Multitask Deep Learning for Joint Detection of Necrotizing Viral and Noninfectious Retinitis From Common Blood and Serology Test Data.

Purpose: Necrotizing viral retinitis is a serious eye infection that requires immediate treatment to prevent permanent vision loss. Uncertain clinical suspicion can result in delayed diagnosis, inappropriate administration of corticosteroids, or repeated intraocular sampling. To quickly and accurately distinguish between viral and noninfectious retinitis, we aimed to develop deep learning (DL) models solely using noninvasive blood test data. Methods: This cross-sectional study trained DL models using common blood and serology test data from 3080 patients (noninfectious uveitis of the posterior segment [NIU-PS] = 2858, acute retinal necrosis [ARN] = 66, cytomegalovirus [CMV], retinitis = 156). Following the development of separate base DL models for ARN and CMV retinitis, multitask learning (MTL) was employed to enable simultaneous discrimination. Advanced MTL models incorporating adversarial training were used to enhance DL feature extraction from the small, imbalanced data. We evaluated model performance, disease-specific important features, and the causal relationship between DL features and detection results. Results: The presented models all achieved excellent detection performances, with the adversarial MTL model achieving the highest receiver operating characteristic curves (0.932 for ARN and 0.982 for CMV retinitis). Significant features for ARN detection included varicella-zoster virus (VZV) immunoglobulin M (IgM), herpes simplex virus immunoglobulin G, and neutrophil count, while for CMV retinitis, they encompassed VZV IgM, CMV IgM, and lymphocyte count. The adversarial MTL model exhibited substantial changes in detection outcomes when the key features were contaminated, indicating stronger causality between DL features and detection results. Conclusions: The adversarial MTL model, using blood test data, may serve as a reliable adjunct for the expedited diagnosis of ARN, CMV retinitis, and NIU-PS simultaneously in real clinical settings.

Good syndrome and cytomegalovirus retinitis: A literature review.

Good syndrome (GS) is a rare primary immunodeficiency in adults consisting of hypogammaglobulinemia and thymoma that affects both cellular and humoral immunity. It usually appears in patients between the 4th and 6th decade of life and affects both genders equally. Ophthalmological clinical presentation is highly variable; associations with herpetic keratitis, toxoplasmosis, and cytomegalovirus retinitis (CMVR) have been described. GS associated with CMVR is uncommon. Ophthalmologists may be the first to diagnose systemic disease and change the outcome. Only18 cases of CMVR have been described, most of them unilateral with poor visual outcomes. We discuss the clinical features of CMVR in patients with reported GS, pathogenesis, and outline a work-up for diagnosis. CMVR in an apparently healthy patient should encourage the clinician to search for human immunodeficiency virus (HIV) and non-HIV-associated immunosuppression.

Ocular syphilis masquerading as CMV retinitis in a transplanted patient.

BACKGROUND: Syphilis has historically been referred to as "the great imitator", for the extent of disease manifestations secondary to infection. Ocular manifestations include a wide range of intra-ocular inflammation. METHODS: In this study, we report the case of a 52 years-old male patient with syphilitic hemorrhagic necrotizing retinitis. RESULTS: The patient presented to the emergency room for rapid and progressive vision loss and ocular redness lasting three weeks and was under immunosuppressive treatment. The diagnosis was syphilitic hemorrhagic necrotizing retinitis mimicking the typical clinical picture of retinitis caused by Cytomegalovirus infection in immunocompromised patients. CONCLUSIONS: The presented case highlights the need to consider ocular syphilis as a great masquerader even in the presence of atypical presentations such as hemorrhagic retinitis. Syphilis should be tested for treponemal and non-treponemal tests, and it should be ruled out as an etiological agent in every case of new-onset intra-ocular inflammation.

GOOD SYNDROME: CYTOMEGALOVIRUS RETINITIS CASE CHALLENGE.

