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.

[Current aspects of vernal and atopic keratoconjunctivitis]. / Aktuelles zur Keratoconjunctivitis vernalis und atopica.

BACKGROUND: Vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC) are complex and rare diseases. Thus, their diagnosis and treatment are often a challenge. OBJECTIVE: Discussion on the epidemiology, new pathogenetic concepts, interesting clinical findings, diagnostic possibilities and new treatment options and their side effects in severe ocular allergies. Analysis of the presentation of VKC in the internet. MATERIAL AND METHODS: Evaluation of recent review articles, original publications, and case reports on the topics of VKC and AKC over the past 5 years. RESULTS: Ocular allergies have significantly increased over the last decades. Recent concepts discussed in the pathogenesis of VKC and AKC are the role of the local and gut microbiome as well as the influence of neuroinflammation. Keratoconus is significantly more common in patients with VKC and AKC compared to the normal population. It is associated with faster progression and a more severe course of disease. A conjunctival provocation test is only rarely necessary in the diagnosis of allergic conjunctivitis. Treatment of atopic dermatitis with dupilumab, an interleukin 4 receptor alpha (IL-4Ra) antagonist, can cause ocular side effects. Unfortunately, information available on the internet for patients and parents on the topic of VKC is sometimes dangerously incorrect. CONCLUSION: From the abovementioned new pathogenetic concepts, preventive and personalized treatment options could be developed in the future. Keratoconus in AKC/VKC must be recognized and treated early. Official guidelines are now available for a standardized conjunctival provocation test in the diagnosis of allergic conjunctivitis. The unwanted ocular side effects of dupilumab are often difficult to discriminate from the actual underlying AKC and respond well to anti-inflammatory treatment. Patients with VKC must be informed about the incorrect information on the internet regarding their disease.

Corneal topometric indices and proclivity toward corneal ectasia in vernal keratoconjunctivitis.

PURPOSE: To investigate changes in topometric corneal indices and proclivity toward corneal ectasia, as well as keratometric indices and anterior chamber dimensions in palpebral vernal keratoconjunctivitis (VKC). METHODS: This study included 80 patients with clinically established symptoms of grade 0 or grade 1 palpebral VKC (group 1) and 66 healthy participants (group 2). After a comprehensive ophthalmic examination including best-corrected visual acuity, intraocular pressure measurements and slit-lamp biomicroscopy, pachymetric indices and anterior chamber dimensions were measured using the Pentacam HR rotating Scheimpflug device. Topometric indices, which are particularly useful for determining proclivity toward corneal ectasia, were extracted from a topometric map. RESULTS: In groups 1 and 2, the mean ages were 13.11±5.22 and 16.45±5.09 years, respectively. The mean age at disease onset in group 1 was 10.09±5.03 years, and the mean disease duration was 36.23±8.43 months. Group 1 had significantly higher mean topometric indices than group 2, particularly the index of surface variance (P=0.001), index of vertical asymmetry (P=0.007), center keratoconus index (P=0.050), and Belin/Ambrosio enhanced ectasia total deviation value (P=0.032). Mean posterior corneal astigmatism differed significantly between groups 1 and 2 (P=0.003). CONCLUSIONS: Significantly higher mean topometric indices in VKC indicate a proclivity for corneal ectasia, which could be attributed to general changes in the corneal ultrastructure caused by persistent itching-induced eye rubbing.

Efficacy of a Cationic Emulsion of Cyclosporine in Moderate Vernal Keratoconjunctivitis.

