|Year : 2022 | Volume
| Issue : 2 | Page : 174-179
Analysis of hemorrhagic cystitis and BK viremia in children after hematopoietic stem cell transplantation
Ayça Koca Yozgat1, Ikbal Ok Bozkaya1, Tekin Aksu1, Pamir Isik1, Mehtap Kanbur1, Tugrul Tiryaki2, Nese Yarali1, Namik Yasar Özbek1
1 Department of Pediatric Hematology-Oncology, Bone Marrow Transplantation Unit, Ankara Diskapi Child Health and Diseases Hematology Oncology Training and Research Hospital, University of Health Sciences, Ankara, Turkey
2 Department of Pediatric Urology, Ankara Diskapi Child Health and Diseases Hematology Oncology Training and Research Hospital, University of Health Sciences, Ankara, Turkey
|Date of Submission||09-Sep-2021|
|Date of Acceptance||18-Jan-2022|
|Date of Web Publication||30-Jun-2022|
Dr. Ayça Koca Yozgat
Department of Pediatric Hematology and Oncology, Ankara City Hospital of Ankara Health Sciences University, Ankara
Source of Support: None, Conflict of Interest: None
Purpose: Hemorrhagic cystitis (HC) which occurs in 9%–31% of recipients after hematopoietic stem cell transplantation (HSCT) is an important cause of morbidity and mortality. Various treatment approaches have been applied for such as conservative treatments (hydration, analgesic agents, antibiotics), intravesical treatments (bladder irrigation, hyaluronic acid, and prostaglandin E), intravenous or intravesical antiviral agents, hyperbaric oxygen, and surgical treatments. Materials and Methods: This retrospective study included two hundred thirty-three children who underwent HSCT in Pediatric Bone Marrow Transplantation unit between April 2010 and June 2017. Results: Ten patients (4.2%) developed HC. The mean age of patients was 12.8 years and the mean duration of the onset of HC was 20 days. Urine and blood BK polyomavirus were positive in nine and four patients, respectively. Six patients received intravesical hyaluronic acid, three patients received intravesical prostaglandin E, three patients received intravenous ganciclovir, two patients received intravenous and/or intravesical cidofovir and hyperbaric oxygen treatment. The mean time of recovery from hematuria was 43 days. This study showed that the BK polyomavirus has an important role in the development of HC in HSCT patients, as in harmony with the literature. HC has been successfully treated in eight patients with supportive measures and/or intravesical hyaluronic acid. Conclusions: BK polyomavirus plays an important role in the development of HC pediatric patients. Intravesical hyaluronic acid, besides supportive measures, was effective for the treatment of HC and hyperbaric oxygen may be reserved for refractory cases.
Keywords: BK polyomavirus, hematopoietic stem cell transplantation, hemorrhagic cystitis
|How to cite this article:|
Yozgat AK, Bozkaya IO, Aksu T, Isik P, Kanbur M, Tiryaki T, Yarali N, Özbek NY. Analysis of hemorrhagic cystitis and BK viremia in children after hematopoietic stem cell transplantation. Indian J Transplant 2022;16:174-9
|How to cite this URL:|
Yozgat AK, Bozkaya IO, Aksu T, Isik P, Kanbur M, Tiryaki T, Yarali N, Özbek NY. Analysis of hemorrhagic cystitis and BK viremia in children after hematopoietic stem cell transplantation. Indian J Transplant [serial online] 2022 [cited 2022 Sep 25];16:174-9. Available from: https://www.ijtonline.in/text.asp?2022/16/2/174/349348
| Introduction|| |