PURPOSE: To describe cytomegalovirus retinitis in a patient with Good syndrome (hypogammaglobulinemia and thymoma), ocular progression despite treatment and fatal outcome. METHODS: A 71-year-old woman with unilateral panuveitis of unknown cause and a history of thymoma resection was referred to the clinic. Visual acuity was 20/100 in her right eye and light perception in her left eye. In slit-lamp examination, the right eye had inferior, fine, pigmented keratic precipitates, 2+ anterior chamber cells, cataract, and 2+ vitreous cells, with no fundus detail and normal ocular ultrasound results. Left eye presented a white cataract, chronic hypotony, and increased choroidal thickness with calcifications. Laboratory evaluations showed normal or negative results for common causes of infection and inflammation. Prednisolone acetate eye drops were started, with improvement of AC inflammation. Cataract surgery was performed, reaching visual acuity of 20/30. Two years later, visual acuity had decreased and 2+ vitritis and retinitis were found. On clinical suspicion of masquerade syndrome, a vitrectomy biopsy was performed; pathologic assessments reported no data on ocular lymphoma. Leukopenia and lymphopenia were found: immunoglobulin levels, CD4 count, and viral load revealed systemic immunosuppression. The aqueous tap was positive for cytomegalovirus. Oral valganciclovir and intravitreal ganciclovir were initiated. RESULTS: In a patient with previous resection of thymoma and hypogammaglobulinemia, final diagnosis was Good syndrome, with cytomegalovirus retinitis being secondary to immunosuppression. Despite treatment, cytomegalovirus retinitis progressed and systemic deterioration resulted in mortal outcome. CONCLUSION: Good syndrome is an extremely rare disease, and association with cytomegalovirus retinitis is uncommon. To the authors' knowledge, only 14 cases exist in the literature.

Diffuse retinal dysfunction following immune reconstitution uveitis in patients with prior cytomegalovirus retinitis: a novel observation.

PURPOSE: To report continuing diffuse retinal dysfunction following resolution of immune reconstitution uveitis (IRU) in patients with cytomegalovirus retinitis (CMVR). METHODS: Retrospective case series describing two patients with IRU following CMVR who underwent serial fundus photography and macular optical coherence tomography. One patient had serial electrophysiology. RESULTS: Both patients had CMVR successfully treated with antiviral medication. The affected eyes later developed IRU that resolved with steroids. However, following resolution, chronic retinal damage was evidenced by ellipsoid line loss in one case and gradual optic disc cupping in the other. Electrophysiology in both cases revealed generalized retinal dysfunction worse in the eye with more severe IRU and demonstrated objectively the efficacy of treatment intervention in the patient with serial recordings. CONCLUSIONS: Patients with IRU following CMV retinitis may have continuing diffuse retinal dysfunction despite apparent recovery and normal visual acuity. An aggressive approach to inflammation control may be warranted in such patients.

Comparison of two different intravitreal treatment regimens combined with systemic antiviral therapy for cytomegalovirus retinitis in patients with AIDS.

PURPOSE: To compare the efficacy and injection frequency of intravitreal low-dose vs. intermediate-dose ganciclovir therapy in acquired immune deficiency syndrome (AIDS) patients exhibiting cytomegalovirus retinitis (CMVR). METHODS: A prospective, single-centre, double-blinded, randomized controlled interventional study was conducted. Fifty patients with a total of 67 included eyes were randomly divided into low-dose (0.4 mg ganciclovir per week) and intermediate-dose (1.0 mg ganciclovir per week) groups. The primary clinical outcomes were the changes in best corrected visual acuity (BCVA) from baseline to the end of treatment and the 12-month follow-up visit as well as the number of intravitreal injections. RESULTS: In both groups, the median BCVA, expressed as the logarithm of the minimum angle of resolution (logMAR), improved significantly from baseline to the end of treatment (both p < 0.001), while vision loss from CMVR continued to occur at the 12-month visit. The mean number of injections was 5.8 in the low-dose group and 5.4 in the intermediate-dose group. No significant differences were detected between the two groups (p > 0.05). Regarding the location of CMVR, we found that Zone I lesions led to a worse visual outcome, more injections and a higher occurrence rate of complications than lesions in other zones (p < 0.05). CONCLUSIONS: The efficacy and frequency of injections to treat CMVR in AIDS patients were not significantly different between low and intermediate doses. Zone I lesions were associated with a worse visual outcome, more injections and a higher occurrence rate of CMVR-related complications than lesions in other zones.

