Risk factor analysis of hemorrhagic cystitis (HC) after allogeneic hematopoietic stem cell transplantation in children with severe thalassemia

doi:10.21203/rs.3.rs-2622752/v1

Purpose

To explore the possible risk factors for hemorrhagic cystitis (HC).

Methods

We retrospectively analyzed 152 cases of severe thalassemia in allogeneic hematopoietic stem cell transplantation from January 2011 to December 2021 in our hospital. Evaluating incidence rate、occurrence time and duration of HC. Analysis of age,the degree of blood type compatibility, HLA matching configuration,the amount of CD34 + cells, Cyclosporin A concentration, Whether complications such as infection, GvHD and other complications were combined, Classification of risk of thalassemia (pretransplant assessment), different types of transplantation, in which that degree of the iron overload before and aft transplantation is related to the occurrence of HC.

Results

The results showed that the incidence of HC after transplantation was 27.63%.The median time for the occurrence of HC is 21d, and the duration is 11d.Only one cases were early onset HC (EOHC), and the other 41 were delayed HC (LOHC).The incidence rate of 4 years of age or older children with HC (33.70%) is higher than the age < 4 years old children (16.67%).The difference was statistically significant (P = 0.021).

Conclusion

Iron overload may have an impact on the occurrence of HC.As the level of SF increased, the incidence of HC increased significantly.iron overload may have an effect on HC occurrence.With the increase of SF, the incidence of HC increased significantly, especially when SF was greater than 7969.84.Children younger than 4 years of age were more likely to deelop HC after transplantation.

children with severe thalassaemia

allogeneic hematopoietic stem cell transplantation

hemorrhagic cystitis

Hemorrhagic cystitis (HC) is another common and important complication of the urinary system after hematopoietic stem cell transplantation, resulting in prolonged hospital stay, decreased quality of life, and even renal function[1]. Severe bladder hemorrhage, blockage of clots leads to obstruction of the urinary tract.It can cause obstructive renal failure and endanger life. HC has a high incidence of clinical morbidity, but the pathogenesis and mechanism are unknown. The relevant factors of the research report of each transplantation center are different[2–3]. In this paper, 152 cases of allogeneic hematopoietic stem cell transplantation in children with heavy Mediterranean anemia (Allo - HSCT) after the clinical characteristics of HC, and we analysis of related risk factors from factors such as the disease characteristics of thalassemia.

1.1 Research objects:

From January 2011 to December 2021,152 patients under the age of 15 years old with hematopoietic stem cell transplantation in the first affiliated hospital of guang xi medical university were treated with severe thalassemia. Median age is 4 years (1–15 years),among them,108 males and 44 females. The labor characteristics of children are shown in table 1.

1.2 Pre-transplant Risk Assessment:

Pesara risk classification for thalassemia, which is used internationally, requires liver biopsy to understand liver fibrosis. It is difficult to carry out in the country, so according to Italy standard indexing methods. The Affiliated Hospital of Southern Medical University developed a suitable for China's risk classification standard of thalassemia before transplantation. We use the standard from southern hospital to grade the risk of thalanemic children. It is specific as shown in table 2.

Base the poor classification standard, selected 152 cases of children with poor before transplantation of risk classification is divided into Ⅰ degrees (68 cases), Ⅱ degrees (69 cases), Ⅲ degrees (15 cases).

1.3 evaluation of iron overload degree after transplantation.

According to the monitoring after transplantation of serum ferritin (SF), judgment in children with iron overload, and refer to the south hospital transplantation before risk classification of SF, the judgment standard cases will be divided into three groups: Iron overload groupⅠdegrees SF < 3000µg/L(n = 18);Iron overload groupⅡdegrees SF: 3000µg/L -5000µg/L(n = 37)༛Iron overload group Ⅲ degrees SF > 5000µg/L(n = 97).

1.4 preparation before transplantation.

1.4.1 high frequency blood transfusion before transplantation.

According to the specific situation of the children, 45 days before transplantation, the patients were given a moderate amount of blood transfusion with high frequency to Keep hemoglobin above 120-140g/L. The aim is to feed back the high proliferative state of the bone marrow by continuous peripheral blood hyperhemoglobin. Meanwhile, it can improve cardiac enlargement, hepatosplenomegaly and hypersplenism and other conditions that the anemia caused by.