PURPOSE: The aim of this study was to demonstrate the efficacy of cyclosporine A 0.1% cationic emulsion (CsA CE) eye drops 4 times a day in pediatric patients affected by a moderate form of vernal keratoconjunctivitis (VKC). METHODS: This was a prospective study of pediatric patients, aged 5-16 years, with an active moderate form of VKC who were poor responders to topical antihistamines treatment and were treated 4 times a day with CsA CE. The clinical signs were graded for analysis as follows: hyperemia, tarsal papillae, and limbal papillae. RESULTS: Twenty-eight patients (22 males and 6 females) with a minimum follow-up period of 3 months were included in the analysis. Statistical analysis excluded tarsal papillae because of the very low baseline value. The clinical score of hyperemia and limbal papillae improved from the first evaluation and was maintained over the follow-up. No side effects were noted. CONCLUSION: CsA CE has been proposed as a treatment for severe forms of VKC. This study has shown that administration 4 times a day is also effective in the treatment of moderate forms of VKC in children.

Epinastine Cream: A Novel Once-Daily Therapeutic Agent for Allergic Conjunctivitis.

Purpose: To investigate the in vivo efficacy of epinastine cream in type I allergic models. Methods: The dose, timing, and antiallergic effect of epinastine cream on the conjunctiva were evaluated postapplication to the eyelid skin of guinea pigs with histamine- or ovalbumin-induced allergic conjunctivitis. Additionally, we assessed its antiallergic effects on the skin postapplication to the dorsal skin of guinea pigs with ovalbumin-induced passive cutaneous anaphylaxis. Efficacy was estimated by determining the amount of dye that leaked from conjunctival or dorsal skin tissue vessels as a measure of vascular permeability, scoring the severity of allergic symptoms, and observing the scratching behaviors using clinical parameters. Results: In the histamine-induced conjunctivitis model, epinastine cream strongly inhibited conjunctival vascular permeability in a dose-dependent manner. The inhibitory effect of 0.5% epinastine cream 24 h postapplication was significantly higher than that of 0.1% epinastine hydrochloride ophthalmic solution 8 h postadministration. Additionally, the 0.5% epinastine cream inhibited conjunctival vascular permeability 15 min postapplication, and the effect was sustained over 24 h. Furthermore, the 0.5% epinastine cream effectively suppressed clinical symptom scores and exhibited ameliorated scratching bouts in conjunctival allergic reactions in the experimental allergic conjunctivitis model. Additionally, it significantly inhibited vascular permeability in skin allergic reactions in the passive cutaneous anaphylaxis model. Conclusions: The results suggest that epinastine cream is a strong, long-lasting, and skin-penetrating inhibitor of type I allergic reactions. The 0.5% epinastine cream applied once daily could be a promising, potent, and long-acting therapeutic agent for allergic conjunctivitis.

Tear Fluid Inflammatory Proteome Analysis Highlights Similarities Between Keratoconus and Allergic Conjunctivitis.

Purpose: Keratoconus is characterized by the progressive thinning of the cornea, which leads to a cone-like appearance of the eye over time. Although conventionally defined as a noninflammatory condition, a number of recent studies have associated keratoconus (KC) with allergic conjunctivitis (AC) based on clinical parameters. This study aimed to consolidate this association by performing a proteomic analysis of tear fluid from patients with keratoconus and/or allergic conjunctivitis. Methods: Of 51 patients, 17 were diagnosed with KC, 17 were diagnosed with AC, and 17 were diagnosed with both KC and AC (combined). Nine of 34 patients with KC had a progressive form of the disease. Tear fluid samples (n = 51, one eye per patient) were collected by the Schirmer's strips. Tear proteins were extracted from the Schirmer's strips. Proteomic profiling of 384 inflammatory proteins was assessed by a multiplex proximity extension assay (Olink Explore 384 Inflammation Panel I). Results: A total of 384 inflammatory proteins were measured. Two hundred seventy-two of the 384 proteins passed stringent data cleaning and were compared among the patient groups. Compared to the 2 other groups, LGALS9 was upregulated uniquely in KC, whereas FGF19, PDGFB, HPCAL1, OSM, and FCAR were downregulated in KC. Similarly, TNFRSF4 and CCL13 were specifically upregulated in AC, whereas ectodysplasin A receptor (EDAR) was uniquely downregulated in AC. Conclusions: High-throughput proteomic profiling of tear fluid confirms the association between KC and AC on a molecular level and raise the importance of redefining KC as an inflammatory condition.