Clinical features of Cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome and efficacy of the current therapy.

Background: Cytomegalovirus retinitis (CMVR) is the most common and sight-threatening opportunistic retinal infection in patients with acquired immunodeficiency syndrome (AIDS) and several controversies remain to be settled. We aimed to summarize the current evidence and clarify the clinical features and prognosis of CMVR in AIDS patients. Methods: The databases PubMed, EMBASE, and Ovid from inception to April 2022 were searched to identify the relevant studies. R software version 3.6.3 was used to perform the statistical analyses. Results in proportion with 95% confidence interval (CI) were calculated using the Freeman-Tukey variant of arcsine square transformation. Results: We finally included 236 studies comprising 20,214 patients. CMVR in AIDS was male-dominated (88%, 95%CI 86%-89%), with 57% (95%CI 55%-60%) aged <41 years and 44% (95%CI 41%-47%) being bilaterally involved. CMVR was preponderant in AIDS patients with the following characteristics: white and non-Hispanic, homosexual, HIV RNA load ≥ 400 copies/mL, and CD4+ T-cells <50 cells/µL. The positivity of CMV-DNA in blood, aqueous humor, and vitreous humor was 66% (95%CI 52%-79%), 87% (95%CI 76%-96%), and 95% (95%CI 85%-100%), respectively. The most common symptoms were blurred vision (55%, 95%CI 46%-65%), followed by asymptomatic, visual field defect, and floaters. CMVR was first diagnosed and regarded as the clue to AIDS diagnosis in 9% (95%CI 6%-13%) of CMVR patients. Approximately 85% (95%CI 76%-93%) of the CMVR patients have received cART. CMVR remission was observed in 72%-92% of patients depending on the specific category of anti-CMV therapy. The general incidence of CMVR-related RD in the entire course was 24% (95%CI 18%-29%), of which most patients received PPV with SO or gas tamponade and the rate of anatomic success was 89% (95%CI 85%-93%). Conclusion: CMVR is a common opportunistic infection with diverse clinical features in AIDS patients, preponderant in those who are male, homosexual, or with CD4+ T-cells <50 cells/µL. Current therapies for CMVR and CMVR-related RD were shown to be effective. Early detection and routine ophthalmic screening should be promoted in AIDS patients. Systematic review registration: PROSPERO, identifier CRD42022363105.

Association Between Torque Teno Virus and Systemic Immunodeficiency in Patients With Uveitis With a Suspected Infectious Etiology.

PURPOSE: To determine the correlation between the presence of torque teno virus (TTV) in the aqueous humor of patients with uveitis and clinical information, including immunodeficiency history. DESIGN: Multicenter, retrospective, cross-sectional study. METHODS: Fifty-eight patients with uveitis with a suspected infectious etiology and 24 controls with cataract or age-related macular degeneration were included. We used quantitative polymerase chain reaction to test all subjects for TTV and multiplex polymerase chain reaction to test uveitis subjects for common ocular pathogens. When possible, both serum and aqueous humor samples were tested. Ocular TTV positivity was compared with age, sex, and a history of systemic immunodeficiency with logistic analysis. RESULTS: Ocular TTV positivity was found in 23%, 11%, and 0% of patients with herpetic uveitis, nonherpetic uveitis, and controls, respectively. Among patients with herpes infection, positivity for ocular TTV was found in 43%, 8%, 14%, and 50% of patients with cytomegalovirus retinitis, iridocyclitis, acute retinal necrosis, and Epstein-Barr virus-positive uveitis, respectively. Patients with cytomegalovirus retinitis showed a significantly higher rate of ocular TTV infection than controls (P = .008). Serum analysis revealed TTV positivity in 90% of patients with uveitis and in 100% of controls. Age- and gender-adjusted logistic analysis revealed a correlation between ocular TTV positivity and systemic immunodeficiency (P = .01), but no correlations between ocular TTV and age, gender, or viral pathogenic type. CONCLUSIONS: These findings suggest that positivity for ocular TTV was correlated with a clinical history of systemic immunodeficiency.

