Current Literature Review of COVID Eye Infections in the Pediatric Population and the Beneficial Effect of Isolated Treatment of COVID Uveitis (Panuveitis) in a Child after Isolated Administration of Depomedrol under the Tenon Capsule — a Case Report (preprint)

Coronavirus disease 2019 (COVID-19), can manifest with ocular symptoms. These symptoms can be divided into isolated events attributed to COVID-19 and those occurring in multisystem inflammatory syndrome in children (MIS-C), a newly diagnosed disease entity associated with COVID-19 infection. Currently, the literature lacks specific guidelines and treatment regimens for COVID-19 ocular symptoms, especially in children.

Bibliometric analysis of the Vogt‒Koyanagi‒Harada disease literature (preprint)

Background:  As an autoimmune disease, Vogt‒Koyanagi‒Harada disease (VKHD) is one of the main types of uveitis in many countries and regions significantly impacting patent’s vision. At present, information regarding VKHD is still limited, and further research is needed. We conducted a bibliometric analysis to characterize the overall status, current trends, and current focus of VKHD research. Methods:  Literature published from 1975 to 2022 was obtained from the Web of Science core collection and analyzed by the R-language packages Bibliometrix, VOSviewer, and CiteSpace software. Results:  A total of 1050 papers on VKHD were retrieved from 261 journals and 16,084 references were obtained from the papers in the original search. The average annual number of published articles is approximately 21.9, and the number of publications rapidly increased after 2004. Ocular Immunology and Inflammation is the journal that published the most papers on VKHD, while the American Journal of Ophthalmology has the highest cited frequency. The leading countries were Japan, China (PRC), and the United States of America (USA). Yang PZ. from Chongqing Medical University is the most prolific and cited author. The most frequently cited literature is the literature on the revision of VKHD diagnostic criteria. An analysis of high-frequency keywords showed that the research focused on the treatment, diagnosis, and pathogenesis of VKHD and its relationship with other related diseases. At present, the urgent research direction is the relationship and specific mechanism between COVID-19 or COVID-19 vaccines and VKHD. Conclusion: Bibliometrics can clearly show the research history, development trends, and research hotspots of VKHD through dynamic and visualization tools. It is an efficient way to study the literature and is helpful for future researchers.

COVID-19 vaccination, dengue hepatitis, and recurrent unilateral anterior uveitis.

A 36-year-old Asian Indian male presented with redness and pain in his right eye of 1 week duration. He was diagnosed to have right acute anterior uveitis and had a history of being admitted at a local hospital for dengue hepatitis a month earlier. He had been on adalimumab 40 mg three weekly once and oral methotrexate 20 mg/week for human leucocyte antigen (HLA) B27 spondyloarthropathy and recurrent anterior uveitis. Our patient had re-activation of his anterior chamber inflammation on three distinct occasions: first, 3 weeks following recovery from coronavirus disease 2019 (COVID-19), the second after the second dose of COVID-19 vaccination, and the third after recovery from dengue fever-associated hepatitis. We propose molecular mimicry and bystander activation as the postulated mechanisms for the re-activation of his anterior uveitis. In conclusion, patients with auto-immune diseases can have recurrent ocular inflammation following COVID-19 or its vaccination or dengue fever as seen in our patient. The anterior uveitis is usually mild and responds to topical steroids. Additional immuno-suppression may not be needed. Mild ocular inflammation following vaccination should not deter individuals from getting COVID-19 vaccination.

Navigating Coronavirus Disease 2019 Vaccination and Uveitis: Identifying the Rates and Risk of Recurrent Uveitis after Coronavirus Disease Vaccination.

