Intravitreal Antiviral Therapy Research Articles

924. Cytomegalovirus (CMV) Retinitis during Maintenance Chemotherapy for Acute Lymphoblastic Leukemia

Abstract Background Acute leukemia patients are at risk for cytomegalovirus (CMV) retinitis following hematopoietic stem cell transplantation, though the disease can also occur in non-transplant adult leukemia patients. Emerging data suggest a shift to pediatric-inspired chemotherapy regimens in adults with acute lymphoblastic leukemia (ALL) can lead to increasing cytopenias and impaired functional immunity, placing these patients at risk for this opportunistic infection. Here we describe a case of CMV retinitis in an ALL patient following a lower-intensity regimen during maintenance chemotherapy. Methods Chart review. Results A 55-year-old male with ALL presented to his optometrist with complaints of visual changes including “fogginess” and “floaters”. The patient had completed 8 cycles of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R) and achieved complete remission. He had been on maintenance chemotherapy with 6-mercaptopurine, vincristine, methotrexate, and prednisone (POMP) for 2 months at the time of symptom onset. He was referred to his local ophthalmologist who had concerns for bilateral, zone 1 CMV retinitis based on fundoscopic exam (Figure 1). Vitreous aspiration was performed and CMV DNA PCR returned positive at 1.6 million IUs/ml. Peripheral blood CMV DNA PCR was also positive at 1133 IU/ml. He was started on combination therapy with intravitreal ganciclovir injections and oral valganciclovir 900 mg twice daily (Figure 2). The patient received 14 intravitreal injections with resultant stability of his eye exam, though he remained on induction valganciclovir for 5 months due to persistent blood CMV DNAemia. Letermovir was added to help suppress his peripheral CMV DNAemia and he attained partial vision recovery. Figure 1. Fundoscopic images Conclusion CMV retinitis is an uncommon and highly morbid infection that can occur during maintenance chemotherapy in adult non-transplant ALL patients. Early identification of the disease is imperative as delay can result in blindness or further systemic CMV disease. Treatment is challenging, involving systemic and intravitreal antiviral therapy, serial ophthalmologic exams, serum CMV monitoring, and close coordination with the treating hematologist. Disclosures Michael Boeckh, MD PhD, AlloVir (Consultant)Ansun Biopharma (Grant/Research Support)Astellas (Grant/Research Support)EvrysBio (Consultant, Other Financial or Material Support, Options to acquire equity, but have not exercised them)Gilead Sciences (Consultant, Grant/Research Support)GlaxoSmithKline (Consultant)Helocyte (Consultant, Other Financial or Material Support, Options to acquire equity, but have not exercised them)Janssen (Grant/Research Support)Kyorin (Consultant)Merck (Consultant, Grant/Research Support)Moderna (Consultant)Symbio (Consultant)Takeda (formerly known as Shire) (Consultant, Grant/Research Support)VirBio (Consultant, Grant/Research Support) Ryan Cassaday, MD, Amgen (Grant/Research Support, Advisor or Review Panel member)Kite/Gilead (Grant/Research Support, Advisor or Review Panel member)Merck (Grant/Research Support)Pfizer (Grant/Research Support, Advisor or Review Panel member)Seagen (Other Financial or Material Support, Spouse is employee and hold stock)Vanda Pharmaceuticals (Grant/Research Support)

Diagnostic retinal biopsy in the management of secondary non-CNS vitreoretinal lymphoma masquerading as viral retinitis: a case report

BackgroundIntraocular lymphoma accounts for fewer than 1% of intraocular tumors. When the posterior segment is involved, it can be further classified as vitreoretinal or choroidal lymphoma. Vitreoretinal lymphoma (VRL) can rarely masquerade as an infectious retinitis making diagnosis and management challenging.ResultsA 73-year-old woman with a history of non-central nervous system (CNS) involving diffuse large B-cell lymphoma (DLBCL) was referred for worsening blurry vision—visual acuity of count figures at 2 ft—in her right eye for 8 months. Dilated fundus examination of the right eye was significant for retinal whitening and dot-blot hemorrhages, which was concerning for a viral retinitis and guided initial management. Secondary intraocular lymphoma was also considered. The retinal disease continued to progress despite intravitreal and systemic antiviral therapy, and a diagnostic vitrectomy was inconclusive. A retinal biopsy was then performed, which showed DLBCL, confirming a diagnosis of secondary VRL. Three subsequent treatments with intravitreal methotrexate led to regression of the VRL.ConclusionsOur case highlights the utility of a retinal biopsy after an inconclusive diagnostic vitrectomy in a challenging scenario of VRL to establish a diagnosis and initiate successful treatment. A multidisciplinary team of providers was essential for diagnosis, comprehensive workup, medical and surgical management of the patient.