Viral-specific T cells for Cytomegalovirus retinitis following hematopoietic stem cell transplantation: A success story.

Cytomegalovirus retinitis (CMVR) following hematopoietic stem cell transplantation (HCT) for a primary immunodeficiency is a rare but highly morbid condition with potential irreversible consequences despite optimal antiviral pharmacotherapy. Viral-specific T cells (VSTs) pose a promising and safe approach eradicating intractable viral disease. We describe the case of a 21-month-old male with Wiskott-Aldrich syndrome (WAS) and CMVR post HCT with sustained long-term virologic and clinical response after CMV-specific T-cell therapy. This case highlights the need to consider VST as an adjunct upfront strategy in refractory CMVR and for routine ophthalmologic screening and surveillance in high-risk patients post HCT.

Human immunodeficiency virus retinopathy with presumed cytomegalovirus retinitis with macular oedema in a diabetic.

A man in his early 50s on regular follow-up for a stable non-proliferative diabetic retinopathy (NPDR) presented with decreased vision, worsening of retinal pathology and macular oedema in both eyes. His corrected distance visual acuity (CDVA) was 6/9 in the right eye and 6/15 in the left eye and fundus examination showed multiple intraretinal haemorrhages in all quadrants. His systemic workup revealed a severe thrombocytopaenia, which prompted a further detailed systemic evaluation revealing him to be positive for HIV with retinopathy complicating the pre-existing NPDR. Given the significant inflammation and macular oedema, a cocktail of intravitreal bevacizumab, ganciclovir and dexamethasone was administered. The retinopathy and macular oedema resolved and the CDVA improved to 6/6 in both eyes over a 6-month follow-up period. Any sudden worsening of fundus findings in a patient with diabetes necessitates immediate and detailed ocular and systemic evaluation, especially when the immune status is unknown.

Blurred Vision After a Kidney Transplant.

A patient with cytomegalovirus viremia who underwent kidney transplant developed floaters in both eyes that did not improve after painful intravitreal injections of foscarnet and ganciclovir. What would you do next?

First-line management of necrotizing herpetic retinitis by prioritizing the investigation of immune status and prognostic factors for poor visual outcomes.

PURPOSE: To review management, treatment, and outcomes of patients with necrotizing herpetic retinitis (NHR) to propose an algorithm for first-line management of NHR. METHODS: Retrospective evaluation of a series of patients with NHR at our tertiary center between 2012 and 2021 using demographic, clinical, ophthalmologic, virological, therapeutic, and prognostic characteristics was performed. Patients were classified by NHR type: acute retinal necrosis (ARN), progressive outer retinal necrosis (PORN), cytomegalovirus (CMV) retinitis. RESULTS: Forty-one patients with NHR were included: 59% with ARN, 7% with PORN, and 34% with CMV retinitis. All patients with CMV retinitis and PORN were immunocompromised versus 21% of patients with ARN. CMV infection was found in 14 (34%) patients, varicella zoster virus infection in 14 (34%) patients, herpes simplex virus type 2 infection in 8 (20%) and type 1 infection in 5 (12%) patients. Intravenous antiviral therapy was received by 98% of patients and intravitreal antiviral injections by 90% of patients. The overall complication rate during follow-up was 83% of eyes. Most frequent complications were retinal detachment (33% eyes) and retinal break (29% eyes). Prognostic factors for poor visual outcomes were pre-existing monocular vision loss in contralateral eye among 17% of patients, bilateral NHR in 17% of patients, posterior pole involvement in 46% of eyes, and involvement > 2 retinal quadrants in 46% of eyes. CONCLUSIONS: The visual prognosis of patients with NHR remains poor. Prompt investigation of immune status and presence of factors justifying intravitreal antiviral injections must be prioritized to initiate and adapt management while awaiting causative virus confirmation.