PURPOSE: To identify rates of uveitis reactivation both before and after the coronavirus disease (COVID) 2019 vaccine in subjects with a previous diagnosis of uveitis. DESIGN: Retrospective study. PARTICIPANTS: Subjects were identified from the Inflammatory Eye Disease Registry at Auckland District Health Board diagnosed with uveitis between January 1, 2010, and December 31, 2020. METHODS: Date of COVID vaccination was determined from the patient clinical record. Rate of flare was calculated for 3 months before vaccination and 3 months after each vaccination. MAIN OUTCOME MEASURE: Uveitis flare was defined as the presence of new uveitis activity or increased activity that required a change in uveitis treatment. RESULTS: A total of 4184 eyes of 3008 patients were included in the study with a total of 8474 vaccinations given during the study period. Median age was 54.8 years, and 1474 (49.0%) were female. Noninfectious etiology was most common, occurring in 2296 patients (76.3%) and infectious etiology occurring in 712 patients (23.7%). Rate of uveitis flare was 12.3 per 1000 patient-months at baseline, 20.7 after the first dose, 15.0 after the second dose, 12.8 after the third dose, and 23.9 after the fourth dose. The median period of quiescence before flare was 3.9 years. An increase in uveitis flare was seen in both infectious uveitis (baseline 13.1 compared with 20.2 after first dose, 154% increase) and noninfectious uveitis (baseline 12.4 compared with 20.9 after first dose, 169% increase). Risk factors for uveitis flare were identified to be recurrent uveitis, chronic uveitis, shorter period of quiescence, and first dose of vaccine. Median time to uveitis flare was 0.53 months after the first vaccination, 1.74 months after the second vaccination, and 1.35 months after the third vaccination. CONCLUSIONS: The current study demonstrates an increased risk of uveitis flare after the first dose of COVID vaccination. This risk was highest in those with previous recurrences, chronic uveitis, and shorter period of quiescence. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Bilateral keratouveitis associated with COVID-19 multisystem inflammatory syndrome in children.

We report the case of a 16-year-old girl admitted to hospital with multisystem inflammatory syndrome in children (MIS-C) secondary to COVID-19. Conjunctivitis-like symptoms prompted ocular examination, which demonstrated peripheral confluent corneal opacities and anterior uveitis. Uveitis laboratory investigations were negative, and with topical steroid treatment her signs and symptoms resolved completely. These features may be overlooked in the setting of MIS-C, where patients are systemically unwell and are typically examined at the bedside.

Ophthalmic and immunopathological characterization of systemic infectious diseases in cats.

Ocular involvement in systemic diseases is frequent in cats; however, without concurrent clinical and ophthalmic examinations with gross and/or histologic analysis of the eye, these findings can be underdiagnosed. This article aims to provide gross, histologic, and immunohistochemical characteristics of ocular lesions from cats submitted to necropsy, focusing on those caused by systemic infectious agents. Cats that died due to a systemic infectious disease were selected based on necropsy diagnosis and presence of ocular lesions. Gross, histologic, and immunohistochemical findings were recorded. From April 2018 to September 2019, 849 eyes of 428 cats were evaluated. Histologic abnormalities were seen in 29% of cases, which were classified as inflammatory (41%), neoplastic (32%), degenerative (19%), and metabolic/vascular (8%). Macroscopic changes were present in one-third of eyes with histologic lesions. Of these, 40% were attributed to inflammatory or neoplastic diseases associated with infectious agents. The most important infectious agents causing ocular disease in this study were feline leukemia virus, feline infectious peritonitis virus, and Cryptococcus sp. The most common ocular abnormalities associated with infectious agents were uveitis (anterior, posterior, or panuveitis), optic neuritis, and meningitis of the optic nerve. Ocular lesions secondary to systemic infections in cats are frequent; however, these are not always diagnosed because gross lesions are less common than histologic lesions. Therefore, both gross and histologic evaluation of the eyes of cats is recommended, mainly for cases in which the clinical suspicion or necropsy diagnosis suggests that an infectious agent might be related to the cause of death.

Role of Recent PCR Tests for Infectious Ocular Diseases: From Laboratory-Based Studies to the Clinic.

Infectious uveitis is a vision-threatening condition that requires prompt clinical diagnosis and proper treatment. However, rapid and proper diagnosis in infectious uveitis remains challenging. Several examination tests, including polymerase chain reaction (PCR) tests, are transitioning from laboratory-based basic research-level tests to bedside clinical tests, and recently tests have changed to where they can be performed right next to clinicians. In this review, we introduce an updated overview of recent studies that are representative of the current trends in clinical microbiological techniques including PCR tests for infectious uveitis.

