Deep learning system for screening AIDS-related cytomegalovirus retinitis with ultra-wide-field fundus images.

Background: Ophthalmological screening for cytomegalovirus retinitis (CMVR) for HIV/AIDS patients is important to prevent lifelong blindness. Previous studies have shown good properties of automated CMVR screening using digital fundus images. However, the application of a deep learning (DL) system to CMVR with ultra-wide-field (UWF) fundus images has not been studied, and the feasibility and efficiency of this method are uncertain. Methods: In this study, we developed, internally validated, externally validated, and prospectively validated a DL system to detect AIDS-related from UWF fundus images from different clinical datasets. We independently used the InceptionResnetV2 network to develop and internally validate a DL system for identifying active CMVR, inactive CMVR, and non-CMVR in 6960 UWF fundus images from 862 AIDS patients and validated the system in a prospective and an external validation data set using the area under the curve (AUC), accuracy, sensitivity, and specificity. A heat map identified the most important area (lesions) used by the DL system for differentiating CMVR. Results: The DL system showed AUCs of 0.945 (95 % confidence interval [CI]: 0.929, 0.962), 0.964 (95 % CI: 0.870, 0.999) and 0.968 (95 % CI: 0.860, 1.000) for detecting active CMVR from non-CMVR and 0.923 (95 % CI: 0.908, 0.938), 0.902 (0.857, 0.948) and 0.884 (0.851, 0.917) for detecting active CMVR from non-CMVR in the internal cross-validation, external validation, and prospective validation, respectively. Deep learning performed promisingly in screening CMVR. It also showed the ability to differentiate active CMVR from non-CMVR and inactive CMVR as well as to identify active CMVR and inactive CMVR from non-CMVR (all AUCs in the three independent data sets >0.900). The heat maps successfully highlighted lesion locations. Conclusions: Our UWF fundus image-based DL system showed reliable performance for screening AIDS-related CMVR showing its potential for screening CMVR in HIV/AIDS patients, especially in the absence of ophthalmic resources.

Fluocinolone intravitreal implant (Iluvien) for macular edema secondary to immune recovery uveitis in patient with acute myeloid leukemia.

PURPOSE: To report the use of Fluocinolone intravitreal implant (Iluvien) for the treatment of persistent cystoid macular edema (CME) due to immune recovery uveitis syndrome in a patient with previous cytomegalovirus retinitis and acute myeloid leukemia. DESIGN: Case report. METHODS: The clinical history of a patient who received an Iluvien implant in one eye for the treatment of cystoid macular edema due to immune recovery uveitis syndrome, previously treated with peribulbar Triamcinolone and intravitreal Dexamethasone injections, was reviewed. RESULTS: A 48-year-old woman presented with cystoid macular edema due to immune recovery uveitis syndrome. The patient had a history of cytomegalovirus retinitis 3.5 years prior, secondary to immunosuppressive treatment for an acute myeloid leukemia. Three periocular triamcinolone injections and two dexamethasone intravitreal implants were performed, but the edema recurred, so fluocinolone intravitreal implant was used, achieving a sustained control of the condition at one year of follow-up. CONCLUSION: The Fluocinolone intravitreal implant may be an effective treatment for persistent CME in patients with immune recovery uveitis syndrome.

Bilateral Cytomegalovirus Retinitis After Chimeric Antigen Receptor T-cell Therapy for B-cell Lymphoma.

Cytomegalovirus (CMV) retinitis is commonly associated with immunosuppression and can cause irreversible vision loss. Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as an effective cancer treatment option but requires immunosuppression, thereby increasing the possibility of acquiring opportunistic infections such as CMV. We present the case of a 76-year-old female with a history of hypertension and type 2 diabetes mellitus who initially presented with shortness of breath and was diagnosed with the activated B-cell subset of diffuse large B-cell lymphoma (DLBCL). She received multiple cycles of chemotherapy and experienced relapses with cardiac involvement. The patient developed vision loss in the right eye and was diagnosed with bilateral posterior vitritis. She underwent various treatments, including radiotherapy, systemic chemotherapy, cataract extraction, and vitrectomy. After CAR-T therapy, she developed bilateral CMV retinitis, confirmed through polymerase chain reaction testing and managed by valganciclovir. Overall, this case report describes the first reported case of bilateral CMV retinitis following CAR-T therapy for DLBCL. It emphasizes the need for early recognition and treatment of CMV retinitis to prevent permanent vision loss. The report also underscores the importance of regular ocular screening and consideration of prophylactic measures in patients undergoing CAR-T therapy.

