Discussion
This is the first meta-analysis to explore the risk factors for HC in children undergoing HSCT. Zhou et al. [
22] reported the risk factors related to BK virus-associated HC (BKV-HC). They found that male sex, haploidentical donor, MAC, acute GVHD, chronic GVHD, and CMV reactivation were risk factors for BKV-HC in patients who underwent allogeneic HSCT. Owing to the limited number of included studies, they did not perform a subgroup analysis of pediatric patients and only investigated virus-induced HC. Therefore, the risk factors for pediatric patients undergoing HSCT remain unclear. This meta-analysis included 12 studies involving 2,764 patients that explored the risk factors for HC in children undergoing HSCT, and 17 potential risk factors were evaluated. The results of the pooled analysis indicated that male sex, allogeneic donor, HLA-mismatched donor, unrelated donor, MAC, use of busulfan or ATG, and CMV reactivation were risk factors for HC in children undergoing HSCT.
Our study revealed that boys were more likely to develop HC after HSCT than girls, which is consistent with the results of previous studies [
9,
23,
24]. A possible reason for this finding may be that estrogen exerts a protective effect in the bladder mucosa, which contributes to a lower incidence of HC in female HSCT recipients than in male recipients [
25].
In our analysis, no significant differences were observed in the risk of HC between patients with malignant and nonmalignant diseases. All studies included in this meta-analysis consistently indicated that patients with malignant disease did not exhibit a higher risk of HC than those with nonmalignant disease. However, in patients with malignant disease, intensive chemotherapy may cause injury to the bladder mucosa and contribute to the occurrence of HC after HSCT. Although our analysis did not suggest that malignant disease is a risk factor for HC in children undergoing HSCT, further studies are warranted to explore this relationship.
The types of HSCT include autologous and allogeneic, owing to the different sources of stem cells (the patients or others). Recipients of allogeneic transplantation may have a higher incidence of HC [
14,
26], which is consistent with our results. We speculate that this association may be attributable to the higher dose of cyclophosphamide (which can injure the bladder mucosa) employed in the conditioning regimen of allogeneic transplant recipients. However, the reliability of this finding is constrained due to the inclusion of only two studies. Further studies with large sample sizes are warranted to elucidate the relationship between HC and the type of HSCT.
The stem cell sources generally included bone marrow, peripheral blood, and cord blood. The results revealed that the risk of HC did not differ significantly according to the source of stem cells, which is consistent with the findings of previous studies [
10,
18,
27]. Although our analysis did not find an association between cord blood transplantation and the risk of HC in pediatric HSCT recipients, Jiang et al. [
28] reported that HLA matching ≤ 6/8 was an independent risk factor for the occurrence of late-onset HC. HLA compatibility of cord blood units may play an essential role in the relationship between cord blood transplantation and the occurrence of HC. However, we could not assess this relationship owing to the limited data available. Further studies are required to assess the relationship between HLA mismatching and the risk of HC.
Previous studies have reported that the risk of HC is higher in HSCT recipients who receive cells from an unrelated donor [
19,
29], which is consistent with the findings of our study. However, other studies have found that an HLA-mismatched donor is not a risk factor for HC [
5,
15]. Our analysis results indicated that receiving cells from both HLA-mismatched and unrelated donors was associated with an increased risk of HC. This may be because recipients of cells from an unrelated donor require more intensive immunosuppression therapy, which may contribute to the development of HC [
2]. Therefore, a matched-related donor is preferred to prevent the occurrence of HC in children undergoing HSCT. However, this conclusion may be unreliable owing to the limited number of studies included, and further high-quality studies are warranted to further explore the relationship between HLA-mismatched donors and HCs.
According to the different intensities of immunosuppression, the conditioning regimen was divided into two general categories: MAC and RIC. The HC risk was higher in patients who received MAC than in those who received RIC, which is consistent with the findings of several previous studies [
5,
30]. This finding can be attributed to the lower toxicity of RIC, which causes milder damage to the mucosa of the bladder and, subsequently, a lower incidence of HC. Cyclophosphamide administration has previously been reported to be associated with an increased risk of HC [
31]; however, our results indicate that it does not increase the risk of HC [
31]. This may be because most of the studies included in this analysis investigated late-onset HC, whereas cyclophosphamide is more often associated with early-onset HC [
32]. Busulfan, an alkylating agent commonly used in conditioning regimens, has previously been reported to be associated with an increased risk of HC [
6], which is consistent with the results of this meta-analysis. The increased risk of HC associated with busulfan use may be attributable to the urothelial changes caused by busulfan [
33]. The use of ATG was also associated with an increased risk of HC in this meta-analysis. This may be attributable to the higher risk of viral infections in patients who receive this drug [
34]. Similarly, Fu et al. [
35] suggested that a higher dose of ATG may be associated with an increased risk of HC in haploidentical HSCT recipients. TBI is another key component of conditioning for HSCT. Several previous studies have not found an association between TBI and the risk of HC [
12,
18,
27], which is consistent with the results of our analysis.
