When hematology meets ophthalmology: Cytomegalovirus retinitis in pediatric stem cell recipients

Abstract

Cytomegalovirus (CMV) retinitis is a significant yet infrequent complication in pediatric hematopoietic stem cell transplant recipients, occurring in approximately 4% of cases. Its presentation typically coincides with immune reconstitution, between 6 weeks to 6 months post-transplant, emphasizing the need for timely detection. Symptoms often develop insidiously, underscoring the role of fundus examinations during episodes of CMV viremia. However, the low incidence challenges the necessity of routine screenings, as they may strain clinical resources without clear benefits to patient outcomes. Management includes systemic and intravitreal antivirals, such as ganciclovir and foscarnet, and adoptive T-cell therapy for refractory cases. Tailored follow-up strategies are crucial, with considerations for lesion activity and CMV viremia status to determine the duration of therapy. Baseline and post-transplant screenings remain a topic of debate, with evolving guidelines needed to balance patient safety and clinical feasibility. Future research is needed to address optimal screening intervals and investigate the role of pre-existing CMV serostatus in transplant eligibility and outcomes.

Key Words: Cytomegalovirus retinitis; Pediatric stem cell transplant; Hematopoietic stem cell transplantation; Cytomegalovirus viremia; Ocular complications; Antiviral therapy; Immune reconstitution; T-cell therapy; Screening protocols

Core Tip: Cytomegalovirus retinitis in pediatric hematopoietic stem cell transplant recipients is a complex and potentially devastating complication, but with early detection and appropriate management, outcomes can be significantly improved. Screening protocols continue to evolve, with the emphasis on identifying high-risk patients during periods of immune reconstitution. Management of cytomegalovirus retinitis in pediatric patients post-hematopoietic stem cell transplant requires a comprehensive approach that balances effective viral suppression with the mitigation of drug-related toxicities. Antiviral therapies, whether systemic, intravitreal, or implantable, remain central to treatment. Adjunctive immunotherapies, particularly adoptive T-cell therapy, offer promising outcomes in refractory cases. Emerging modalities, including high-dose intravitreal regimens and novel antivirals, hold potential for future advancements. Individualized treatment plans, guided by patient-specific risk factors and disease severity, are crucial to optimize outcomes and preserve vision in this vulnerable population.

INTRODUCTION

Cytomegalovirus (CMV) retinitis is a rare but potentially sight-threatening complication of hematopoietic stem cell transplant (HSCT), particularly in pediatric patients[1]. Although uncommon, its impact is profound, as untreated cases can lead to irreversible vision loss. The condition typically arises during the period of immune reconstitution, usually 6 weeks to 6 months post-transplant, when the immune system begins to recover following intensive immunosuppressive therapy and donor cell engraftment. During this vulnerable phase, CMV reactivation is common and can result in significant complications, including retinitis[2-5].

In contrast to HIV-associated cases, CMV retinitis in the HSCT setting presents a more heterogeneous and complex scenario. Immunity arises from a combination of residual recipient immune cells and donor-derived immune cells, both of which are influenced by pharmacologic immunosuppression used to prevent or treat graft-vs-host disease (GVHD) or transplant rejection[2]. In pediatric patients, CMV retinitis presents unique challenges due to their developing immune systems and the potential for subtle or delayed symptoms. Advances in transplantation protocols and antiviral therapies have improved outcomes; however, vigilance is critical to prevent the devastating consequences of delayed diagnosis and treatment[1,2]. This review examines the risk factors, clinical presentation, management strategies, and the evolving protocols for screening and treatment in pediatric HSCT recipients.

Epidemiology of CMV retinitis post-stem cell transplant in pediatric patients

The incidence of CMV retinitis in the pediatric population varies across studies, reflecting differences in patient demographics, transplant protocols, and monitoring practices. A retrospective study conducted at Children’s Hospital Colorado between 2010 and 2014 reported a notable increase in CMV retinitis cases among pediatric allogeneic HSCT recipients. From 2010 to 2013, none of the 101 patients developed CMV retinitis. However, in 2014, 5 out of 28 patients (18%) were diagnosed with the condition, indicating a significant rise in incidence. This observation prompted the development of an ophthalmic screening protocol to facilitate early detection and treatment[1]. The study, while providing valuable insights, was limited by its retrospective nature, which prevented the determination of the definitive cause of the increased incidence of CMV retinitis[1,6].

Another study from University College London, spanning 5 years, found that 13 out of 304 pediatric HSCT recipients (approximately 4%) developed CMV retinitis[2]. The incidence of CMV retinitis has also been reported by Zöllner et al[7] to be higher in leukemic patients post-HSCT, at approximately 14.2%. These studies suggest that while CMV retinitis remains relatively rare among pediatric HSCT recipients, certain centers have observed periods of increased incidence. The variability in reported rates may be attributed to differences in surveillance practices, patient populations, and transplant-related factors. Consequently, there is a growing emphasis on the importance of vigilant monitoring and early intervention to mitigate the risk of vision loss associated with CMV retinitis in this vulnerable population[1,6].

Risk factors for CMV retinitis in pediatric HSCT recipients

Several factors contribute to the development of CMV retinitis in pediatric patients following HSCT, particularly during the period of immune reconstitution. This critical phase, occurring within 6 weeks to 6 months post-transplant, marks the gradual recovery of immune function and heightens vulnerability to opportunistic infections like CMV[2-5]. The intensity of immunosuppressive therapy is a central risk factor, as prolonged use of corticosteroids and other agents for GVHD prophylaxis or treatment significantly increases susceptibility to CMV reactivation, including retinitis[4]. Interruptions in antiviral prophylaxis or delays in its initiation, whether due to toxicity or resistance, further elevate this risk.

CMV serostatus of both the donor and recipient plays a pivotal role in determining risk. Pediatric recipients who are seropositive before transplantation (R+) are at a higher risk of reactivation, particularly when the donor is CMV-seronegative (D-), as the graft lacks CMV-specific immunity[2,4]. Studies, including those by Xhaard et al[8], have demonstrated that mismatched serostatus, especially in D-/R+ combinations, not only increases the incidence of CMV complications but also negatively impacts survival rates. Active CMV viremia before transplantation further exacerbates this risk, as it may serve as a reservoir for reactivation[9,10].

