Herpesviral Keratitis Following COVID-19 Vaccination: Analysis of NHIS Database in Korea.

PURPOSE: The purpose of this study was to determine the risk of herpesviral keratitis associated with 4 coronavirus disease 2019 (COVID-19) vaccines approved in South Korea, using large-scale data from the National Health Insurance Service. METHODS: The study included 8,528,254 individuals, with cohorts categorized based on COVID-19 vaccination status. Two investigations were conducted: The first aimed to assess the risk of new-onset herpesviral keratitis while the second study focused on the risk of relapse in individuals with a preexisting diagnosis. Propensity score matching was used for cohort balancing, and various covariates, including vaccine types and comorbidities, were considered. Statistical analyses, including Cox proportional hazard regression, were used to calculate adjusted hazard ratio (aHR) and assess the risk of herpesviral keratitis. RESULTS: Individuals receiving COVID-19 vaccination exhibited a higher risk of new-onset herpesviral keratitis compared with the unvaccinated control group (aHR 1.43, 95% confidence interval, 1.19-1.73). Both mRNA and non-mRNA vaccines demonstrated an increased risk. Individuals with preexisting herpetic keratitis who received COVID-19 vaccination showed a higher risk of relapse herpesviral keratitis compared with the unvaccinated control group (aHR 1.98, 95% CI, 1.29-3.03). Sensitivity analyses supported the robustness of the results. CONCLUSIONS: This analysis of a large national health insurance database suggests an increased risk of both new-onset and relapse of herpesviral keratitis associated with COVID-19 vaccination in South Korea. While COVID-19 vaccination is crucial for pandemic control, health care providers should be aware of potential herpesvirus reactivation and consider appropriate prophylaxis and treatment for at-risk individuals.

Clinical Comparison of Fusarium Keratitis according to the Initial Potassium Hydroxide (KOH) Smear: A Retrospective Study in South Korea.

Purpose: This study aimed to compare predisposing factors, clinical characteristics, treatment, and prognosis of Fusarium keratitis according to the result of the initial potassium hydroxide (KOH) smear. Methods: This is a retrospective study of cases with Fusarium keratitis between January 2000 and December 2019 at two tertiary hospitals in South Korea. Patients were divided into two groups depending on the KOH smear result (KOH-positive and KOH-negative group), and its clinical factors were analyzed. Results: Among 319 fungal keratitis, seventy-nine cases were identified with Fusarium keratitis. Forty-seven cases (59.5%) were negative in the initial KOH smear prior to their diagnosis. The most common predisposing factor for Fusarium keratitis was ocular trauma (55.7%). There were no significant differences in sex, occupation, ulcer size or shape, hypopyon, and initial visual acuity between the two groups. Differences were observed between the KOH-positive group and the KOH-negative group in terms of deep corneal infiltration (50.0% vs. 78.7%, p=0.008) and evisceration treatment (3.1% vs. 25.5%, p=0.008). The delayed time to initiate antifungal eye drops was longer in the KOH-negative group (1.13 ± 0.49 vs. 3.93 ± 4.89, p=0.002). Only the KOH-negative group combined bacterial infection. The significant risk factors for poor clinical outcomes were the central corneal lesion (odds ratio (OR) 3.50, p=0.047), a large ulcer size (size ≥ 7.5 mm2) (OR 4.98, p=0.009), and endothelial plaque (OR 7.00, p=0.031). Conclusion: Initial KOH-negative patients often needed evisceration and had worse final visual outcomes. The delay of prompt initiation of antifungal treatment and combined bacterial infection result in a poor prognosis. This study highlights the initial KOH effect on early diagnosis and early treatment of Fusarium keratitis.

A Case Report of Herpes Zoster Ophthalmicus and Meningitis After COVID-19 Vaccination.