Dendritic Cell Density and Morphology Can Be Used to Differentiate Vernal Keratoconjunctivitis from Allergic Conjunctivitis.

The aim of the study was to compare the distribution of corneal and conjunctival epithelial dendritic cells (DCs) in vernal keratoconjunctivitis (VKC), allergic conjunctivitis (AC), and non-allergic controls to examine if the allergy type causes differences in immune cell activation. The prospective study included 60 participants: 20 with VKC, 20 with AC, and 20 non-allergic controls. In vivo confocal microscopy was performed on the right eye. The locations scanned included the corneal centre, inferior whorl, corneal periphery, corneal limbus, and bulbar conjunctiva. The DCs were counted manually, and their morphology was assessed for the largest cell body size, the presence of dendrites, and the presence of long and thick dendrites. The DC density was higher in VKC and AC compared to non-allergic group at all locations (p ≤ 0.01) except at the inferior whorl. The DC density in VKC participants was significantly higher than in AC at the limbus (p < 0.001) but not at other locations. Both the AC and the VKC group had larger DC bodies at the corneal periphery and limbus compared to the non-allergic group (p ≤ 0.03). The study found a higher proportion of participants with DCs exhibiting long dendrites at both the corneal periphery in AC (p = 0.01) and at the corneal centre, periphery, and limbus in VKC, compared to the non-allergic group (p ≤ 0.001). In conclusion, a higher DC density at the limbus may be a marker of more severe VKC. DCs with larger cell bodies and a greater proportion of participants with DCs displaying long dendrites can be potential markers to differentiate allergy from non-allergy, and more severe forms of allergy from milder forms.

[Allergic and immunopathological diseases of the ocular surface]. / A szemfelszín allergiás és immunpatológiai betegségei.

Allergic and immunopathological diseases of the ocular surface are inflammations that can occur with mild to severe symptoms that cause visual impairment. Allergic inflammations mainly affect the conjunctiva, causing acute and/or chronic conjunctivitis. Several forms are distinguished: seasonal allergic conjunctivitis, vernal conjunctivitis, atopic keratoconjunctivitis, contact allergy, giant papillary conjunctivitis. The most common is the seasonal form, which is linked to seasons. Allergic ocular surface processes require local treatment with artificial tears, anti-allergic eye drops. If complications occur, topical corticosteroid and cyclosporin treatment may be used. Immunopathological inflammations of the ocular surface are associated with systemic diseases. Keratoconjunctivitis sicca, although occurring in the absence of systemic disease, is a common companion of Sjögren's syndrome and collagen diseases. Ocular pemphigoid belongs to the group of mucous membrane pemphigoids. After the initial conjunctivitis symptoms, subconjunctival fibrosis begins, leading to the development of sym- and ankyloblepharon. In the final stage, the ocular surface is covered by scar tissue (ocular cicatricial pemphigoid) which practically results in loss of vision. Peripheral ulcerative keratitis is usually associated with collagen vascular disease, rheumatoid arthritis. A 3-4 mm long, curved infiltration starting near the limbus becomes ulcerated and then perforates, on which the iris may prolapse. First, systemic treatment is required, which is an interdisciplinary task. Topical corticosteroid and cyclosporine eye drops may be administered. In the case of corneal perforation, amniotic membrane transplantation and/or keratoplasty may be performed. Orv Hetil. 2023; 164(43): 1686-1692.

Biomarkers of ocular allergy and dry eye disease.

