Susceptibilidad de las mucosas oculares al SARS COV-2: bioseguridad sanitaria / Susceptibility of eye mucosa to SARS CoV-2: sanitary biosecurity

RESUMEN: El SARS CoV-2, agente causal de la enfermedad llamada Covid-19, infecta las mucosas digestivas y respiratorias, afectando las células epiteliales. El virus ingresa a través del receptor de membrana ACE2 provocando la disrupción de la homeostasis celular. Frecuentes reportes indican la presencia de conjuntivitis ocular en pacientes diagnosticadas con Covid-19, lo cual ha alertado a los científicos sobre el potencial foco de infección viral de las secresiones lagrimales.Los epitelios de la conjuntiva ocular sub-palpebral y corneal, se caracterizan por presentar el receptor de la enzima convertidora de angiotensina 2 (ACE2) y proteasa transmembrana asociada serina 2 (TMPRSS2), cuya interacción activa los mecanismos de liberación de citoquinas, capaces de instalar un proceso de conjuntivitis infecciosa por SARS CoV-2, pero no necesariamente hacer extensiva la infección hacia los sistemas digestivo y respiratorio.Aunque este proceso inflamatorio es más frecuente como una expresión de la infección general y más grave. Sin embargo, cualquiera sea la vía de infección o ingreso del virus SARS CoV-2 es importante considerar el riesgo de infectividad de las lágrimas y las secresiones conjuntivales en los pacientes. Este estudio pretende llamar la atención sobre las medidas de cuidados y control sanitario, incorporando mejores normas de protección personal y bioseguridad, especialmente en el áreas de oftalmología, asumiendo que la mucosa ocular puede ser una vía de entrada del virus y a la vez una fuente de contagio.También considerar la potenciación de la infección viral con las enfermedades de base asociadas, como glaucoma y diabetes.Se sugiere además incorporar estudios histológicos de la mucosa ocular para diferenciar epitelios sanos e infectados.

SUMMARY: SARS CoV-2, the causal agent of the Covid- 19 disease, infects the digestive and respiratory mucosa, affecting epithelial cells. The virus enters through the ACE2 membrane receptor causing the disruption of cell homeostasis. Frequent reports indicate the presence of ocular conjunctivitis in patients diagnosed with Covid-19, which has alerted scientists to the potential source of viral infection from lacrimal secretions. The epithelia of the sub-palpebral and corneal ocular conjunctiva are characterized by presenting the receptor for angiotensin-converting enzyme 2 (ACE2) and associated transmembrane protease serine 2 (TMPRSS2), whose interaction activates cytokine release mechanisms, with the ability to start the infectious conjunctivitis process by SARS CoV-2, but not necessarily extend the infection to the digestive and respiratory systems. Although this inflammatory process is more frequent as an expression of the general and more serious infection. However, whatever the route of infection or entry of the SARS CoV-2 virus, it is important to consider the risk of infection of tears and conjunctival secretions in patients. This study aims to draw attention to health care and control measures, incorporating better standards of personal protection and biosafety, especially in the areas of ophthalmology, assuming that the ocular mucosa can be a route of entry for the virus, and at the same time a source of contagion. A further consideration is the potential of viral infection with associated underlying diseases, such as glaucoma and diabetes. It is also suggested to incorporate histological studies of the ocular mucosa to differentiate healthy and infected epithelia.

The characteristics of Posner-Schlossman syndrome: A comparison in the surgical outcome between cytomegalovirus-positive and cytomegalovirus-negative patients.

