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Original article

BK polyomavirus as the cause of hemorrhagic cystitis in patients treated with allogeneic stem cell transplantation

Stefan Stanković1, Irena Đunić1

ABSTRACT

Introduction: BK polyomavirus is a double-stranded DNA virus from the Polyomaviridae family. According to DNA sequences, this virus can be classified into six genotypes. In hematological patients enrolled in allogeneic hematopoietic stem cell transplantation (HSCT) programs, it can lead to hemorrhagic cystitis.

Aim: The aim of this study is calculating the prevalence of BK polyomavirus PCR (polymerase chain reaction) positivity in the blood and urine of patients involved in allogeneic HSCT, determining the predictive factors for clinical presentation of BK polyomavirus-associated hemorrhagic cystitis, as well as determining its effects on overall survival (OS) of the patients.

Materials and methods: This retrospective cohort study enrolled 42 patients from the Clinic of Hematology of the University Clinical Center of Serbia. The presence of the virus in blood and urine was determined by the PCR method. The survival rate of the patients in relation to hemorrhagic cystitis was calculated with the Kaplan-Meier method and comparison was performed with the log-rank test.

Results: A positive PCR result in the blood was found in 97.6% of the subjects, while urine tested positive in 100% of patients. The estimated survival time in patients without hemorrhagic cystitis was 44.357 months, while the group with the clinical presentation of hemorrhagic cystitis had an estimated survival time of 17.395 months. Based on the log-rank test, we found a significant difference in survival between those groups of patients (p = 0.049). With regards to leukocyte engraftment day, patients engrafted after D+14, had a higher frequency of hemorrhagic cystitis (p = 0.037).

Conclusion: BK polyomavirus-associated hemorrhagic cystitis is a common complication of treatment in patients suffering from hematological malignancies who are enrolled in an alo-HSCT program, and has a significant impact on OS.


INTRODUCTION

BK polyomavirus is a double-stranded DNA virus from the Polyomaviridae family. Based on the DNA sequences, the virus can be classified into six genotypes. The most frequent genotype is type I (80%), followed by type IV (15%) [1]. The virus is ubiquitous, and it is believed that, in 90% of the population, primo-infection occurs in the preschool period. After primo-infection, the virus remains latent in the renal tubule cells and in the epithelium of the urinary bladder, where it can become reactivated when the body is in a state of immunosuppression, causing viremia and producing different forms of clinical presentation. The male sex, age, and high doses of immunosuppressive therapy are the most significant risk factors for the reactivation of this virus.

During reactivation, kidneys are the organs most commonly affected – nephropathy develops in patients with a kidney transplant [2], followed by the urinary bladder, with clinical presentation of hemorrhagic cystitis in patients enrolled in the program of allogeneic bone marrow transplantation. There have been cases of infection recorded, following heart, liver, and lung transplantation [3],[4],[5], as well as a case of BK viral infection with multiorgan dysfunction in a child with a transplanted heart [6].

In the world, the incidence of the development of hemorrhagic cystitis following allogeneic bone marrow transplantation (allogeneic hematopoietic stem cell transplantation – allo-HSCT) is between 13% and 40% [7],[8], while the results of everyday clinical practice at the Clinic for Hematology of the University Clinical Center of Serbia (UCCS) have shown a higher incidence in the tested patients.

The primary goal of this study is determining positivity in the blood and urine of patients involved in allogeneic HSCT, by means of the PCR (polymerase chain reaction) test. The secondary goal is determining the incidence of the predictors for the development of the clinical presentation of BK polyomavirus-associated hemorrhagic cystitis (BK-PyVHC), as well as determining its effects on overall survival (OS) of the patients enrolled in the program of allogeneic HSCT.

MATERIALS AND METHODS

The retrospective cohort study included 42 patients of the Clinic for Hematology of the UCCS, of whom 21 were male and 21 female patients, with the median age of 38 years, ranging from 19 to 57 years. The patients were diagnosed with Hodgkin lymphoma (HL), Non-Hodgkin Lymphoma (NHL), acute lymphoblastic leukemia (ALL), acute myeloblastic leukemia (AML), or myelodysplastic/ myeloproliferative syndrome (MDS/MPN).