Cytomegalovirus Retinitis Associated With Intravitreal Dexamethasone Implant Injection.

Purpose: To describe an immunocompetent patient with cytomegalovirus (CMV) retinitis after dexamethasone implant injection and review previously documented cases. Methods: A review of case reports and literature was performed. Results: A 75-year-old man presented with acute decreased vision in the left eye. He had a vitrectomy and membrane peeling for an epiretinal membrane with recurrent cystoid macular edema and was receiving intravitreal dexamethasone implant injections at an outside hospital. The visual acuity in the left eye was hand motions, and an examination found patchy retinal whitening with hemorrhages. Aqueous polymerase chain reaction was positive for CMV. The laboratory evaluation was negative for immunodeficiencies. He was treated successfully with intravitreal and oral antivirals; however, his vision remained poor at most recent follow-up. A literature review found 8 previous cases of CMV retinitis after dexamethasone implant injection, although most had underlying immune dysregulation. Conclusions: CMV retinitis after intravitreal dexamethasone implant injection is rare. Awareness of this complication is essential because of the risk for devastating blindness.

Immune recovery uveitis: a focus review.

Immune recovery uveitis (IRU) is an intraocular inflammation that typically occurs as part of immune reconstitution inflammatory syndrome (IRIS) in the eye. Typically, it affects human immunodeficiency virus (HIV)-infected patients with recognized or unrecognized cytomegalovirus (CMV) retinitis who are receiving highly active antiretroviral therapy (HAART). IRU is a common cause of new vision loss in these patients, and it manifests with a wide range of symptoms and an increased risk of inflammatory complications, such as macular edema. Recently, similar IRU-like responses have been observed in non-HIV individuals with immune reconstitution following immunosuppression of diverse etiologies, posing challenges in diagnosis and treatment. This review provides an updated overview of the current literature on the epidemiology, pathophysiology, biomarkers, clinical manifestations, diagnosis, differential diagnosis, and treatment strategies for IRU.

Cytomegalovirus Retinitis in a Patient Taking Upadacitinib: A Case Report.

Upadacitinib is a relatively new drug used to treat autoimmune diseases. However, patients treated with upadacitinib may develop infections. We report a case of cytomegalovirus (CMV) retinitis that developed during upadacitinib administration. A 79-year-old woman presented with progressively decreasing vision in both eyes. Her decimal best-corrected visual acuity (BCVA) was 0.2 in the right and 0.01 in the left eye. The patient was taking upadacitinib for one year. Fundus examination revealed vitreous opacities and extensive white retinal lesions with hemorrhage in both eyes. CMV was detected in the anterior aqueous humor, vitreous humor, and blood samples. We diagnosed her with panuveitis and CMV retinitis, performed a vitrectomy in both eyes, and administered intravenous ganciclovir and steroids. After treatment, her BCVA improved to 0.6 in the right and 0.1 in the left eye. Ophthalmologists and physicians should be aware of CMV infections in patients being treated with upadacitinib.

Ocular Manifestations of Human Immunodeficiency Virus Infection in the Combination Antiretroviral Therapy Era.

Since the introduction of combination antiretroviral therapy (cART) in Japan in 2008, the spectrum of ocular manifestations in patients with human immunodeficiency virus (HIV) has changed. This study, conducted at Tokyo Medical and Dental University Hospital between January 2012 and August 2023, aimed to understand the epidemiology and clinical features of ocular manifestations in patients with HIV during the cART era. Of the 218 patients diagnosed with HIV, 23 (10.55%) exhibited ocular manifestations; all were male, aged 32-73. The most prevalent ocular complication was uveitis (60.67%). Notably, the prevalence of uveitis in this cART era has surged compared to earlier Japanese studies. Our data also suggest a potential direct link between uveitis and HIV, particularly in patients who have not yet undergone cART. However, cytomegalovirus retinitis, another prevalent ocular disease in our study, appeared more strongly associated with patients who commenced cART. Neither ocular condition was significantly correlated with CD4+ T-cell count. Importantly, our observed ocular manifestation prevalence (10.55%) was lower than that in previous studies, emphasizing the potential influence of cART and national healthcare support. These findings provide unique insights into the evolution of ocular manifestations in patients with HIV in Japan amidst cART availability.

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.

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.

Analysis of Clinical Characteristics of Patients with Recurrent Cytomegalovirus Retinitis after Hematopoietic Stem Cell Transplantation.