This retrospective observational study aims to report the clinical characteristics and surgical results in eyes with Posner-Schlossman syndrome (PSS), and compare these outcomes between cytomegalovirus (CMV)-positive and -negative eyes.We reviewed the medical records of 21 consecutive immunocompetent patients clinically diagnosed with PSS between the years 2010 and 2018. Aqueous humor was collected from all the affected eyes to detect if CMV was present, and polymerase chain reaction (PCR) was performed using the herpesvirus family primers.The average period between the initial PSS attack and aqueous humor sampling at our institute was 9.3 years. Out of the 21 patients, 62% were CMV-positive. Regardless of CMV status, the mean intraocular pressure (IOP), mean deviation (MD), and central corneal endothelium cell (CEC) density, at the initial examination at our institute were already significantly worse in the affected eyes than in the unaffected eyes (all P values < .05). The average visual acuity (VA) was only significantly worse in the CMV-positive group (P = .02). Out of all the patients, those that were CMV-positive had undergone more glaucoma surgeries (P = .056). Fourteen patients underwent either a trabeculectomy (TRAB) or a trabeculotomy (LOT), and their IOP significantly reduced following surgery (P < .001). In 85.7% of those that had surgery, their IOP was successfully lowered to less than 20 mm Hg.Long-lasting PSS causes a decrease in VA, MD, and the CEC density. A prompt diagnosis is required, and an appropriate treatment plan should be formulated. In those patients with PSS that develop uncontrolled glaucoma, both TRAB and LOT may be effective in controlling IOP.

Zika Virus Infects Trabecular Meshwork and Causes Trabeculitis and Glaucomatous Pathology in Mouse Eyes.

Zika virus (ZIKV) infection during pregnancy leads to devastating fetal outcomes, including neurological (microcephaly) and ocular pathologies such as retinal lesions, optic nerve abnormalities, chorioretinal atrophy, and congenital glaucoma. Only clinical case reports have linked ZIKV infection to causing glaucoma, a major blinding eye disease. In the present study, we have investigated the role of ZIKV in glaucoma pathophysiology using in vitro and in vivo experimental models. We showed that human primary trabecular meshwork (Pr. TM) cells, as well as a human GTM3 cell line, were permissive to ZIKV infection. ZIKV induced the transcription of various genes expressing pattern recognition receptors (TLR2, TLR3, and RIG-I), cytokines/chemokines (TNF-α, IL-1ß, CCL5, and CXCL10), interferons (IFN-α2, IFN-ß1, and IFN-γ), and interferon-stimulated genes (ISG15 and OAS2) in Pr. TM cells. ZIKV infection in IFNAR1-/- and wild-type (WT) mouse eyes resulted in increased intraocular pressure (IOP) and the development of chorioretinal atrophy. Anterior chamber (AC) inoculation of ZIKV caused infectivity in iridocorneal angle and TM, leading to the death of TM cells in the mouse eyes. Moreover, anterior segment tissue of infected eyes exhibited increased expression of inflammatory mediators and interferons. Furthermore, ZIKV infection in IFNAR1-/- mice resulted in retinal ganglion cell (RGC) death and loss, coinciding with optic nerve infectivity and disruption of anterograde axonal transport. Because of similarity in glaucomatous pathologies in our study and other experimental glaucoma models, ZIKV infection can be used to study infectious triggers of glaucoma, currently an understudied area of investigation.IMPORTANCE Ocular complications due to ZIKV infection remains a major public health concern because of their ability to cause visual impairment or blindness. Most of the previous studies have shown ZIKV-induced ocular pathology in the posterior segment (i.e., retina) of the eye. However, some recent clinical reports from affected countries highlighted the importance of ZIKV in affecting the anterior segment of the eye and causing congenital glaucoma. Because glaucoma is the second leading cause of blindness worldwide, it is imperative to study ZIKV infection in causing glaucoma to identify potential targets for therapeutic intervention. In this study, we discovered that ZIKV permissively infects human TM cells and evokes inflammatory responses causing trabeculitis. Using a mouse model, we demonstrated that ZIKV infection resulted in higher IOP, increased RGC loss, and optic nerve abnormalities, the classical hallmarks of glaucoma. Collectively, our study provides new insights into ocular ZIKV infection resulting in glaucomatous pathology.

Cytomegalovirus-related uncontrolled glaucoma in an immunocompetent patient: a case report and systematic review.