Hemorrhagic cystitis (HC) which occurs in 9%–31% of recipients after hematopoietic stem cell transplantation (HSCT) is a common complication and an important cause of morbidity and mortality. Ultimately, it may cause urinary tract obstruction that leads to renal failure and death. Early-onset HC which occurs within 1 week after HSCT mostly develops due to the regimen-related toxicity, while late-onset HC after engraftment is usually caused by viruses. In the early period, chemotherapeutic agents such as cyclophosphamide, busulfan, etoposide, and radiation therapy could directly cause urinary epithelium damage. In the late period, viral infections, especially BK Polyomavirus (BKPyV), adenovirus, cytomegalovirus (CMV), and graft-versus-host disease (GvHD) are the most common causes. BKPyV DNA is detected in the urine of 50%–100% of patients with late-onset HC, suggesting that in the majority of such HC cases, the virus is implicated. Several risk factors for late-onset HC have been described including conditioning regimens, positive BKPyV viral loads in the urine and/or blood, acute GvHD, transplantation with mismatched human leukocyte antigen (HLA), reactivation of CMV infection, delayed immune reconstitution. Various treatment approaches have been applied for such as conservative treatments (hydration, analgesic agents, anticholinergics, antibiotics), intravesical treatments (bladder irrigation, hyaluronic acid, and prostaglandin E), intravenous or intravesical antiviral agents, steroids, conjugated estrogen, hyperbaric oxygen, and eventually surgical treatments.,,, It is important to maintain platelets above 50 × 109/L. Nonsevere cases of BKPyV associated HC usually resolve spontaneously over 2 weeks with supportive care only. In severe cases with significant bleeding and urinary tract obstruction, cystoscopy and catheterization must be performed to preserve the function of the kidneys. In profuse bleeding, and life-threatening conditions, surgical intervention must be considered.
The aim of this study was to determine the incidence, clinical course, and outcome of HC in pediatric patients after allogeneic hematopoietic cell transplantation.
| Materials and Methods|| |
The study included all children who underwent first and/or second allogeneic HSCT at Ankara Dışkapı Child Health and Diseases Hematology Oncology Training and Research Hospital Pediatric Bone Marrow Transplantation Unit between April 2010 and June 2017. Data regarding the patients' characteristics and treatment regimens were retrospectively collected using the institutional computerized database. Baseline demographic and transplantation data were age, sex, underlying disease, HLA compatibility, donor type, conditioning regimen, stem cell source, GvHD prophylaxis, the onset of HC, and survival at last follow-up.
Diagnosis of hemorrhagic cystitis
HC was defined as the presence of sustained hematuria and urinary symptoms after the beginning of conditioning therapy in the absence of gynecological-related bleeding, generalized bleeding diathesis, and urinary tract infection. The date of onset of HC was defined as the 1st day of symptoms or laboratory evidence appearing after HSCT. HC was clinically graded as follows: grade 1 is microscopic HC with functional urinary symptoms; Grade 2 is macroscopic HC without blood clots; Grade 3 is HC with clots; Grade 4 is HC with nephropathy or when an endovesical intervention is required. Early onset for HC occuring during the first 7-day post-HSCT and late-onset occuring after 1 week. For patients who had urinary symptoms or gross hematuria, blood and urine BKPyV and blood CMV testing by a quantitative polymerase chain reaction (PCR)-based method were performed to identify the presence of the virus.
Patients were treated with three regimens as following: reduced toxicity regimens consisted mainly of fludarabine (160 mg/m2) and treosulfan (36–42 mg/kg) with thiotepa (10 mg/kg), cyclophosphamide (120 mg/kg), or melphalan (140 mg/m2); reduced intensity regimen consisted fludarabine with either melphalan or low nonmyeloablative doses of busulfan (2 mg/kg); myeloablative conditioning regimen consisted myeloablative doses (12.8–19.6 mg/kg) of busulfan or on total body irradiation at a median dose of 12 Gy. BKV viruria was defined if ≥500 copies/mL were detected by PCR at any time point. High BKV viruria was defined if ≥1 × 107 copies/mL were detected, without threshold for viremia.