There are several reports that herpes zoster characterized by reactivation of varicella zoster virus (VZV) following coronavirus disease 2019 (COVID-19) vaccines can occur. Herein, we report VZV meningitis, herpes zoster ophthalmicus (HZO), and late neurotrophic keratitis after receiving a second dose of messenger RNA (mRNA) COVID-19 vaccine. A 74-year-old man developed a vesicular skin rash on the forehead, scalp, nose, and left upper eyelid with a severe headache. Five days earlier, he received a second dose of the BNT162b2 mRNA vaccine on his left arm. Ocular examination revealed conjunctival hyperemia and pseudodendrite in the peripheral cornea. VZV was detected in the cerebrospinal fluid using polymerase chain reaction. The patient was diagnosed with HZO and meningitis. The patient was treated with intravenous acyclovir and topical acyclovir ointment and levofloxacin 1.5% eye drops. One month later, he developed a central epithelial defect with a rolled margin, typical of a neurotrophic ulcer. Treatment with a therapeutic contact lens and a combination of topical recombinant human epithelial growth factor and ofloxacin ointment was initiated. At six months after vaccination, the slit-lamp examination findings were stable with a mild corneal superficial stromal haze.

Clinical characteristics of dry eye with ocular neuropathic pain features: comparison according to the types of sensitization based on the Ocular Pain Assessment Survey.

BACKGROUND: To compare the clinical characteristics of dry eye patients with ocular neuropathic pain features according to the types of sensitization based on the Ocular Pain Assessment Survey (OPAS). METHODS: Cross-sectional study of 33 patients with dry eye and ocular neuropathic pain features. All patients had a comprehensive ophthalmic assessment including detailed history, the intensity and duration of ocular pain, the tear film, ocular surface, and Meibomian gland examination, and OPAS. Patients with < 50% improvement in pain intensity after proparacaine challenge test were assigned to the central-dominant sensitization group (central group) and those with ≥50% improvement were assigned to the peripheral-dominant sensitization group (peripheral group). All variables were compared between the two groups. RESULTS: No significant differences were observed in age, sex, underlying diseases, history of ocular surgery, duration of ocular pain, tear film, ocular surface and Meibomian gland parameters (all p > 0.05). Ocular pain and non-ocular pain severity and the percentage of time spent thinking about non-ocular pain were significantly higher in the central group than in the peripheral group (all p < 0.05). Central group complained more commonly of a burning sensation than did the peripheral group (p = 0.01). CONCLUSIONS: Patients with central-dominant sensitization may experience more intense ocular and non-ocular pain than the others and burning sensation may be a key symptom in those patients.

Therapeutic Effect of Topical Adiponectin-Derived Short Peptides Compared with Globular Adiponectin in Experimental Dry Eye and Alkali Burn.

Purpose: To evaluate the efficacy of adiponectin (APN)-derived short peptides (ADPs) 355 compared with globular APN in a mouse model of experimental dry eye (EDE) and corneal alkali burn. Methods: EDE and chemical burn were induced in C57BL/6 mice by desiccating stress and application of NaOH, respectively. Eye drops consisting of 0.01% globular APN, 0.01% ADPs, 0.1% ADPs, or balanced salt solution (BSS) were applied. Tear volume, tear film break-up time, and corneal staining scores were measured. Concentrations of interleukin (IL)-1ß, interferon (IFN)-γ, IL-6, CXCL-9, and CXCL-10 using multiplex immunobead assay were evaluated, and flow cytometry were performed. Corneal epithelial defects and haze degree were analyzed, and enzyme-linked immunosorbent assay for IL-1ß and transforming growth factor (TGF)-ß levels were observed. Results: All treatment groups showed an improvement in clinical parameters and CD4+CCR5+ T cell and CD11b+ cell infiltrations in the conjunctiva (all P < 0.05). Both ADPs groups had significantly decreased concentrations of IL-1ß, IFN-γ, IL-6, CXCL-9, and CXCL-10 in the conjunctiva than the EDE or BSS group. Significantly improved parameters of epithelial defect, degree of haze, and concentrations of IL-1ß and TGF-ß were observed in all treatment groups. However, no significant differences were noted in clinical or experimental parameters among treatment groups. Conclusion: Topical ADPs could effectively improve clinical signs and inflammation of ocular surface in the EDE or alkali burn, and its efficacy and potency were similar to those of globular APN.

The influences of smartphone use on the status of the tear film and ocular surface.

