(OpenEpi version 2.3.1, www.OpenEpi.com). We undertook a complementary analysis to assess the sam-pling distribution of continuous variables. The central limit the-orem states that if a population is repeatedly sampled, the means of these samples are approximately normally distributed. The mean of the sample means (x) approximates the. OpenEpi is a free open-source epidemiological statistics toolset. The tools are all web-based, programmed in HTML and JavaScript. Released in September 2010, version 2.3.1 was long the latest version of the software. However, an update in the form of version 3.0 was released on April 4, 2013, featuring better support for mobile devices.
The clinical epidemiology of BK virus (BKV) disease after allogeneic hematopoietic stem cell transplantation (HSCT) is not well defined. We evaluated 491 patients transplanted from January 2010 to December 2011 at a single transplant center to assess incidence, severity, and risk factors for BKV disease after HSCT.
BKV disease was defined as BKV detection in urine by PCR testing in association with genitourinary symptoms without other concurrent genitourinary conditions. BKV disease occurred in 78 patients (15.9%), for an incidence rate of.47/1000 patient-days (95% confidence interval CI,.37 to.59); BKV disease was considered severe in 27 patients (5.5%). In multivariate Cox modeling, time-dependent acute graft-versus-host disease (aGVHD) grades II to IV (adjusted hazard ratio aHR 4.25; 95% CI, 2.51 to 7.21), cord blood HSCT (aHR 2.28; 95% CI, 1.01 to 5.15), post-transplant mycophenolate use (aHR 3.31; 95% CI, 1.83 to 5.99), and high-dose cyclophosphamide conditioning (aHR 2.34, 95% CI 1.45 to 3.77) were significant predictors of BKV disease. Time-dependent aGVHD grades III to IV (aHR 10.5; 95% CI, 4.44 to 25.0) and cord blood HSCT (aHR 5.40; 95% CI, 1.94 to 15.0) were independent risk factors for severe BKV disease. BKV disease is common and is associated with significant and prolonged morbidity after HSCT. Prospective studies are needed to better define the morbidity of post-HSCT BKV disease and inform the design of prophylaxis and treatment trials.
Immunoincompetence associated with allogeneic hematopoietic stem cell transplantation (HSCT) causes heightened susceptibility to infection x 1 Copelan, E.A. Hematopoietic stem-cell transplantation.
N Engl J Med. 2006; 354: 1813–1826 , x 2 Pasquini M, Wang Z. Current use and outcome of hematopoietic stem cell transplantation. Available at:. Accessed April 21, 2012. BK virus (BKV) is a human polyomavirus x 3 Gardner, S., Field, A., Coleman, D., and Hulme, B. New papovavirus (B.K.) isolated from urine after renal transplantion.
1971; 1: 253–257 3 that is typically acquired in early childhood and becomes latent in urothelial cells of the kidney and urinary tract x 4 Chesters, P.M., Heritage, J., and McCance, D.J. Persistence of DNA sequences of BK virus and JC virus in normal persistence human tissues and in diseased tissues. J Infect Dis. 1983; 147: 676–684 4. BKV reactivation after allogeneic HSCT is associated with manifestations ranging from asymptomatic viruria to severe hemorrhagic cystitis (HC) x 5 Reploeg, M.D., Storch, G.A., and Clifford, D.B. Bk virus: a clinical review. Clin Infect Dis.
2001; 33: 191–202 5. HC occurs in 5% to 68% of HSCT recipients x 6 Arthur, R.R., Shah, K.V., Baust, S.J., Santos, G.W., and Saral, R. Association of BK viruria with hemorrhagic cystitis in recipients of bone marrow transplants. N Engl J Med. 1986; 315: 230–234 , x 7 Bedi, A., Miller, C.B., Hanson, J.L. Association of BK virus with failure of prophylaxis against hemorrhagic cystitis following bone marrow transplantation.
J Clin Oncol. 1995; 13: 1103–1109 and may result in hospitalization, renal dysfunction x 8 Lekakis, L.J., Macrinici, V., Baraboutis, I.G. BK virus nephropathy after allogeneic stem cell transplantation: a case report and literature review. Am J Hematol. 2009; 84: 243–246 , x 9 Limaye, A.P., Smith, K.D., Cook, L.
Polyomavirus nephropathy in native kidneys of non-renal transplant recipients. Am J Transplant. 2005; 5: 614–620 , and increased mortality x 10 Dalianis, T.
And Ljungman, P. Full myeloablative conditioning and an unrelated HLA mismatched donor increase the risk for BK virus-positive hemorrhagic cystitis in allogeneic hematopoetic stem cell transplanted patients. Anticancer Res. 2011; 31: 939–944 , x 11 Dropulic, L.K. And Jones, R.J. Polyomavirus BK infection in blood and marrow transplant recipients. Bone Marrow Transplant.
2008; 41: 11–18. BKV loads can be measured in urine and serum by quantification of viral DNA with PCR testing x 12 Bennett, S.M., Broekema, N.M., and Imperiale, M.J. BK polyomavirus: Emerging pathogen. Microbes Infect.