BACKGROUND: Cytomegalovirus can cause ocular anterior uveitis with ocular hypertension. Basis on the therapy, ocular pressure usually can be controlled. We report a case of a man who had unilateral cytomegalovirus anterior uveitis with refractory glaucoma during the process of treatment. CASE PRESENTATION: A 57-year-old man who was diagnosed Posner-Schlossman syndrome and was admitted for repeatly attacks of raised IOP in left eye for 4 months. We found the cytomegalovirus -DNA was high (1800 copies/ml) in his aqueous. After systemic used of antiviral drug accompany with topical used of anti-inflammation, anti-glaucoma agents and genciclovir gel, the ocular pressure was dropped to normal. While the pressure elevated again in a month after stopping systemic antiviral treatment. Furthermore, the second test showed cytomegalovirus in aqueous humor decreased to 526 copies/ml. Intravenous drugs to antiviral, anti-inflammatory and anti-glaucoma were applied, but the ocular pressure was still high. In the progression of glaucomatous damage in the eye, glaucoma surgery was operated with no cytomegalovirus was detected. At last, the postoperative ocular pressure has been controlled. CONCLUSIONS: CMV infection is not rare. Patients have unilateral mild anterior inflammation with relapsed attacks of elevated intraocular pressure should be considered for CMV infection. We found that concurrent use of systemic and topical ganciclovir in a short period could reduce ocular CMV significantly, while ocular hypertension recurred. The antiviral treatment should be individualized. Glaucoma surgery could be offered to protect CEC loss and glaucomatous damage.

Enhanced cytomegalovirus infection in human trabecular meshwork cells and its implication in glaucoma pathogenesis.

Cytomegalovirus (CMV) is one of the infectious causes of hypertensive anterior uveitis, which is characterized by recurrent episodes of elevated intraocular pressure (IOP) and mild anterior uveitis. Despite the potentially vision-threatening complications of this disease, the underlying mechanisms remain largely undefined. We aimed to investigate whether human trabecular meshwork (TM) cells, the key cell type that regulates IOP, could support CMV replication, as well as demonstrate the relevant pathological changes in TM. When human TM cells were infected with CMV AD169, immediate early antigens were detected 1 day post-infection (dpi); cytopathic changes including rounding, a ballooned appearance with disorganization, and a decreased number of stress fibers were noted in TM cells. The marked increase in viral DNA accumulation was observed most notably at 5 and 7 dpi, suggesting that the active viral infection in human TM cells could be the key mechanism underlying the elevation of IOP in anterior viral uveitis. Notably, CMV infection enhanced the production of transforming growth factor (TGF)-ß1, an upstream molecule that increases the resistance of the outflow pathway in human TM cells. The increase of TGF-ß1 was countervailed by additional treatment with corticosteroids. Our results provide a pathogenic mechanism for IOP elevation in viral anterior uveitis.

Retinal Nerve Fiber and Optic Disc Morphology in Patients with Human Immunodeficiency Virus Using the Heidelberg Retina Tomography 3.

PURPOSE: To use novel confocal scanning ophthalmoscopy technology to test hypothesis that HIV-seropositive patients without history of retinitis with a history of a low CD4 count are more likely to have damage to their retinal nerve fiber layer (RNFL) when compared to patients with high CD4 count. In addition, we compared optic disc morphologic changes with glaucoma. DESIGN: Cross-sectional study. PARTICIPANTS AND CONTROLS: 171 patients were divided into four groups. The control group consisted of 40 eyes of 20 HIV-seronegative patients. The second group consisted of 80 eyes of 41 HIV-positive patients whose CD4 cell count never dropped below 100 (1.0 x 10(9)/L). The third group consisted of 44 eyes of 26 HIV-positive patients with a history of low CD4 counts <100. Fourth group consisted of 79 eyes of 79 patients with confirmed glaucoma who served as positive controls. TESTING: Confocal scanning laser ophthalmoscopy was performed with the Heidelberg Retina Tomograph (HRT3) and data were analyzed with HRT3, software (Heyex version 1.5.10.0). MAIN OUTCOME MEASURES: Disc area, cup area, cup volume, rim volume, mean cup depth, maximum cup depth, cup-to-disc ration, mean RNFL thickness, and RNFL cross-sectional area. RESULTS: Analysis of the global optic nerve and cup parameters showed no difference in disk area among the four groups. There was also no difference in cup, rim volume, mean cup depth, or maximum cup depth among the first three groups but they were all different from glaucoma group. The RNFL was thinner in glaucoma and both HIV-positive groups compared to HIV-seronegative subjects. The cross sectional RNFL area was thinner in both high and low CD4 HIV-positive groups compared to HIV-seronegative group in the nasal and temporal/inferior sectors, respectively. Glaucoma group showed thinning in all sectors. CONCLUSIONS: HIV retinopathy results in retinal nerve fiber layer loss without structural optic nerve supportive tissue change. RNFL damage may occur early in HIV disease by mechanism different than in glaucoma.