PURPOSE: To investigate the influences of smartphone use on ocular symptoms, status of the tear film, and oxidative stress indices in the tears and at the ocular surface. METHODS: Eighty healthy volunteers were enrolled in the study. Subjective symptoms and asthenopia were evaluated using the ocular surface disease index (OSDI), visual analogue scale (VAS), and computer vision syndrome (CVS) score before and after smartphone or computer display (control) use. The status of the tear film was evaluated using fluorescein film break-up time (FBUT), non-invasive keratograph break up time (NIKBUT), Schirmer score, keratoepitheliopathy (KEP), and tear meniscus height (TMH). Oxidative stress markers in the tear film including hexanoyl lysine (HEL), 4-hydroxy-2-nonenal (4-HNE), malondialdehyde (MDA), and 8-oxo-2'-deoxyguanosine (8-OHdG) in the tear film were measured using ELISA. Reactive oxygen species (ROS) at the ocular surface were measured through 2',7'-dichloro-dihydrofluorescein diacetate. All measurements were conducted at baseline, and after use for 1 and 4 h. RESULTS: All parameters showed no significant group-wise differences at baseline. Scores of OSDI, VAS, fatigue, burning sensation, and dryness showed significant increases after 1 and 4 h of smartphone use compared with those at baseline (all P < 0.05). The smartphone group showed higher OSDI, fatigue, burning, and dryness scores than the control group at 4 h. Smartphone use showed significantly decreased FBUT and NIBUT at 4 h than those at baseline (P < 0.01). In the smartphone group, the concentration of HEL significantly increased at 4 h compared with that at baseline and 1 h (P < 0.01). Both groups showed increased ROS with higher value in the smartphone group versus the control group at 4 h (P < 0.01). CONCLUSIONS: Smartphone use could not only aggravate subjective symptom indices such as the OSDI, VAS, and CVS but also induce tear film instability and oxidative stress indices in the tears and at the ocular surface.

Comparison of 0.1%, 0.18%, and 0.3% Hyaluronic Acid Eye Drops in the Treatment of Experimental Dry Eye.

PURPOSE: To compare the efficacy of 0.1%, 0.18%, and 0.3% hyaluronic acid (HA) artificial tear in the treatment of experimental dry eye (EDE). METHODS: EDE was established in female C57BL/6 mice through an air draft and subcutaneous scopolamine injection. The mice were divided into 5 groups according to topical treatment regimens (n = 5 each): EDE control, balanced salt solution (BSS), preservative-free 0.1% HA, 0.18% HA, and 0.3% HA. The tear film break-up time (TBUT) and corneal fluorescein staining scores were measured 5, 10, 14, 21, and 28 days after treatment. The corneal smoothness scores were measured. In addition, periodic acid-Schiff (PAS) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were performed. RESULTS: The values for TBUT and corneal fluorescein staining showed greater improvements in all the HA groups (P < 0.05) than in the EDE and BSS groups after 10 days of treatment. Mice treated with 0.3% HA showed a more significant improvement in all clinical parameters than did those in the EDE control, BSS, 0.1% HA, and 0.18% HA groups (all P < 0.05) after 28 days of treatment. The goblet cell counts were higher in the 0.3% and 0.18% HA groups than in the 0.1% HA group. The number of TUNEL-positive cells was the lowest in the 0.3% HA group. CONCLUSIONS: In EDE, 0.3% HA artificial tears are more effective than the 0.1% and 0.18% HA in improving tear film instability and ocular surface staining and irregularity, in increasing the number of conjunctival goblet cells, and in decreasing corneal epithelial apoptosis.

Effectiveness of Combined Tear Film Therapy in Patients with Evaporative Dry Eye with Short Tear Film Breakup Time.