2012; 14: 672–683 12. BKV viruria is associated with HC x 6 Arthur, R.R., Shah, K.V., Baust, S.J., Santos, G.W., and Saral, R. Association of BK viruria with hemorrhagic cystitis in recipients of bone marrow transplants. N Engl J Med. 1986; 315: 230–234 , x 13 Leung, A.Y.H., Suen, C., Lie, A.
Quantification of polyoma BK viruria in hemorrhagic cystitis complicating bone marrow transplantation. 2001; 98: 1971–1978 , x 14 O’Donnell, P.H., Swanson, K., Josephson, M.A. BK virus infection is associated with hematuria and renal impairment in recipients of allogeneic hematopoietic stem cell transplants. Blood Marrow Transplant. 2009; 15: 1038–1048 , x 15 Apperley, J.F., Rice, S.J., Bishop, J.A. Late-onset hemorrhagic cystitis associated with urinary excretion of polyomaviruses after bone marrow transplantation.
1987; 43: 108–112 , x 16 Erard, V., Storer, B., Corey, L. BK virus infection in hematopoietic stem cell transplant recipients: frequency, risk factors, and association with postengraftment hemorrhagic cystitis. Clin Infect Dis. 2004; 39: 1861–1865 , x 17 Erard, V., Kim, H.W., Corey, L. BK DNA viral load in plasma: evidence for an association with hemorrhagic cystitis in allogeneic hematopoietic cell transplant recipients. 2005; 106: 1130–1132 but also occurs in asymptomatic patients x 7 Bedi, A., Miller, C.B., Hanson, J.L.
Association of BK virus with failure of prophylaxis against hemorrhagic cystitis following bone marrow transplantation. J Clin Oncol. 1995; 13: 1103–1109 , x 13 Leung, A.Y.H., Suen, C., Lie, A. Quantification of polyoma BK viruria in hemorrhagic cystitis complicating bone marrow transplantation. 2001; 98: 1971–1978. Various studies have defined risk factors for development of HC x 17 Erard, V., Kim, H.W., Corey, L.
BK DNA viral load in plasma: evidence for an association with hemorrhagic cystitis in allogeneic hematopoietic cell transplant recipients. 2005; 106: 1130–1132 , x 18 Sencer, S.F., Haake, R.J., and Weisdorf, D.J. Hemorrhagic cystitis after bone marrow transplantation. 1993; 56: 875–879 , x 19 Seber, A., Shu, X.O., Defor, T. Risk factors for severe hemorrhagic cystitis following BMT. Bone Marrow Transplant.
1999; 23: 35–40 , x 20 Leung, A.Y.H., Mak, R., Lie, A.K.W. Clinicopathological features and risk factors of clinically overt haemorrhagic cystitis complicating bone marrow transplantation. Bone Marrow Transplant.
2002; 29: 509–513 , x 21 Asano, Y., Kanda, Y., Ogawa, N. Male predominance among Japanese adult patients with late-onset hemorrhagic cystitis after hematopoietic stem cell transplantation.
Bone Marrow Transplant. 2003; 32: 1175–1179 , x 22 Tsuboi, K., Kishi, K., Ohmachi, K. Multivariate analysis of risk factors for hemorrhagic cystitis after hematopoietic stem cell transplantation. Bone Marrow Transplant. 2003; 32: 903–907 , x 23 Yamamoto, R., Kusumi, E., Kami, M.
Late hemorrhagic cystitis after reduced-intensity hematopoietic stem cell transplantation (RIST). Bone Marrow Transplant. 2003; 32: 1089–1095 , x 24 El-Zimaity, M., Saliba, R., Chan, K.
Hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation: donor type matters. 2004; 103: 4674–4680 , x 25 Giraud, G., Bogdanovic, G., Priftakis, P. The incidence of hemorrhagic cystitis and BK-viruria in allogeneic hematopoietic stem cell recipients according to intensity of the conditioning regimen.
2006; 91: 401–404 , x 26 Wong, A.S.Y., Chan, K.-H., Cheng, V.C.C. Relationship of pretransplantation polyoma BK virus serologic findings and BK viral reactivation after hematopoietic stem cell transplantation. Clin Infect Dis.
2007; 44: 830–837 , x 27 Giraud, G., Priftakis, P., Bogdanovic, G. BK-viruria and haemorrhagic cystitis are more frequent in allogeneic haematopoietic stem cell transplant patients receiving full conditioning and unrelated-HLA-mismatched grafts. Bone Marrow Transplant.
2008; 41: 737–742 , x 28 Tanaka, K., Hori, T., Hatakeyama, N. Quantification of BK polyoma viruria in Japanese children and adults with hemorrhagic cystitis complicating stem cell transplantation. 2008; 80: 2108–2112 , x 29 De Padua Silva, L., Patah, P., Saliba, R.M. Hemorrhagic cystitis after allogeneic hematopoietic stem cell transplants is the complex result of BK virus infection, preparative regimen intensity and donor type. 2010; 95: 1183–1190 , x 30 Arai, Y., Maeda, T., Sugiura, H.