Trabeculectomy ab interno (trabectome): yet another possibility in the treatment of uncontrolled glaucomatocyclitic crisis under systemic valganciclovir therapy?

PURPOSE: To assess the outcome of trabectome surgery in the treatment of glaucomatocyclitic crisis (Posner-Schlossman syndrome) in patients with uncontrolled intraocular pressure (IOP). PATIENTS/METHODS: Trabectome surgery was performed in seven patients with diagnosed glaucomatocyclitic crisis and uncontrolled IOP where cytomegalovirus DNA was verified by polymerase chain reaction in aqueous humour samples. All patients were treated with oral valganciclovir. After surgery the patients were followed-up for 12 months. RESULTS: Mean IOP before trabectome surgery was 40±10 mm Hg (range 33-58 mm Hg). The mean number of antiglaucoma medication prior to surgery was 3.1±0.4. By the end of the 12 months, IOP in all patients was reduced to normal level (13±1 mm Hg) and their antiglaucoma medication was decreased to 0.8±1.1. No recurring attack of glaucomatocyclitic crisis occurred. DISCUSSION: In addition to oral valganciclovir therapy, trabectome surgery seems to be a reliable and effective tool for the management of glaucomatocyclitic crisis with uncontrolled IOP.

Unilateral recalcitrant glaucoma associated with cytomegalovirus in an immunocompromised child with Wiskott-Aldrich syndrome.

We report a case of anterior uveitis and unilateral recalcitrant glaucoma in an immunocompromised 6-year-old boy diagnosed with Wiskott-Aldrich syndrome who presented with elevated intraocular pressure (IOP), mild anterior uveitis, and unilateral acute glaucoma. Polymerase chain reaction from the aqueous was positive for cytomegalovirus (CMV). After initially responding to ganciclovir, the IOP rose again. With worsening optic nerve status, the patient underwent glaucoma filtration surgery with mitomycin C, and a postoperative regimen for CMV retinitis was initiated.

Aqueous cytokine changes associated with Posner-Schlossman syndrome with and without human cytomegalovirus.

AIM: To study the differences in aqueous cytokines in Posner-Schlossman Syndrome (PSS) patients with and without human cytomegalovirus (CMV) DNA in the aqueous humor. METHODS: This is a prospective study. Fifty-three uveitis patients with clinical signs of PSS were enrolled and aqueous humor samples were collected. Fourteen PSS patients were positive of CMV DNA in the aqueous by polymerase chain reaction (PCR) analysis. These eyes were negative of common ocular pathogens such as herpes simplex virus, varicella-zoster virus, rubella virus and toxoplasma. Twenty-five otherwise healthy cataract patients were enrolled as controls. Cytokine concentration was measured by a magnetic color-bead-based multiplex assay and analyzed using statistical and classification approaches. RESULTS: The average age of 53 PSS patients was 48.74±13.43 years (yrs) (mean ± standard deviation) and 66.3±15.0 yrs for the controls. The median CMV viral DNA copy number was 26000/mL aqueous (range 1400 to 85000 copies/mL) in 14 CMV positive patients as determined by quantitative PCR. PSS aqueous had significantly higher Interleukin (IL)-8 (CXCL8), monocyte chemotactic protein-1 (CCL2), macrophage inhibitory protein 1-ß (CCL4), granulocyte colony-stimulating factor (GCSF) and transforming growth factor-ß (TGF-ß) levels than controls after adjusted by age and gender. IL-2, IL-12, tumor necrosis factor-α (TNF-α) and interferon-α (IFN-α) levels were significantly lower in PSS aqueous than controls. No difference between CMV positive PSS and CMV negative PSS aqueous was observed. Over 97% of PSS samples were distinguished from controls by elevated CXCL10 (>500 ng/mL), CXCL8 (>30 ng/mL) and CCL2 (>60 ng/mL) levels. CONCLUSION: PSS eyes were characterized by elevated aqueous chemokine concentration. The presence of CMV viral DNA was not associated with significant change of the type of cytokine expression in PSS patients.