OBJECTIVE: To analyze and summarize the clinical and imaging characteristics of patients with cytomegalovirus retinitis (CMVR) relapse after hematopoietic stem cell transplantation (HSCT). METHODS: This retrospective case series study recruited patients with CMVR after HSCT. The study compared the patients with stable lesions and CMV-negative aqueous humor after treatment with those with relapse lesions and a CMV DNA load in aqueous humor which had increased again after treatment. The observation indexes were basic clinical information, best-corrected visual acuity, wide-angle fundus photography, optical coherence tomography (OCT), blood CD4+ T lymphocyte count, and aqueous humor CMV load of the patients. We summarized the data and statistically analyzed the differences between the relapse and non-relapse groups, as well as the correlations of the observed indicators. RESULTS: The study recruited 52 patients with CMVR (82 eyes) after HSCT, of whom 11 patients (15 eyes) had recurrence after treatment (21.2%). The recurrence interval was 6.4 ± 4.9 months. The final best-corrected visual acuity of recurrent patients was 0.3 ± 0.3. The number of CD4+ T lymphocytes in recurrence patients at the time of onset was 126.7 ± 80.2/mm3. The median CMV DNA load detected in aqueous humor at the time of recurrence was 8.63 × 103 copies/mL. There was a significant difference in the CD4+ T lymphocyte count between the recurrence and the non-recurrence groups at onset. The onset of visual acuity in recurrence patients was significantly correlated with final visual acuity and recurrence lesion area. The fundus of recurred CMVR showed increased marginal activity of the original stable lesion. Concurrently, yellow-white new lesions appeared around the stable, atrophic, and necrotic lesions. OCT showed new diffuse hyperreflexic lesions in the retinal neuroepithelial layer near the old lesions. Inflammatory punctate hyperreflexes were observed in the vitreous, with vitreous liquefaction and contraction. CONCLUSION: This study suggests that the clinical features, fundus manifestations, and imaging features of CMVR recurrence after HSCT are different from those at the initial onset. Patients should be closely followed up after their condition is stable to be alert for CMVR recurrence.

Uncovering the Unusual: A Case of Mixed Connective Tissue Disease With Rare Presentation, Atypical Complications, and Therapeutic Dilemmas.

Mixed connective tissue disease (MCTD) is an overlap syndrome characterized by features of systemic lupus erythematosus, scleroderma, and polymyositis, along with the presence of the U1RNP antibody. A 46-year-old female patient presented with severe anemia, cough, and breathlessness, and was diagnosed with cold agglutinin disease, a type of autoimmune hemolytic anemia (AIHA). Autoimmune workup revealed MCTD by positive antinuclear and U1RNP antibodies. She had bilateral miliary mottling on X-ray and a tree-in-bud appearance on high-resolution computed tomography of the thorax, which were suggestive of pulmonary tuberculosis. Standard therapy with steroids was not advisable. She was subsequently started on anti-tuberculosis treatment (anti-Koch's therapy), followed by steroid therapy and immunosuppressive therapy after three weeks. The patient responded well to treatment, but after two months, she developed cytomegalovirus (CMV) retinitis. Adult-onset CMV disease may occur as a result of primary infection, reinfection, or activation of a latent infection. Although not directly related, it can occur as an atypical association in the setting of immunosuppressive therapy. Morbidity and mortality are significantly increased in this population secondary to infectious potentiation: immunosuppression causes infections, and infections cause AIHA. The management of MCTD and secondary AIHA and immunosuppression poses a therapeutic challenge.

Predictors for Recurrence of Cytomegalovirus Retinitis in HIV-Negative Patients.

PURPOSE: To investigate the incidence of and predictive factors for recurrent cytomegalovirus retinitis (CMVR) in human immunodeficiency virus (HIV)-negative patients. METHODS: A retrospective review of HIV-negative patients who were newly diagnosed with CMVR between January 2005 and February 2019. RESULTS: Of 28 patients (44 eyes), 35.9% of eyes had a recurrence of CMVR after discontinuation of anti-CMV therapy. The incidence of CMVR recurrence was 17 per 100 eye-years. The factors significantly associated with CMVR recurrence were eyes with retinitis area of more than 25% (P = .013), absence of vitreous haze (P = .003), neutropenia at presentation (P = .001), and absence of systemic immunosuppression therapy prior to presentation (P = .002). CONCLUSION: Eyes with a large area of retinitis, absence of vitreous haze, and neutropenia at presentation are predictive of CMVR recurrence while receiving systemic immunosuppression prior to CMVR presentation has a lower risk of CMVR recurrence.