1.4.2 Bone Marrow And Immunosuppressive Therapy

In order to suppress and reduce the high proliferative state of bone marrow, reduce the burden of pretreatment, increase the chance of implantation and reduce the rejection after transplantation. one month before transplantation, oral hydroxyurea (20-30mg/kg/day) was given to the children. From pretreatment to the day before the transplantation, the allopurinol tablets were taken orally to prevent the damage of renal tubule caused by chemotherapy drugs.

1.5 Pretreatment Scheme

The pretreatment scheme using busulfan (BU) + cyclophosphamide (CY) + fludarabine (FLU) + antithymocyte globulin (rabbit) (ATG). The specific usage is as follows:

Busulfan(Busulfan,BU):dose16mg/kg. It is administered intravenously for four days.༈-9dཞ-6d)

Fludarabine (FLU):dose 150mg/M². It is administered intravenously for three days.(-11dཞ-9d)

Cyclophosphate (CY):dose 200mg/kg. It is administered intravenously for four days.(-5dཞ-2d)

Antihuman thymus immunoglobulin (ATG):dose 6-10mg/kg. Divide it into four intravenous drip.

1.6 Diagnosis and prevention of hemorrhagic cystitis (HC).

After the transplantation, the children appear to be in a microscopic or macroscopic hematuria, with or without urinary frequency, urgency, urinary pain and other bladder irritation symptoms. Cystoscopy showed local or diffuse bleeding and inflammatory changes in the bladder mucosa. Exclusion of bacterial infection, drug-induced hematuria and other, such as disseminated intravascular coagulation, multiple organ dysfunction or sepsis.It can be diagnosed. According to the degree of hematuria, the clinical classification of HC is as follows:

Ⅰ degrees: Hematuria under microscope

Ⅱ degrees: Gross hematuria

Ⅲ degrees: Naked eye hematuria with clot

Ⅳ degrees: Clot obstruction urethra, this should take measures to remove blood clots or require surgical intervention.

According to the occurrence time, there are two types of early hairstyles HC (EOHC) and late hair HC (LOHC). EOHC occurs more frequently in pretreatment and within 72 hours, and LOHC occurs more than 2 weeks after transplantation.

Prevention of hemorrhagic cystitis (HC): To give full hydration alkalinization, diuresis, and drop of the sodium hydrochloride. With Intermittenting diuresis, encouraging urination, strengthening support therapy, injecting of irradiated red blood cells, platelets and gamma globulin, and monitoring urine routine.

1.6 statistical methods

We use SPSS 20.0 statistical software. Single factor analysis use variance analysis. A significant single factor analysis is performed using multifactor non-conditional Logistic regression analysis. There were significant differences in the risk level of the pretransplant, the different types of transplantation and the different degree of iron overload after transplantation(P < 0.05 has statistical significance), and the Bonferroni test level adjustment method was adopted with compared to each other.

3.1 The incidence, time, type and classification of HC after transplantation

Of the 152 cases of thalassemia, there were 42 patients with HC. The incidence was 27.63%.The median time of occurrence of HC is 21d (Fig. 1). The duration is 11d (Fig. 2). According to the severity of the disease, 16 cases (38.10%) had mild HC (I – II degrees), and 26 cases (61.90%) were severe (Ⅲ degrees or above). In addition to 1 cases of early onset HC (EOHC) (death), the other 41 cases were delayed HC (LOHC).

3.2 Univariate analysis of risk factors of HC for continuous variable

Using the rank sum test to compare the age of the HC group and the non-HC group, the amount of CD34 + cells entered, the concentration of cyclosporine A, the pre-transplant SF level, and the neutral implantation time, etc. The results showed that there was no statistical difference between the two groups (P༞0.05). (see table 3 for details)

According to the median age, 152 Patients were divided into two groups for chi-square test. With comparing the incidence of HC in the two groups, The incidence of HC in children who were older than 4 years old (n = 60)was higher than that in children under 4 years old༈n = 61༉. X2 = 5.346, OR = 2.541, P = 0.021.

3.3 single factor analysis of HC enumeration data after transplantation.