Risk factors for and prognosis of hemorrhagic cystitis after allogeneic stem cell transplantation: Retrospective analysis in a single institution. 2012; 17: 207–214 , x 31 Mori, Y., Miyamoto, T., Kato, K. Different risk factors related to adenovirus- or BK virus-associated hemorrhagic cystitis following allogeneic stem cell transplantation.
Biol Blood Marrow Transplant. 2012; 18: 458–465 , BKV viruria x 14 O’Donnell, P.H., Swanson, K., Josephson, M.A. BK virus infection is associated with hematuria and renal impairment in recipients of allogeneic hematopoietic stem cell transplants.
Blood Marrow Transplant. 2009; 15: 1038–1048 14, and BKV viremia x 14 O’Donnell, P.H., Swanson, K., Josephson, M.A. BK virus infection is associated with hematuria and renal impairment in recipients of allogeneic hematopoietic stem cell transplants. Blood Marrow Transplant. 2009; 15: 1038–1048 , x 16 Erard, V., Storer, B., Corey, L. BK virus infection in hematopoietic stem cell transplant recipients: frequency, risk factors, and association with postengraftment hemorrhagic cystitis. Clin Infect Dis.
2004; 39: 1861–1865 after HSCT, but these studies did not distinguish asymptomatic BKV viruria or viremia from clinical disease other than HC. Some clinicians equate BKV PCR detection with disease when in practice HSCT patients may develop asymptomatic BKV viruria without clinical consequences. Furthermore, previous case-control studies have focused on HC, but in clinical practice a broader spectrum of urinary tract disease is associated with BKV reactivation ranging from cystitis without hematuria to renal failure. Better understanding of the spectrum and natural history of clinical BKV disease is critical for the design of clinical trials and drug development in this area. We assess and quantify the incidence, severity, risk factors, and outcome of clinical BKV disease after allogeneic HSCT in a contemporary cohort. Data on covariates and outcomes of interest were identified through the data repository of the DFCI/BWH HSCT program, queries of the Partners HealthCare Research Patient Data Registry, and review of electronic medical records. Collected data included age at time of transplantation, gender, race, primary disease that required HSCT, transplant conditioning regimen, donor relatedness, HLA donor matching, stem cell source, development and maximal grade of acute graft-versus-host-disease (aGVHD), aGVHD prophylaxis regimens, recipient cytomegalovirus seropositivity before transplant, and days to engraftment.
Transplantation conditioning regimens were classified as either myeloablative or reduced-intensity conditioning based on conditioning agents and dose used. Myeloablative conditioning consisted of different combinations of chemotherapeutic agents with or without total body irradiation (TBI). Most patients received cyclophosphamide (1800 mg/m 2 × 2 days) and TBI with a total dose of 1400 cGy delivered in 7 fractions. Other chemotherapeutic agents used for myeloablative conditioning were high-dose i.v. Busulfan and fludarabine x 32 Alyea, E.P., Kim, H.T., Ho, V.
Comparative outcome of nonmyeloablative and myeloablative allogeneic hematopoietic cell transplantation for patients older than 50 years of age. 2005; 105: 1810–1814 32. Reduced-intensity conditioning mainly consisted of fludarabine with low-dose i.v.
Combinations of fludarabine and melphalan or fludarabine and cyclophosphamide were also used for reduced-intensity conditioning, sometimes in combination with a single dose of TBI of 200 cGy x 32 Alyea, E.P., Kim, H.T., Ho, V. Comparative outcome of nonmyeloablative and myeloablative allogeneic hematopoietic cell transplantation for patients older than 50 years of age. 2005; 105: 1810–1814 32. Additional rabbit or horse antithymocyte globulin (ATG) was primarily used in patients who received cord blood HSCT or in patients with aplastic anemia as primary disease and in some unrelated donor transplantation patients with acute myelogenous leukemia participating in a study protocol x 33 Mohty, M. And Gaugler, B.
Advances in umbilical cord transplantation: the role of thymoglobulin/ATG in cord blood transplantation. Best Pract Res Clin Haematol. 2010; 23: 275–282 , x 34 Cutler, C., Stevenson, K., Kim, H.T. Double umbilical cord blood transplantation with reduced intensity conditioning and sirolimus-based GVHD prophylaxis. Bone Marrow Transplant.
2011; 46: 659–667. Hyperhydration was used for prevention of cyclophosphamide-associated HC in patients receiving high-dose cyclophosphamide x 35 Shepherd, B.J.D., Pringle, L.E., Barnett, M.J. Mesna versus hyperhydration for the prevention of cyclophosphamide-induced hemorrhagic cystitis in bone marrow transplantation.
J Clin Oncol. 1991; 9: 2016–2020 35.