#50: Cytomegalovirus Retinitis Among Pediatric Hematopoietic Stem Cell and Solid Organ Transplantation Recipients: A Contemporary Review

Abstract Background Cytomegalovirus infection can cause significant morbidity and mortality after transplantation. Cytomegalovirus retinitis (CMVR) can be a major complication of tissue invasive CMV disease in transplant recipients. There are little data regarding the contemporary incidence and outcomes of CMVR among pediatric transplant recipients. Methods We performed a retrospective cohort analysis of allogeneic hematopoietic (allo-HCT) and solid organ transplant (SOT) recipients who received medical care at Nationwide Children’s Hospital (NCH) from 1/1/10–11/30/20 and had a diagnosis of CMVR to describe the incidence, timing post-transplant, ocular manifestations, management, and outcomes. Basic demographic and clinical data, pre-transplant donor/recipient CMV serostatus, and post-transplant CMV infection data were collected. Graft-specific CMV surveillance and prophylaxis strategies were performed according to NCH hospital guidelines. During the study period, quantitative plasma CMV PCR assays included copies/mL (2010–2013) and WHO international standard IU/mL (2013–2020). Results During the 10-year study period, 347 patients underwent allo-HCT (N=214) or SOT (N=133; heart N=46, liver N=36, kidney N= 52; 1 patient had concomitant kidney and liver transplantation); median age was 8.6 years [range 0.1–25.9] and 198 (56.5%) were male. In total, 98 patients had CMV DNAemia post-transplant, and CMVR was diagnosed in 3 (HCT=2, SOT=1), for an overall CMVR incidence of 0.86% among all transplant recipients and occurring in 3% of patients with CMV DNAemia. No CMVR was diagnosed in patients without CMV DNAemia. An ophthalmologic examination was performed in 58 (59%) of patients with any DNAemia compared with 67 (27%) of patients without DNAemia. CMVR was diagnosed on funduscopic examination a median of 183 days [range 34–512] post-transplant based on visual symptomatology (N=2) or by routine eye screening prompted by DNAemia (N=1). CMV DNAemia at the time of CMVR was 1,463 copies/mL, 3,000, and 14,204 IU/mL; all patients had prolonged (>3 months) CMV detection before CMVR. One SOT recipient had concomitant pathology confirming CMV gastrointestinal tract disease. Two of the 3 CMVR cases occurred in the setting of genotypic UL94 CMV resistance mutations (A594V, H520Q)(Figure 1). Two patients were already receiving CMV antiviral therapy (maribavir N=1; valganciclovir=1) at the time of CMVR diagnosis. After the CMVR diagnosis, all patients were prescribed systemic foscarnet. Adjunctive therapies included concurrent intravitreal antiviral therapy (ganciclovir N=1; foscarnet N=1) and adoptive immunotherapy with CMV antiviral specific T-cells (N=1, HCT). Improvement of ocular symptoms occurred in 2 patients at 15 and 20 days after starting targeted CMV antiviral therapy; one patient developed permanently impaired vision. Conclusion CMVR remains as an important complication in transplant recipients. Although CMVR incidence was low in our cohort of transplant recipients, it occurred most frequently in cases of CMV resistance, prolonged DNAemia, and led to permanent visual impairment in 1 of 3 patients. The development of resistant CMV may have a role in the occurrence, progression, and severity of CMVR. Additional pediatric-specific data are needed to better characterize CMVR and inform optimal prevention strategies.

Ocular Outcomes after Treatment of Cytomegalovirus Retinitis Using Adoptive Immunotherapy with Cytomegalovirus-Specific Cytotoxic T Lymphocytes