All patients diagnosed with HC received supportive treatment, including hydration with normal saline, forced diuresis, analgesics, and ciprofloxacin. Urinary catheterization and bladder irrigation, intravesical hyaluronic acid, and prostaglandin E were considered for patients who had no response to supportive care. Patients who did not response to supportive treatment were given intravesical hyaluronic acid first, and if there was no response intravesical prostaglandin E was given. Gancyclovir and cidofovir treatment were considered for patients whose urine/blood BKPyV or CMV are positive.
Comparative variables were reported as mean and range. All analyses were conducted using SPSS version 21 (SPSS Inc., Chicago, IL, United States).
The patient consent has been taken for participation in the study and for publication of clinical details and images. Patients understand that the names and initials would not be published, and all standard protocols will be followed to conceal their identity.
Ankara Dışkapı Child Heath and Diseases Hematology Oncology Training and Research Hospital Lokal Ethics Committee, 2019, 2019/048. The study was performed according to the guidelines in Declaration of Helsinki.
| Results|| |
Two hundred thirty-three children who underwent HSCT in our unit between April 2010 and June 2017 have been investigated. Ninety-four percentage of children have undergone matched sibling/family donor transplantation. Among them, ten patients (4.2%) developed HC (mean age 12.8 years [9–16]; male/female ratio 3/7). Among ten patients, eight patients have undergone HSCT from full-matched sibling or family member donors, except 2 (Cases 6, 9) who had HSCT from 7/10 HLA matched family donors. All patients who received a cyclophosphamide regimen were given mesna prophylaxis.
The mean duration of the onset of HC was 20 days (2–44) for eight patients excluding two patients who developed HC at 80 days and 16 months after HSCT. Urine adenovirus was negative in all patients.
Urine and blood BKPyV were positive in nine and four patients, respectively. No patient was positive for BKV viremia at baseline (admission for HSCT), and the median time to the first positive BKPyV DNA value on urine was 8 days (range, 1–78 days), whereas the median time to the first BKPyV DNA value >107 on plasma was 13 days (range, 5–92 days). The demographic characteristics of the patients with HC are presented in [Table 1].
All of our patients received hydration and ciprofloxacin as initial treatment. Six patients received intravesical hyaluronic acid (HA; 2–12 times), three patients received intravesical prostaglandin E (2 times). Intravesical HA was used as the first-line treatment in 5 of them (Case 6, 7, 8, 9, 10). After intravesical HA treatment, hematuria resolved in Cases 6, 8, 9. Two patients (Case 7 and 10) did not respond to HA treatment and subsequently, intravesical prostaglandin E treatment was given to these two patients (Case 7 and 10) without improvement. Prostaglandin E treatment was given as first-line treatment in Case 2 on day + 34. However, she eventually died of gastrointestinal GvHD on day + 44 without further treatment. The meantime of recovery from hematuria in patients was 43 days (7–100) except for the 15-year-old patient (Case 10) who died of HC and GvHD.
Three patients received intravenous ganciclovir if their CMV DNA copies were >1.000/mL. Two patients received intravenous and/or intravesical cidofovir and hyperbaric oxygen treatment (Cases 7 and 10). Intravenous cidofovir (5 mg/kg) with probenecid (3 + 1 g or 1.5 + 0.5 g orally depending on body weight and/or age) was used once a week until the absence of clinical symptoms or virus negativity, whichever occurred first. Intravesicular cidofovir at the dose of 5 mg/kg/week was used in case of very severe HC, where intravenous cidofovir was not efficient enough. While renal failure was not observed in BKPyV positive patients before the treatment, the renal functions of the patients were impaired after cidofovir treatment. While the glomerular filtration rate of the patients was above 100 before treatment, it decreased to 72 and 30, respectively, after cidofovir treatment. Renal failure was developed in patient 10 and needed dialysis.
One patient received antibiotic treatment after obtaining ESBL (+) Escherichia Coli in urine culture (Case 3). No signs of microbial growth observed in the other patients' cultures. Here, two refractory HC cases were reported in detail.