Patients received 1 of several GVHD prophylactic regimens, including glucocorticoids, methotrexate, mycophenolate mofetil (MMF), sirolimus, and tacrolimus. GVHD prophylaxis mainly consisted of a combination of tacrolimus with methotrexate and/or sirolimus in marrow or peripheral HSCT and tacrolimus/sirolimus in cord blood HSCT. Methotrexate was administered on days 1, 3, 6, and 11 after transplantation x 36 Ho, V.T., Aldridge, J., Kim, H.T. Comparison of tacrolimus and sirolimus (Tac/Sir) versus tacrolimus, sirolimus, and mini-methotrexate (Tac/Sir/MTX) as acute graft-versus-host disease prophylaxis after reduced-intensity conditioning allogeneic peripheral blood stem cell transplantation. Biol Blood Marrow Transplant.
2009; 15: 844–850 , x 37 Cutler, C., Li, S., Ho, V.T. Extended follow-up of methotrexate-free immunosuppression using sirolimus and tacrolimus in related and unrelated donor peripheral blood stem cell transplantation. 2007; 109: 3108–3114. MMF was used to substitute for tacrolimus or methotrexate at the discretion of the physician if severe mucositis, hepatic or renal dysfunction, or thrombotic microangiopathy occurred early post-transplantation. GVHD prophylactic medications were generally tapered starting between day +60 and day +100 and were discontinued by 6 to 9 months after HSCT in the absence of GVHD. All GVHD prophylactic regimens were included individually in the analysis and modeled as baseline risks considering the exposure pattern outlined earlier x 38 Marty, F.M., Bryar, J., Browne, S.K. Sirolimus-based graft-versus-host disease prophylaxis protects against cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation: a cohort analysis.
2007; 110: 2–4 38. AGVHD was graded according to the consensus system x 39 Przepiorka, D., Weisdorf, D., Martin, P. 1994 Consensus Conference on Acute GVHD Grading.
Bone Marrow Transplant. 1995; 15: 825–828 39. Conditioning regimens and aGVHD prophylaxis were administered either in the setting of a single-arm or randomized study protocols or at the discretion of the treating transplant physician x 38 Marty, F.M., Bryar, J., Browne, S.K.
Sirolimus-based graft-versus-host disease prophylaxis protects against cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation: a cohort analysis. 2007; 110: 2–4 , x 40 Hill, J.A., Koo, S., Guzman Suarez, B.B. Cord-blood hematopoietic stem cell transplant confers an increased risk for human herpesvirus-6-associated acute limbic encephalitis: a cohort analysis. Blood Marrow Transplant. 2012; 18: 1638–1648.
Engraftment day was defined as the first of 3 consecutive days of an absolute neutrophil count 500 cells/μL. BKV testing was performed at the discretion of the treating clinicians usually for dysuria or hematuria. In some cases conditions such as fever and change of mental status led to BKV testing. Inpatient BKV DNA PCR testing was performed at the BWH clinical microbiology laboratory using a real-time PCR assay (Roche Diagnostics, Indianapolis, IN) with a quantifiable range of 500 to 5 × 10 8 copies/mL. Outpatient DFCI BKV DNA testing of plasma and urine was performed at Viracor-IBT laboratories (Lee's Summit, MO) using a real-time quantitative PCR assay: urine range of 500 to 1 × 10 10 copies/mL and plasma range of 100 to 1 × 10 10 copies/mL. For certain analyses in which BKV load was used as a continuous covariate, detectable BK PCR virus loads below the lower limit of quantification were assigned values of half the lower limit of quantification; BKV loads above the upper limit of quantification were assigned values of twice the upper limit of quantification to acquire standardized numbers for analysis.
BKV disease was defined as detection of BKV by PCR testing in association with genitourinary symptoms along with well-documented clinical course in absence of concurrent genitourinary conditions that could influence symptom presentation. Time to BKV disease was defined as time between date of HSCT and date of first detected BKV PCR. Time to first symptoms was captured as time between date of HSCT and date of first reported genitourinary symptoms. End of symptoms was captured as documented in the medical record. Time between onset of symptoms and end of symptoms during BKV PCR positivity was considered as a BKV disease episode.
For patients who underwent BKV testing, we recorded reasons for testing, clinical course, imaging results, pathology results, treatments, concomitant conditions, and other urinary tract infections. Symptoms were categorized into 7 groups: bladder spasms, dysuria, flank pain, frequency, hematuria, urgency, and other. Other reasons for testing that did not fit into 1 of the 7 groups included fever and mental status changes. Hematuria was graded on a scale of 0 to 4, according to established criteria x 6 Arthur, R.R., Shah, K.V., Baust, S.J., Santos, G.W., and Saral, R. Association of BK viruria with hemorrhagic cystitis in recipients of bone marrow transplants. N Engl J Med. 1986; 315: 230–234 , x 7 Bedi, A., Miller, C.B., Hanson, J.L.
Association of BK virus with failure of prophylaxis against hemorrhagic cystitis following bone marrow transplantation. J Clin Oncol. 1995; 13: 1103–1109. Imaging results were reviewed for signs compatible with BKV disease and categorized into 5 groups: bladder wall thickening, urinary clots and/or hemorrhage, hydronephrosis, perivesical stranding, and ureteral thickening x 41 Schulze, M., Beck, R., Igney, A.
