BK Virus In Patients Research Articles

BK Virus Viremia in the First Days After Bone Marrow Transplantation: A Case-Control Study

Background: Reactivation of BK virus (BKV), viremia is a major clinical complication in transplant recipients. There are many studies of BKV infection among tissue transplant recipients, especially renal-transplant recipients. Although the presence of BKV in patients’ urine occurs frequently, the detection of BKV in the blood of transplant recipients, especially after bone marrow transplantation (BMT), is less studied. Objectives: The aim of this study was to detect BKV in 54 blood samples of BMT recipients in the first days after transplantation. Methods: This case-control study was performed in a university-affiliated hospital, Tehran, Iran, from October 2017 to October 2018. Blood samples were collected from 54 hematopoietic stem cell transplant recipients, and 54 healthy subjects without any tissue transplantation, and tested daily for BKV DNA using the quantitative real-time PCR technique. Results: In this study, two patients (3.7%) developed BK viremia at a median of 10 days (range: 1 - 10 days) after BMT, while none of the control subjects was positive for BKV in blood samples. The analysis of data showed no significant difference between the case and control groups (CI: 0.986 - 1.094, P < 0.153). Conclusions: Our data suggest that BKV viremia involved in active infection may not occur in the first days after BMT. This finding can affect controlling and managing BMT patients.

Molecular characterization of BK virus in patients infected with human immunodeficiency virus.

Immunosuppression seems to be the most important cause of BKPyV reactivation. Recently, a spectrum of diseases associated with BKPyV infection has been reported in HIV-infected patients. BKPyV isolates can be classified into four subtypes based on nucleotide polymorphisms within VP1 coding region. Mutations within the BC loop of the VP1 may be associated with an increase in the viral pathogenicity. The aims of this study were to determine prevalence and distribution of BKPyV subtypes, sequence variation and mutations within VP1 among HIV-infected patients and healthy donors. Urine samples from 114 HIV-infected patients and 120 healthy donors were collected. PCR followed by sequence analysis was carried out using primers specific for VP1 and NCRR of the virus genome. The predominant BKPyV subtype was I, followed by IV. In isolates from HIV-infected patients, the majority of non-synonymous alterations were located within the BC loop. BKV sequences from healthy donors showed non-synonymous alterations outside of the receptor loops in the β-sheets. The higher frequency of mutations in the BC loop of VP1 protein was detected among HIV-infected patients. The most frequent mutation was E82D. All HIV-infected patients who harbored mutations had CD4(+) cell counts less than 200cell/mm(3). It seems that immunosuppression is a very important factor for BKPyV reactivation that can increase viral replication rate and leads to higher frequency of mutations in the BC loop of the VP1. These mutations may change receptor specificity, and further studies are needed to determine the effect of these mutations on the biological properties of the BKPyV.

The polyomavirus puzzle: is host immune response beneficial in controlling BK virus after adult hematopoietic cell transplantion?

BK virus (BKV), a ubiquitous human polyomavirus, usually does not cause disease in healthy individuals. BKV reactivation and disease can occur in immunosuppressed individuals, such as those who have undergone renal transplantation or hematopoietic cell transplantation (HCT). Clinical manifestations of BKV disease include graft dysfunction and failure in renal transplant recipients; HCT recipients frequently experience hematuria, cystitis, hemorrhagic cystitis (HC), and renal dysfunction. Studies of HCT patients have identified several risk factors for the development of BKV disease including myeloablative conditioning, acute graft-versus-host disease, and undergoing an umbilical cord blood (uCB) HCT. Although these risk factors indicate that alterations in the immune system are necessary for BKV pathogenesis in HCT patients, few studies have examined the interactions between host immune responses and viral reactivation in BKV disease. Specifically, having BKV immunoglobulin-G before HCT does not protect against BKV infection and disease after HCT. A limited number of studies have demonstrated BKV-specific cytotoxic T cells in healthy adults as well as in post-HCT patients who had experienced HC. New areas of research are required for a better understanding of this emerging infectious disease post HCT, including prospective studies examining BK viruria, viremia, and their relationship with clinical disease, a detailed analysis of urothelial histopathology, and laboratory evaluation of systemic and local cellular and humoral immune responses to BKV in patients receiving HCT from different sources, including uCB and haploidentical donors.