Microbiological methods

Reactivation of the BK polyomavirus was determined from blood and urine samples with the PCR method. The analysis included only positive results registered until the 100th day following the allogeneic HSTC procedure (D+100); the PCR test was performed every 7 days. In all patients, the PCR status regarding the BK polyomavirus in the blood and urine was determined once a week, until D+100. The day when the neutrophil count was above 1x109 and the platelet count was above 20x1012 was taken to be the day of engraftment. The diagnosis of hemorrhagic cystitis was established on the basis of microbiological findings and the presence of hematuria.

Prophylaxis and treatment

The development of hemorrhagic cystitis is prevented by administering polyspecific immunoglobulins, on days one, three, seven, fourteen, twenty-one, twenty-eight, fifty-six, seventy-four, and eighty-four after the beginning of transplantation.

Treatment of hemorrhagic cystitis is performed by hydration (3L/m2 ), urine alkalization, the application of uroprotectors (mesna), as well as with the application of quinolone antibiotics. The clinically most severe forms are treated by irrigating the urinary bladder with a solution of mannitol and sorbitol. As of 2019, the antiviral drug – cidofovir, which had previously been unavailable, has been used for treatment.

Prior to the allo-HSCT procedure, patients undergo conditioning regimens. Conditioning regimens involve the application of chemotherapeutic agents and/or radiation therapy prior to allogeneic HSCT, and, depending on their strength, they can be categorized as: myeloablative conditioning (MAC), which results in complete ablation of bone marrow, and reduced-intensity conditioning (RIC), which uses smaller doses of radiation and does not lead to the ablation of the patient’s bone marrow.

Statistical processing

Initially, a database was compiled by grouping and categorizing results in tables, according to the analyzed patient characteristics.

Descriptive statistical parameters have been expressed as the median and mode.

The fourteenth day following stem cell transplantation was designated D+14.

Overall patient survival covered the period from the moment of diagnosis until the lethal outcome, or concluding with the year 2019, in living patients.

Patient survival in relation to treatment was analyzed with the Kaplan-Meier method and was compared with the log-rank method.

RESULTS

The study included 42 patients – 21 men (50%) and 21 women (50%). The patient age ranged from 19 to 57 years, with the median age being 38 years. The age at diagnosis ranged from 14 to 56 years, with the median age being 34 years (Table 1). The frequency of diagnoses in patients included in the study were as follows: ALL (35.7%), AML (33.3%), HL (19.0%), NHL (4.8%), MDS/ MPN (4.8%), chronic lymphoblastic leukemia – CLL (2.4%), (Table 2). In the follow-up period until D+100, all of the subjects (100%) had a positive BK polyomavirus PCR test result in the urine, while 97.6% of them had a positive PCR test result in the blood. A total of 18 (42.9%) patients developed a clinical presentation, of whom 13 (72.3%) patients developed a severe clinical presentation of hemorrhagic cystitis.

Table 1. Demographic characteristics

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Table 2. Frequency of diagnoses

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Leukocyte engraftment did not occur in three patients, therefore, out of a total of 39 patients, in 14 (35.9%) patients engraftment occurred by D+14, while in 25 (64.1%) patients, engraftment occurred after D+14. Thrombocyte engraftment did not occur in 7 patients, and out of a total of 35 patients, in 4 (11.4%) patients, engraftment occurred by D+14, while in 31 (88.6%) patients, engraftment occurred after D+14 (Table 3).

Table 3. Clinical characteristics

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In 30 (71.4%) patients, the MAC regimen was applied, while the remaining 12 (28.6%) patients were on the RIC regimen.

The frequency of the applied pre-transplant conditioning regimens was as follows: Flamsa-Bu – in 18 (42.9%) cases, FluBU2 – in 9 (21.4%) cases, TBF-PostCy – in 8 (19.0%) patients, BuCy – in 4 (9.5%) patients, Threo Flu – in 3 (7.1%) cases (Table 4).

Table 4. Frequency of conditioning regimens applied in allogenic HSCT

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Based on the Kaplan-Meier survival curve, the average survival time for patients without the clinical presentation of hemorrhagic cystitis was 44.357 months (CI 95% = 43.3 – 168.6), while it was 17.395 months (CI 95% = 43.3 – 168.6) for patients with a developed clinical presentation. Based on the log-rank test, a statistically significant difference in survival was found in these two groups of patients (p = 0.049), (Graph 1).