To describe ocular outcomes in eyes with cytomegalovirus (CMV) retinitis treated with adoptive immunotherapy using systemic administration of CMV-specific cytotoxic Tlymphocytes (CMV-specific CTLs). Retrospective cohort study. Patients with active CMV retinitis evaluated at a tertiary care academic center. Treatment of CMV retinitis with standard-of-care therapy (systemic or intravitreal antivirals) or CMV-specific CTLs (with or without concurrent standard-of-care therapies). The electronic medical record was reviewed to determine baseline characteristics, treatment course, and ocular outcomes, including best-corrected visual acuity (BCVA), treatments administered (CMV-specific CTLs, systemic antivirals, intravitreal antivirals), resolution of CMV retinitis, any occurrence of immune recovery uveitis, cystoid macular edema, retinal detachment, or a combination thereof. Seven patients (3 of whom had bilateral disease [n= 10 eyes]) were treated with CMV-specific CTLs, whereas 20 patients (6 of whom had bilateral disease [n= 26 eyes]) received standard-of-care treatment. Indications for CMV-specific CTL therapy included persistent or progressive CMV retinitis (71.4% of patients); CMV UL54 or UL97 antiviral resistance mutations (42.9%); side effects or toxicity from antiviral agents (57.1%); patient intolerance to longstanding, frequent antiviral therapy for persistent retinitis (28.6%); or a combination thereof. Two patients (28.6%; 4 eyes [40%]) received CMV-specific CTL therapy without concurrent systemic or intravitreal antiviral therapy for active CMV retinitis, whereas 5 patients (71.4%; 6 eyes [60%]) continued to receive concurrent antiviral therapies. Resolution of CMV retinitis was achieved in 9 eyes (90%) treated with CMV-specific CTLs, with BCVA stabilizing (4 eyes [40%]) or improving (4 eyes [40%]) in 80% of eyes over an average follow-up of 33.4 months. Rates of immune recovery uveitis, new-onset cystoid macular edema, and retinal detachment were 0%, 10% (1 eye), and 20% (2 eyes), respectively. These outcomes compared favorably with a nonrandomized cohort of eyes treated with standard-of-care therapy alone, despite potentially worse baseline characteristics. CMV-specific CTL therapy may represent a novel monotherapy or adjunctive therapy, or both, for CMV retinitis, especially in eyes that are resistant, refractory, or intolerant of standard-of-care antiviral therapies. More generally, adoptive cell transfer and adoptive immunotherapy may have a role in refractory CMV retinitis. Larger prospective, randomized trials are necessary.

RETINAL DETACHMENT AFTER ACUTE RETINAL NECROSIS AND THE EFFICACIES OF DIFFERENT INTERVENTIONS: A Systematic Review and Metaanalysis.

To estimate the rate of retinal detachment (RD) after acute retinal necrosis (ARN) and evaluate the efficacies of different interventions. The databases Medline and EMBASE from inception to March 2020 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 were calculated using generalized linear mixed models. Sixty-seven studies involving 1,811 patients were finally included. The pooling results suggested the general RD rate of ARN was 47%. The RD rate increased with the extent of retinitis and was slightly lower when involved Zone III. The RD rate was 37% for herpes simplex virus ARN and 46% for varicella-zoster virus ARN; 52% for immunocompetent patients and 39% for immunocompromised patients. Retinal detachment presented in 2% of eyes at the first visit. Systemic antiviral therapy could lower the RD rate significantly from 67% to 43%, and prophylactic vitrectomy could lower the RD rate significantly from 45% to 22%. Systemic antiviral therapy plus vitrectomy achieved the lowest RD rate to 18%. Although the efficacy of prophylactic laser or intravitreal antiviral therapy was still limited. Prophylactic vitrectomy might significantly increase the incidence of proliferative vitreoretinopathy from 7% to 32%. About half of the eyes might develop RD during the entire course of ARN. Systemic antiviral therapy and prophylactic vitrectomy are effective interventions to prevent RD, whereas the roles of prophylactic laser or adjunctive intravitreal antiviral therapy are still unclear. Varicella-zoster virus ARN and cases with extensive retinitis might need intensified interventions.

Outcomes of Combination Systemic and Intravitreal Antiviral Therapy for Acute Retinal Necrosis

Determine the efficacy of combination intravitreal and systemic antiviral therapy for the treatment of acute retinal necrosis (ARN) and risk factors impacting visual acuity (VA) and retinal detachment (RD) outcomes. Single-center retrospective case series. Patients with an ARN diagnosis based on clinical features and polymerase chain reaction confirmation who were treated at a tertiary referral, university-based academic practice. Patient records were reviewed for demographic information including age and gender. Snellen VA, disease findings including RD outcomes, optic nerve involvement, and treatments were recorded. Incidence rates of major VA and RD outcomes were calculated based on the number of events and exposure times. Cox proportional hazards regression modeling and survival analyses were used to identify factors related to VA and RD outcomes over time. Logarithm of the minimal angle of resolution VA, 2-line or more VA gain, severe vision loss (SVL) of 20/200 or worse, RD development, and fellow eye involvement. Twenty-three eyes of 21 patients (11 male, 10 female) were reviewed. Thirteen patients (62%) had herpes simplex virus and 8 patients (38%) had varicella zoster virus. The event rate for 2-line or more VA gain was 0.49 events/eye-year (95% confidence interval [CI], 0.26-0.86 events/eye-year), whereas the rate of SVL was 0.61 events/eye-year (95% CI, 0.34-1.02 events/eye-year). Retinal detachment development was observed at a rate of 0.59 events/eye-year (95% CI, 0.33-1.00 events/eye-year). Thirteen of 23 eyes (57%) demonstrated RD with a mean time of 120 days after ARN diagnosis. With each additional quadrant of retina involved, a greater risk of RD development over time was observed (hazard ratio, 2.21; 95% CI, 1.12-4.35). Nine percent of eyes progressed with additional quadrantic involvement, despite combination systemic and intravitreal antiviral therapy; however, none of the 19 patients demonstrating unilateral ARN showed fellow-eye involvement after initiation of therapy. Combination intravitreal and systemic antiviral therapy for ARN can be effective in improving VA and limiting retinitis progression. Each additional quadrant of retina involved was associated with a 2.2-fold greater risk of RD, which may impact monitoring, timing of intervention, and patient counseling.