The type of transplant significantly influences susceptibility. Allogeneic HSCT poses a much higher risk than autologous transplants, with HLA-mismatched unrelated donor grafts carrying the greatest risk[2,10-12]. Cord blood transplantation is particularly concerning due to delayed immune reconstitution, which is characterized by impaired thymopoiesis and skewing of memory T-cell populations, as noted by Komanduri et al[13]. Additionally, the use of T-cell-depleted grafts—either ex vivo or in vivo—compromises immune recovery, increasing the likelihood of CMV reactivation and subsequent retinitis[4]. Kalra et al[14] found that CMV serostatus significantly impacts outcomes in anti-thymocyte globulin-conditioned hematopoietic cell transplantation. Seronegative recipients with seropositive donors (D+/R-) had better survival, while seropositive recipients with seronegative donors (D-/R+) faced higher CMV reactivation and complications. These findings highlight the importance of donor-recipient serostatus in guiding post-transplant strategies[14]. Younger age at transplantation, especially in infants, can further heighten risk. Immature immune systems in younger children may result in prolonged immune reconstitution, compounding their susceptibility[1,2].

GVHD and its treatment represent another major risk factor. GVHD delays immune recovery, while intensified immunosuppressive therapy required for its management creates an environment conducive to CMV reactivation[13]. Patients with lymphoid malignancies or those treated with newer immunosuppressive agents such as alemtuzumab, rituximab, or post-transplant cyclophosphamide are at particularly high risk[10,13,15]. Despite advancements in preemptive antiviral therapy, late CMV antigenemia is frequently observed in these cases, underscoring the need for ongoing vigilance[15].

Variability in CMV strain virulence and the potential for co-infections with other pathogens like Epstein-Barr virus or fungi further complicate immune recovery and increase the likelihood of severe CMV complications[10,12,16]. The indication for HSCT can influence the risk of CMV retinitis. Zhang et al[17] identified severe aplastic anemia as a significant risk factor, with pre-transplant platelet refractoriness and the use of alternative donors further elevating susceptibility. Not all individuals with these risk factors develop CMV retinitis, highlighting the role of host-specific factors such as genetic predisposition and variability in CMV-specific T-cell responses. Furthermore, the presence of multiple risk factors significantly heightens the likelihood of developing CMV retinitis. These observations underscore the need for a personalized approach to monitor and manage CMV reactivation in pediatric HSCT recipients[16]. Understanding these risk factors is essential for early identification and management of CMV complications post-HSCT. A detailed summary can be found in Table 1.

Table 1 A summary of the major risk factors contributing to cytomegalovirus reactivation and cytomegalovirus retinitis post-hematopoietic stem cell transplant in pediatric patients.

Risk factor	Explanation	Percentage of incidence
Immune reconstitution phase	Occurs within 6 weeks to 6 months post-transplant, increasing vulnerability to CMV due to delayed immune recovery	-
Antiviral prophylaxis vs preemptive therapy	More intensive antiviral prophylaxis reduces CMV reactivation risk compared to standard prophylaxis. Antiviral prophylaxis is superior to preemptive therapy in preventing CMV infection	CMV reactivation occurred in 81% of patients on traditional prophylaxis vs 53% on intensified strategies[66]. Letermovir prophylaxis reduced CMV infection risk from 60% to 37.5% compared to preemptive therapy (P < 0.001)[67]
CMV serostatus (donor & recipient)	High risk in seropositive recipients (R+) with seronegative donors (D-)	A study found that 22 out of 43 (51%) seropositive recipients (R+) transplanted from seronegative donors (D-) experienced CMV reactivation, significantly higher than the 32 out of 143 (22%) in other combinations (P < 0.001)[68]
Pre-transplant viremia	Pre-transplant viremia increases risk of CMV reactivation and CMV disease post-HSCT	Research indicates that patients with pre-HCT CMV reactivation had a significantly increased risk of CMV reactivation by day 100 post-transplant and a higher risk of CMV disease[69]
Type of transplant	Allogeneic HSCT poses a higher risk than autologous, with the highest risk in mismatched unrelated donor grafts. Cord blood transplantation is particularly concerning due to delayed immune recovery	Incidence in allogeneic HSCT recipients: 2.5% at 6 months post-transplant, with a median onset at 34 days (range: 21-118 days)[70]
T-cell depletion	T-cell-depleted grafts impair immune recovery, increasing the risk of CMV reactivation	CMV reactivation rates in patients receiving TCR αβ and CD19 cell-depleted HSCT range from 7.27% to 75%. The exact risk increase compared to non-T-cell-depleted grafts varies across studies but is consistently higher[71]
Younger age at transplantation	Infants and younger children have immature immune systems, leading to prolonged immune reconstitution and higher risk	Pediatric HSCT recipients: Median onset at 199 days post-transplant, suggesting a later occurrence compared to adults[2]
GVHD	GVHD delays immune recovery; intensified immunosuppressive therapy for GVHD treatment further predisposes to CMV	Acute GVHD (grades II-IV) is reported as a significant risk factor for CMV reactivation[72]. No quantitative data reported
Intensity of immunosuppression	Prolonged corticosteroid use and other immunosuppressants (e.g., for GVHD) elevate CMV reactivation risk	No quantitative data on percentage increase in risk of CMV reactivation
Novel immunosuppressants	Patients treated with alemtuzumab, rituximab, or PTCy are at higher risk	66% of chronic lymphocytic leukemia patients treated with alemtuzumab experienced CMV reactivation, as detected by antigenemia and/or CMV DNA[73]. Rituximab impacts B-cell function and causes B-cell depletion, which could influence CMV immunity. Further research is needed to establish a definitive link[74]. PTCy is associated with an increased risk of CMV infection, regardless of donor type. Reports show CMV reactivation rates ranging from 42% to 69.2% among these patients[71]
Co-infections (e.g., EBV)	Other co-infections complicate immune recovery and increase CMV-related complications	CMV and EBV co-reactivation occurs in approximately 22.9% of HSCT patients[75]. Co-reactivation of CMV and EBV has been associated with decreased one-year overall survival rates, primarily due to increased non-relapse mortality[75]
HSCT indication	SAA and platelet refractoriness pre-transplant are associated with higher CMV risk	A study involving 361 SAA patients found that those with platelet refractoriness had an odds ratio of 5.41 for developing CMV retinitis compared to those without this condition[17]
Host-specific factors	Protective factors: HLA alleles such as HLA-B*07:02 and HLA-A2 are associated with a reduced risk of CMV reactivation after HSCT, likely due to enhanced immune responses, particularly through CMV-specific T cells. Currently, no report on HLA alleles that increase the risk of CMV reactivation	HLA-B*07:02: This allele has been linked to a decreased risk of CMV reactivation post-HSCT. A study observed that patients with HLA-B*07:02 had a hazard ratio of 0.59 for CMV reactivation compared to those without this allele[76]. Research comparing CMV-specific CD8+ T lymphocyte responses in HLA-A2 and HLA-B35 patients on day 35 post-transplantation found that HLA-A2 patients had significantly higher CMV-specific CD8+ percentages and activity compared to HLA-B35 patients[77]