The most common disorders of the ocular surface are dry eye disease (DED) and ocular allergy (OA). These conditions are frequently coexisting with or without a clinical overlap and can cause a severe impact on the patient's quality of life. Therefore, it can sometimes be hard to distinguish between DED and OA because similar changes and manifestations may be present. Atopic patients can also develop DED, which can aggravate their manifestations. Moreover, patients with DED can develop ocular allergies, so these two pathological entities of the ocular surface can be considered as mutual conditions that share the same background. Nowadays, by using different techniques to collect tissue from ocular surfaces, the changes in molecular homeostasis can be detected and this can lead to a precise diagnosis. The article provides an up-to-date review of the various ocular surface biomarkers that have been identified in DED, OA, or both conditions. Abbreviations: DED = dry eye disease, OA = ocular allergy, SS = Sjogren syndrome, TBUT = tear break up time, TFO = tear film osmolarity, AKC = Atopic keratoconjunctivitis, ANXA1 = Annexin 1, ANXA11 = Annexin 11, CALT = Conjunctival associated lymphoid tissue, CCL2/MIP-1 = Chemokine (C-C motif) ligand2/Monocyte chemoattractant protein 1, CCL3/MIP-1α = Chemokine (C-C motif) ligand 3/Macrophage inflammatory protein 1 alpha, CCL4/MIP-1ß = Chemokine (C-C motif) ligand 4/Macrophage inflammatory protein 1 beta, CCL5/RANTES = Chemokine (C-C motif) ligand 5 /Regulated on Activation, Normal T cell Expressed and Secreted, CCR2 = Chemokine (C-C motif) receptor 2, CCR5 = Chemokine (C-C motif) receptor 5, CD3+ = Cluster of differentiation 3 positive, CD4+ = Cluster of differentiation 4 positive, CD8+ = Cluster of differentiation 8 positive, CGRP = Calcitonin-gene-related peptide, CX3CL1 C-X3 = C motif -chemokine ligand 1 /Fractalkine, CXCL8 = Chemokine (C-X-C motif) ligand 8, CXCL9 = Chemokine (C-X-C motif) ligand 9, CXCL10 = Chemokine (C-X-C motif) ligand 10, CXCL11 = Chemokine (C-X-C motif) ligand 11, CXCL12 = Chemokine (C-X-C motif) ligand 12, CXCR4 = Chemokine (C-X-C motif) receptor 4, EGF = Epidermal growth factor, HLA-DR = Human leukocyte antigen-D-related, ICAM-1 = Intercellular adhesion molecule 1, IFN-γ = Interferon-gamma, IgG = Immunoglobulin G, IgE = Immunoglobulin E, IL-1 = Interleukin-1, IL-1α = Interleukin-1 alpha, IL-1ß = Interleukin-1 beta, CGRP = Calcitonin-Gene-Related Peptide, IL-3 = Interleukin-3, IL-4 = Interleukin-4, IL-6 = Interleukin-6, IL-8 = Interleukin-8, IL-10 = Interleukin-10, IL-17 = Interleukin-17, IL-17A = Interleukin-17A, LPRR3 = Lacrimal proline-rich protein 3, LPRR4 = Lacrimal proline-rich protein 4, MUC5AC = Mucin 5 subtype AC, oligomeric mucus/gel-forming, MUC16 = Mucin 16, OCT = Optical coherence tomography, OGVHD = Ocular graft versus host disease, PAX6 = Paired-box protein 6, VKC = Vernal keratoconjunctivitis, TGF-ß = Transforming growth factor ß, S100 = proteins Calcium activated signaling proteins, Th1 = T helper 1 cell, Th17 = T helper 17 cell, MGD = Meibomian gland dysfunction, TFOS = Tear film and ocular surface society, SS-KCS = Keratoconjunctivitis Sicca, MMP-9 = Matrix metalloproteinase 9, MMP-1 = Matrix metalloproteinase 1, ZAG = Zinc alpha glycoprotein, CBA = Cytometric bead array, MALDI TOF-MS = matrix assisted laser desorption ionization-time of flight, SELDI TOF-MS = surface-enhanced laser desorption ionization-time of flight, IVCM = in vivo confocal microscopy, AS-OCT = anterior segment optical coherence tomography, iTRAQ = Isobaric tags for relative and absolute quantitation, LC-MS = Liquid chromatography-mass spectrometry, LCN-1 = lipocalin 1, PIP = prolactin induced protein, NGF = Nerve growth factor, PRR4 = proline rich protein 4, VIP = Vasoactive intestinal peptide, ELISA = enzyme linked immunoassay, TNF-α = tumor necrosis factor alpha, PAC = perennial allergic conjunctivitis, SAC = seasonal allergic conjunctivitis, IC = impression cytology, RT-PCR = reverse transcription polymerase chain reaction, PCR = polymerase chain reaction, APCs = antigen-presenting cells, NK cells = natural killer cells, HEL = hexanoyl-lysine, 4-HNE = 4-hydroxy-2-nonenal, MDA = malondialdehyde.