A 16-year-old girl who underwent HSCT for thalassemia major from her full-matched sibling developed painful urination and microscopic hematuria at day + 13. She received ganciclovir for 28 days after obtaining positive CMV-PCR (9 × 103copies/ml) in blood until it decreased to 147 copies/ml. At this time, BKPyV was positive both in blood and urine. Both intravesical (1 mg/kg, 2 times) and iv cidofovir (1 mg/kg, twice a week) were given to treat BKPyV. Deterioration of renal function manifested as the rise of serum creatinine from 0,52 to 1.16 mg/dl and moderate pancytopenia have been observed as the side effects of cidofovir. Urine BKPyV copy decreased from 19 × 108‒5 × 106 copies/ml with this treatment. In her cystoscopy, due to excessive bleeding, the bladder mucosa could not be evaluated clearly, the active bleeding focus could not be detected. As she had ongoing symptoms, she received intravesical HA every other day (60 mg, 20 times), intravesical prostaglandin E (2 times), and recombinant factor VIIa for 2 days (60 mcgr/kg, at 2-h intervals). She failed to respond to all the treatments. After the second session of hyperbaric oxygen treatment started at day + 85, gross hematuria disappeared. She continued to receive hyperbaric oxygen twice a week for 20 sessions and HC resolved at + 100 days. She is well after 22 months of HSCT.
A 15-year-old girl received HSCT from an HLA identical (10/10 matched) cousin for aplastic anemia, myelodysplastic syndrome, and paroxysmal nocturnal hemoglobinuria. Although she was under cyclosporine treatment, acute skin, oral mucosa, gastrointestinal, and liver GvHD developed 60 days after HSCT. Methylprednisolone was started with 5 mg/kg/dose and mycophenolate mofetil added to cyclosporine treatment. She developed HC symptoms at day + 80. Bladder ultrasound imaging revealed a 7 cm × 5 cm hematoma. In her cystoscopic intervention, there were several bleeding areas in the bladder mucosa. She received bladder irrigation and intravesical HA two to three times a week (60 mg for 12 times) without response. Thereafter, hyperbaric oxygen treatment started and continued to 26 sessions, but again without response. BKPyV was found to be positive both in blood and urine at this time and iv cidofovir (1–3 mg/kg, once a week) was added to the treatment and applied 4 times. At the same time, recombinant factor VIIa was given 24 times (60 mcgr/kg, 6-h intervals, 6 days). With this treatment, hematuria was resolved for a short time. In addition, prostaglandin therapy was added at day + 127 without success. Thereafter, she received intravesical irrigation with aluminum. Her symptoms were alleviated for 5 days after the first dose but recurred and did not respond to the second dose of aluminum. Ultimately, after all, treatment her renal function was impaired and dialysis treatment has been started. She eventually died of renal failure, HC, and GvHD 164 days after HSCT.
| Discussion|| |
Due to the increased number of HSCT in recent years, the frequency of HC has increased. Possible risk factors associated with HC are mismatched transplantation, myeloablative conditioning, use of cyclophosphamide and busulfan, GvHD, and viral infection, especially with BKPyV. Recent literature revealed viral-induced HC frequency between 11% and 30%., In our experience, the incidence of HC was 4.2%. We attributed this low frequency to our center's donor choice which is mostly from full matched related donors. However, 2 of our patients (Cases 6, 9) who had HSCT from 7/10 HLA matched donors we were able to treated HC. Whereas two patients who had severe HC (Cases 7, 10) have been transplanted from full matched donors. A study that includes more patients who transplanted from different types of donors is necessary to conclude if the donor type is a significant adverse event for the development of HC or its severity.
All patients received supportive treatment including hydration with saline, analgesics, and ciprofloxacin. For patients who had no response to supportive care, we preferred intravesical HA in five patients as the first-line treatment and it was successful in 3 of them. In a study by Miodosky et al., complete remission was achieved in five out of seven patients, and one patient had a partial response. In addition, Cipe et al. had achieved a complete response with intravesical HA treatment in a late-onset severe HC case. Furthermore, intravesical prostaglandin E has been shown to be effective in HC treatment. Intravesical treatment seems to be promising in patients with HC, yet so many consequences concerning the number and intervals of administration need further studies.