Bilateral cytomegalovirus retinitis comorbid with diabetic macular edema

Cytomegalovirus (CMV) retinitis comorbid with diabetic retinopathy is uncommon. We report a case of bilateral CMV retinitis and diabetic retinopathy in a patient who underwent pancreas transplantation and share the experience of the treatment outcome. An 18-year-old male diagnosed with type-1 diabetes mellitus received pancreas transplantation and immunosuppressive therapy suffered from progressively blurred vision in both eyes for several days. His visual acuity was 20/100 in the right eye and 20/50 in the left eye. Ophthalmic examination revealed bilateral diabetic macular edema (DME) without intraocular inflammatory signs in either eye. The DME subsided after 2 monthly intravitreal injections of aflibercept. However, bilateral panuveitis with CMV retinitis was observed after antivascular endothelial growth factor therapy. The retinitis subsided gradually but completely after systemic and intravitreal antiviral therapy. However, bilateral DME recurred and persisted despite repeated injections of aflibercept during the resting follow-up period. Our case suggests that CMV retinitis can coexist with other retinal diseases, including diabetic retinopathy. Treatment is difficult in such cases.

Management of Cytomegalovirus Retinitis in HIV and Non-HIV Patients.

As CMVR continues to affect HIV-positive and non-HIV immunosuppressed patients, ophthalmologists must continue to tailor diagnostics and therapeutics to individual cases. In HIV-related disease, ocular fluid sampling and intravitreal drug delivery are considerations, but systemic antiviral therapy is paramount in the initial management from both ophthalmic and systemic morbidity standpoints. Non-HIV-related disease should be approached with a multidisciplinary team, including an ophthalmologist/vitreoretinal/uveitis specialist for consideration of intravitreal antiviral therapy with qualitative and quantitative aqueous PCR monitoring, and consideration of PCR genome sequencing for CMV strains that may become resistant to antiviral therapies from long-term antiviral prophylactic exposure. Hematologists or oncologists may help with patients who remain bone marrow-suppressed following transplantation or systemic chemotherapy. Because of related toxicities of the anti-CMV medications and immunosuppressive medications (eg, bone marrow suppression and cytopenias), infectious disease consultation can help in the treatment and monitoring of side effects.

Acute retinal necrosis in the United Kingdom: results of a prospective surveillance study

To determine the incidence of acute retinal necrosis (ARN) in the United Kingdom and to describe the demographics, management, and visual outcome in these patients. This was a prospective study carried out by the British Ophthalmological Surveillance Unit (BOSU) between September 2007 and October 2008. Initial and 6-month questionnaires were sent to UK ophthalmologists who reported cases of ARN via the monthly BOSU report card system. In all, 45 confirmed cases (52 eyes) of ARN were reported in the 14-month study period, giving a minimum incidence of 0.63 cases per million population per year. There were 20 females and 25 males. Age ranged from 10 to 94 years. Eight patients had a history of herpetic CNS disease. Aqueous sampling was carried out in 13 patients, vitreous in 27, and cerebrospinal fluid (CSF) in 4. Varicella-zoster virus followed by herpes simplex were the most common causative agents. Treatment in 76% of the cases was with intravenous antivirals; however, 24% received only oral antivirals. In all, 47% of patients had intravitreal antiviral therapy. Visual outcome at 6 months was <6/60 in 48% of the affected eyes. The minimum incidence of ARN in the UK is 0.63 cases per million. Patients with a history of herpetic CNS disease should be warned to immediately report any visual symptoms. There is increased use of oral and intravitreal antivirals in initial treatment.