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Figure 1. Kaplan-Meier curve showing different overall survival of patients with/without hemorrhagic cystitis

In relation to the leukocyte engraftment day (before or after D+14), the Fisher exact probability test did not establish a statistically significant difference in relation to the PCR test positivity of blood samples (p = 0.641), while the Pearson’s chi-squared test showed a significant connection with the frequency of the development of the clinical presentation of hemorrhagic cystitis (p = 0.037).

With the help of the Fisher exact probability test, relative to the thrombocyte engraftment day, significant statistical difference was not found in relation to a positive PCR blood test (p = 0.886), nor in relation to the development of clinical presentation of hemorrhagic cystitis (p = 1.000).

DISCUSSION

The incidence of hemorrhagic cystitis, in patients involved in the program of allogeneic HSCT at the Clinic for Hematology of the University Clinical Center of Serbia, was higher than the incidence reported in literature to date [7],[8],[9]. In their study, Atilla et al. used ciprofloxacin as prophylaxis, and the incidence of hemorrhagic cystitis was 37%. Which is lower when compared to our results [9]. Viremia, i.e., PCR positivity of blood samples, was more frequent in our hospital, as compared to the study carried out by Wu et al., where viremia occurred in 67% of the transplant cases [10].

Viruria, i.e., PCR positivity of the tests performed on urine samples, was more common in our hospital, as compared to the prospective study carried out by Laskin et al., which included children and young adults. The results of their study indicate positivity in 45% of the cases [11]. These two pieces of information may speak to a higher level of seroprevalence of the BK polyomavirus in our population.

Our Kaplan-Meier survival curve results coincide with the results of the study by Kerbauy et al., which included 34 patients enrolled in the program of bone marrow transplantation [12].

In literature published so far, there are no data on the connection between the day of thrombocyte engraftment and the occurrence of the clinical presentation of BK polyomavirus-associated hemorrhagic cystitis, which is also what our results have shown. However, our research has shown a significant connection between the day of leukocyte engraftment and the development of the clinical presentation of BK polyomavirus-associated hemorrhagic cystitis (p = 0.037), however, we did not find results similar to ours published in literature.

Our study had several limitations. The observed population of patients was heterogenous, the analysis was retrospective, whereas the therapy of hemorrhagic cystitis has changed in the past years with the introduction of cidofovir, whereby the treatment outcome has become more successful since then, consequently prolonging overall survival.

CONCLUSION

The reactivation of BK polyomavirus and the occurrence of viremia are practically inevitable in the population of our hospital, however, these parameters have not proven to be significant predictors. The high incidence of BK polyomavirus PCR positivity in our subjects suggests that it would be necessary to investigate the genetic makeup of the virus and determine whether there are differences, in comparison to other populations. The most significant predictor for the development of the clinical presentation of hemorrhagic cystitis was the day of leukocyte engraftment. The incidence of the development of the clinical presentation and its more severe forms increased if the time to engraftment exceeded 14 days (>D+14).

BK polyomavirus-associated hemorrhagic cystitis is a frequent complication in the treatment of patients suffering from malignant hematological diseases enrolled in the program of allogeneic hematopoietic stem cell transplantation. It shortens average survival and increases treatment costs. Introducing prophylaxis, in the form of an appropriate antiviral agent, would be potentially useful in the prevention of this infection.

LIST OF ACRONYMS AND ABBREVIATIONS

HSCT – hematopoietic stem cell transplantation
UCCS – University Clinical Center of Serbia
PCR – polymerase chain reaction
OS – overall survival
HL – Hodgkin lymphoma
NHL – Non-Hodgkin lymphoma
ALL – acute lymphoblastic leukemia
AML – acute myeloblastic leukemia
MDS/MPN – myelodysplastic/myeloproliferative syndrome
MAC – myeloablative conditioning
RIC – reduced-intensity conditioning

  • Conflict of interest:
    None declared.