CMV: Cytomegalovirus; HSCT: Hematopoietic stem cell transplant; HCT: Hematopoietic cell transplantation; TCR: T-cell receptor; EBV: Epstein-Barr virus; GVHD: Graft-vs-host disease; PTCy: Post-transplant cyclophosphamide; SAA: Severe aplastic anemia.

Clinical presentation

CMV retinitis typically presents insidiously, with many patients remaining asymptomatic until the retinitis progresses. Common symptoms include blurred vision, floaters, and flashes, often without overt pain[18]. Unique challenges arise in the pediatric population, as young children may struggle to communicate visual symptoms, and the condition may be asymptomatic or initially present with subtle signs[1,2,8]. Unlike adults, who may notice and report visual disturbances, young children are typically unable to articulate these symptoms. Infants and toddlers, in particular, may not recognize changes in their vision or may adapt behaviorally, making the condition harder to detect in its early stages[1,2,7]. Instead, caregivers and clinicians may observe indirect signs such as a lack of interest in visual stimuli, failure to track objects, strabismus, or nystagmus. In older children, complaints of difficulty reading or changes in school performance might be the first indication of a visual problem. These subtle and non-specific signs often delay the diagnosis, allowing the disease to progress silently until it reaches an advanced stage[1,2,7].

On ophthalmic examination, CMV retinitis presents as creamy yellow-white areas of retinal necrosis, often in the peripheral retina, accompanied by associated retinal hemorrhages and signs of vasculitis such as vessel sheathing or perivascular whitening. Vitritis is also frequently observed, contributing to haziness that can obscure retinal details[7,19-21]. If left unchecked, the disease progresses rapidly, with retinal lesions expanding at a rate of 250-350 μm per week. Advanced stages often result in severe retinal destruction, potentially causing complications such as retinal detachment and blindness[21]. These findings, however, may not be immediately apparent in the early stages, and patients with CMV viremia but no symptoms could still be at risk. Therefore, retinal imaging and serial fundus photographs play a pivotal role in screening and diagnosis, especially in high-risk patients[21]. Bilateral involvement is seen in approximately 60% of cases, significantly increasing the risk of profound visual impairment[22].

Investigations and diagnosis

The diagnosis of CMV retinitis in pediatric patients following HSCT requires a multifaceted approach, including clinical evaluation, imaging modalities, and laboratory testing. A comprehensive ophthalmic examination remains central to the diagnostic process. When retinal visualization is hindered by inflammation, such as vitritis, imaging becomes essential. However, the diagnosis primarily relies on clinical findings, with imaging serving a supplementary role[21].

Advanced imaging modalities, such as optical coherence tomography (OCT), fundus autofluorescence imaging (FAF) and fluorescein angiography are invaluable tools in diagnosing CMV retinitis. OCT findings in CMV retinitis reveal retinal thickening and edema in the early stages, with hyperreflective lesions indicating necrosis and active inflammation. As the disease progresses, retinal thinning, atrophy, and disruption of the outer retinal layers, including the photoreceptor layer and retinal pigment epithelium (RPE), become prominent. Vitreoretinal interface changes, such as hyperreflective dots from vitritis, and subretinal fluid or exudates may also be observed[23]. Spectral-domain OCT has further highlighted macular involvement, with disruption of the inner and outer retinal layers, cystoid macular edema, and epiretinal membrane formation in some cases. These findings make OCT an indispensable tool for monitoring disease progression, evaluating treatment response, and assessing long-term structural retinal changes[24].

FAF imaging in CMV retinitis provides valuable insights into the disease’s activity and structural changes. Active lesions typically show areas of hypoautofluorescence corresponding to necrotic retina, indicating the loss of autofluorescent material in the RPE. Surrounding these regions, hyperautofluorescent borders are often observed, representing active inflammation at the advancing edges of the lesions. As CMV retinitis progresses, healed areas display persistent hypoautofluorescence due to RPE atrophy and scarring[25]. Ultra-widefield FAF extends this analysis by enabling visualization of peripheral retinal involvement, highlighting extensive hypoautofluorescent zones with hyperautofluorescent margins that correlate with the extent of disease[26]. FAF imaging is particularly useful for non-invasive monitoring, helping to differentiate between active and inactive lesions and assess the effectiveness of treatment over time[25,26].

Fluorescein angiography reveals retinal non-perfusion, vascular leakage, and microvascular changes like capillary dropout and telangiectasia. These findings indicate retinal ischemia and inflammation, aiding in disease monitoring and treatment assessment[1]. Serial retinal photography is crucial for monitoring CMV retinitis, allowing detailed documentation of disease progression, recurrence, and response to therapy. It enables objective comparison of changes in lesion size, activity, and complications like retinal detachment. This tool is particularly valuable in pediatric patients, aiding in accurate assessment and collaborative care when direct examination is challenging[21].

Visual field testing often reveals scotomas corresponding to areas of retinal damage. Patients may present with peripheral visual field loss, reflecting peripheral retinal involvement, or central scotomas if the macula is affected. These defects typically correlate with the extent and location of retinal necrosis and ischemia seen clinically or on imaging. Serial visual field testing is valuable for monitoring disease progression, assessing treatment response, and detecting complications like retinal detachment or immune recovery uveitis that may worsen visual loss. However, this test can only be performed if the child is old enough to understand and cooperate with the testing procedures[1].