We use the chi square test of HC after transplantation in children with thalassemia. In gender, donor sex matched/mismatched donors, matched/mismatched, ethnic (Han/Zhuang),HLA typing, cytomegalovirus infection, bacterial infection and HVOD, AKI, GvHD and other factors of HC. the incidence of HC in patients were compared. These factors were not correlated with the occurrence of HC. See table 4.

3.4 Comparison of incidence rates of HC associated to different grades of Thalassemia

Using chi-square test to lean Ⅰ degrees, Ⅱ and Ⅲ degrees of three groups of patients the incidence of HC after transplantation, the results show no difference. The results are shown in table 5.

3.5 Comparison of incidence rates of HC associated to different types of HSCT

Using chi-square test to compare the incidence of HC with different transplantation types after transplantation, the results showed no statistical significance. See table 6.

3.6.The effect of the degree of iron overload after transplantation on the occurrence of HC.

With the increase of SF level after transplantation, the incidence of HC appears to be increasing. The incidence of HC in group III (> 5000 mu g/L) was 31.96%, It was higher than that of I and II. The results were compared with the chi square test, and the results showed no statistical significance. See table 7.

According to the average value of group SF after transplantation, high ferritin group (≥ 7969.84 g/L) was higher than that in low protein group (< 7969.84 g/L)about the incidence of HC. The incidence of HC in the two groups was compared by chi-square test, and the results showed that the difference was statistically significant. As shown in table 8.

Incidence of HC after transplantation

Currently, HC diagnosis largely depends on clinical manifestations. Previous studies have reported incidence rates for HC after transplantation varying from 10–60% [4–6], which is probably because of diverse criteria and diagnosis levels of HC. Giraud [7] showed that HC occurs at 16 to 95 days after HSCT, mostly within 1 month. A multicenter large sample retrospective analysis conducted by Gargiulo and colleagues [8] revealed a median time to post-transplantation HC of 23 days, with a median duration of 20 days.

HC after HSCT is mainly LOHC (Late Onset Hemorrhagic Cystitis), while EOHC (Early Onset Hemorrhagic Cystitis) has an incidence of 5–25%. The onset peak time of LOHC was one month after neutrophil implantation, lasting from 1 week to several months, which was consistent with the outcomes reported by Yin et al [9]. The subjects in this study were children with thalassemia major, who were observed for more than 100 days after HSCT; 41 children had LOHC at 13 to 39 days with a median time of 21 days and an incidence rate of 27.63%, except for one case of EOHC that developed after two days. The patient with EOHC died while the other 41 were cured or relieved after treatment with a disease course of 3 to 62 days, averaging 11 days. Our conditioning regimen didn’t include radiotherapy, while it involved cyclophosphamide, and hydration enforcement and alkalization. In addition, the metabolic rate (drug and water/electrolytes) in children was generally faster than that of adults; thus, this study found a lower rate of HC.

Risk factors for HC after transplantation

Currently, the exact pathogenesis of HC remains unknown and may include complex interactions. Patients with conditioning regimens tend to acquire infections through blood and the urinary tract via invasive viruses and activated latent viruses, which invade the mucous membrane of the bladder, eventually leading to HC. Associations of various activated viruses, especially BK virus (BKV) infection with LOHC, have been previously reported. In 1986, Arthur et al [10] firstly reported papovavirus in the urine of patients with HC. After HSCT, about 10–25% of patients with HC were infected by BKV that, in most cases, occurred two weeks later. Furthermore, BKV amounts in the urine of patients with HC tend to be remarkably high, and the higher the BKV titer, the higher the risk of HC. Erardet and colleagues [11] showed that the risk of HC increases significantly with a plasma BKV titer above 104 copies/ml. With the continuous improvement of research methods, the link between BKV and HC after HSCT has been well confirmed [12, 13]. Meanwhile, there are many other potential risk factors for HC besides BKV, such as adenovirus (ADA)[14, 15] and cytomegalovirus (CMV)[16]. Sahu et al [17] reported one case of acute myeloid leukemia that developed adenovirus related hemorrhagic cystitis. They revealed that atypical pathogens should be considered after ruling out common disease-causing organisms.

Previous studies [18] have indicated that infection by CMV is the main risk factor for LOHC. Hu J [19] reported infection by the opportunistic polyomavirus in HSCT recipients, especially those with HCMV co-infection or a mismatched HLA transplant. Moreover, JC virus infection is associated with unexplained liver function deterioration.