Tubulointerstitial nephritis and uveitis in children during the COVID-19 pandemic: report of four cases.

Tubulointerstitial nephritis and uveitis (TINU) is a rare autoimmune disorder often triggered by drugs and infections. Since the onset of the COVID-19 pandemic, we have observed an unusual cluster of paediatric cases. Four children (3 females) were diagnosed with TINU (median age 13 years) following a kidney biopsy and ophthalmologic assessment. Presenting symptoms included abdominal pain (3 cases), fatigue, weight loss and vomiting (2 cases). At presentation, median eGFR was 50.3 ml/min/1.73m2 (range 19.2-69.3). Anaemia was common (3 cases) with median haemoglobin of 10.45 g/dL (range 8.4-12.1). Two patients were hypokalaemic and 3 had non-hyperglycaemic glycosuria. Median urine protein:creatinine ratio was 117 mg/mmol (range 68-167). SARS-CoV-2 antibodies were detected in 3 cases at presentation. All were asymptomatic for COVID-19 with a negative PCR. Kidney function improved following high-dose steroids. However, disease relapse was observed during steroid tapering (2 cases) and upon discontinuation (2 cases). All patients responded well to further high dose steroids. Mycophenolate mofetil was introduced as a steroid-sparing agent. At latest follow up (range 11-16 months), median eGFR was 109.8 ml/min/1.73m2. All four patients continue on mycophenolate mofetil, with 2 patients applying topical steroids for uveitis. Our data suggest that SARS-CoV-2 infection might be a trigger for TINU.

Granulomatous anterior uveitis following mRNA-based COVID-19 vaccination: A case report.

A 23-year-old patient presented with complaints of redness, pain, photophobia, and blurred vision in the right eye 15 days after she received the third dose of BNT162b2 vaccination. Ocular examination revealed 2+ cellular reactions in the anterior chamber and mutton fat keratic precipitate with no vitritis or retinal alterations. Active uveitis findings regressed with corticosteroid and cycloplegic eye drops. We present a case of unilateral granulomatous anterior uveitis following the BNT162b2 vaccination, with no etiologic factor in uveitis work-up and no previous history of uveitis before vaccination. This report demonstrates a potential causal association of coronavirus disease 2019 (COVID-19) vaccine with granulomatous anterior uveitis.

Changing face of non-infectious pediatric uveitis in the pre-pandemic and pandemic periods: a comparison study.

OBJECTIVE: Our aim in this study was to reveal the clinical features of pediatric uveitis in the pandemic period and to compare it with the pre-pandemic era. METHODS: This retrospective study included 187 children diagnosed with uveitis between the 11th of March 2017 and the 11th of March 2022. The patients were divided into two groups based on the date of diagnosis as follows; Group 1: Patients diagnosed in the pre-pandemic period (11th March 2017-11th March 2020); Group 2: Patients diagnosed in the pandemic period (12th March 2020-11th March 2022). Demographic data, characteristics of uveitis, underlying diseases, systemic treatment modalities, and complications were compared between the two groups. RESULTS: A total of 187 (pre-pandemic 71, and pandemic 114) pediatric uveitis patients were recruited to the study. Fifty one percent (51%) of the patients were female. The number of patients diagnosed with uveitis increased approximately twice during the pandemic period compared to the pre-pandemic period. The frequency of anterior uveitis was found to be significantly higher in the pandemic period than in the pre-pandemic period (p = 0.037). It was mostly presented as symptomatic uveitis. There was a decrease in the diagnosis of JIA-related uveitis. ANA positivity increased in the pandemic period (p = 0.029). The response to treatment was better and the complication rate decreased in the pandemic period. CONCLUSION: The present study involved a large number of pediatric patients with uveitis. There are some differences in the characteristics of pediatric uveitis cases comparing the pandemic period and the pre-pandemic period. This increased frequency and changing clinical features of pediatric uveitis seems to be a result of COVID-19 infection.

Ocular leptospirosis: lack of awareness among ophthalmologists and challenges in diagnosis.