Laboratory confirmation is also supportive in suspected cases of CMV retinitis, particularly when clinical findings are inconclusive. Polymerase chain reaction (PCR) assays are highly sensitive and specific for detecting CMV DNA in ocular fluids, such as in aqueous humor or vitreous samples, as well as in blood[27,28]. These tests are particularly useful for confirming CMV infection in immunocompromised patients where multiple pathogens could contribute to ocular findings[28]. Blood CMV DNA levels indicate infection when they exceed established thresholds, such as 500 copies/mL in PCR testing, as reported by Diaz et al[29]. Larochelle et al[1] also utilized PCR testing on aqueous humor samples. In addition to PCR, the measurement of CMV-specific antibodies can provide supportive evidence of infection, though these are less specific in immunosuppressed populations. Rozanova et al[30] identified CMV antibodies in the tear fluid of patients with CMV retinitis, highlighting a potential non-invasive diagnostic marker. The study demonstrated a correlation between antibody levels in tear fluid and disease activity, suggesting its usefulness in monitoring CMV retinitis progression and response to treatment. A summary of the investigations and diagnostic methods for CMV retinitis is provided in Table 2.

Table 2 A Summary of the investigations and diagnostic methods for cytomegalovirus retinitis.

Investigation	Findings and utility
Comprehensive ophthalmic examination	Central to diagnosis, identifies characteristic retinal lesions; limited by media opacity (e.g., vitritis)[21]
OCT	Retinal thickening, hyperreflective necrotic lesions (early); retinal thinning, atrophy, photoreceptor, and RPE disruption (late); detects macular involvement[23,24]
FAF	Hypoautofluorescence in necrotic retina; hyperautofluorescent borders indicate active inflammation[25]; ultra-widefield FAF helps assess peripheral involvement[26]
FA	Retinal ischemia, vascular leakage, capillary dropout, telangiectasia; aids in disease monitoring[1]
Serial retinal photography	Tracks disease progression, recurrence, and treatment response; useful in pediatric patients where direct examination is challenging[21]
Visual field testing	Detects scotomas correlating with retinal damage; useful for assessing functional impact of CMV retinitis; requires patient cooperation[1]
PCR for CMV DNA	Highly sensitive and specific for CMV detection in ocular fluids (aqueous/vitreous) and blood; useful in immunocompromised patients[1,27-29]
CMV-specific antibodies	Supportive but less specific in immunosuppressed patients; potential role of tear fluid antibody levels in monitoring disease activity[30]

OCT: Optical coherence tomography; RPE: Retinal pigment epithelium; FAF: Fundus autofluorescence; FA: Fluorescein angiography; PCR: Polymerase chain reaction; CMV: Cytomegalovirus.

Differential diagnosis

Several conditions mimic CMV retinitis in pediatric post-stem cell transplant patients. Progressive outer retinal necrosis, caused by varicella-zoster virus, presents with rapidly progressive retinal necrosis, minimal inflammation, and no significant hemorrhage, unlike CMV retinitis. Toxoplasmic retinochoroiditis is distinguished by focal necrotizing retinitis near a chorioretinal scar, significant vitreous inflammation, and positive toxoplasma serology. Fungal endophthalmitis, often caused by Candida, features fluffy white lesions with vitreous haze and is associated with systemic fungal infection. Noninfectious uveitis lacks infection markers and responds to corticosteroid therapy. Comprehensive evaluation with history, examination, and diagnostic tests is essential for accurate differentiation and management[31].

Screening protocols for CMV retinitis in pediatric HSCT recipients

Currently, there is no standardized screening protocol for CMV retinitis in pediatric HSCT recipients, and recommendations vary across studies. While some articles advocate for routine ophthalmic screening in all HSCT patients regardless of CMV serological status, others highlight the low incidence of CMV retinitis and suggest that routine examinations may not be necessary. Instead, these studies recommend targeted screening for children with positive CMV laboratory findings who also present with identified risk factors[1,2,32].

In a landmark study by Hiwarkar et al[2], a targeted ophthalmic screening protocol was proposed for high-risk pediatric HSCT recipients to monitor and manage CMV retinitis effectively. Screening begins in all pediatric HSCT recipients with significant CMV viremia (i.e., ≥ 4000 copies/mL) and any identified risk factors, including pre-transplant viremia, primary immunodeficiency, acute GVHD of grade ≥ 2, or mismatched grafts. According to Hiwarkar et al[2], this level of CMV viremia is linked to a higher likelihood of developing CMV retinitis. Since CMV retinitis has been observed during cellular immune reconstitution, even when peripheral blood CMV levels are low, the protocol emphasizes continuing ophthalmic surveillance in high-risk patients until CMV viremia fully resolves, regardless of numerical evidence of T-cell recovery. This comprehensive approach aims to mitigate the risk of delayed diagnosis and optimize patient outcomes.

Blood-based tests, such as quantitative PCR for CMV DNA and pp65 antigenemia assays, play a crucial role in identifying patients with significant CMV viremia. Hiwarkar et al[2] defined significant CMV DNA levels as ≥ 4000 copies/mL using PCR, while Jeon et al[11] suggested a higher threshold of > 7.64 × 10⁴ copies/mL. This discrepancy underscores the variability in defining significant CMV viremia among studies[32]. Additionally, differences in PCR standardization across laboratories further complicate the direct application of these findings to clinical practice, emphasizing the urgent need for uniform testing protocols to ensure consistency and reliability in identifying at-risk patients[33].

Optimal timing and frequency of screening

The timing, frequency, and duration of CMV retinitis screening remain topics of debate. Certain centers have implemented more rigorous screening protocols for high-risk populations. Larochelle et al[1], in a retrospective study conducted at the Children’s Hospital Colorado, identified a concerning increase in the incidence of CMV retinitis among pediatric patients following allogeneic stem cell transplantation. In response to these findings, they proposed a more aggressive screening strategy to address this issue effectively.