Ocular manifestations in herpes zoster ophthalmicus.

BACKGROUND: Ocular complications of herpes zoster ophthalmicus (HZO) may lead to substantial visual disability, severe post-herpetic neuralgia and rarely fatal cerebral complications. AIM: To identify the pattern of ocular manifestation in herpes zoster ophthalmicus. MATERIALS AND METHODS: A cross-sectional descriptive study was under taken including the clinically diagnosed cases of HZO. All of them underwent a complete ophthalmological evaluation. RESULTS: Sixty-eight cases of HZO were examined, of which 37 (54.4 %) were male and 31 (45.6%) female. The mean age was 48.7 ± 18.5 years. Most of the patients (64.7 %) were above the age of 40 years. 77.94 % of the patients had some form of ocular involvement. Pain (77.9 %) was the commonest ocular complaint. In young patients less than 35 years, HIV was the most common risk factor (19.3 %).Visual status was good in the majority (73.5 %) of patients at presentation. Lid and adnexal findings (45.8 %) were most common ocular involvement followed by conjunctivitis (41.1 %). Corneal complication was seen in 38.2 % of cases, uveitis in 19.1 % and post-herpetic neuralgia (PHN) and secondary glaucoma each in 5.8 %. CONCLUSION: Eyelid and ocular adnexal involvement is most commonly found in patients with herpes zoster ophthalmicus followed by corneal complication and uveitis. There needs to be awareness of ocular involvement, which can be sight threatening, among the HZO patients and other medical departments and an increased emphasis on regular ophthalmic examination.

[Cytomegalovirus research using polymerase chain reaction in Posner-Schlossman syndrome]. / Intérêt de la recherche du cytomégalovirus par polymerase chain reaction dans le syndrome de Posner-Schlossman.

PURPOSE: To investigate the possible association between cytomegalovirus (CMV) infection and Posner-Schlossman syndrome using PCR. To evaluate the clinical effect of valganciclovir treatment. PATIENTS AND METHODS: Patients with anterior uveitis associated with suspected Posner-Schlossman syndrome had their aqueous humor prospectively analyzed for viral deoxyribonucleic acid by HXFL4 gene detection using quantitative real-time PCR. RESULTS: Seven patients (two females and five males from 15 to 56 years old) with clinical signs of Posner-Schlossman syndrome (anterior nongranulomatous hypertensive uveitis with anterior chamber cells, central keratic precipitates, anisocoria, without iris atrophy) were tested. Examinations of the aqueous humor by polymerase chain reaction demonstrated CMV-DNA in five patients and were negative for other herpes viruses in all patients. Two patients were treated with oral antiviral therapy (valganciclovir). Relapses occurred in all cases after cessation of therapy. DISCUSSION: Aqueous humor analysis by PCR is useful in differentiating between CMV and other herpes viruses and in making a positive etiological diagnosis in anterior hypertensive uveitis. Valganciclovir may be effective in treating CMV anterior uveitis, but its exact role should be determined in larger studies with a longer follow-up. CONCLUSION: Cytomegalovirus detection in aqueous humor using polymerase chain reaction is useful in the management of patients with Posner-Schlossman syndrome.

Detection of herpes simplex virus in pseudoexfoliation syndrome and exfoliation glaucoma.

PURPOSE: The pathogenesis of pseudoexfoliation syndrome (PEX) remains unknown. An infection, possibly viral, is one of the proposed pathogenetic mechanisms. This study examines the presence of herpes simplex virus (HSV) and varicella-zoster virus (VZV) in iris and anterior capsule specimens of PEX and non-PEX patients. METHODS: Iris and anterior capsule specimens were obtained from 64 patients with PEX (study group, SG) and 61 patients without PEX (control group, CG). The presence of HSV and VZV DNA was evaluated with a polymerase chain reaction (PCR). RESULTS: Herpes simplex virus type I was detected significantly more often in iris specimens from the SG (13.79%), compared to those from the CG (1.75%). Varicella-zoster virus DNA was not detected in any of the examined specimens. CONCLUSION: Results imply a possible relationship between HSV type I and PEX, although no aetiological role of HSV infection in PEX pathogenesis can be established. Results also advocate against any association between VZV and PEX.