corneal complications between Hispanic and non-Hispanic patients were not statistically significant, although severe corneal complications including perforation occurred only in the Hispanic group. CONCLUSIONS: This study presents a modern cohort of phlyctenulosis at a tertiary center in the United States and includes a larger proportion of Hispanic patients than expected. Phlyctenulosis carries high corneal morbidity and may frequently result in reduced visual acuity. Similar rates of corneal complications were seen in Hispanic versus non-Hispanic patients, but severe corneal complications were seen only in the Hispanic group.

Microsporidia-Associated Anterior Uveitis After Keratoconjunctivitis.

OBJECTIVE: The aim of this study was to describe the clinical features and management of uveitis associated with microsporidial keratoconjunctivitis (MKC). METHODS: The medical records of clinically diagnosed or microbiologically proven patients with MKC between July 2016 and August 2021 were reviewed. Patients with documented evidence of keratic precipitates (KPs) or anterior chamber cells were analyzed for their demography, clinical features, and treatment. Patients with microsporidial stromal keratitis and herpes simplex virus keratouveitis were excluded from the study. RESULTS: Of the 2212 patients reviewed within the study period 171 of 172 eyes (7.7%) had documented evidence of KPs and/or anterior chamber cells. The patients' mean age was 43.8 ± 13.8 years, and there were more men (n = 120). The mean duration of appearance of KPs was 6.9 ± 5.5 days, and 28% (n = 48 of 171) appeared on the day of presentation. Superficial punctate keratitis was central and diffuse in 48 and 49 patients, respectively. The treatment was either lubricant alone (45.3%; 78 eyes) or combined with topical steroids (54.7%; 94 eyes). The mean duration of the resolution was longer in the "corticosteroid" than "no corticosteroid" group: KPs: 15.3 ± 6.5 days versus 12.3 ± 5.8 days ( P = 0.007) and superficial punctate keratitises: 15.4 ± 9.4 days versus 11.7 ± 6.2 days ( P = 0.01). The presenting visual acuity with a pinhole was 0.26 ± 0.26 (logMAR) and it improved to 0.03 ± 0.07 on resolution ( P < 0.0001, paired t test). CONCLUSIONS: Uveitis after MKC is a self-limiting entity that often resolves without corticosteroid. One must exercise caution in using steroids in the presence of active corneal lesions.

Human MPox (Monkeypox) Virus Membranous Keratoconjunctivitis With Transient Corneal Hypoesthesia and Late Symblepharon Formation: A Novel Case and Clinical Implications.

PURPOSE: The aim of this study was to describe a case of corneal involvement as an early manifestation of ocular disease in the 2022 human mpox (monkeypox) virus outbreak. METHODS: This is a single case report with longitudinal care. RESULTS: A 47-year-old immunocompetent man presented with viral conjunctivitis before development of skin lesions or systemic symptoms. Subsequently, he developed membranous keratoconjunctivitis and a corneal epithelial defect. Orthopoxvirus-positive polymerase chain reaction test from his ocular surface was positive. The epithelial defect did not heal with conservative treatment but was successfully treated with amniotic membrane transplantation over 8 days. Reduced corneal sensation was noted after epithelial healing, and polymerase chain reaction from the ocular surface remained positive at 17 days from symptom onset, with slowly recovering conjunctivitis at 21 days. Continued membrane formation required repeated removal but significantly improved with topical corticosteroid treatment after epithelial healing by 29 days of symptom onset. Corneal sensation normalized by 87 days from symptom onset at which time symblepharon were noted but PCR testing from the ocular surface was negative. CONCLUSIONS: Early corneal involvement of human monkeypox virus is possible. Transient corneal hypoesthesia may be due to acute inflammation. Chronic inflammatory changes can result in symblepharon. These findings have potential implications in patient care and corneal donation.

Establishing an accurate and sensitive in vitro drug screening system for human adenovirus infection with human corneal cells.

Epidemic keratoconjunctivitis (EKC) is a hazardous and highly contagious disease, with the potential to cause epidemic outbreaks in hospitals and other community settings. There are currently no approved drugs for human adenovirus (HAdV), the causative agent of EKC. To establish a novel drug screening system for ocular HAdV infections, we employed CRL11516, a non-cancerous but immortalized human corneal epithelial cell line. Brincidoforvir and 3'-deoxy-3'-fluorothymidine inhibit replication of HAdV species C type 1 (C1), C2, E4, and C6 to the same extent. This alternative assay system may allow for the evaluation of anti-HAdV activity and cell cytotoxicity of compounds within 2 days and without the need of the rabbit eye infection model.

Keratoconjunctivitis as a Single Entity in X-linked Agammaglobulinemia?