Computed tomography findings of human polyomavirus BK (BKV)-associated cystitis in allogeneic hematopoietic stem cell transplant recipients. 2008; 49: 1187–1194 41. Autopsy, urine cytology, and bladder biopsy results were also reviewed for evidence of BKV disease when available. Treatments for BKV disease were captured during BKV disease episodes, including fluoroquinolone use even if BKV disease was not the main indication, because of putative prophylactic efficacy x 42 Leung, A.Y.H., Chan, M.T.L., Yuen, K. Ciprofloxacin decreased polyoma BK virus load in patients who underwent allogeneic hematopoietic stem cell transplantation. Clin Infect Dis. 2005; 40: 528–537 , x 43 Miller, A.N., Glode, A., Hogan, K.R.
Efficacy and safety of ciprofloxacin for prophylaxis of polyomavirus BK virus-associated hemorrhagic cystitis in allogeneic hematopoietic stem cell transplantation recipients. Biol Blood Marrow Transplant. 2011; 17: 1176–1181.
Foley catheter placement, bladder irrigation, intravesicular use of cidofovir or alum, cystoscopy, and percutaneous nephrostomy placement were considered urologic interventions. Antispasmodics, analgesics, renal replacement therapy including hemodialysis, continuous venovenous hemofiltration, and use of finasteride and tamsulosin were captured. BKV disease was defined as severe when patients had at least 1 of the following: grade 3 or 4 hematuria, imaging with findings compatible with genitourinary tract inflammation or intraluminal clot formation with or without associated hydronephrosis, need for invasive genitourinary interventions, or hospitalization for BKV disease management. Patients were considered to have a second episode of BKV disease if symptoms recurred and BKV was documented more than 30 days after symptom resolution. Baseline characteristics were compared using 2-sided Fisher's exact test, Wilcoxon rank-sum test, or chi-square test where appropriate. Kaplan-Meier curves were generated for survival and time-to-event analyses. Characteristics associated with BKV disease or severe BKV disease were evaluated using Cox modeling.
AGVHD and neutropenia were modeled as time-dependent covariates. Candidate covariates were included in the multivariate models if they were associated with BKV disease or severe BKV disease in the univariate analysis or to explore potential confounders of characteristics associated with BKV disease. SAS version 9.2 (SAS Institute Inc., Cary, NC) was used for these analyses. Incidence rates of BKV disease and severe BKV disease and their 95% confidence intervals (CI) were calculated by Fisher's method using OpenEpi version 2.3.1 (, Atlanta, GA). Descriptive statistical analyses of clinical features of BKV disease were performed by JMP Pro 10.0 2012 (SAS Institute Inc., Cary, NC). During the study period, 491 patients underwent a first allogeneic HSCT at DFCI/BWH, and 168 (34.2%) patients were tested for BKV. Median time to testing was 54.5 days (range, 0 to 559; interquartile range IQR, 14.5 to 137.5 days).
Seventy-eight patients (15.9%; 46.4% of patients tested) met criteria for clinical BKV disease for an overall incidence rate of.47/1000 patient-days (95% CI,.37 to.59). Ten additional patients had documented BKV viruria but were not considered to have BKV disease due to concomitant conditions that could explain genitourinary symptoms (bacterial urinary tract infections in 2, adenovirus disease in 1) or due to no well-documented symptoms (7 patients).
Median time to diagnosis was 58.5 days (range, 2 to 663; IQR, 19 to 111 days). Baseline characteristics of the HSCT cohort and patients with and without BKV disease are presented in Table 1. Among the 78 patients with BKV disease, the most common documented symptoms were dysuria (56, 71.8%), hematuria (40, 51.3%), and urinary frequency (39, 50.0%). Among 66 patients with documented symptom onset and resolution, median symptom duration during the BKV disease episode was 33.5 days (range, 2 to 385; IQR, 11 to 70 days). Forty-six patients with BKV disease (10.4% of cohort) met criteria for diagnosis of HC (ie, clinical symptoms of cystitis with grade 1 hematuria or higher). Hematuria with clot formation was seen in 16 of 78 patients (20.5%).
Management of BKV associated symptoms was the reason for hospitalization in 4 patients (5.1%). Imaging was performed in 39 patients (50.0%), and results compatible with BKV disease were seen in 14 patients (17.9%), including bladder wall (12, 15.4%) or ureteral thickening (5, 6.4%), clot formation/hemorrhage (5, 6.4%), perivesicular stranding (5, 6.4%), and hydronephrosis (3, 3.8%). In 5 patients (6.4%), pathological evaluation of urine cytology or bladder biopsy was done. In 2 patients (2.6%), evidence of human polyomavirus was seen in urine cytology or bladder biopsy. Invasive urologic interventions were performed in 14 patients (18.0%), including Foley catheter placement in 9, bladder irrigation in 7, intravesicular administration of cidofovir in 3, alum instillation in 1, cystoscopy in 2, and bilateral percutaneous nephrostomy tube placement in 1.