A recent study revealed 12 patients who had positive urine BKPyV. Among them, 11 had received iv cidofovir, and one patient had received both intravesical and iv cidofovir. Decreased BKPyV viral load has been observed in 11 patients and all recovered from HC. Another study observed HC in 14 of 74 patients who had HSCT (19%). Positive urine BKPyV was found in 79% of them. Three children required cystoscopy, intravesical pentosan polysulfate, heparin, granulocyte-macrophage colony-stimulating factor, and iv cidofovir treatments. The mean duration of HC was 76 days. Only one patient died from respiratory failure and sepsis. We detected that BKPyV was positive in nine patients (90%) in accordance with this literature. One of our patients received iv (Case 10) cidofovir and died of HC and GvHD. Another patient received iv and intravesical cidofovir (case 7) who failed to respond to cidofovir treatment but well responded to hyperbaric oxygen treatment. Gorczynska et al. showed that a clinical and a virological response, determined by quantitative PCR on urine, was being observed in pediatric patients treated with cidofovir. One issue still debated is the optimal dosage of cidofovir. Bernhoff et al. found that a concentration of cidofovir of 40 mg/mL reduced the BKPyV load by an average of 90%. At the same concentration, cidofovir determined a cell toxicity by reducing DNA replication and metabolic activity. Cidofovir treatment has been applied in patients who had HC due to BKPyV, however, the response rate is not certain. Prospective studies are needed to reduce the uncertainty on this topic and give more solid evidence of the role of cidofovir in the treatment of BKPyV HC.
Hyperbaric oxygen has been utilized as primary or adjunctive therapy for several medical conditions where tissue damage is triggered by hypoxic injury. Urbaniak-Kujda et al. evaluated five patients after allogeneic HSCT from a matched unrelated donor with HC. All patients received hyperbaric oxygen treatment 5 days per week and a complete response was achieved in all the patients after a mean of 13 sessions. Another report presented a case of a 32-year-old woman who had cord blood transplantation and developed severe BKPyV HC on day 24. In spite of supportive therapies, macroscopic hematuria persisted for over a month. Hyperbaric oxygen therapy was started on day 64 and macroscopic and microscopic hematuria was resolved within 2 weeks as is Case 7. In our study, we preferred hyperbaric oxygen for refractory cases (case no 7, 10) with a regimen 2 days per week. In Case no 7, gross hematuria disappeared after the second session of therapy, patient 10 did not respond to the extended hyperbaric oxygen therapy and eventually died from GvHD while HC continues. Hyperbaric oxygen is a well-known treatment, however, there is no conclusion when to start the treatment. In these patients, this treatment modality was reserved in refractory cases. Whether the early use is more beneficial in need of further studies.
The recombinant clotting factor concentrates, including factors XIII and VII, has been described in case reports in the treatment of HC. The authors have suggested that clotting factors facilitate the mucosal recovery through stabilization of the fibrin clot and promote fibroblast proliferation and collagen synthesis. In HC treatment their role is restricted by limited availability, high cost and doubtful efficacy.
Intravesical aluminum application also causes the precipitation of cellular proteins that have a hemostatic effect on bladder mucosa. Its use in BKPyV related HC has been inspired by its efficacy in radiation-induced HC cases. Neurological complications may arise from the systemic absorption of alum.
| Conclusions|| |
In conclusion, the management of HC among HSCT recipients is a challenging task for clinicians. Development of this significant complication poses a potential threat to the survival and successful outcome of HSCT among affected patients. We found that BKPyV has an important role in the development of HC in HSCT patients, as in harmony with the literature., HC has been successfully treated in eight patients with supportive measures and/or intravesical HA. We believe intravesical HA besides supportive measures was effective and hyperbaric oxygen may be reserved for refractory cases.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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