All patients undergo a baseline ophthalmic examination, including a dilated fundus exam and fundus photography, prior to allogeneic stem cell transplantation. Following the transplant, they are monitored for CMV viremia using PCR testing[1]. Ljungman et al[34] and Hakki et al[35] recommend starting CMV PCR testing at approximately day 7 after transplant, typically within the first 7 to 14 days. Weekly monitoring is advised during the first 100 days, which represents the highest risk period for CMV reactivation due to delayed immune recovery. After day 100, patients with ongoing risk factors such as GVHD, prolonged immunosuppression, or prior CMV viremia should continue to be monitored weekly or every 2 weeks. The duration and frequency of monitoring should be guided by the patient’s clinical status and the extent of immune reconstitution. If CMV viremia does not develop, screening ophthalmic exams are repeated at 3 months and 12 months post-transplant. If CMV viremia is detected, a follow-up ophthalmic exam is performed immediately, with another exam scheduled 2 weeks later. If the follow-up exam is normal, regular monitoring with a dilated fundus exam is conducted every 6 to 8 weeks while the patient remains viremic, until immune reconstitution occurs. Any new symptoms warrant an immediate ophthalmic examination. If CMV retinitis is diagnosed, confirmatory investigations should be performed, and appropriate treatment initiated promptly[1]. Figure 1 depicts a summary of the optimal timing and frequency of screening for CMV retinitis detailed above adopted from three reference articles[1,34,35].

Figure 1 Optimal timing and frequency of cytomegalovirus retinitis screening following hematopoietic stem cell transplantation in pediatric patients. This flow chart is adapted from published data and recommendations in three key sources: Larochelle et al[1], Ljungman et al[34], and Hakki et al[35], integrating current evidence on the timing of cytomegalovirus polymerase chain reaction testing, high-risk periods for reactivation, and indications for continued ophthalmic surveillance in vulnerable populations. CMV: Cytomegalovirus.

Currently, there is still no consensus on when to stop screening. The increasing use of CMV-specific T-cell immunotherapy and better antiviral regimens may influence future guidelines. Overall, the general agreement is that early involvement of ophthalmologists for a thorough retinal examination can prevent delays in diagnosing CMV retinitis, which often begins subtly and may progress rapidly without timely intervention[1].

Management of CMV retinitis in pediatric patients post-stem cell transplant

The management of CMV retinitis involves a multifaceted approach that can be categorized into antiviral therapies and adjunctive immunotherapy. Each approach offers unique benefits and risks, necessitating individualized treatment plans based on patient-specific factors such as the severity of retinitis, immune status, and potential drug toxicities[36].

ANTIVIRAL THERAPIES

Antiviral agents remain the cornerstone of CMV retinitis management. These are further subclassified into systemic, intravitreal, and implantable delivery systems[36].

Systemic antiviral therapy

Systemic antivirals are critical for controlling CMV viremia and preventing the dissemination of the virus to other organs[36,37].

Ganciclovir and valganciclovir: Ganciclovir is a first-line systemic therapy and is commonly administered intravenously. Valganciclovir, an oral prodrug of ganciclovir, offers a more convenient alternative with comparable efficacy. However, systemic use is often associated with significant myelosuppression, particularly in pediatric patients undergoing HSCT[36].

Foscarnet: Foscarnet serves as an alternative for patients with ganciclovir-resistant CMV strains or patients who cannot tolerate ganciclovir. Although effective, it carries risks of nephrotoxicity and electrolyte imbalances[37].

Cidofovir: While effective, its use is limited due to the risk of nephrotoxicity. Advances in dosing schedules and hydration protocols have aimed to mitigate these side effects[36].

Intravitreal antiviral therapy

Intravitreal injections provide high localized drug concentrations while minimizing systemic side effects. For patients with severe retinitis, these therapies are essential in preventing vision loss. Long-term intravitreal therapy may be required for patients with recurrent disease or resistance to systemic therapies. Recent studies, such as those by Miao et al[38], have suggested that a combination of systemic and intravitreal antivirals provides superior outcomes compared to systemic therapy alone. This dual approach is especially important for preserving vision in severe cases. Intravitreal antiviral medications are typically administered weekly or biweekly[38], which can be problematic in pediatric patients due to the frequent need for general anesthesia (GA). This repeated exposure to GA increases the risk of potential side effects associated with anesthesia[39]. A sedoanalgesia approach, as suggested by Alselaimy et al[39] in the management of retinopathy of prematurity with intravitreal medication injections, could offer a safer alternative. This approach may help minimize the risks associated with frequent GA exposure, providing an effective option for pediatric patients undergoing these procedures[39].

Intravitreal ganciclovir: Multiple injections of ganciclovir effectively manage CMV retinitis, especially in patients with severe systemic toxicity or inadequate response to systemic therapy[38]. Recent advancements have introduced innovative strategies to manage refractory or recurrent cases of CMV retinitis. Chen et al[40] conducted a randomized controlled trial comparing high-dose (6 mg) and low-dose (3 mg) intravitreal ganciclovir. The high-dose regimen demonstrated superior efficacy in achieving retinal healing, albeit with an increased risk of local toxicity.

Intravitreal foscarnet: Foscarnet injections are used for ganciclovir-resistant CMV strains. In one case, a combination of intravitreal foscarnet and systemic CMV-specific immunoglobulin therapy demonstrated successful outcomes[41].

Sustained-release implants: The ganciclovir implant delivers continuous intravitreal drug release, maintaining therapeutic levels for extended periods. Ghosh et al[42] reported successful outcomes using sustained-release implants for bilateral severe CMV retinitis, highlighting their utility in patients with recurrent disease or poor compliance. The development of newer antivirals with improved safety profiles is ongoing. These agents aim to reduce the burden of drug-related toxicities while maintaining efficacy against resistant CMV strains[36]. Further details on the mechanism of action, route of administration, advantages, disadvantages, and side effects of these antiviral medications are summarized in Table 3.

Table 3 Summary of antiviral medications used for cytomegalovirus retinitis treatment post-hematopoietic stem cell transplant.