Informations

Volume 3 No 3

Volume 3 No 3

September 2022

Pages 346-353
  • Keywords:
    allogenic HSCT, BK polyomavirus, hemorrhagic cystitis
  • Received:
    20 May 2022
  • Revised:
    15 June 2022
  • Accepted:
    07 July 2022
  • Online first:
    25 September 2022
  • DOI:
Corresponding author

Stefan Stanković
Clinic for Hematology, University Clinical Center of Serbia
2 Dr Koste Todorovića Street, 11000 Belgrade, Serbia
E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.


  • 1. Takasaka T, Goya N, Tokumoto T, Tanabe K, Toma H, Ogawa Y, et al. Subtypes of BK virus prevalent in Japan and variation in their transcriptional control region. J Gen Virol. 2004 Oct;85(Pt 10):2821-7. doi: 10.1099/vir.0.80363-0. [CROSSREF]

    2. Mackenzie EF, Poulding JM, Harrison PR, Amer B. Human polyoma virus (HPV)--a significant pathogen in renal transplantation. Proc Eur Dial Transplant Assoc. 1978;15:352-60.

    3. Barber CE, Hewlett TJ, Geldenhuys L, Kiberd BA, Acott PD, Hatchette TF. BK virus nephropathy in a heart transplant recipient: case report and review of the literature. Transpl Infect Dis. 2006 Jun;8(2):113-21. doi: 10.1111/j.1399- 3062.2006.00163.x. [CROSSREF]

    4. Loeches B, Valerio M, Pérez M, Bañares R, Ledesma J, Fogeda M, et al; BKV Study Group of the Gregorio Marañón Hospital. BK virus in liver transplant recipients: a prospective study. Transplant Proc. 2009 Apr;41(3):1033-7. doi: 10.1016/j.transproceed.2009.02.021. [CROSSREF]

    5. Muñoz P, Fogeda M, Bouza E, Verde E, Palomo J, Bañares R; BKV Study Group. Prevalence of BK virus replication among recipients of solid organ transplants. Clin Infect Dis. 2005 Dec 15;41(12):1720-5. doi: 10.1086/498118. Epub 2005 Nov 10. [CROSSREF]

    6. Lee Y, Kim YJ, Cho H. BK virus nephropathy and multiorgan involvement in a child with heart transplantation . Clin Nephrol. 2019 Feb;91(2):107-113. doi: 10.5414/CN109520. [CROSSREF]

    7. Gilis L, Morisset S, Billaud G, Ducastelle-Leprêtre S, Labussière-Wallet H, Nicolini FE, et al; Lyon BK virus Study group. High burden of BK virus-associated hemorrhagic cystitis in patients undergoing allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2014 May;49(5):664-70. doi: 10.1038/bmt.2013.235. [CROSSREF]

    8. Leung AY, Suen CK, Lie AK, Liang RH, Yuen KY, Kwong YL. Quantification of polyoma BK viruria in hemorrhagic cystitis complicating bone marrow transplantation. Blood. 2001 Sep 15;98(6):1971-8. doi: 10.1182/blood.v98.6.1971. [CROSSREF]

    9. Atilla E, Ateş C, Uslu A, Ataca Atilla P, Dolapçı I, Tekeli A, Topçuoğlu P. Prospective Analysis of Hemorrhagic Cystitis and BK Viremia in Allogeneic Hematopoietic Stem Cell Transplantation. Turk J Haematol. 2020 Aug 28;37(3):186- 92. doi: 10.4274/tjh.galenos.2019.2019.0296. [CROSSREF]

    10. Wu HL, Weber WC, Shriver-Munsch C, Swanson T, Northrup M, Price H, et al. Viral opportunistic infections in Mauritian cynomolgus macaques undergoing allogeneic stem cell transplantation mirror human transplant infectious disease complications. Xenotransplantation. 2020 Jul;27(4):e12578. doi: 10.1111/xen.12578. [CROSSREF]

    11. Laskin BL, Denburg MR, Furth SL, Moatz T, Altrich M, Kleiboeker S, et al. The Natural History of BK Polyomavirus and the Host Immune Response After Stem Cell Transplantation. Clin Infect Dis. 2020 Dec 15;71(12):3044-54. doi: 10.1093/cid/ciz1194. [CROSSREF]