PURPOSE OF REVIEW: Systemic leptospirosis exists worldwide. But leptospiral uveitis, an important late complication is not identified by ophthalmologists in several countries. RECENT FINDINGS: In the last 18 months numerous publications, especially on epidemiology, surveillances, and novel rapid diagnostic kits to test at the point of care site on leptospirosis have been published from all over the world. However, publications from ophthalmologists are very scarce. Remarkably ophthalmologists should know the global burden of leptospirosis, prevalence of the disease in their country, demographic factors associated, risk factors, and systemic signs to elicit relevant history and travel history. They should be aware of recent advances in investigations to confirm their clinical diagnosis. SUMMARY: It is quite evident from this work that leptospirosis is prevalent worldwide. Ophthalmologists' awareness has to improve to identify the etiological diagnosis. They should have access to simple, less expensive, and less cumbersome laboratory tests.

Drug-induced bilateral ciliochoroidal detachment and uveitis in a patient with COVID-19 (preprint)

Background: To describe a case of bilateral transient myopia with shallow anterior chamber, ciliochoroidal detachment and uveitis in both eyes induced by indapamide intake following SARS-CoV-2 infection. Case presentation: A 37-year-old man with COVID-19 was referred to our department for bilateral visual blurring. He had been treated with ibuprofen for fever and indapamide to treat the uncontrolled blood pressure. After indapamide intake for four days, he started complaining of bilateral visual blurring. On ocular examination, the uncorrected visual acuity was 20/400 OD and 20/400 OS. Slit-lamp examination revealed shallow anterior chamber. In the patient’s subsequent visit on the next day, he complained of pain and redness in both eyes from the previous night. On ocular examination, the IOP decreased significantly compared to the previous day, 11 mmHg and 12 mmHg in OD and OS respectively. Slit-lamp examination revealed conjunctival injection and inflammatory cells (2+) in the shallow anterior chamber of both eyes. Ultrasound biomicroscopy revealed ciliary body detachment, and B-scan ultrasound showed peripheral shallow choroidal detachment in both eyes. Stopping the indapamide and treatment with oral prednisolone, topical tobramycin dexamethasone and tropicamide phenylephrine eye drops resulted in rapid recovery of the signs and symptoms after 3 days. Conclusions: Indapamide intake can induce bilateral shallow anterior chamber, ciliochoroidal detachment in both eyes, and the preexisting hyperinflammation induced by COVID-19 might increase the susceptibility; drug usage and SARS-CoV-2 infection might commonly contribute to the uveitis. Timely diagnosis and treatment can result in good prognosis.

Early vs Deferred Non-Messenger RNA COVID-19 Vaccination Among Chinese Patients With a History of Inactive Uveitis: A Randomized Clinical Trial.

Importance: Improper host response to COVID-19 vaccines could trigger immune-mediated adverse events. The question remains whether COVID-19 vaccination should be postponed until complete remission in patients with uveitis, a preexisting immune-related condition. Objective: To compare recommendations for early and deferred COVID-19 vaccination with respect to uveitis outcomes. Design, Setting, and Participants: This open-label, randomized clinical trial at a large, specialized teaching center for uveitis care in China enrolled unvaccinated patients with inactive uveitis between August 10, 2021, and February 22, 2022, with follow-up to June 6, 2022. Interventions: Participants were randomly assigned to receive recommendation for early or deferred COVID-19 vaccination after complete remission of uveitis. Non-messenger RNA (non-mRNA) COVID-19 vaccines were available in China during the trial. Main Outcomes and Measures: The primary outcome was the time to symptomatic uveitis worsening during 3 months of follow-up. Secondary outcomes included uveitis activity and best-corrected visual acuity at 3 months. Results: Of the 543 participants (304 women [56.0%]; median age, 35 [IQR, 26-49] years), 262 were recommended for early vaccination and 281 for deferred vaccination. By month 3, 109 patients (41.6%) in the early group had been vaccinated compared with 14 (5.0%) in the deferred recommendation group. In the intention-to-treat population, the time to symptomatic uveitis worsening was shorter in the early group than in the deferred group (hazard ratio, 1.68 [95% CI, 1.09-2.59]; P = .01 by log-rank test). Changes in anterior chamber cells, vitreous haze, and best-corrected visual acuity from baseline to month 3 appeared similar in the 2 groups in the evaluable population after the month 3 in-person visit. Conclusions and Relevance: In this randomized clinical trial of patients with inactive uveitis, recommendation for early non-mRNA COVID-19 vaccination resulted in a higher incidence of self-reported symptomatic uveitis worsening with possible reporting bias compared with recommendation for deferred vaccination, but no adverse effects were observed in disease and visual prognosis at 3 months. These findings would be useful to guide the individual timing choices of non-mRNA COVID-19 vaccination in this clinically vulnerable population. Trial Registration: Chinese Clinical Trial Registry: ChiCTR2100049467.