PURPOSE: The aim of this study was to evaluate the effectiveness of combined tear film therapy targeted to aqueous, mucin, and lipid layers in patients with refractory evaporative dry eye (EDE) with short tear film breakup time (TBUT). METHODS: The patients who had EDE with short TBUT and severe symptoms refractory to artificial tears were treated with hyaluronic acid (HA) 0.15% and diquafosol tetrasodium (DQS) 3% (Group 1), HA and carbomer-based lipid-containing eyedrops (Liposic EDO Gel, LPO) (Group 2), or HA, DQS, and LPO (Group 3). Ocular Surface Disease Index (OSDI) score, visual analog scale (VAS) symptom score, TBUT, Schirmer score, and corneal and conjunctival staining scores were evaluated, and noninvasive tear film breakup time (NIBUT) and tear meniscus height were measured using Keratograph® 5 M before and 1 and 3 months after treatment. RESULTS: OSDI scores, VAS scores, TBUT, and NIBUT were improved at 1 and 3 months after treatment in all groups (all P < 0.05). At each follow-up visit, the total OSDI, OSDI symptom, and all VAS scores were significantly lower in group 3 compared with groups 1 and 2 (all P < 0.05). In addition, TBUT and NIBUT were significantly higher in group 3 compared with groups 1 and 2 (all P < 0.05). No significant adverse effects were noted in the groups during treatment. CONCLUSIONS: Mucin or lipid-targeting agents combined with aqueous supplements in patients with refractory EDE with short TBUT might improve subjective symptoms and TBUT. Of this, targeting whole tear film layers was most effective in improving ocular symptoms and tear film quality.

Expression of Lipid Peroxidation Markers in the Tear Film and Ocular Surface of Patients with Non-Sjogren Syndrome: Potential Biomarkers for Dry Eye Disease.

PURPOSE: To investigate the expression of lipid peroxidation markers in the tear film and ocular surface and their correlation with disease severity in patients with dry eye disease. METHODS: The concentrations of hexanoyl-lysine (HEL), 4-hydroxy-2-nonenal (HNE), and malondialdehyde (MDA) were measured with enzyme-linked immunosorbent assays in tears obtained from 44 patients with non-Sjogren syndrome dry eye and 33 control subjects. The correlations between the marker levels and the tear film and ocular surface parameters, including tear film break-up time (BUT), Schirmer tear value, tear clearance rate, keratoepitheliopathy scores, corneal sensitivity, conjunctival goblet cell density, and symptom score, were analyzed. The expression of the lipid peroxidation markers HEL, 4-HNE, and MDA in the conjunctiva was evaluated using immunohistochemistry. RESULTS: The concentrations of HEL, 4-HNE, and MDA were 279.84 ± 69.98 nmol/L, 0.02 ± 0.01 µg/mL, and 3.80 ± 1.05 pmol/mg in control subjects and 283.21 ± 89.67 nmol/L (p = 0.97), 0.20 ± 0.03 µg/mL (p < 0.01), and 13.32 ± 4.03 pmol/mg (p < 0.01) in dry eye patients. 4-HNE and MDA levels significantly correlated with BUT, Schirmer tear value, tear clearance rate, keratoepitheliopathy scores, conjunctival goblet cell density, and symptom score (p < 0.05), whereas HEL levels did not correlate with these parameters. Staining intensities for 4-HNE and MDA increased in dry eye patients. CONCLUSIONS: The expression of late lipid peroxidation markers, 4-HNE and MDA, increases in the tear film and ocular surface of patients with dry eye. The levels correlate with various tear film and ocular surface parameters and may reflect the severity of dry eye disease.

Factors Affecting Treatment Outcome of Graft Infection Following Penetrating Keratoplasty.

PURPOSE: To evaluate the factors affecting treatment outcome of graft infection following penetrating keratoplasty (PKP). METHODS: In this retrospective study, 28 patients who underwent PKP between January 2005 and January 2013 and who were diagnosed with graft infection were classified into a treatment success group or a treatment failure group. Demographic and clinical characteristics, as well as the results of the microbiologic investigation, were analyzed and compared. A subsequent binary logistic regression analysis was performed to identify the prognostic factors affecting treatment outcome. RESULTS: Graft infection occurred at a mean of 38.29 ± 36.16 months (range, 1 to 96 months) after PKP. Seventeen patients developed bacterial keratitis, and 11 patients developed fungal keratitis. Overall, of the 28 patients, nine (32.1%) were classified in the treatment failure group. Multivariate analysis identified pre-existing graft failure (p = 0.019), interval longer than 72 hours between donor death and PKP (p = 0.010), and fungal infection (p = 0.026) as significant risk factors for treatment failure. CONCLUSIONS: Pre-existing graft failure, extended interval between donor death and PKP, and fungal infection were important risk factors for treatment failure of graft infection following PKP.