Antiviral drug	Route of administration	Mechanism of action	Advantages	Disadvantages	Side effects
Ganciclovir[7,36-38,40,42]	Systemic: IV infusion. Local: Intravitreal injection, sustained-release implant	Inhibits viral DNA polymerase (UL54)	Selective activation by viral kinases reduces toxicity to uninfected cells. Multiple administration routes. Localized high concentration: Intravitreal injections and implants. Proven efficacy: Widely studied with established protocols for use in CMV retinitis. Adjunctive potential: Can be combined with other therapies, such as adoptive T-cell therapy, for refractory cases	Hematologic toxicity limits its systemic use in some patients. Limited oral bioavailability. Drug resistance: May develop with prolonged use. Local administration challenges: Intravitreal injections or implants are invasive and may cause complications (e.g., retinal detachment or endophthalmitis). High cost: Treatment, especially with implants or frequent intravitreal injections, can be expensive. Not curative: Requires long-term or recurrent treatment to manage chronic infection	Hematologic: Neutropenia, anemia, thrombocytopenia. Gastrointestinal: Nausea, vomiting, diarrhea, abdominal pain. Neurological: Headache, dizziness, confusion, seizures (rare). Renal: Increased serum creatinine, acute kidney injury (rare, but possible with IV administration). Ophthalmologic (intravitreal use): Retinal detachment, endophthalmitis, vitreous hemorrhage. Others: Fever, fatigue, rash or itching, injection site reactions (for IV or intravitreal routes). Rare but serious side effects: Teratogenicity, carcinogenicity, reproductive toxicity, hypersensitivity reactions
Valganciclovir[36,37]	Systemic: Oral	Prodrug of ganciclovir. After activation, inhibits viral DNA polymerase	Improved oral bioavailability compared to ganciclovir		Same side effect profile as ganciclovir
Foscarnet[7,37,38,41]	Systemic: IV infusion. Local: Intravitreal injection	Directly inhibits viral DNA polymerase (UL54)	Unlike ganciclovir, it does not require activation by viral or cellular kinases. Effective for resistant CMV: Useful in cases of ganciclovir-resistant CMV infections. Broad spectrum: Active against various herpesviruses, including CMV, HSV, and VZV. IV administration: Allows for direct delivery in severe cases or when oral therapy is not feasible	Frequent infusions: Requires multiple daily infusions, which can be burdensome. Limited use in pediatrics: Fewer pediatric-specific safety data compared to other antivirals	Nephrotoxicity: Acute kidney injury is a significant concern. Electrolyte disturbances: Hypocalcemia, hypomagnesemia, and hypokalemia. Gastrointestinal issues: Nausea, vomiting, and diarrhea. Central nervous system effects: Seizures or confusion, particularly in patients with electrolyte imbalances
Cidofovir[36]	Systemic: IV infusion	Nucleotide analog. Competitively inhibits viral DNA polymerase and incorporates into the viral DNA, leading to chain termination	Effective for resistant CMV: Active against ganciclovir-resistant CMV strains. Broad-spectrum activity: Effective against other herpesviruses, including HSV and VZV. Single weekly dosing: Less frequent administration compared to other antivirals like foscarnet	Limited pediatric data: Fewer safety and efficacy data in pediatric patients, especially post-HSCT. Requires probenecid co-administration: To reduce nephrotoxicity, probenecid is required, which adds complexity	Nephrotoxicity: Can lead to acute renal failure if not monitored carefully. Gastrointestinal symptoms: Nausea, vomiting, and diarrhea. Ocular toxicity: Potential for retinal toxicity with prolonged use. Bone marrow suppression: Can cause neutropenia or thrombocytopenia in some patients

CMV: Cytomegalovirus; HSV: Herpes simplex virus; VZV: Varicella-zoster virus; HSCT: Hematopoietic stem cell transplant.

ADJUNCTIVE IMMUNOTHERAPY

Adjunctive therapies aim to boost the immune response to CMV in immunocompromised patients[43].

CMV-specific immunoglobulins

CMV immunoglobulin therapy provides passive immunity, reducing viral load and complementing antiviral therapy[43]. Chiu et al[43] demonstrated the efficacy of CMV immunoglobulin in reducing recurrence and progression when used alongside antivirals in pediatric HSCT recipients.

Adoptive T-cell therapy

Adoptive transfer of CMV-specific cytotoxic T lymphocytes (CTLs) has shown promise in treating refractory CMV retinitis. This strategy involves infusing CMV-specific CTLs into the patient’s system, with the aim of boosting the immune response to CMV[44,45]. Gupta et al[44] reported significant ocular improvements and reduced systemic CMV burden following CTL therapy. This approach is particularly beneficial in patients with prolonged immune suppression or resistance to conventional antivirals. Seo et al[45] documented successful outcomes in pediatric patients, emphasizing the potential of personalized T-cell therapies in severe cases.

Viral-specific T cells represent a promising strategy for managing refractory or recurrent CMV retinitis. Montiel-Esparza et al[46] reported significant improvements in visual acuity and resolution of retinitis lesions in patients treated with viral-specific T cells. They emphasized their effectiveness in treating persistent cases, noting their ability to specifically target CMV-infected cells and promote viral clearance with minimal systemic toxicity. This therapy is particularly useful in cases where conventional antiviral therapy fails or is associated with significant toxicity. However, challenges remain regarding the availability of CMV-specific T cells and the feasibility of widespread use[46]. Further details on the available formulations, their mechanism of action, route of administration, indication, advantages, disadvantages, and side effects of these adjunctive immunotherapy medications are summarized in Table 4.

Table 4 Summary of adjunctive immunotherapy medications used for cytomegalovirus retinitis treatment post-hematopoietic stem cell transplant.