PURPOSE: To report a case of a male patient with a severe corneal and conjunctival immunopathy likely caused by an X-linked agammaglobulinemia. METHODS: A clinical case report with observation results from 2001-2021. RESULTS: A severe corneal immunopathy of both eyes is reported in a retrospective long-term observation of nearly twenty years in a 32-year-old male patient with X-linked agammaglobulinemia (XLA). A chronic progressive corneal scarring with a loss of visual acuity and typical symptoms of a phlyctenular keratoconjunctivitis were observed. CONCLUSION: Whereas steroid eye drops like dexamethasone could control the symptoms and the corneal scarring progression as short time therapy options, ciclosporin A eye drops showed problems in therapy adherence in long-time use. Antibiotic eye drops supported the anti-inflammatory therapy effects, but no typical pathogen was detected. Antineovascular subconjunctival application did not show any relevant effect in one-time use. Artificial tears were needed as basic therapy.

Topical cyclosporine A 1 mg/ml for atopic keratoconjunctivitis: Five-year case series of 99 children and young people.

PURPOSE: To explore the effects of cyclosporine A (CsA) in the management of atopic keratoconjunctivitis (AKC). METHODS: Open single-group interventional consecutive cohort study (case series) at a single eye care facility in the UK. We reviewed the electronic patient records of 99 children and young people (CYP) aged 3.4-18 years with AKC treated with topical CsA 1 mg/ml. Main outcome measures were number of prescriptions and hospital clinic visits over 12 months before and after the start of CsA and the proportion of CYP affected by adverse effects. RESULTS: The median number of inflammatory episodes requiring treatment with topical corticosteroids (tCS) fell from 3 (interquartile range IQR 1-4) during the 12 months prior to CsA to 1 (IQR 0-3) during the 12 months after, excluding tCS prescriptions with the first CsA prescription (Wilcoxon signed ranks test, 2 tailed, p < 0.01). In the 12-month period following initiation of CsA 1 mg/ml with concomitant prescription of tCS (n = 66), daily dosage of steroids was reduced in 62 CYP (93.9%), and they were discontinued in 43 (65.2%). The median number of hospital visits fell from 4 (IQR 3-6) to 3 (IQR 2-5; Wilcoxon p < 0.01). Adverse events leading to discontinuation of CsA were stinging (instillation site pain; 9/99, 9%) and a transient skin rash (1/99, 1%). CONCLUSIONS: Off-label use of commercial preparations of CsA 1 mg/ml significantly reduces the need for concomitant topical corticosteroids and hospital clinic visits in CYP with AKC. Stinging and skin rash can lead to discontinuation.

Efficacy and Safety of Ophthalmic Preparations of Glucocorticoids in Patients with Epidemic Keratoconjunctivitis: A Systematic Review and Meta-analysis.

BACKGROUND: Epidemic keratoconjunctivitis (EKC) is a highly contagious infectious ocular disease that has been widespread worldwide. Ophthalmic preparations of glucocorticoids (OPGs) are the supportive therapies for EKC; however, they are still controversial. METHODS: We performed a systematic review and meta-analysis to evaluate the efficacy and safety of OPGs in patients with EKC. Electronic searches were conducted in PubMed, Embase, the Cochrane Library, ClinicalTrials.gov, China National Knowledge Internet (CNKI), and Wanfang Database from inception to 25 Aug 2022. We included and analyzed randomized controlled trials (RCTs) and cohort studies that compared OPGs to other positive drugs or placebo in patients with EKC. RESULTS: Six studies (five RCTs and one retrospective cohort) involving 286 patients were included in the analysis. Compared with artificial tears, OPGs could relieve ocular symptoms faster in the acute phase of epidemic keratoconjunctivitis (AEKC). There was no significant difference in the incidence of corneal subepithelial infiltrates (SEIs) in AEKC when OPGs were used for 7 days, but there was a substantial difference for 21 and 28 days. In the chronic phase of epidemic keratoconjunctivitis (CEKC), there was no significant difference in the rate of complete elimination of SEIs at 6 months of OPGs treatment compared with immunosuppressants [RR = 1.07,95%CI (0.71,1.61), p = 0.75], as well as in the recurrence rate of SEIs after 6 months [RR = 2.05,95%CI (0.82,5.12), P = 0.13]. OPGs significantly increased intraocular pressure (IOP) at 6 months compared with immunosuppressants [MD = - 1.13,95%CI (- 1.97, - 0.30), P = 0.007]. There was no significant difference in cessation of therapy due to drug intolerance between OPGs and immunosuppressants [RR = 0.69,95%CI (0.16,2.94), p = 0.62]. CONCLUSIONS: OPGs might relieve ocular symptoms and reduce the incidence of SEIs in AEKC, whereas not recommended the therapy in CEKC. More high-quality clinical evidence is required to confirm our findings.