Age-Related Conjunctival Disease in the C57BL/6.NOD-Aec1Aec2 Mouse Model of Sjögren Syndrome Develops Independent of Lacrimal Dysfunction.

PURPOSE: To investigate parameters of ocular surface disease in C57BL/6.NOD-Aec1Aec2 (Aec) mice with aging and their correlation with development of Sjögren syndrome (SS)-like lacrimal gland (LG) disease. METHODS: Aec and C57BL/6 wild-type (B6) female mice were evaluated at 4, 12, and 20 weeks of age. Whole LG and eyes and adnexa were excised for histology and gene expression analysis and evaluated by flow cytometry and immunohistochemistry. Tear volume and goblet cell density was measured. Quantitative PCR evaluated T-cell-related cytokine expression in cornea and conjunctiva. RESULTS: Both strains showed age-related conjunctival goblet cell loss that was more pronounced in the Aec strain and significantly greater than in B6 mice at 12 weeks. This was accompanied by CD4+ T-cell infiltration of the conjunctiva that was greater in Aec strain at 20 weeks. Aec mice had higher levels of IL-17A, IL-17R, IL-1α, IL-1ß, and TNF-α in the conjunctiva, and they significantly increase with aging. Aec mice had greater lymphocytic infiltration of the LG and conjunctiva at 20 weeks that consisted of a mixture of CD4+ and CD8+ cells. Flow cytometry showed a significant increase in CD4+ T cells in Aec LG compared to B6 mice. Tear volume was significantly increased in both strains at 20 weeks. CONCLUSIONS: Aec mice developed greater conjunctival goblet cell loss associated with lymphocytic infiltration of the LG and conjunctiva with aging. Increased expression of certain T helper or inflammatory cytokines in these tissues was observed in Aec mice. The conjunctival disease appeared to be due to inflammation and not a decrease in tear volume.

Macrophage Phenotype in the Ocular Surface of Experimental Murine Dry Eye Disease.

To evaluate the phenotype of macrophages in the cornea and conjunctiva of C57BL/6 mice with induced experimental dry eye. C57BL/6 mice exposed to desiccating stress (DS) were evaluated at 1, 5, and 10 days and C57BL/6 mice maintained in non-stressed environment were used as controls. Whole eyes and adnexa were excised for histology or used for gene expression analysis. Location and phenotype of macrophages infiltrating the cornea and conjunctiva was evaluated by immunofluorescence analysis. Quantitative polymerase chain reaction evaluated macrophage markers and T cell-related and inflammatory cytokine expression in cornea and conjunctiva. Immunofluorescence staining demonstrated that macrophages reside in the conjunctiva of control and dry eye mice and their number did not change with DS. Real-time RT-PCR demonstrated that the level of M1 macrophage marker, iNOS, increased prominently in the conjunctiva at DS 10 days. In contrast, there was a non-significant decrease of the M2 marker Arg1 with DS. The levels of inflammatory cytokine, IL-12a mRNA transcript in the conjunctiva increased significantly at DS1 and decreased at DS5, while levels of IL-18 were significantly increased at DS 10. Macrophages reside in the ocular surface tissues of C57BL/6 mice. Although the number of macrophages in the conjunctiva does not change, evidence of inflammatory M1 activation after desiccating stress was observed. Better understanding of phagocyte diversity and activation in dry eye disease provide a basis for the development of phagocyte-targeted therapeutic strategies.

Kimura disease involving a caruncle.

A 35-year-old woman presented with history of a painless, slow-growing nodule in a left eye caruncle over the last 2 months. The visual acuity was 20 / 20 and the ocular movements were in the normal range. The venereal disease research laboratory test, erythrocyte sedimentation rate, serum angiotensin converting enzyme level, and chest radiograph were all normal. An excisional biopsy was done to confirm the diagnosis. A 1.3 × 0.5 × 0.3 cm sized nodule was extracted and sent for histopathologic examination. Hematoxylin-eosin staining showed follicular hyperplasia with perifollicular fibrosis, an eosinophil infiltrate, and proliferation of capillary vessels. The capillaries were lined by normal-appearing, flat, spindle-shaped endothelial cells. On the basis of these histopathologic findings, the diagnosis of Kimura disease in a caruncle was established. This is the first report describing Kimura disease localized to a caruncle. Kimura disease should be suspected and included in the differential diagnosis of a caruncular mass lesion.