Adjunctive immunotherapy	Route of administration	Mechanism of action	Indication	Advantages	Disadvantages	Side effect
CMV-specific immunoglobulins: Cytogam®[43,78]	IV infusion	Hyperimmune globulin enriched with high titers of antibodies against CMV. Provides passive immunity by supplying CMV-specific antibodies, which neutralize the virus and enhance immune-mediated clearance	Adjunct to antivirals in treatment of active CMV retinitis: To augment the immune response while antivirals control viral replication. Prevention of relapse (prophylaxis). Severe immunosuppression e.g., prolonged neutropenia, T-cell depletion, or GVHD	Enhanced immune response. Potential reduction in antiviral toxicity (may allow for lower doses of antiviral drugs). Broader immunomodulatory effects. Reduced CMV-related mortality	Limited efficacy in isolation: Ineffective as monotherapy; requires combination with antivirals. Cost: Expensive, limiting accessibility. Unclear pediatric-specific data: Limited evidence on efficacy and safety specific to pediatric CMV retinitis cases	Infusion-related reactions: Fever, chills, flushing, nausea, and hypotension. Allergic reactions: Rash, pruritus, and, rarely, anaphylaxis. Headache: Commonly reported during or after infusion. Gastrointestinal symptoms: Nausea, vomiting, and abdominal discomfort. Hypertension or hypotension: Blood pressure fluctuations during infusion. Thrombotic events: Rare but possible in predisposed patients. Renal dysfunction: Risk of acute kidney injury, particularly with rapid infusion or concurrent nephrotoxic drugs
Cytomegalovirus-specific cytotoxic T lymphocyte therapy: Viralym-M[44-46,79,80]	Intravenous infusion	Allogeneic T-cell therapy. Provides adoptive immunity by transferring CMV-specific cytotoxic T lymphocytes, which actively target and eliminate CMV-infected cells	Resistant or refractory CMV retinitis. Restoration of immunity in severe immunosuppression	Targeted immune response: Restores virus-specific immunity directly against CMV. Effective in resistant cases: Addresses CMV infections refractory to antivirals. Reduced toxicity: Avoids the systemic toxicity associated with antivirals	High cost: Expensive therapy, limiting accessibility. Limited availability: Requires specialized facilities for manufacturing and administration. Delayed onset: Time needed for T-cell preparation and expansion. Complex logistics: Requires precise HLA matching and rigorous pre-treatment screening	GVHD: Potential risk in allogeneic T-cell therapy. Infusion reactions: Fever, chills, or allergic reactions. Cytokine release syndrome: Rare but possible with immune cell therapies. Immune rejection: Host immune system may reject infused T cells in some cases
Multivirus-specific T-cell therapy: Posoleucel (ALVR105)[81-83]	Intravenous infusion	It is derived from healthy donors whose T cells are selectively expanded to recognize six viruses commonly affecting immunocompromised patients, including: Cytomegalovirus, Epstein-Barr virus, adenovirus, BK virus, human herpesvirus 6 and JC virus. It contains CD4+ and CD8+ T cells that are pre-sensitized to viral antigens. These T cells can recognize and bind viral peptides presented on infected host cells through HLA molecules. They then trigger apoptosis of the infected cell	Resistant or refractory CMV retinitis. Restoration of immunity in severe immunosuppression. Prophylaxis of viral infections after allo-HCT. Treatment of other concomitant viral infections: Can target other viral infections like adenovirus, BK virus, Epstein-Barr virus, and human herpesvirus-6	Effective in resistant cases: Addresses CMV infections refractory to antivirals. Multivirus efficacy: Can target other opportunistic viral infections. Reduced toxicity: Avoids the systemic toxicity associated with antivirals

CMV: Cytomegalovirus; GVHD: Graft-vs-host disease; allo-HCT: Allogeneic hematopoietic cell transplantation.

Maintenance therapy and follow-up

After achieving negative CMV viremia and resolution of retinitis lesions, patients may require ongoing maintenance therapy to prevent relapse. The decision to stop antiviral treatment is based on several factors, including the resolution of the retinitis lesion, the absence of active viremia, and the patient’s overall immune status. For patients with scarring of the retina, management may focus on surveillance rather than active antiviral treatment, as the risk of reactivation is lower in such cases[1]. The frequency of follow-up visits after therapy discontinuation varies, but patients should be monitored for at least 6-12 months following treatment cessation to detect any signs of relapse. Follow-up typically includes periodic fundus examinations and monitoring of CMV viremia[1,2].

Recurrent CMV retinitis

Recurrent CMV retinitis in patients post-HSCT differs in clinical presentation from primary episodes. Recurrences typically manifest around 6.4 months after initial treatment and are associated with significantly lower CD4+ T lymphocyte counts (average 126.7 cells/mm³). Fundoscopic findings include increased marginal activity of previously stable lesions and new yellow-white lesions adjacent to areas of atrophy and necrosis. OCT imaging reveals diffuse hyperreflective lesions in the retinal neuroepithelial layer near old lesions, inflammatory punctate hyperreflective spots in the vitreous, and evidence of vitreous liquefaction and contraction. These findings underscore the need for vigilant long-term monitoring of CMV retinitis in post-HSCT patients, even after initial stabilization[47].

Prevention strategies: Prophylaxis vs preemptive treatment

Before diving into the prevention strategies for CMV retinitis, understanding the distinction between CMV reactivation, viremia, and disease is essential. CMV reactivation involves asymptomatic viral replication detected via PCR or pp65 antigenemia assays, while CMV viremia refers to the presence of viral DNA or RNA in the bloodstream, signaling an increased risk of progression to CMV disease, which causes symptomatic and often irreversible tissue damage, such as retinitis[29].

Prevention strategies for CMV infection are based either on prophylactic or preemptive approaches. The prophylactic approach involves administering antiviral medications to all at-risk patients after HSCT, regardless of CMV reactivation status, aiming to prevent infection entirely. In contrast, the preemptive approach focuses on closely monitoring patients for early signs of CMV reactivation, such as rising CMV DNA levels in blood, and initiating antiviral treatment only in those who test positive, thereby reducing unnecessary drug exposure and associated side effects[1].

Larochelle et al[1] outline specific prophylactic and preemptive strategies for managing CMV disease in allogeneic HSCT patients. For prophylaxis, all patients receive acyclovir for at least 12 months post-transplant or until CD4 counts exceed 400/μL. If significant CMV viremia occurs during this period, the prophylactic regimen is discontinued, and preemptive treatment is initiated. The preemptive approach involves starting antiviral therapy if CMV PCR levels reach ≥ 1000 copies/mL in the blood. Treatment options include foscarnet (60 mg/kg every 8 hours or 90 mg/kg every 12 hours) or ganciclovir (5 mg/kg every 12 hours if the patient is well-engrafted). Once the viral load decreases to a low positive range (100-999 copies/mL) or becomes undetectable, the dosing is reduced to daily maintenance. Therapy continues for at least two weeks and until CMV PCR results are negative.