A randomised control trial to evaluate the effectiveness of a commercial vaccine for pinkeye in Australian beef cattle.

Pinkeye (a generic term to describe infectious bovine keratoconjunctivitis) is a significant disease of cattle worldwide, impacting productivity and animal welfare. One commercial pinkeye vaccine, a systematically administered Moraxella bovis bacterin, has been available in Australia since 2007. This is the first field trial of the effectiveness of this vaccine for the prevention of naturally occurring disease in Australia. Extensively run beef herds in southwest Queensland that regularly experienced pinkeye were enrolled in the trial and animals were randomly allocated to vaccinated and control groups in different proportions in each herd. The subsequent incidence of clinical pinkeye between the two groups was compared for animals less than one-year-old. Data were analysed from 649 cattle from five herds over two pinkeye seasons: three herds of 390 calves from 1st November 2019 to 20th January 2020 and two herds of 259 calves from 23rd September 2020 to 21st April 2021. Pinkeye was common with 24% of all calves (156/649) contracting the disease during the trial. Univariable and multivariable binary logistic mixed-effect models were fitted to account for clustered data and potential residual confounding due to sex, weight, breed, coat colour, and periocular pigmentation. The incidence of pinkeye was not significantly different between vaccinated and control groups, both alone (p = 0.67) and after adjusting for sex and weight differences (p = 0.69). The vaccine was not protective against naturally occurring pinkeye under the field conditions.

In Vitro efficacy of cyclosporine a and various antiseptics and antiviral drugs on adenovirus genotype 8, a common cause of epidemic keratoconjunctivitis.

PURPOSE: To evaluate the in vitro efficacy of cidofovir, ganciclovir, povidone-iodine, chlorhexidine, and cyclosporine A on adenovirus genotype 8. METHODS: Conjunctival samples were collected from patients with adenoviral conjunctivitis and cultured in A549 cells. Adenovirus diagnosis was confirmed by RT-PCR. For each drug, the 50% cytotoxic concentration (CC 50 ) was determined. Subsequently, the antiviral activity was tested at concentrations below CC 50, and the 50% inhibitor concentration (IC 50 ) of drugs was determined RESULTS: While the IC 50 of cidofovir against adenovirus genotype 8 was 3.07 ± 0.8 µM, ganciclovir, povidone-iodine, chlorhexidine, and cyclosporine A were not found to be effective against adenovirus genotype 8 at concentrations below the CC 50 value. CONCLUSIONS: Cidofovir was found effective and the IC 50 value was within the ranges in the literature. Ganciclovir and cyclosporine A were found to be ineffective at doses below the cytotoxic dose, povidone-iodine and chlorhexidine was found to be highly cytotoxic.

Clinical Characteristics and Therapeutic Outcomes of Pediatric Blepharokeratoconjunctivitis.

PURPOSE: The purpose of this study was to determine the clinical characteristics, disease course, therapeutic outcomes, and prognostic factors for pediatric patients with blepharokeratoconjunctivitis (BKC). METHODS: A retrospective medical chart review was performed for patients aged 15 years or younger who had been diagnosed with BKC between 2004 and 2020 at 2 tertiary hospitals in Korea. The following data were collected: demographics, medical history, ocular findings, geometric profiling of corneal lesion, medical management, and outcomes. RESULTS: A total of 137 patients (90 female and 47 male) were included. The patients' mean age was 8.3 ± 3.8 years at disease onset. Both eyes were involved in 57.7% of cases. The most common corneal lesion was corneal neovascularization (77.4%), followed by clinically visible corneal infiltration (51.8%) and stromal scarring (43.1%). Most of the corneal lesions involved a single quadrant, most commonly the inferior quadrant. After treatment, disease remission was achieved in 95% of patients, and visual acuities improved from 0.2 ± 0.3 logarithm of minimal angle of resolution at disease presentation to 0.1 ± 0.3 logarithm of minimal angle of resolution at final follow-up ( P = 0.001). Recurrence occurred in 52.6% of patients. Cylinder power was significantly higher in patients with recurrence than in those without. The number of cases of recurrence was positively associated with final cylinder power. CONCLUSIONS: Although the treatment induced disease remission in 95% of children with BKC, recurrence occurred in 52.6% of those cases. Because recurrence resulted in significant astigmatism, careful observation for recurrence and prompt management are warranted for preservation of vision in pediatric patients with BKC.

[Diagnosis and treatment of adenoviral keratoconjunctivitis]. / Diagnostika i lechenie adenovirusnogo keratokon"yunktivita.