A nerve-goblet cell association promotes allergic conjunctivitis through rapid antigen passage.

The penetration of allergens through the epithelial layer is the initial step in the development of allergic conjunctivitis. Although pollinosis patients manifest symptoms within minutes after pollen exposure, the mechanisms of the rapid transport of the allergens remain unclear. In the present study, we found that the instillation of pollen shells rapidly induces a large number of goblet cell-associated antigen passages (GAPs) in the conjunctiva. Antigen acquisition by stromal cells, including macrophages and CD11b+ dendritic cells, correlated with surface GAP formation. Furthermore, a substantial amount of antigen was transported to the stroma during the first 10 minutes of pollen exposure, which was sufficient for the full induction of an allergic conjunctivitis mouse model. This inducible, rapid GAP formation and antigen acquisition were suppressed by topical lidocaine or trigeminal nerve ablation, indicating that the sensory nervous system plays an essential role. Interestingly, pollen shell-stimulated GAP formation was not suppressed by topical atropine, suggesting that the conjunctival GAPs and intestinal GAPs are differentially regulated. These results identify pollen shell-induced GAP as a therapeutic target for allergic conjunctivitis.

Allergen-specific IgE in the tear fluid of Chinese patients with common allergic conjunctivitis in autumn and winter.

PURPOSE: In this study, we determined the positive rates of allergen-specific immunoglobulin E (IgE) in the tear fluid of Chinese patients with common allergic conjunctivitis (AC) in autumn and winter, compared systemic and ocular allergen tests, and explored the correlation between the numbers and categories of allergens and clinical AC features. METHODS: This cross-sectional study recruited 44 patients with AC (86 eyes). Specific IgEs for allergens common in China (house dust mite, cat/dog dander, mugwort/ragweed pollen, cottonwood/willow/elm pollen, milk, egg whites, soybeans) were measured in collected tears using kits for allergen-specific IgE antibodies. AC signs and symptoms were graded according to severity. RESULTS: Specific IgE in tears was positive in 87.2% of eyes. House dust mite was the most common allergen (86.0%), followed by cat (24.4%) and dog (7.0%) dander; tree and grass pollen accounted for only 4.7% and 2.3%, respectively. Food allergens were not detected. The positive rates of the systemic allergen tests were lower than in tear fluid tests in both eyes, especially for house dust mites (P = 0.000). In patients with more allergens, itching was more severe (P = 0.035), while conjunctival hyperemia was milder (P = 0.002). CONCLUSION: In autumn and winter, the most common AC allergen in Chinese patients was house dust mites. Compared with systemic allergen tests, measuring specific IgE in tears may be a non-invasive method to diagnose and evaluate AC severity, which may be more suitable to reflect the local conditions of ocular surface inflammation due to its high positive rate and convenience.

Prevalence and clinical characteristics of vernal keratoconjunctivitis in sub-Saharan Africa.