GVHD is another common complication in patients undergoing HSCT, which limits the use of HSCT and is a leading cause of morbidity and mortality [
36]. Acute GVHD has been reported to be associated with an increased risk of HC [
5]. This may be attributable to the immunosuppressive therapy used for treating acute GVHD, which increases the risk of viral infection and subsequently causes the occurrence of HC. Alternatively, HC may be a manifestation of GVHD, which generally involves multiple systems [
37]. However, the pooled results of our meta-analysis indicate that acute GVHD does not increase the risk of HC. However, this finding may be unreliable owing to the limited number of included studies and the significant heterogeneity between studies. Several previous studies have explored the relationship between chronic GVHD and HC but have found no association [
9,
19], which is consistent with our results. However, this finding may be unreliable owing to the limited data available in the included studies and the relatively high heterogeneity between studies.
Our analysis indicated that CMV reactivation was a risk factor for HC in HSCT recipients. Zhang et al. [
38] reported that the incidence rate of HC was higher in patients with CMV infection than in those without CMV infection. This may be because CMV infection causes impaired T-cell immunity and weak T-cell responses, which contribute to an increased risk of BKV infection and, consequently, the occurrence of HC [
39]. However, this finding may be unreliable owing to the small number of studies included in the analysis. Further studies with large sample sizes are warranted to further explore the relationship between CMV reactivation and HC.
Owing to the limited data available in the included studies, we could not analyze the risk factors for the severity of HC. However, Leung et al. [
40] reported that a 3-log increase in the BKV load in adult patients undergoing HSCT was an independent risk factor for severe HC. Another recently published study showed that BKV infection and multiple infections were predictors of HC severity in children undergoing HSCT [
41]. Ost et al. [
37] reported that the severity of acute GVHD was related to the severity of HC. BKV infection and GVHD may play key roles in the development of HC and cause more severe disease. Therefore, managing BKV infection and GVHD is important for preventing HC in children undergoing HSCT.
Other potential risk factors reported in previous studies include age and T-cell depletion. However, owing to the limited data available and the lack of standardization of reporting, these factors were not investigated in this meta-analysis. Previous studies have reported that in pediatric HSCT recipients, the incidence of HC is lower in younger children [
6,
11,
42]. This may be attributable to the lower incidence of viral infection in younger children. Regarding T-cell depletion, a previous study found that patients with T-cell depletion had a higher risk of developing HC [
9]. This may be because T-cell depletion results in substantial immunosuppression, which increases the risk of viral infection and HC. Further high-quality prospective studies are warranted to further explore the relationship between these factors and the development of HC.
Therapeutic options for HC are diverse and differ according to the disease severity and the presence of viral infection. Preventive therapy and conservative and supportive therapy should be used as the first steps in non-severe cases. In patients with more severe HC, continuous bladder irrigation and intravesical therapy may be considered. Moreover, in very severe cases, surgical procedures may be required to remove clots and stop bleeding [
8]. Cidofovir, an antiviral drug, has high specificity against the BKV and has been shown to be effective in preventing and treating BKV-HC [
43,
44]. Other antiviral drugs, such as leflunomide, have also been reported to be effective against BKV-HC [
45,
46]. Virus-specific T cells (VSTs), which are derived from a patient’s stem cell donor (donor-derived) or a third-party donor, are a safe and effective therapy for viral infections in children undergoing HSCT [
47,
48]. In a cohort of 56 patients undergoing HSCT, gross hematuria was completely resolved in 13 of 14 patients with BKV-HC who received VST infusion for six weeks, whereas four of the five patients who did not receive VST infusion developed disease progression [
49]. Another clinical trial conducted by Olson et al. [
50] reported that the clinical response of patients with HC who received VST was better than that of historical controls. These findings indicate that VSTs may be a feasible option for treating HC, especially BKV-HC, in patients undergoing HSCT. Other treatment strategies, such as estrogen, hyperbaric oxygen therapy, and mesenchymal stromal cells, have also been reported to be effective and can be used as alternative strategies.
This meta-analysis has several limitations. First, combining prospective and retrospective studies may result in potential bias. Second, owing to the limited number of included studies, it was not possible to perform multivariate or subgroup analyses. Third, the large time span of included studies and different transplantation protocols may limit the generalizability of our findings. Fourth, the criteria for the diagnosis of HC differed in different studies, which may contribute to bias.
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