Letermovir, a newer antiviral agent, has emerged as a promising option for CMV prophylaxis in HSCT recipients. While its use is currently approved only for CMV-seropositive adults, several recent studies have explored its off-label use in pediatric patients. Evidence suggests that letermovir is effective and well-tolerated for primary prophylaxis in high-risk pediatric HSCT recipients, significantly reducing the incidence of clinically significant CMV infection without notable toxicity[48-50]. Although its role in preemptive treatment is less established, limited case series and reports suggest potential benefits in select situations, such as ganciclovir-resistant CMV or intolerance to standard antivirals[51,52]. However, letermovir is not recommended for the treatment of CMV retinitis or other established tissue-invasive disease, as it lacks activity against CMV replication within tissues[53].

Mesenchymal stromal cell therapy: A promising adjunct in managing CMV risk after pediatric stem cell transplantation

Mesenchymal stromal cells (MSCs), often referred to as MSCs though this term is debated, are increasingly used as supportive therapy in HSCT. These cells, typically derived from bone marrow or other tissues and expanded in vitro, have shown promise in reducing the severity of GVHD and lowering the risk of post-transplant infections[54,55]. MSCs help modulate the immune system in a targeted manner. Rather than causing broad immune suppression like traditional agents, they suppress harmful inflammation by altering T-cell function, encouraging regulatory T-cell production, and decreasing inflammatory cytokines like tumor necrosis factor-α and interferon-γ[56,57]. This fine-tuned approach allows the immune system to recover while minimizing complications like GVHD and infections.

Emerging evidence also supports the infection-limiting benefits of MSCs. A study involving HSCT recipients found that those treated with MSCs experienced fewer viral infections, including CMV, compared to those on conventional immunosuppressants[58]. This is particularly relevant in the pediatric transplant setting, where CMV viremia poses a major risk for complications like retinitis. Beyond live-cell therapy, researchers are exploring MSC-derived products such as extracellular vesicles and secretomes, which contain beneficial signaling molecules. These cell-free therapies may offer similar benefits in managing inflammation and promoting immune recovery, with potentially fewer safety concerns than live-cell infusions[59,60].

The term “MSC” can be misleading. Most therapies use a heterogeneous population of mesenchymal cells, only a fraction of which are true stem cells. This distinction matters, especially as regulatory bodies and researchers continue to debate proper terminology and classification for these therapies[61,62]. Incorporating MSCs or their derivatives into HSCT care could offer a more adaptive and functional approach to post-transplant immune recovery. By controlling GVHD and supporting pathogen-specific immunity, MSC therapy may reduce the risk of opportunistic infections such as CMV, especially during the vulnerable early post-transplant period.

Complications of CMV retinitis

CMV retinitis is a potentially devastating condition that can lead to significant ocular morbidity, even with prompt antiviral therapy. One of the most severe complications is retinal detachment, which occurs due to extensive necrosis and thinning of the retina. Studies report retinal detachment in 10.3% of affected eyes, often requiring surgical intervention such as vitrectomy[20].

Immune recovery uveitis, a paradoxical inflammatory response following immune reconstitution, is another complication. It can exacerbate retinal damage and, in some cases, contribute to rhegmatogenous retinal detachment, as seen in a patient during CMV treatment[22]. However, this complication is rarely seen in pediatric patients following HSCT[1]. Progressive retinal necrosis and structural damage can result in irreversible vision loss, including blindness. In some cases, patients with CMV retinitis have experienced near-total unilateral blindness despite adequate antiviral therapy. Other complications may include cystoid macular edema, secondary glaucoma, and optic nerve involvement, further jeopardizing visual outcomes[63]. These complications highlight the importance of a multidisciplinary approach, combining aggressive antiviral treatment, close ophthalmologic monitoring, and timely surgical intervention to mitigate long-term vision loss[22].

Prognosis of CMV retinitis

The prognosis is influenced by disease severity, treatment response, and associated complications. Eid et al[22] reported varied visual outcomes over a mean follow-up of 20 months: Visual acuity improved in 28.5% of eyes, remained stable in another 28.5%, and worsened in 43%. Son et al[20] identified key prognostic factors affecting outcomes. Using multivariate logistic regression analysis, they demonstrated that concurrent CMV disease significantly increased the risk of poor prognosis (odds ratio = 14.11, P = 0.009). Foveal involvement was an even stronger predictor of adverse outcomes, with an odds ratio of 114.85 (P = 0.001), underscoring the critical role of the fovea in central vision preservation. These findings emphasize the need for early detection and aggressive management to prevent recurrence, minimize complications, and optimize visual outcomes in this vulnerable population[1,64,65].

CONCLUSION

CMV retinitis in pediatric HSCT recipients is a complex and potentially devastating complication, but with early detection and appropriate management, outcomes can be significantly improved. Screening protocols continue to evolve, with the emphasis on identifying high-risk patients during periods of immune reconstitution. Management of CMV retinitis in pediatric patients post-HSCT requires a comprehensive approach that balances effective viral suppression with the mitigation of drug-related toxicities. Antiviral therapies, whether systemic, intravitreal, or implantable, remain central to treatment. Adjunctive immunotherapies, particularly adoptive T-cell therapy, offer promising outcomes in refractory cases. Emerging modalities, including high-dose intravitreal regimens and novel antivirals, hold potential for future advancements. Individualized treatment plans, guided by patient-specific risk factors and disease severity, are crucial for optimizing outcomes and preserving vision in this vulnerable population. However, several gaps in knowledge remain. No articles have specifically addressed the type of immunosuppressants that pose the greatest risk for CMV retinitis in pediatric HSCT recipients. Additionally, the question of whether patients with inactive CMV infections prior to transplantation should be excluded from transplant programs warrants further investigation. Ongoing research into optimal screening strategies, individualized management plans, and the role of pre-transplant CMV serostatus will continue to shape the future of CMV retinitis management in pediatric HSCT recipients.