PURPOSE OF REVIEW: Vernal keratoconjunctivitis (VKC) is a chronic bilateral allergic inflammatory disease of the conjunctiva and cornea that affects children and young adults, especially in sub-Saharan Africa. A limbal form (tropical endemic limbo conjunctivitis) is thought to be more common in the tropics where research on this vision-impairing condition is scanty. We sought to review current literature from sub-Saharan Africa, with a focus on the prevalence of VKC and its clinical presentation. RECENT FINDINGS: There is a variable prevalence of VKC in SSA, up to 32.9% of children, especially in male individuals less than 5 years old, and has been diagnosed in a 4-month-old baby. Associated factors include exposure to dust, personal and family history of atopy, Vitamin D3 deficiency and HIV. The mixed form of VKC is the most frequent form seen and conjunctival pigmentation might be an early diagnostic sign. SUMMARY: Childhood screening programs for VKC should be established to reduce the morbidity, decreased quality of life and school absenteeism that is seen in these patients. VKC-related research should be encouraged in this milieu to bring to light the particularities of VKC in SSA.

Association between keratoconus and allergic conjunctivitis in children attending a Tertiary Hospital in Nigeria.

Objective: To ascertain an association between keratoconus and allergic conjunctivitis and to know if it is necessary to investigate all patients with allergic conjunctivitis for keratoconus. Methods: A hospital-based prospective study in which the eyes of children presenting with ocular allergic diseases were examined. Social demographics and clinical data were captured in a questionnaire. All the patients underwent keratometry using the autorefractor-keratometer and the pachymeter was used to measure the central corneal thickness. Data analysis was done with IBM SPSS version 28 for Windows. Frequency and chi-square were used as descriptive statistics to determine the association between dependent and independent variables. Inferential statistics using one-way ANOVA and t-test. P - Value at <0.05 was considered statistically significant. Results: 121 children with allergic conjunctivitis were reviewed. Males were 72 and females 49. The visual acuity was 6/ 6-6/ 18 in 116, and mild visual impairment - 6/ 18-6/ 60 in 5. The most common complaint was frequent itching in 109 (90.1%). Keratometry was normal in 120 (99.5%), while probable keratoconus was found by keratometry in only one patient (0.5%). Central corneal thickness was within the normal range in 33 (27.3%) children, 43 (35.5%) had thin corneas, while 45 (37.2%) had cornea thickness of more than 560 microns. Discussion: Pediatric keratoconus tends to be more aggressive than adult keratoconus with an increased risk of corneal opacities and subsequent keratoplasty. As a result of these negative impacts, early detection and prompt treatment are mandatory. Conclusion: The prevalence of keratoconus was not found to be high in this study population, but with facts emerging between the association of allergic conjunctivitis, and increased prevalence of keratoconus, it is pertinent to integrate keratoconus screening as part of the management of allergic conjunctivitis using an appropriate tool such as video keratography and slit lamp biomicroscope. Abbreviations: KC = Keratoconus, CLEK = Collaborative Longitudinal Evaluation of Keratoconus, SAC = Seasonal Allergic Conjunctivitis, PAC = Perennial Allergic Conjunctivitis, VKC = Vernal Keratoconjunctivitis, IOP = Intraocular Pressure, CCT = Central Corneal Thickness, TNF-α = Tumor Necrosis Factor-Alpha, IL = Interleukin.

Diagnostic criteria of chronic conjunctivitis: atopic keratoconjunctivitis and vernal keratoconjunctivitis.

PURPOSE OF REVIEW: Chronic ocular allergies, vernal (VKC) and atopic keratoconjunctivitis (AKC) are relatively rare conditions that require definite diagnostic criteria to the most appropriate therapeutical approach. RECENT FINDINGS: The diagnosis of both VKC and AKC is generally based on clinical history, signs and symptoms, and the results of allergic tests, which allow to identify the different diseases phenotypes. However, other subtypes of the two diseases and/or overlaps may occur making the diagnosis non always so clear, such as VKC and AKC overlaps or adult-like VKC disease. Each of these phenotypes may be sustained by different mechanisms which are still not well defined but not only related to a type 2 inflammation. The further challenges will be to correlate clinical or molecular biomarkers to a single subtype or disease severity. SUMMARY: Definite criteria of chronic allergies will further guide to more specific therapeutical approaches.