Medical treatments prescribed during BKV disease episodes included quinolones (35, 44.9%), antispasmodics (29, 37.2%), i.v. Immunoglobulin (19, 24.4%), pain medications (17, 21.8%), and drugs for lower urinary tract symptoms (3, 3.9%). Intravenous cidofovir was used in 5 patients (6.4%) and leflunomide in 8 (10.3%). Four patients (5.1%) required renal replacement therapy. Transfusion of platelets was needed in 10 patients (12.8%), and 4 patients (5.1%) received packed RBC transfusion for hematuria.
During the study period, 29 of 78 patients with BKV disease died (37.2%). Autopsies were performed in 12 patients and showed hemorrhagic and inflammatory changes in the bladder of 5 patients (6.4%). Viral cytopathic changes consistent with BKV infection were documented in microscopic examination of the bladder of 1 patient (1.3%). No cases of BKV nephropathy were identified on autopsy.
One patient died during hospitalization for BKV disease management due to hemorrhagic complications associated with BKV HC. Seventeen patients (21.8%) experienced recurrent BKV disease during the study period but were not analyzed further. Among 80 patients without BKV viruria, 8 patients had a bacterial urinary tract infection, 17 had acute kidney injury, and 21 had hematuria. Figure 1 summarizes the clinical features.
Univariate and multivariate hazard ratios (HRs) for each covariate associated with BKV disease in the initial analysis ( P. AHR indicates adjusted HR, adjusted for the 5 variables included in the multivariate Cox model. The increased HR of myeloablative conditioning was mainly due to cyclophosphamide use, observed in multivariable modeling of these 2 covariates. A similar pattern was seen with TBI use; when adjusted to cyclophosphamide use in a multivariate model, the increased HR of TBI was no longer significantly increased. Myeloablative conditioning regimens were more frequently used in younger patients; thus, age at HSCT as a risk for BKV disease was confounded by indication. Neutropenia as a BKV disease risk factor was confounded by cord blood HSCT; these patients had significantly ( P. Among patients with BKV disease, median initial urine BKV load was 5.1 × 10 8 copies/mL (range 600, 1.00 × 10 10; IQR, 6.99 × 10 5, 1.00 × 10 10 copies/mL).
Median peak urine BKV load during BKV disease episode was 1.5 × 10 9 copies/mL (range 600, 1.00 × 10 10; IQR, 1.50 × 10 6, 1.00 × 10 10 copies/mL). Blood BKV loads were obtained in 30 patients with median initial blood BKV load of 850 copies/mL (range 0, 1.52 × 10 6; IQR 0, 4,620 copies/mL) and median peak BKV load of 1705 copies/mL (range 0, 1.52 × 10 6; IQR 0, 1.49 × 10 3 copies/mL).
Twenty-seven patients met criteria for severe BKV disease (34.6%, 5.5% of the cohort): 16 patients had hematuria with clot formation, 14 patients demonstrated imaging results compatible with BKV disease, 4 patients were hospitalized for management of BKV disease–associated symptoms, and 14 patients required invasive urologic interventions. The incidence rate of severe BKV disease was.15/1000 patient-days (95% CI,.10 to.22). Detection of BKV viremia was 75% sensitive and 36% specific for severe BKV disease. Kaplan-Meier curves for severe BKV disease by aGVHD grade indicated that aGVHD grades III to IV but not grade II aGVHD were associated with development of severe BKV disease. Significant risk factors for severe BKV disease are shown in Table 3. Increased HR of neutropenia was mainly driven by cord blood HSCT.
In multivariable modeling, time-dependent aGVHD grades III to IV (adjusted HR 10.5; 95% CI, 4.44 to 25.0) and cord blood HSCT (adjusted HR 5.40; 95% CI, 1.94 to 15.0) remained independent risk factors for severe BKV disease. Table 3 Proportional Hazards Modeling of Risk of Severe BKV Disease (n = 27) after Allogeneic HSCT Characteristics Univariate HR (95% CI) P Multivariate aHR (95% CI) P Age at transplant.97 (.95-1.00).03 — — HLA match and donor relatedness Mismatched donor 3.39 (1.52-7.57).003 — — Stem cell source Cord blood HSCT 3.78 (1.43-9.99).007 4.47 (1.65-12.1).003 Conditioning regimen Myeloablative conditioning 2.29 (1.07-4.88).03 — — Conditioning agents Cyclophosphamide 2.48 (1.16-5.29).02 2.03 (.90-4.58).09 TBI 2.11 (.99-4.48).05 — — aGVHD Grades III-IV 11.9 (5.13-27.5). We analyzed the cohort based on a less-specific BKV disease definition that included all 88 patients with BKV viruria, including 10 patients with undocumented symptoms or concomitant genitourinary diseases. Incidence rates and characteristics of BKV viruria were similar to those of BKV disease. The final multivariable model of risk factors for BKV viruria was similar to the final model of BKV disease. However, in this group only 3 risk factors remained significant: MMF aGVHD prophylaxis ( P.