    12. Kerbauy LN, Kerbauy MN, Bautzer V, Chapchap EC, de Mattos VRP, da Rocha JDA, et al. Severe hemorrhagic cystitis caused by the BK polyomavirus is associated with decreased survival post-allogeneic hematopoietic stem cell transplantation. Transpl Infect Dis. 2019 Oct;21(5):e13101. doi: 10.1111/tid.13101. [CROSSREF]


REFERENCES

1. Takasaka T, Goya N, Tokumoto T, Tanabe K, Toma H, Ogawa Y, et al. Subtypes of BK virus prevalent in Japan and variation in their transcriptional control region. J Gen Virol. 2004 Oct;85(Pt 10):2821-7. doi: 10.1099/vir.0.80363-0. [CROSSREF]

2. Mackenzie EF, Poulding JM, Harrison PR, Amer B. Human polyoma virus (HPV)--a significant pathogen in renal transplantation. Proc Eur Dial Transplant Assoc. 1978;15:352-60.

3. Barber CE, Hewlett TJ, Geldenhuys L, Kiberd BA, Acott PD, Hatchette TF. BK virus nephropathy in a heart transplant recipient: case report and review of the literature. Transpl Infect Dis. 2006 Jun;8(2):113-21. doi: 10.1111/j.1399- 3062.2006.00163.x. [CROSSREF]

4. Loeches B, Valerio M, Pérez M, Bañares R, Ledesma J, Fogeda M, et al; BKV Study Group of the Gregorio Marañón Hospital. BK virus in liver transplant recipients: a prospective study. Transplant Proc. 2009 Apr;41(3):1033-7. doi: 10.1016/j.transproceed.2009.02.021. [CROSSREF]

5. Muñoz P, Fogeda M, Bouza E, Verde E, Palomo J, Bañares R; BKV Study Group. Prevalence of BK virus replication among recipients of solid organ transplants. Clin Infect Dis. 2005 Dec 15;41(12):1720-5. doi: 10.1086/498118. Epub 2005 Nov 10. [CROSSREF]

6. Lee Y, Kim YJ, Cho H. BK virus nephropathy and multiorgan involvement in a child with heart transplantation . Clin Nephrol. 2019 Feb;91(2):107-113. doi: 10.5414/CN109520. [CROSSREF]

7. Gilis L, Morisset S, Billaud G, Ducastelle-Leprêtre S, Labussière-Wallet H, Nicolini FE, et al; Lyon BK virus Study group. High burden of BK virus-associated hemorrhagic cystitis in patients undergoing allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2014 May;49(5):664-70. doi: 10.1038/bmt.2013.235. [CROSSREF]

8. Leung AY, Suen CK, Lie AK, Liang RH, Yuen KY, Kwong YL. Quantification of polyoma BK viruria in hemorrhagic cystitis complicating bone marrow transplantation. Blood. 2001 Sep 15;98(6):1971-8. doi: 10.1182/blood.v98.6.1971. [CROSSREF]

9. Atilla E, Ateş C, Uslu A, Ataca Atilla P, Dolapçı I, Tekeli A, Topçuoğlu P. Prospective Analysis of Hemorrhagic Cystitis and BK Viremia in Allogeneic Hematopoietic Stem Cell Transplantation. Turk J Haematol. 2020 Aug 28;37(3):186- 92. doi: 10.4274/tjh.galenos.2019.2019.0296. [CROSSREF]

10. Wu HL, Weber WC, Shriver-Munsch C, Swanson T, Northrup M, Price H, et al. Viral opportunistic infections in Mauritian cynomolgus macaques undergoing allogeneic stem cell transplantation mirror human transplant infectious disease complications. Xenotransplantation. 2020 Jul;27(4):e12578. doi: 10.1111/xen.12578. [CROSSREF]

11. Laskin BL, Denburg MR, Furth SL, Moatz T, Altrich M, Kleiboeker S, et al. The Natural History of BK Polyomavirus and the Host Immune Response After Stem Cell Transplantation. Clin Infect Dis. 2020 Dec 15;71(12):3044-54. doi: 10.1093/cid/ciz1194. [CROSSREF]

12. Kerbauy LN, Kerbauy MN, Bautzer V, Chapchap EC, de Mattos VRP, da Rocha JDA, et al. Severe hemorrhagic cystitis caused by the BK polyomavirus is associated with decreased survival post-allogeneic hematopoietic stem cell transplantation. Transpl Infect Dis. 2019 Oct;21(5):e13101. doi: 10.1111/tid.13101. [CROSSREF]