In this study, the HC rate related to CMV infection was 29.8%, but not statistically significant, which was not consistent with the premise that CMV infection is a risk factor for HC occurrence. This may be due to the active treatment of CMV during the conditioning regimen stage and after transplantation in this study, which reduces the odds of subsequent CMV infection or controls potential infections. Other viruses were not assessed in the present study because of the limitations of the medical setting; thus, further clinical and lab studies are needed in the future.

Over the past few years, an increasing number of studies have pointed out that HC occurrence is related to aGvHD (acute graft-versus-host disease). Lee et al.[16] demonstrated that grade III-IV aGvHD is a high-risk factor for HC after HSCT, and also reported a relationship between cGvHD (chronic graft-versus-host disease) and HC. Hassan et al.[20] also suggested aGvHD as a risk factor for HC and pointed out that severe HC is particularly associated with aGvHD. However, contradictory opinions exist in the field. Early on, Bedi et al[21] reported that GvHD was not associated with HC, which was further confirmed by other studies[13, 22] and consistent with our findings.

Age Is Independently Associated With Hc

A cumulative HC incidence in patients older than 4 was 33.3%, while it was 16.67% in children younger than 4, which was consistent with multiple previous studies [9, 23, 24]. Particularly, in a study of hematopoietic stem cell transplantation in β- severe thalassemia, Yin [9] considered age as the main risk factor for HC, with the HC occurrence rate in children over 6 being higher than that in children younger than six years old, which corroborated our findings. This may be related to the immaturity of young children's central nervous system and urinary system. Such young children have not yet developed urination habits, and frequent urination reduces drug amounts in the bladder and irritation to the bladder mucosa, thus decreasing HC incidence. Another reason may be the relatively low viral infection rate in young children with decreased HC caused by viral infections. In adults, El-Zimaity et al [25] reported an HC occurrence rate of 40% in patients under 26, compared to 17% in those over 26 years of age. Age-related prevalence of latent viral infections might provide a possible explanation. Still, the exact causes remain uncertain. Nevertheless, the latter findings also support age as an independent factor affecting HC occurrence.

Some studies [9] have shown that HC occurrence is unrelated to the matching rate of HLA, while others [22] reported that gender and non-kin donors for HSCT are risk factors for HC. However, this remains controversial.

In this study, the following factors were not related to HC occurrence: donor gender, blood type matching status, HLA matching degree, ethnicity (Han/Zhuang), blood SF levels before transplantation, CD34 + cell amounts, and cyclosporine A levels. There were no statistically significant associations of cytomegalovirus infection, bacterial infection, AKI, GvHD, HVOD, and other complications with HC occurrence. We took active measures for GvHD prophylaxis and CMV infection, with plenty of alkalinization, hydration during HSCT, and active support treatment, which may have significantly and efficiently decreased the occurrence rate of HC.

Impact Of Thalassemia Characteristics On Hc

Rare reports are assessing the associations of HC with the risk level of thalassemia and different types of transplantation. Yaghobi et al [26] showed that patients with class II and III thalassemia had high HC incidence after transplantation, with BMT being likely a risk factor for HC. According to Yin et al [9], HC incidence was not associated with the risk levels of thalassemia and different types of transplantation. Meanwhile, some studies [22, 25] have shown that an unrelated donor is a risk factor for HC. The present study found no associations of HC with a risk level of thalassemia and different types of transplantation.

An iron overload could damage the hematopoietic function and decrease hematopoiesis; thus, affecting proliferation and apoptosis in the hematopoietic microenvironment, which in turn results in delayed graft implantation and promotes infection. Pullarkat et al [27] found that patients tend to develop GvHD and become infected at SF levels over 1000µg/L before HSCT. Some scholars, however, reported contradictory data [28, 29]. Mahindra and colleagues [28] suggested that patients with iron overload have a low incidence of GvHD. Meanwhile, Sivgin et al [30] indicated that the degree of iron overload was closely related to the incidence rates of bacterial and fungal infections. Considering the effect of iron overload on complications after transplantation, studies [31, 32] proposed that pre-transplantation SF levels over 1000 g/L could represent a key risk factor for HVOD development post-transplantation. There is a certain degree of iron overload in children with thalassemia before transplantation. After HSCT, erythrocyte infusion, which is adopted after bone marrow suppression, continually increases SF levels, thus representing a serious condition of iron overload. A previous study has shown that iron overload has a negative impact on HSCT in thalassemia patients [33].