Acute tubulointerstitial nephritis with or without uveitis: a novel form of post-acute COVID-19 syndrome in children (preprint)

Background COVID-19 is a complex multisystem disease, frequently associated with kidney injury. Since the beginning of the COVID-19 pandemic, we observed a striking increase in the incidence of acute tubulointerstitial nephritis (aTIN) without or with uveitis (TINUs) among children. This prompted us to examine whether SARS-CoV-2 might be the underlying trigger. Methods We conducted a French nationwide retrospective cohort study. We included all consecutive children diagnosed with aTIN or TINUs of undetermined cause between April-2020 and March-2021. SARS-CoV-2 antibody responses were tested by a luciferase immunoprecipitation system and compared to age-matched controls. Immunohistochemistry, immunofluorescence and molecular microbiology analyses were performed on kidney biopsies. Results Forty-eight children were included with a median age at diagnosis of 14.7 years (9.4-17.6). aTIN and TINUs incidence rates increased 3-fold and 12-fold, respectively, compared to pre-pandemic years. All patients had impaired kidney function with a median eGFR of 31.9 ml/min/1.73m2 at diagnosis. Kidney biopsies showed lesions of acute tubulointerstitial nephritis and 25% of patients had fibrosis. No patient had concomitant acute COVID-19. All 16 children tested had high anti-N IgG titers and one had anti-S IgGs. Next-generation sequencing failed to detect any infectious agents in kidney biopsies. However, SARS-CoV-2 RNA was detected by PCR in two kidney samples supporting a potential direct link between SARS-CoV-2 and aTIN/TINUs. Conclusions We describe a novel form of post-acute COVID-19 syndrome in children, unique in its exclusive kidney and eye involvement, and its distinctive anti-SARS-CoV-2 N+/S- serological profile. Our results support a causal association linking SARS-CoV-2 infection to this newly-reported burst of renal/eye inflammation.

Potential relationships between uveitis and COVID-19: a bioinformatic study based on CEO database (preprint)

Purpose Coronavirus Disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been a great impact on human survival and a great threat to public health in countries all over the world. The link between COVID-19 and ocular illness has received increasing attention due to SARS-CoV-2 infection can be transmitted through eye contact. Using bioinformatics methods, we sought to investigate the potential molecular mechanisms between uveitis and COVID-19, providing rationales and directions for further exploration.Methods Transcriptomic data of uveitis and COVID-19 patient blood samples were accessed from the Gene Expression Omnibus public database. Common differentially expressed genes were identified. Genetic Ontology analysis, Kyoto Encyclopedia of Genes and Genomes pathway analysis, Protein-Protein Interaction network analysis were performed on intersected genes. We screened 5 hub genes by using the maximum clustering centrality algorithm. The Least Absolute Shrinkage and Selection Operator regression analysis identified the potential biomarkers for uveitis and COVID-19. Finally, the expression level and diagnostic value of the biomarker in the two diseases were determined.Results 50 intersected genes were extracted from differential expression analysis in uveitis and COVID-19. These genes were functionally enriched in cytokine-mediated signaling pathway, vesicle lumen, receptor ligand activity. Through KEGG analysis, these genes were found to be involved in viral protein interaction with cytokine and cytokine receptor, and cytokine-cytokine receptor interaction. HORMAD1 was obtained by Least Absolute Shrinkage and Selection Operator regression analysis, which was high expression in both uveitis and COVID-19 when compared to controls. Receiver Operating Characteristic values and AUC statistics indicated that HORMAD1 had diagnostic value for uveitis and COVID-19.Conclusions Bioinformatic analysis predicts HORMAD1 involvement in etiology and therapeutic targets of uveitis and COVID-19. However, additional clinical trials and studies are needed to confirm the role of HORMAD1.