1. Takasaka T, Goya N, Tokumoto T, Tanabe K, Toma H, Ogawa Y, et al. Subtypes of BK virus prevalent in Japan and variation in their transcriptional control region. J Gen Virol. 2004 Oct;85(Pt 10):2821-7. doi: 10.1099/vir.0.80363-0. [CROSSREF]

2. Mackenzie EF, Poulding JM, Harrison PR, Amer B. Human polyoma virus (HPV)--a significant pathogen in renal transplantation. Proc Eur Dial Transplant Assoc. 1978;15:352-60.

3. Barber CE, Hewlett TJ, Geldenhuys L, Kiberd BA, Acott PD, Hatchette TF. BK virus nephropathy in a heart transplant recipient: case report and review of the literature. Transpl Infect Dis. 2006 Jun;8(2):113-21. doi: 10.1111/j.1399- 3062.2006.00163.x. [CROSSREF]

4. Loeches B, Valerio M, Pérez M, Bañares R, Ledesma J, Fogeda M, et al; BKV Study Group of the Gregorio Marañón Hospital. BK virus in liver transplant recipients: a prospective study. Transplant Proc. 2009 Apr;41(3):1033-7. doi: 10.1016/j.transproceed.2009.02.021. [CROSSREF]

5. Muñoz P, Fogeda M, Bouza E, Verde E, Palomo J, Bañares R; BKV Study Group. Prevalence of BK virus replication among recipients of solid organ transplants. Clin Infect Dis. 2005 Dec 15;41(12):1720-5. doi: 10.1086/498118. Epub 2005 Nov 10. [CROSSREF]

6. Lee Y, Kim YJ, Cho H. BK virus nephropathy and multiorgan involvement in a child with heart transplantation . Clin Nephrol. 2019 Feb;91(2):107-113. doi: 10.5414/CN109520. [CROSSREF]

7. Gilis L, Morisset S, Billaud G, Ducastelle-Leprêtre S, Labussière-Wallet H, Nicolini FE, et al; Lyon BK virus Study group. High burden of BK virus-associated hemorrhagic cystitis in patients undergoing allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2014 May;49(5):664-70. doi: 10.1038/bmt.2013.235. [CROSSREF]

8. Leung AY, Suen CK, Lie AK, Liang RH, Yuen KY, Kwong YL. Quantification of polyoma BK viruria in hemorrhagic cystitis complicating bone marrow transplantation. Blood. 2001 Sep 15;98(6):1971-8. doi: 10.1182/blood.v98.6.1971. [CROSSREF]

9. Atilla E, Ateş C, Uslu A, Ataca Atilla P, Dolapçı I, Tekeli A, Topçuoğlu P. Prospective Analysis of Hemorrhagic Cystitis and BK Viremia in Allogeneic Hematopoietic Stem Cell Transplantation. Turk J Haematol. 2020 Aug 28;37(3):186- 92. doi: 10.4274/tjh.galenos.2019.2019.0296. [CROSSREF]

10. Wu HL, Weber WC, Shriver-Munsch C, Swanson T, Northrup M, Price H, et al. Viral opportunistic infections in Mauritian cynomolgus macaques undergoing allogeneic stem cell transplantation mirror human transplant infectious disease complications. Xenotransplantation. 2020 Jul;27(4):e12578. doi: 10.1111/xen.12578. [CROSSREF]

11. Laskin BL, Denburg MR, Furth SL, Moatz T, Altrich M, Kleiboeker S, et al. The Natural History of BK Polyomavirus and the Host Immune Response After Stem Cell Transplantation. Clin Infect Dis. 2020 Dec 15;71(12):3044-54. doi: 10.1093/cid/ciz1194. [CROSSREF]

12. Kerbauy LN, Kerbauy MN, Bautzer V, Chapchap EC, de Mattos VRP, da Rocha JDA, et al. Severe hemorrhagic cystitis caused by the BK polyomavirus is associated with decreased survival post-allogeneic hematopoietic stem cell transplantation. Transpl Infect Dis. 2019 Oct;21(5):e13101. doi: 10.1111/tid.13101. [CROSSREF]


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