In our study, the incidence of HC in patients with thalassemia after hematopoietic stem cell transplantation was 27.63%.HC was more likely to occur in children older than 4 years of age, compared with children younger than 4 years old. Iron overload may have an impact on HC. As the level of SF increased, the incidence of HC increased significantly. But the infection of cytomegalovirus (CMV) has no effect on the occurrence of HC. Of course, our research has limitations:our donors are basically all compatriots, and the time of observation is limited. There may be more complete and more expected results if the number of patients and various types of transplantation are enlarged.

HC

Hemorrhagic cystitis

SF

Serum ferritin

GvHD

Graft-versus-host disease

CMV

Cytomegalovirus

HSCT

Hematopoietic stem cell transplant

HLA

Human leukocyte antigen

AKI

Acute kidney injury

HVOD

Hepatic venous occlusive disease

BKV

Bakiniz virus

Acknowledgments

This work was supported in part by the Stem cell transplantation center of the First Affiliated Hospital, Guangxi Medical University. We wish to especially thank Fanyu Wu from the Second Affiliated Hospital, Chongqing Medical University, for contributions in statistics and translation work.

Conflict of interest

The authors declare no conflicts of interest.

Funding

None of authors/co-authors have finan[1]cial disclosure to declare

Availability of data and materials

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

Authorship statement

H.H.D. and Y.J.Z. gathered clinical and biological data. J.M.L ,Y.H.Q.and J.G.W. interpreted results.H.H.D. and Y.J.Z wrote first draft of the manuscript, and all authors reviewed the manuscript. All authors have read and agreed to the published version of the manuscript.

Consent for publication

Not applicable.

Ethics approval and consent to participate

The research project is in accordance with the ethical principles of“Declaration of Helsinki” and“International Ethical Guidelines for Biomedical Research Involving Human Subjects” promulgated by the Council for International Organization of Medical Sciences. The research was reviewed and approved by the Ethical Committee of The First Affiliated Hospital, Guangxi Medical University, reference number 2023-E131-01. The need for informed consent was waived by the Ethical Committee of The First Affiliated Hospital, Guangxi Medical University, because of the retrospective nature of the study.

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Table 1 Clinical characterristics of 152patients

	The number of cases	The percentage
Median age (year)	4(1-15)
male	108	71.05
female	44	28.95
Mediterranean anemia type
homozygous	28	18.42
Double heterozygote	115	75.66
mixed type	9	5.92
Nation
Han nationality	100	65.79
Zhuang nationality	39	25.66
other nationalities	13	8.55
Donor gender
consistency	69	45.39
Female for male use	54	35.53
Male for female use	29	19.08
Blood type
consistency	85	55.92
incompatibility	67	44.08
HLA matching type
consistency	146	96.05
incompatibility	6	3.95
Risk of Mediterranean anemia
classification
Ⅰ degrees	68	44.74
Ⅱ degrees	69	45.40
Ⅲ degrees	15	9.86
Transplant type
compatriots
CBT+BMT	54	35.76
CBT+PBSCT	6	3.95
BMT+PBSCT	67	44.37
BMT	4	2.65
nonaffinity
PBSCT	20	13.25
complications
GvHD	41	30.83
AKI	36	27.07
HC	42	31.58
HVOD	14	10.53

Table 2 Thalassemia major indexing standards（NF-index of categorization of NF-08-TM）

		Ferritin(μg/L)	Liver(cm/ Under the right rib)	Age(y)
Ⅰ degrees	＜3000		＜2.5	＜4
Ⅱ degrees	Do not meet low risk and high risk criteria.
Ⅲ degrees	＞5000		＞4	＞8

Table 3 Univariate analysis of risk factors of HC for continuous variable

	grouping	N	M	IQR	P
age	No HC	110	4.00	3.00	0.94
age	HC	42	5.00	3.00	0.94
CD34 +	No HC	110	8.57	18.93	0.185
CD34 +	HC	42	16.42	18.57	0.185
CsA	No HC	110	149.20	141.25	0.905
CsA	HC	42	160.45	140.20	0.905
SF	No HC	110	2647.49	1925.26	0.239
SF	HC	42	2776.06	1828.82	0.239
Neutrophil insertion time.	No HC	94	11	3.75	0.193
Neutrophil insertion time.	HC	34	11	2.00	0.193