PURPOSE: To improve the treatment of adenoviral lesions of the eye based on express diagnostics by the fluorescent antibody technique (FAT) and the use of modern drugs. MATERIAL AND METHODS: The study included 184 patients (333 eyes) with various manifestations of adenoviral lesions of the ocular surface, who were divided into two groups: group 1 (149 patients, 196 eyes) - acute form, and group 2 (76 patients, 137 eyes) - long lasting form. Effectiveness of the proposed treatment was evaluated against separate group 3 (controls) consisting of 28 people (46 eyes) with completed acute adenovirus infection, who had previously received antibiotic and corticosteroid therapy in other clinics. Conjunctival scrapings of study patients were examined with FAT in our proposed modification. Study patients received local therapy with modern drugs (Okomistin, Aktipol). RESULTS: FAT detected the adenovirus antigen in 169 cases in group 1 (86%) and in 99 cases in group 2 (72%). Treatment duration amounted to 12±6 days in group 1, 18±8 days in group 2, and 29±7 days in controls. In both study groups, the duration of treatment was significantly reduced in comparison with the controls (p<0.01). Stable clinical effect and complete restoration of visual acuity have been achieved in most cases. There were no allergic and side effects from the therapy. CONCLUSION: Fluorescent antibody technique is a fast and effective way to diagnose adenovirus infection in ophthalmology. In terms of therapy, the use of an antiseptic, an antiviral drug and diluted corticosteroids is the most rational approach.

[Focus on the diagnosis and treatment of blepharokeratoconjunctivitis in children].

Blepharokeratoconjunctivitis, (BKC) is a common ocular surface chronic inflammatory disease in children. It can cause eye irritation or even visual impairment. At present, the etiology of BKC in children is not clear and relevant studies are in the initial stage, consequently, there has not been an authoritative applicable expert consensus in China. Compared with adults, the clinical manifestations of pediatric patients are often atypical, coupled with the lack of understanding, so inadequate diagnosis and treatment are still exist in pediatric BKC. This article reviews the etiology, diagnosis and treatment status, clinical characteristics, standardized diagnosis and treatment of pediatric BKC, in order to arouse the attention of ophthalmologists.

Importance of Corneal Angiography in Subclinical Limbitis in a Case of Atopic Keratoconjunctivitis.

PURPOSE: The aim of this study was to report corneal angiography features in subclinical limbitis in a patient with atopic keratoconjunctivitis. METHODS: This is a case report. RESULTS: A 22-year-old woman with a medical history of atopic keratoconjunctivitis was referred for bilateral corneal neovascularization with scarring. On examination, no signs of active disease were noticed at the slit lamp. Ocular surface angiography detected active corneal limbitis, showing as limbal leakage at fluorescein angiography in the early phase and leakage after indocyanine green angiography in the late phase. The patient was treated with topical corticosteroid. At follow-up, the fluorescein angiography and indocyanine green angiography no longer showed limbal leakage, whereas the slit lamp examination was unchanged. CONCLUSIONS: Active allergic corneal limbitis may present as subclinical inflammation, with no signs of activity at the slit lamp examination. Therefore, its diagnosis can be challenging without the use of corneal angiography.

Topical Pharmacologic Interventions Versus Active Control, Placebo, or No Treatment for Epidemic Keratoconjunctivitis: Findings From a Cochrane Systematic Review.

PURPOSE: To summarize key findings from a Cochrane systematic review of the effectiveness and safety of topical pharmacologic interventions compared with active control or placebo for epidemic keratoconjunctivitis (EKC). DESIGN: Systematic review. METHODS: We included randomized controlled trials that compared antiseptic agents, virustatic agents, or immune-modulating topical therapies with placebo or an active control. We adhered to Cochrane methods for trial selection, data extraction, risk of bias evaluation, and data synthesis. RESULTS: Ten randomized controlled trials with 892 participants with acute or chronic EKC were included. Eight trials compared interventions with artificial tears or saline (n = 4) or with steroids (n = 4); two 3-arm trials contributed data to both comparisons. Estimates suggested that compared with tears, after povidone-iodine (PVP-I) alone (2 studies, 409 participants) more participants with acute EKC had resolution of symptoms (risk ratio [RR] 1.15 [95% confidence interval {CI} 1.07-1.24]) and signs (RR 3.19 [95% CI 2.29-4.45]) within 10 days. In 2 trials comparing treatments with steroid alone or steroid with levofloxacin, fewer eyes treated with PVP-I or polyvinyl alcohol iodine (PVA-I) plus steroid developed subepithelial infiltrates within 21 days (RR 0.08 [95% CI 0.01-0.55]; 69 eyes). No treatment was shown to improve resolution of infiltrates. CONCLUSIONS: Low- to very low-level certainty of evidence suggested that PVP-I or PVA-I with steroid may confer some benefit in acute EKC, but imprecision from small sample sizes, the potential risk of bias from inadequate reporting or trial design, and variability in participant selection, outcome measurement, and reporting limit the amount and quality of evidence.