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.