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

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.

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.

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.

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.