Bilateral Retrobulbar Neuritis Due to Varicella Zoster Preceding Retinal Necrosis in a Patient with AIDS

Objective: The purpose of this study is to describe a case report of varicella zoster (VZV) infection presenting as bilateral retrobulbar neuritis affecting optic tracts, chiasm, and bilateral optic nerves preceding bilateral progressive outer retinal necrosis in a single patient with AIDS.Methods:The clinical course of a single patient with confirmed VZV infection will be described including presentation, diagnosis, and treatment.Results:The affected patient presented with acute, bilateral vision loss, and headache. The patient’s history was devoid of past, concurrent, or subsequent development of herpes zoster dermatitis. The patient lacked signs of meningeal irritation or infection. Diagnosis of VZV arachnoiditis and retrobulbar optic neuritis were confirmed by radiological and CSF examination and preceded the clinical identification of retinal involvement. Despite early, aggressive treatment with intravenous antiviral and steroids, as well as intravitreal antiviral therapy, complete bilateral visual loss resulted.Conclusion: Varicella zoster continues to present uniquely in patients with acquired immune deficiency syndrome. Absence of retinal involvement doesn’t rule out retrobulbar visual pathways involvement by VZV. The astute clinician should be aware of this presentation and suspect the involvement of varicella zoster in immunocompromised patients presenting with retrobulbar optic neuritis and meningeal involvement with normal fundus exam.

Prise en charge du syndrome de nécrose rétinienne aiguë compliqué d’œdème maculaire cystoïde

Acute retinal necrosis is a rare but devastating and rapidly progressive viral retinitis. We report the case of a healthy 46-year-old woman who presented bilateral acute retinal necrosis caused by varicella zoster virus (VZV). Intravenous and intravitreal antiviral therapy was given for 6 weeks and followed by oral therapy. After 3 months, the patient presented a bilateral macular edema which was treated first by laterobulbar injections of corticosteroids, then successfully by interferon alpha-2a. This clinical disease, which can cause major visual function impairment, must be known in order to treat it immediately.

Unilateral Recurrent Acute Retinal Necrosis Syndrome Caused by Cytomegalovirus in an Immune-Competent Adult

To report an immune-competent patient with unilateral recurrent acute retinal necrosis syndrome caused by cytomegalovirus, and to highlight the importance of diagnostic vitreous biopsy and specific antiviral therapy in this condition. Case report. A 75-year-old man with good general health had two episodes of acute retinal necrosis syndrome affecting his left eye. Vitreous biopsy was performed in each episode, and polymerase chain reaction analysis on the vitreous specimen was positive for cytomegalovirus and negative for varicella zoster virus and herpes simplex virus 1 and 2. On each occasion, investigations indicated past cytomegalovirus infection but no evidence of a systemic re-activation. No indication of immunodeficiency was found over a 2-year follow-up period. His management, which included systemic and intravitreal antiviral therapy, is discussed. To the authors' knowledge, only two other cases of acute retinal necrosis syndrome caused by cytomegalovirus have been reported previously in immune-competent patients. This case illustrates the importance of vitreous biopsy for viral polymerase chain re-action studies in cases of acute retinal necrosis syndrome, in order to direct appropriate antiviral treatment. It also illustrates the role of an intravitreal antiviral drug that is effective against all three herpetic viruses.

PROGRESSIVE OUTER RETINAL NECROSIS CAUSED BY VARICELLA-ZOSTER VIRUS IN CHILDREN WITH ACQUIRED IMMUNODEFICIENCY SYNDROME

We report three HIV-infected children with bilateral progressive outer retinal necrosis caused by varicella-zoster virus. All three lost vision in both eyes. Aggressive treatment strategies with combination intravenous antiviral therapy in addition to intravitreal antiviral therapy and appropriate surgical management may prevent blindness. Rapid recognition of this distinct clinical syndrome is essential to improve visual outcome.

Successful treatment of varicella zoster virus retinitis with aggressive intravitreal and systemic antiviral therapy

Aims : To describe the successful treatment of varicella zoster virus retinitis (VZVR) using intravenous cidofovir as part of an aggressive management strategy. Case reports : Two patients with bilateral VZVR were treated with a combination of intravenous cidofovir and ganciclovir with adjuvant intravitreal foscarnet or ganciclovir. Both patients maintained good vision in the less severely affected eye. Retinal detachment did not occur in either patient. Conclusions : VZVR should be treated aggressively with a combination of intravenous and intravitreal therapy to improve visual prognosis. Intravenous cidofovir, in the absence of contra-indications, should be considered as part of this aggressive therapeutic approach, especially in patients with AIDS in whom the prognosis is particularly poor.