Intravitreal foscarnet is an effective adjunct after systemic therapy failure in pediatric antiviral-resistant cytomegalovirus retinitis

Abstract

This report describes the case of a school-aged male child with T-cell acute lymphoblastic leukemia who developed cytomegalovirus retinitis despite systemic antiviral therapy. The patient had a history of cytomegalovirus viremia that improved with intravenous foscarnet and oral maribavir; however, routine ophthalmic screening revealed new retinal whitening and hemorrhages in the right eye. Anterior chamber paracentesis confirmed intraocular cytomegalovirus DNA. Although systemic viral loads declined, the retinal lesions progressed toward the macula, prompting initiation of intravitreal foscarnet. Treatment was initiated with a 1.2 mg/0.05 mL injection under anesthesia, followed by 2.4 mg/0.1 mL injections administered twice weekly at the clinic. The regimen was well tolerated and resulted in stabilization and regression of retinitis without central involvement, with fundus photography demonstrating fading whitening and vascular sclerosis.

This case highlights the importance of close ophthalmic monitoring in immunosuppressed pediatric patients with cytomegalovirus viremia and emphasizes intravitreal foscarnet as an effective adjunct when systemic therapy fails. Furthermore, it demonstrates the feasibility of administering multiple intravitreal injections in the pediatric population, underscoring the role of local antiviral delivery in preserving vision in cases of antiviral-resistant cytomegalovirus retinitis.

Introduction

Cytomegalovirus (CMV) is a ubiquitous β-herpesvirus that establishes lifelong latency after primary infection and may reactivate in the setting of impaired cellular immunity.^1,2 CMV retinitis is the most common ocular opportunistic infection in immunocompromised patients, historically affecting up to 30% of individuals with advanced acquired immunodeficiency syndrome prior to the advent of highly active antiretroviral therapy.^3,4 Although the incidence has declined dramatically in patients with an human immunodeficiency virus (HIV) infection, CMV retinitis remains an important cause of morbidity in other immunosuppressed groups, including patients who have undergone hematopoietic stem cell and solid organ transplantation, oncology patients undergoing chemotherapy, and children with hematologic malignancies.^4–7

Pediatric cases of CMV retinitis are rare; however, they are associated with a high risk of vision loss and systemic complications. Studies involving children undergoing hematopoietic stem cell transplantation (HSCT) report an incidence of 0.2%–5.6%, with the disease often presenting asymptomatically and being discovered only on routine screening.^8,9 Isolated reports also describe retinitis in children with acute lymphoblastic leukemia (ALL) receiving chemotherapy, underscoring the vulnerability of this population to CMV reactivation and ocular dissemination.^6,10 Without timely recognition and treatment, CMV retinitis typically progresses from peripheral granular whitening to confluent necrosis and hemorrhage, threatening the macula and optic nerve. ¹

Systemic antiviral therapy with intravenous ganciclovir or foscarnet and oral valganciclovir is standard first-line management for CMV infections, with regimen selection tailored to host factors and resistance profiles.^2,5 However, systemic regimens are limited by hematologic toxicity, poor ocular penetration, and the emergence of resistant viral strains, particularly in patients with prolonged immunosuppression or prior drug exposure.^4,6,7 Intravitreal antiviral injections provide direct local therapy and higher intraocular drug concentrations while minimizing systemic adverse effects. Both ganciclovir and foscarnet have been successfully employed as adjuncts or salvage therapy in resistant or refractory cases, including pediatric and non-HIV immunocompromised patients.^1,2,11

Herein, we present the case of an 8-year-old boy with ALL and CMV viremia who developed polymerase chain reaction (PCR)-proven CMV retinitis despite systemic foscarnet and maribavir. The patient was treated with intravitreal foscarnet, beginning with the administration of a reduced dose during an examination under anesthesia followed by the administration of high-dose injections in an outpatient setting, which were well tolerated and resulted in regression of retinitis with preservation of central vision. Best-corrected visual acuity remained 20/20 throughout the course, and the macula remained uninvolved.

Methods

This case report adheres to the Case Report (CARE) guidelines to ensure thorough and transparent reporting. All patient data were obtained through retrospective analysis of clinical records, ophthalmologic examinations, laboratory investigations, imaging findings, and treatment outcomes. The CARE checklist was completed and is included as supplementary research data with this submission. ¹² Written informed consent for treatment was obtained as part of routine clinical care, and written informed consent for publication of this case report and associated images was obtained from the patient’s legal guardian. All patient details have been deidentified to protect patient anonymity.