RARE COMPLICATION OF COVID -19 DISEASE TINU SYNDROME IN A 11-YEAR-OLD BOY, FEATURES AND MANAGMENT.

Tubulointerstitial nephritis and uveitis syndrome (TINU) is a rare disease defined by a combination of different abnormalities, tubulointerstitial nephritis and uveitis. We describe an 11-year-old boy who got sick with the Covid-19 disease with positive outcome and after 2 weeks developed a complication - tubulointerstitial nephritis with pain in the abdominal cavity, loss of appetite, weakness and low-grade fever with further subsequent attachment of anterior uveitis. Laboratory indicators corresponded to renal insufficiency of tubular origin. Ophthalmological examination conducted against the background of redness of both eyes, photophobia, pain in the eyeball area and decreased vision confirmed bilateral uveitis. Analysis showed high levels of La/SS-B, anti-SARS-CoV-2 IgG with confirmed the suspicion of post-covid TINU syndrome. This case showed a good response to steroid therapy with long-term remission of nephritis and less clinical efficacy in the treatment of uveitis. Special attention should be paid to the occurrence of such a rare syndrome at an early stage after recovery from the Covid-19 disease.

A case of APMPPE-like panuveitis presenting with extensive outer retinal layer impairment following COVID-19 vaccination (preprint)

Background Vaccination against the worldwide pandemic coronavirus disease 2019 (COVID-19) is underway; however, some cases of newly onset uveitis after vaccination have been reported. We report a case of bilateral acute posterior multifocal placoid pigment epitheliopathy-like (AMPPE-like) panuveitis after COVID-19 vaccination in which the patient’s pathological condition was evaluated using multimodal imaging. Case presentation A 31-year-old woman experienced bilateral hyperemia and blurred vision starting 6 days after her second inoculation of the COVID-19 vaccination. At her first visit, her visual acuity was decreased bilaterally, and severe bilateral anterior chamber inflammation and bilateral scattering of cream-white placoid lesions on the fundus were detected. Optical coherence tomography (OCT) showed serous retinal detachment (SRD) and choroidal thickening in both eyes (OU). Fluorescein angiography (FA) revealed hypofluorescence in the early phase and hyperfluorescence in the late phase corresponding to the placoid legions. Indocyanine green angiography (ICGA) showed sharply marginated hypofluorescent dots of various sizes throughout the mid-venous and late phases OU. The patient was diagnosed with APMPPE and was observed without any medications. Three days later, her SRD disappeared spontaneously. However, her anterior chamber inflammation continued, and oral prednisolone (PSL) was given to her. Seven days after the patient’s first visit, the hyperfluorescent lesions on FA and hypofluorescent dots on ICGA partially improved; however, the patient’s best corrected visual acuity (BCVA) dropped to 0.7 OD and 0.6 OS, and the impairment of the outer retinal layer was broadly detected as hyperautofluorescent lesions on fundus autofluorescence (FAF) examination and as irregularity in or disappearance of the ellipsoid and interdigitation zones on OCT, which were quite atypical for the findings of APMPPE. Steroid pulse therapy was performed. Five days later, the hyperfluorescence on FAF had disappeared, and the outer retinal layer improved on OCT. Moreover, the patient’s BCVA recovered to 1.0 OU. Twelve months after the end of treatment, the patient did not show any recurrences. Conclusions We observed a case of APMPPE-like panuveitis after COVID-19 vaccination featuring some atypical findings for APMPPE. COVID-19 vaccination may induce not only known uveitis but also atypical uveitis, and appropriate treatment is required for each case.