Cytomegalovirus retinitis and immune recovery uveitis in a pediatric patient with leukemia.

Immune recovery uveitis (IRU) is an ocular form of immune reconstitution inflammatory syndrome, which is rare in the pediatric population. We report a case of IRU in an 11-year-old girl with a history of cytomegalovirus (CMV) retinitis in the setting of acute leukemia, who developed uveitis, vitritis, retinitis, and vasculitis during immune reconstitution. She was found to have negative CMV antigenemia, and the disease occurred during concurrent systemic antiviral therapy. Anterior chamber tap confirmed the absence of the CMV in the eye, and recurrent blood samples continued to reveal absent CMV viral particles systemically while her lymphocyte count was steadily increasing. The patient responded to oral steroids, leading to resolution of active retinitis. Tapering the steroids caused a mild reactivation of the ocular immune response.

Efficacy of ganciclovir versus foscarnet in ganciclovir-resistant cytomegalovirus retinitis: A case report.

PURPOSE: To report a case of cytomegalovirus (CMV) retinitis improved by treatment with ganciclovir in a patient with ganciclovir-resistant CMV infection associated with Good syndrome. STUDY DESIGN: Case report. RESULT: A 52-year-old gentleman with Good syndrome presented with visual disturbance in his right eye. He had a history of receiving intravitreal ganciclovir treatment with CMV retinitis a year ago. During treatment for CMV colitis three months ago, in systemic blood, UL97 mutation was identified and improved after changing treatment from ganciclovir to foscarnet. CMV retinitis recurred, and intravitreal ganciclovir injection was performed but there was no improvement. Therefore, the treatment was changed to foscarnet, but retinal infiltration progressed. Accordingly, it was changed to ganciclovir again and as a result, the progression of retinitis could be stopped. CONCLUSIONS: Even in the case of CMV retinitis, which has been genetically confirmed to be ganciclovir resistance in systemic blood, ganciclovir treatment can be considered if other anti-CMV agents are not effective.

Cytomegalovirus retinitis in hospitalized people living with HIV in the late antiretroviral therapy era in São Paulo, Brazil.

BACKGROUND: There is scarce information on AIDS-related cytomegalovirus (CMV) retinitis in middle-income countries. The objectives of this study were to identify the prevalence of active CMV retinitis in severely immunosuppressed people living with HIV (PLWHIV) and to describe its main features. METHODS: This retrospective cohort study was carried out at a tertiary center in São Paulo, Brazil. We included hospitalized adults PLWHIV with CD4 count ≤100 cells/µL, ≥ one quantitation of CMV DNA in plasma, and indirect ophthalmoscopy evaluation. RESULTS: Thirty-eight (21.6%) of 176 participants had at least an ophthalmoscopy diagnosis and only 3 (1.7%) individuals presented active CMV retinitis. All these participants were male, and retinitis was asymptomatic in 2 cases. Two participants had extraocular end-organ CMV disease and detectable CMV DNA in plasma. CONCLUSIONS: These results show a low prevalence of active CMV retinitis in the evaluated population. However, 2 of 3 participants had asymptomatic active CMV retinitis and a fifth of participants had at least one ophthalmoscopy diagnosis, suggesting the need for routine ophthalmologic evaluation in hospitalized severely immunosuppressed PLWHIV. The profile of participants with active CMV retinitis was similar to that described in the pre-ART era and quantitation of CMV DNA in plasma was variable.