Case presentation

A school-aged male child with T-cell ALL on maintenance chemotherapy with 6-mercaptopurine and methotrexate was referred to the University of North Carolina at Chapel Hill Department of Ophthalmology in February 2024 for ophthalmic evaluation in the setting of CMV viremia. The patient’s CMV viremia was initially identified through routine surveillance performed by the pediatric hematology–oncology team in the setting of profound immunosuppression associated with chemotherapy for T-cell ALL. CMV loads peaked at approximately 72,000 IU/mL in November 2023, prompting the initiation of oral valganciclovir (450 mg twice daily), which he received for approximately 3 months prior to ophthalmic referral. This therapy resulted in rapid systemic viral suppression, with CMV levels declining to <35 IU/mL by February 2024. The patient was referred to the ophthalmology department for CMV retinitis screening in preparation for a bone marrow transplant. At the time of initial ophthalmic evaluation, the patient was asymptomatic from a visual standpoint, and dilated fundus examination was normal in both eyes. There was no clinical, laboratory, or radiographic evidence of CMV involvement of other end-organ systems at presentation, such as the pulmonary, gastrointestinal, hepatic, or central nervous systems.

Approximately 6 months after the initial detection of CMV viremia, while the patient was being administered systemic antiviral therapy with valganciclovir and later intravenous foscarnet with the addition of maribavir, new retinal findings were noted in the right eye, including a cotton wool spot and a small dot-blot hemorrhage. Within 1 week, discrete white retinal lesions developed along the superior arcade and mid-periphery (Figure 1(a)). Despite escalation of systemic antiviral therapy, retinal lesions continued to progress. Intravenous foscarnet had been initiated in May 2024 in response to persistent CMV viremia and was continued throughout the period of retinal lesion development. Oral maribavir was subsequently added in August 2024, following incomplete virologic and clinical responses to prior therapy. Both agents were administered under the guidance of the infectious disease team using standard weight- and renal function–adjusted dosing protocols. Despite declining systemic CMV loads on combination therapy, serial ophthalmic examinations demonstrated progressive granular retinal whitening with a perivascular distribution along the superior arcade and mid-periphery, a phenotype characteristic of active CMV retinitis, with associated intraretinal hemorrhage and subsequent vascular sclerosis (Figure 1(b)). Anterior chamber paracentesis was performed, and aqueous humor PCR testing was positive for CMV DNA. Concurrent PCR testing for other viral pathogens, including Herpes simplex virus (HSV) and Varicella zoster virus (VZV), was negative.

Figure 1.

Fundus photographs of the right eye demonstrating the evolution of cytomegalovirus retinitis. (a) Early granular retinal whitening with a cotton wool spot along the superior arcade. (b) Progression of granular, perivascular retinal lesions with associated hemorrhage despite systemic antiviral therapy, consistent with active CMV retinitis. (c) Regression of granular whitening and development of vascular sclerosis following initiation of intravitreal foscarnet, with preservation of the macula.

Although systemic viral loads declined from 2860 IU/mL to <100 IU/mL, serial examinations revealed persistent retinal activity. Given the absence of macular involvement and preserved vision (20/20), intravitreal therapy was initially deferred. However, the lesions showed subtle extension toward the macula with associated hemorrhage. Two weeks later, the patient underwent examination under anesthesia with intravitreal foscarnet injection (1.2 mg/0.05 mL) and anterior chamber paracentesis. Systemic anti-CMV therapy was continued without interruption when intravitreal foscarnet was initiated; intravenous foscarnet and oral maribavir were maintained under infectious disease guidance, with local therapy added for ocular disease control. He subsequently transitioned to in-clinic intravitreal foscarnet injections (2.4 mg/0.1 mL twice weekly). The initial injection was administered during an examination performed under anesthesia, while all subsequent injections were safely performed in the outpatient clinic without sedation. He tolerated the injections well despite his age.

Follow-up fundus examinations demonstrated stabilization and regression of retinal whitening with improved granularity without further macular involvement after the administration of 4 intravitreal foscarnet injections over a period of approximately 2 weeks (Figure 1(c)). Systemic viral loads remained suppressed (<35 IU/mL). Fundus photography revealed fading whitening and vascular sclerosis in the superior arcade, consistent with treated CMV retinitis. The patient continued to receive serial intravitreal foscarnet injections; in total, 4 injections were administered over a period of approximately 2 weeks. No corticosteroids were administered at any point during the treatment either locally or systemically. Following this treatment course, the retinal lesions stabilized and demonstrated progressive regression with preservation of central vision.