This study focused not only on occurrence and risk factors of HC but determined also the broader clinical spectrum of clinical BKV disease and associated symptoms in a 2-year contemporary cohort of patients who underwent allogeneic HSCT. By expanding the view beyond HC and using a cohort analysis design, this study provides a more comprehensive insight into the burden of BKV disease.
We also propose a new definition of severe BKV disease that includes additional aspects of severity besides the degree of hematuria. A strength of this study is that it included a cohort of 491 adults who underwent different modalities of allogeneic HSCT from 2010 to 2011; this is the largest adult study population to study this problem in the last decade. The overall cumulative incidence of BKV disease indicates that it is a common complication after allogeneic HSCT, more frequent than other infectious disease complications such as invasive fungal disease x 2 Pasquini M, Wang Z. Current use and outcome of hematopoietic stem cell transplantation. Available at:. Accessed April 21, 2012., x 44 Marty, F.M., Lee, S.J., Fahey, M.M.
Infliximab use in patients with severe graft-versus-host disease and other emerging risk factors of non- Candida invasive fungal infections in allogeneic hematopoietic stem cell transplant recipients: a cohort study. 2003; 102: 2768–2776. BKV disease was associated with increased risk of death (HR 1.74; 95% CI, 1.18 to 2.57, P =.005) in this cohort, although this risk was not significant when adjusted to grades III to IV aGVHD. Besides significant hematuria, patients with severe BKV disease had important radiological findings, hospitalization for BKV disease management, and need for invasive urologic interventions. We found that BKV loads in urine and blood were not accurate predictors of BKV disease severity. We also found that aGVHD grades II to IV, cord blood HSCT, MMF, and cyclophosphamide use were significant risk factors for BKV disease on multivariable analysis.
ATG use was not significant in this model but remained associated with a higher risk for development of BKV disease. For severe BKV disease, time-dependent aGVHD grades III to IV and cord blood HSCT were significant and independent risk factors in multivariate modeling.
These results suggest that occurrence of BKV disease is multifactorial and is associated with both immunological and cytotoxic events that take place during or after HSCT. x 45 Leung, A.Y.H., Yuen, K.-Y., and Kwong, Y.-L. Polyoma BK virus and haemorrhagic cystitis in haematopoietic stem cell transplantation: a changing paradigm. Bone Marrow Transplant. 2005; 36: 929–937 45 proposed a 3-phase etiological model of HC after allogeneic HSCT that may be relevant for patients who received myeloablative conditioning but not for patients who received reduced-intensity conditioning regimens. They proposed that in a first phase the uroepithelium is damaged due to conditioning regimens and subsequent uroepithelial regeneration provides an appropriate milieu for BKV replication. It is well known that cyclophosphamide causes uroepithelial damage by excretion of the metabolite acrolein x 19 Seber, A., Shu, X.O., Defor, T.
Risk factors for severe hemorrhagic cystitis following BMT. Bone Marrow Transplant. 1999; 23: 35–40 19. Although effective prophylaxis with forced diuresis helps prevent cyclophosphamide-induced HC x 35 Shepherd, B.J.D., Pringle, L.E., Barnett, M.J. Mesna versus hyperhydration for the prevention of cyclophosphamide-induced hemorrhagic cystitis in bone marrow transplantation. J Clin Oncol. 1991; 9: 2016–2020 35, it is possible that cyclophosphamide still damages the uroepithelium, making these tissues more vulnerable to BKV reactivation.
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Cord blood transplantation is also generally associated with increased risk of infection due to slow hematological and immunological reconstitution x 1 Copelan, E.A. Hematopoietic stem-cell transplantation. N Engl J Med. 2006; 354: 1813–1826 1. One study proposed umbilical cord blood as a risk factor for development of HC, but umbilical cord blood transplants were grouped with haploidentical transplants for analysis, making a comparison with our results difficult x 29 De Padua Silva, L., Patah, P., Saliba, R.M. Hemorrhagic cystitis after allogeneic hematopoietic stem cell transplants is the complex result of BK virus infection, preparative regimen intensity and donor type. 2010; 95: 1183–1190 29.
It is noteworthy that patients who underwent cord blood HSCT may develop clinical BKV disease before engraftment. Cord blood lacks passively transferred immunity to BKV, suggesting that donor immunity may be relevant to minimize BKV disease. These observations do not support the proposed model of Leung et al.
x 45 Leung, A.Y.H., Yuen, K.-Y., and Kwong, Y.-L. Polyoma BK virus and haemorrhagic cystitis in haematopoietic stem cell transplantation: a changing paradigm. Bone Marrow Transplant. 2005; 36: 929–937 45, which suggests that donor lymphocytes cause mucosal damage and thus contribute to development of BKV-associated HC. The presence and treatment of aGVHD are generally considered risk factors for infection, and a few studies also suggest an association of aGVHD with HC x 20 Leung, A.Y.H., Mak, R., Lie, A.K.W. Clinicopathological features and risk factors of clinically overt haemorrhagic cystitis complicating bone marrow transplantation.