Frosted branch angiitis as an immune recovery response in newly diagnosed acquired immunodeficiency syndrome and systemic cytomegalovirus infection.

Frosted branch angiitis (FBA) is an uncommon form of severe retinal perivasculitis associated with systemic inflammatory/infectious diseases. In this report, we describe a case of FBA and macular edema as a result of immune recovery response in a patient newly diagnosed with HIV infection and cytomegalovirus viremia.

Surgery for Infectious Retinitis - When Medical Therapy Is Not Sufficient: The Moacyr E. Alvaro Pan-American Lecture 2023.

BACKGROUND: Viral retinitis composes a group of infectious ocular diseases with poor prognoses. With the advent of antivirals and HAART, the treatment of these diseases has evolved and ocular outcomes have improved. However, even with prompt medical treatment, a significant number of patients will experience complications that require surgical intervention. While there has been an abundance of research examining the medical treatment of CMV retinitis and acute retinal necrosis, the research examining surgical outcomes of complications such as retinitis-associated retinal detachment is comparatively limited. METHODS: Literature review. RESULTS: In this review, we discuss the current literature examining treatment of CMV retinitis and acute retinal necrosis, with a focus on surgical management of complications such as retinal detachment. CONCLUSIONS: Despite significant improvements in the medical treatment of CMV retinitis and ARN over the last three decades, vision-threatening complications such as retinal detachment are relatively common and require surgical management via PPV, laser photocoagulation, and intraocular gas or silicone oil tamponade.

CMV Retinitis in Wiskott Aldrich Syndrome.

PURPOSE: Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disease whose optimal curative treatment is hematopoietic stem cell transplantation (HSCT). Patients with WAS may suffer from cytomegalovirus retinitis (CMVR) which can cause vision loss. This study is to report the progression and prognosis of patients with WAS and CMVR. METHODS: A retrospective case series of ten patients with WAS and CMVR before and after HSCT who were referred to the Ophthalmology Department of Xinhua Hospital from June 2018 to February 2021. Progression and prognosis were recorded. RESULTS: Five patients were diagnosed with CMVR before receiving HSCT at a median age of 10.5 months (range: 4-23 months). Eight patients developed CMVR post-transplantation with a median interval from HSCT of 3.5 months (range: 1-9 months). CONCLUSION: Regular fundus examinations and prompt treatments in patients with WAS are therefore crucial before they receiving HSCT or approximately 3.5 months after HSCT until complete reconstitution of immune function.

Bilateral cytomegalovirus retinitis as the presenting feature of Dyskeratosis Congenita.

PURPOSE: To describe a young male with bilateral sequential Cytomegalovirus retinitis (CMVR) as the presenting feature of Dyskeratosis Congenita. CASE REPORT: A 25-year-old human immunodeficiency virus (HIV) negative male developed CMVR in his left eye, while on a three week course of oral valganciclovir therapy for CMV retinitis in his right eye. Systemic examination revealed reticular hypopigmentation of the forearms, dystrophic nails, oral leukoplakia and complete blood counts showed pancytopenia. A diagnosis of Dyskeratosis Congenita was confirmed with genetic testing. CONCLUSION: CMVR in non-HIV individuals should be considered as a harbinger of systemic immunosuppressive conditions. Ophthalmologists may be the first ones to suspect and diagnose congenital immunosuppressive disorders like Dyskeratosis Congenita in these patients.

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.

CMV Retinitis with Panretinal Occlusive Vasculitis.

PURPOSE: To report the clinical features of cytomegalovirus (CMV) retinitis with panretinal occlusive vasculitis. METHODS: Retrospective case series. RESULTS: Four eyes in 3 non-HIV patients (male: female = 3:0) were included. Previous medical history included diabetes mellitus (n = 2), age-related macular degeneration (n = 1), and Multiple myeloma under chemotherapy (n = 1). All patients were treated with oral valganciclovir and intravitreal ganciclovir. Slow resolution of retinitis related retinal opacification was noted in all 4 eyes. Two eyes had anti-viral agents discontinued despite the persistent retinitis related opacification and the lesions slowly resolved in the following months. The final decimal visual acuity was equal to or worse than 0.02 in 3 of the 4 eyes. CONCLUSION: In eyes of CMV retinitis with panretinal occlusive vasculitis, rapid resolution of retinitis lesions is an unreliable sign evaluating the therapeutic efficacy of anti-viral agents. Besides, despite treatment of anti-viral agents, deteriorating vascular occlusion may further endanger macular function.