Discussion

CMV retinitis is a well-recognized opportunistic infection occurring in severely immunosuppressed patients; however, it is rare in pediatric oncology patients outside of the transplant setting. The incidence of CMV retinitis among pediatric patients with ALL is not well quantified; however, a seminal report has recorded CMV disease in 3.7% of ALL patients, including those with retinitis, highlighting the susceptibility of this group to viral reactivation during chemotherapy. ¹⁰ In pediatric HSCT recipients, the reported incidence of CMV retinitis ranges from 0.2% to 5.6%, often detected during surveillance activities rather than owing to symptomatic presentation.^8,9 In HIV-infected children, presumed CMV retinitis has been documented in 2%–5% of patients in some cohorts, a rate much lower than that reported in adult HIV populations but still clinically significant. ¹³

Pediatric CMV retinitis is frequently asymptomatic at onset; therefore, regular screening has been advocated for high-risk groups. In pediatric HSCT populations, CMV retinitis has been reported in up to 7.5% of high-risk children, often detected asymptomatically through routine surveillance, supporting the need for regular ophthalmic monitoring.^8,9 Additionally, prospective screening of children with CMV viremia has shown that overall, retinitis is uncommon; however, it is present in up to 4% of those with very high viral loads or persistent viremia, suggesting the need for targeted approaches. ¹⁴

The diagnosis in this patient was confirmed using aqueous humor PCR, which has been shown to accurately reflect intraocular CMV disease activity. Smith et al. have demonstrated that CMV DNA levels in aqueous and vitreous specimens are strongly correlated with the extent of active retinitis and respond predictably to treatment, whereas plasma PCR and blood cultures are poor indicators of ocular involvement. ¹⁵ Similarly, Bae et al. reported a case of CMV retinitis in which vitreous PCR was positive despite negative systemic testing, underscoring that systemic monitoring alone may fail to detect active intraocular disease. ¹⁶ Collectively, these findings highlight the importance of direct ocular fluid analysis in cases with suspected retinitis and support the need for routine ophthalmic screening in high-risk patients even when systemic CMV viremia is low or undetectable.

Systemic antiviral therapy remains the cornerstone of CMV management. Intravenous ganciclovir or oral valganciclovir are considered first-line treatment options, with intravenous foscarnet and cidofovir acting as alternatives in patients with intolerance or resistance.^2,5 In pediatric populations, systemic therapy is often constrained by hematologic toxicity, particularly myelosuppression in children receiving concurrent chemotherapy for leukemia. Moreover, ganciclovir resistance due to UL97 mutations has been described in children, including a 4-month-old infant with resistant retinitis refractory to systemic therapy who required intravitreal salvage. ¹⁷

In the present case, retinitis progressed despite intravenous foscarnet and oral maribavir administration, reflecting the limitations of systemic therapy in treating eyes with an active CMV infection. This is consistent with reports in other immunosuppressed, non-HIV populations. ¹¹

Given the risk of relapse in immunocompromised pediatric patients, close multidisciplinary follow-up is essential after CMV retinitis treatment. In this patient, ongoing monitoring included serial dilated fundus examinations at progressively longer intervals to assess for recurrent retinal activity in coordination with continued systemic CMV surveillance by the infectious disease and oncology teams. Maintenance of systemic antiviral therapy and optimization of immune recovery were prioritized to reduce the risk of reactivation. Prompt ophthalmic re-evaluation was planned for any change in visual symptoms or increase in systemic viral load, recognizing that ocular relapse may occur despite low or undetectable plasma CMV levels.

Conclusion

This case underscores several key lessons. First, CMV retinitis may develop in children with ALL even in the absence of detectable viremia, highlighting that systemic viral suppression does not exclude the risk of ocular disease. Routine screening examinations are therefore essential as pediatric patients are frequently asymptomatic at onset. Second, aqueous PCR remains a reliable tool for confirming intraocular infection when systemic testing is negative. Finally, intravitreal foscarnet (2.4 mg/0.1 mL), administered twice weekly, provided effective local disease control, emphasizing the importance of timely ophthalmic intervention and close collaboration between the ophthalmology, infectious disease, and oncology teams to preserve vision in this vulnerable population.

Supplemental Material

sj-pdf-1-imr-10.1177_03000605261436565 - Supplemental material for Intravitreal foscarnet is an effective adjunct after systemic therapy failure in pediatric antiviral-resistant cytomegalovirus retinitis

Supplemental material, sj-pdf-1-imr-10.1177_03000605261436565 for Intravitreal foscarnet is an effective adjunct after systemic therapy failure in pediatric antiviral-resistant cytomegalovirus retinitis by Iden Amiri, Pooja Shah, Mohammad Soleimani and Alice Yang Zhang in Journal of International Medical Research