Bone Marrow Transplant. 2002; 29: 509–513 , x 21 Asano, Y., Kanda, Y., Ogawa, N. Male predominance among Japanese adult patients with late-onset hemorrhagic cystitis after hematopoietic stem cell transplantation.
Bone Marrow Transplant. 2003; 32: 1175–1179 , x 26 Wong, A.S.Y., Chan, K.-H., Cheng, V.C.C. Relationship of pretransplantation polyoma BK virus serologic findings and BK viral reactivation after hematopoietic stem cell transplantation. Clin Infect Dis. 2007; 44: 830–837 , x 30 Arai, Y., Maeda, T., Sugiura, H. Risk factors for and prognosis of hemorrhagic cystitis after allogeneic stem cell transplantation: Retrospective analysis in a single institution.
2012; 17: 207–214 , x 31 Mori, Y., Miyamoto, T., Kato, K. Different risk factors related to adenovirus- or BK virus-associated hemorrhagic cystitis following allogeneic stem cell transplantation. Biol Blood Marrow Transplant.
2012; 18: 458–465. Our results confirm these findings and also emphasize a strong association between aGVHD and development of BKV disease. In this setting, it seems that reactivation of BKV in the urothelium is facilitated by GVHD and its treatment, rather than BKV disease being a manifestation of bladder GVHD x 45 Leung, A.Y.H., Yuen, K.-Y., and Kwong, Y.-L. Polyoma BK virus and haemorrhagic cystitis in haematopoietic stem cell transplantation: a changing paradigm. Bone Marrow Transplant. 2005; 36: 929–937 45. As suggested by Leung et al.
x 45 Leung, A.Y.H., Yuen, K.-Y., and Kwong, Y.-L. Polyoma BK virus and haemorrhagic cystitis in haematopoietic stem cell transplantation: a changing paradigm. Bone Marrow Transplant. 2005; 36: 929–937 45, clinical BKV disease could then develop in the setting of tapering immunosuppression as an immune reconstitution phenomenon.
Use of MMF as aGVHD prophylaxis has not been previously reported as a risk factor for HC. El-Zimaity et al. x 24 El-Zimaity, M., Saliba, R., Chan, K. Hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation: donor type matters. 2004; 103: 4674–4680 24 proposed a possible interaction between degree of pharmacological immunosuppression, donor type, and development of HC. However, in our cohort patients did not receive MMF as part of a standard aGVHD prophylaxis regimen, but MMF was used to substitute for tacrolimus or methotrexate in patients who had baseline or early organ dysfunction. Therefore, these results may not be representative for patients who receive tacrolimus/MMF as planned aGVHD prophylaxis.
The retrospective study design made it difficult to retrieve more detailed information about clinical course of BKV disease. There was likely under-reporting of symptoms and duration of BKV disease, especially for milder cases. We were unable to systematically capture symptoms commonly mentioned by patients who experience BKV disease, such as the degree urinary frequency experienced, multiple times per hour at times, and sleep deprivation because of urinary frequency or bladder spasms, which are associated with a poor quality of life x 46 Syrjala, K.L., Langer, S.L., Abrams, J.R. Late effects of hematopoietic cell transplantation among 10-year adult survivors compared with case-matched controls.
J Clin Oncol. 2005; 23: 6596–6606 46. Prospective studies that capture details of symptoms using standardized forms or questionnaires would increase the precision of these observations. Another limitation of this study is that there was no systematic BKV screening of urine and blood—the trigger for BKV testing was symptom-based. Therefore, under-reporting is possible due to lack of information available on patients without clinical suspicion of BKV disease. In summary, BKV disease is a common complication of HSCT, associated with significant and prolonged morbidity, especially in the setting of aGVHD, cord blood HSCT, cyclophosphamide use, and probably MMF use. BKV disease is multifactorial in origin and is associated with immunological and cytotoxic events that take place during or after allogeneic HSCT.
Prospective studies are needed to better understand the physiopathology of BKV disease, further define its morbidity, and inform the design of prophylaxis and treatment trials for this common condition after HSCT. Financial disclosure: The Dutch Kidney Foundation, the Dutch Cancer Society, the Marco Polo fund, and the J.K. De Cock foundation provided financial support for N.M.G.R. Conflict of interest statement: F.M.M. Has received consulting honoraria from Chimerix and Vertex and research funding from Chimerix. All other authors declare no competing financial interests.
Authorship statement: F.M.M. N.M.G.R., and S.P.H, conceived of and designed the study. N.M.G.R., M.M.S., G.S., V.T.H., and F.M.M. Collected and assembled the data.
Performed statistical analysis. Prepared the manuscript. M.M.S., G.S., S.P.H., V.T.H., L.R.B., J.H.A., R.J.S., and F.M.M. Reviewed and critically revised the manuscript. References. 1 Copelan, E.A. Hematopoietic stem-cell transplantation.
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