Table 4 Univariate analysis of risk factors of HC

influence factor	grouping	No HC(%)	HC(%)	X²	OR	P
gender	female	31(70.45)	13(29.55)	0.113	0.875	0.736
	male	79(73.15)	29(26.85)
Donor gender	incompatibility	56(67.47)	27(32.53)	2.194	0.576	0.139
	consistency	54(78.26)	15(21.74)
Donor blood type	incompatibility	44(70.97)	18(29.03)	0.103	0.889	0.749
	consistency	66(73.33)	24(26.67)
HLA coincide	incompatibility	4(66.67)	2(33.33)	0.706	2.725	0.401
	consistency	107(73.29)	39(26.71)
Ethnic	Han	73(73.00)	27(27.00)	0.027	0.932	0.871
	Zhuang	29(74.36)	10(25.64)
HVOD	No	102(73.91)	36(26.09)	1.047	2.125	0.306
	Yes	8(57.14)	6(42.86)
AKI	No	81(69.83)	35(30.17)	1.581	0.559	0.209
	Yes	29(80.56)	7(19.44)
GvHD	No	84(75.67)	27(24.33)	2.251	1.795	0.134
	Yes	26(63.41)	15(36.59)
Bacterial infection	No	53(67.95)	25(32.05)	2.097	0.585	0.148
	Yes	58(78.38)	16(21.62)
CMV infection	No	56(73.68)	20(26.32)	0.132	1.141	0.717
	Yes	54(71.05)	22(28.95)

Table 5 Comparison of incidence rates of HC associated to different grades of thalassemia

Level of risk for poverty	No HC(n=110)		HC(n=42)		X²	P
Level of risk for poverty	The number of cases	%	The number of cases	%	X²	P
I degrees	55	80.88	13	19.12	4.315	0.116
II degrees	45	65.22	24	34.78
III degrees	11	73.33	4	26.67

Table 6 Comparison of incidence rates of HC associated to different types of HSCT

Transplant type	No HC(n=110)		HC(n=42)		X²	P
Transplant type	The number of cases	%	The number of cases	%	X²	P
S-CBT+BMT	36	65.55	19	34.45	0.316	4.728
S-CBT+PBSCT	5	83.33	1	16.67
S-BMT+PBSCT	51	76.12	16	23.88
Unrelated PBSCT	14	73.68	5	26.32
S-BMT	4	100.0	0	0.00

Table 7 Comparison of incidence rates of HC associated to different levels of iron overload after HSCT

The levels of SF (μg/L)	No HC(n=110)		HC(n=42)		X²	P
The levels of SF (μg/L)	The number of cases	%	The number of cases	%	X²	P
＜3000	14	77.78	4	22.22	2.576	0.276
3000-5000	30	81.08	7	18.91
＞5000	66	68.04	31	31.96

Table 8 Incidence rates of HC associated to different levels of SF after HSCT

Iron overload grouping	No HC		HC		X²	OR	P
	The number of cases	%	The number of cases	%
Low ferritin group	78	79.59	20	20.41	7.198	2.681	0.007
High ferritin group	32	59.26	22	40.47

No competing interests reported.

Risk factor analysis of hemorrhagic cystitis (HC) after allogeneic hematopoietic stem cell transplantation in children with severe thalassemia

Status:

Version 1

Abstract

Figures

Introduction

Methods

1.1 Research objects:

1.2 Pre-transplant Risk Assessment:

1.4.2 Bone Marrow And Immunosuppressive Therapy

1.5 Pretreatment Scheme

1.6 statistical methods

Results

3.1 The incidence, time, type and classification of HC after transplantation

3.2 Univariate analysis of risk factors of HC for continuous variable

3.4 Comparison of incidence rates of HC associated to different grades of Thalassemia

3.5 Comparison of incidence rates of HC associated to different types of HSCT

Discussion

Incidence of HC after transplantation

Risk factors for HC after transplantation

Age Is Independently Associated With Hc

Impact Of Thalassemia Characteristics On Hc

Conclusion

Abbreviations

Declarations

References

Tables

Additional Declarations

Status:

Version 1