Therapeutic effect of intravitreal injection of triamcinolone in the treatment of endothelial graft rejection: a pilot study.

PURPOSE: To investigate the efficacy of intravitreal triamcinolone acetonide (IVTA) injection in the treatment of endothelial graft rejection and the expression of T-helper type 1 (Th-1) chemokines in the aqueous humor. METHODS: Eleven patients (11 eyes) with acute endothelial graft rejection underwent IVTA (4 mg/0.1 mL) injection in addition to conventional treatment, including systemic and topical steroids and cyclosporine A (group A); 13 patients (13 eyes) received conventional treatment only (group B). Clinical characteristics were analyzed. In group A, Th-1 chemokines (CXCL-9, -10, and -11) in aqueous humor were measured by enzyme-linked immunosorbent assay and CXCR3(+) cells were counted by flow cytometry before treatment and at the period of improvement. RESULTS: There were no significant differences in visual acuity, intraocular pressure, and recurrence rate between the 2 groups. The mean time to improvement was 9.1 ± 3.9 days in group A and 15.4 ± 5.5 days in group B (P = 0.04). The concentrations of CXCL-9, -10, and -11 were 562.7 ± 109.4, 30293.1 ± 12537.1, and 228.3 ± 80.8 pg/mL before treatment and 6.7 ± 6.8 (P < 0.01), 207.5 ± 209.8 (P < 0.01), and 18.9 ± 19.5 (P < 0.01) pg/mL after treatment, respectively. The CXCL-10 level correlated with the time to improvement of graft rejection (P = 0.02). Flow cytometry demonstrated a significantly decreased number of CXCR3(+) and CXCR3(+)CD4(+) cells in the aqueous humor after treatment. CONCLUSION: IVTA injection was effective in reducing the time to improvement of endothelial graft rejection. Increased expression of CXCL-9, -10, and -11, and their receptors in the aqueous humor of patients with endothelial graft rejection decreased after treatment.

Expression of CCR5 and its ligands CCL3, -4, and -5 in the tear film and ocular surface of patients with dry eye disease.

PURPOSE: To evaluate the expression of CCR5 and its ligands CCL3, CCL4, and CCL5 in the tear film and ocular surface and their correlation with disease severity in patients with dry eye disease. MATERIALS AND METHODS: The concentrations of CCL3, CCL4, and CCL5 were measured using enzyme-linked immunosorbent assay in tear samples obtained from forty-three patients with dry eye (17 SS and 26 non-SS patients) and 20 control subjects. The correlation between chemokine levels and tear film and ocular surface parameters was analyzed. Expression of the chemokines and their receptor in the conjunctiva was evaluated using immunohistochemistry. Flow cytometry was performed to detect CCR4+CD4+, CCR5+CD4+, and CCR6+CD4+ cells in the conjunctiva. RESULTS: The concentrations of CCL3, CCL4, and CCL5 were 25.3 ± 24.2, 4.65 ± 3.21, and 93.12 ± 26.31 pg/mL in control subjects, 92.33 ± 13.23, 263.13 ± 116.13, and 253.64 ± 46.29 pg/mL in patients with non-SS, and 215.56 ± 36.1, 697.85 ± 185.65, and 456.12 ± 92.82 pg/mL in patients with SS. The concentrations showed a significant increase in tears of SS patients compared with those of non-SS patients and control subjects (p < 0.05). CCL5 levels showed significant correlation with tear film break-up time, basal tear secretion, tear clearance rate, keratoepitheliopathy score, and goblet cell density (p < 0.01). Staining for the chemokines and their receptor increased in dry eye patients, especially in those with SS patients. Flow cytometry demonstrated increased numbers of CCR5+CD4+, and CCR6+CD4+ cells in dry eye patients in contrast to CCR4+CD4+ cells. CONCLUSIONS: Expression of CCR5 and its ligands CCL3, CCL4, and CCL5 increase in the tear film and ocular surface of patients with dry eye syndrome, especially in those with SS. CCL5 levels correlate significantly with various tear film and ocular surface parameters.