Development of BK Virus-Associated Hemorrhagic Cystitis (HC) Is Associated with Decreased Survival Post-Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT)

AbstractAbstract 1933 Introduction:Infection by BK virus in the allo-HSCT setting is associated with the development of HC, which is a major cause of morbidity. There are few studies evaluating the impact of BK virus-associated HC on survival post allo-HSCT. Objectives:To evaluate the incidence of HC by BK virus in patients after allo-HSCT and its impact on survival. Methods:We retrospectively reviewed the medical charts of 107 patients who underwent allo-HSCT at Hospital Israelita Albert Einstein from July 2007 until November 2011. HC was defined by the presence of any degree of unexplained hematuria and positivity for BK virus in a urine sample by quantitative polymerase chain reaction (PCR) assay. CMV reactivation was defined as positivity in the antigenemia assay or greater than 165 copies in a quantitative PCR assay. Three patients were excluded because PCR results for BK virus were inconclusive, with 104 patients being analyzed in the final cohort. Cumulative incidence (CI) of HC, CMV reactivation and acute graft-versus-host disease (GVHD) were estimated taking into account the competing risk of death. Overall survival (OS) was estimated by the Kaplan-Meier method. Gray model was used for regression analysis of factors associated with the development of HC. Hazard ratios (HRs) were estimated by a Cox multivariable proportional hazards model, considering HC, CMV reactivation and acute GVHD as discrete time-varying covariates. Results:Median age was 28 years (range 6 months–76 years), and 60.5% of patients were male. About 37% had high-risk disease (refractory leukemia/lymphoma or 2nd-transplantation). Source of HSCs included matched related donors (37%), 10/10 HLA-matched unrelated donors (24%) and cord blood/haploidentical donors in 39%. The conditioning regimen was myeloablative in 81% of cases. The median follow-up of the whole cohort was 450 days (range 9–1624 days). At 1 year, the cumulative incidence of HC was 30.5% (95% confidence interval [CI] 21.8%–39.7%). The 1-year incidence of CMV reactivation and acute GVHD (all grades) was 57.1% and 39.7%, respectively. In a multivariate analysis taking into account age, sex, risk of disease, source of HSCs, intensity of conditioning, CMV reactivation and acute GVHD, only receiving cells from cord blood/haploidentical donors was associated with an increased incidence of HC (subhazard ratio 4.04, 95% CI 1.31–12.49, p = 0.015). The 1 year-OS of the whole cohort was 55% (95% CI 44–62%). Patients who developed HC had an inferior OS (1 year: 18% vs. 70%; HR= 4.40, p <0.0001; 95% CI 2.37–8.14). In the multivariate Cox analysis for OS, after adjusting for age, sex, disease risk, source of HSCs, intensity of conditioning, CMV reactivation and development of acute GVHD, development of HC was associated with an increased mortality (table). Conclusion:In this cohort, the development of CH was associated with an inferior OS in patients undergoing allogeneic HSCT. Even after adjusting for several variables, including development of acute GVHD and CMV reactivation, HC still remained an important factor associated with decreased survrival. It is possible that HC is not the direct cause of the increased mortality, but is rather a surrogate marker of a state of severe immunosuppression and increased risk of dying in the post-transplant setting. Nonetheless, our results suggest that the development of BK virus-associated HC in allo-HSCT patients is associated with inferior survival and future studies should confirm this finding and seek strategies to prevent this complication.TableCox multivariable analysis for OSCovariateHR (95% CI)PAge1.00 (0.98-1.01)0.98Male sex (yes vs. no)0.65 (0.33-1.29)0.22Myeloablative conditioning (vs. reduced-intensity conditioning)3.61 (1.41-9.26)0.007Disease risk category• Intermediate (vs. Low)1.11 (0.38-3.18)0.84• High (vs. Low)2.06 (0.77-5.46)0.14Source of Stem Cells• Matched Unrelated Donor (vs. Matched Related Donor)0.46 (0.18-1.17)0.10• Cord Blood/Haploidentical Donor (vs. Matched Related Donor)1.15 (0.53-2.51)0.71Development of BK-virus associated Hemorrhagic Cystitis4.84 (2.51-9.34)<0.0001Development of CMV reactivation1.31 (0.66-2.62)0.41Development of acute GVHD1.74 (0.86-3.51)0.11 Disclosures:No relevant conflicts of interest to declare.

Recombined sequences between the non-coding control regions of JC and BK viruses found in the urine of a renal transplantation patient

Kidney cells are the common host for JC virus (JCV) and BK virus (BKV). Reactivation of JCV and/or BKV in patients after organ transplantation, such as renal transplantation, may cause hemorrhagic cystitis and polyomavirus-associated nephropathy. Furthermore, JCV and BKV may be shed in the urine after reactivation in the kidney. Rearranged as well as archetypal non-coding control regions (NCCRs) of JCV and BKV have been frequently identified in human samples. In this study, three JC/BK recombined NCCR sequences were identified in the urine of a patient who had undergone renal transplantation. They were designated as JC-BK hybrids 1, 2, and 3. The three JC/BK recombinant NCCRs contain up-stream JCV as well as down-stream BKV sequences. Deletions of both JCV and BKV sequences were found in these recombined NCCRs. Recombination of DNA sequences between JCV and BKV may occur during co-infection due to the relatively high homology of the two viral genomes.

Genotyping of the noncoding control region of BK virus in patients with haemorrhagic cystitis after allogeneic haematopoietic stem cell transplantation

Genotyping of the noncoding control region of BK virus in patients with haemorrhagic cystitis after allogeneic haematopoietic stem cell transplantation

Analysis of PCR as a tool for detection of JC virus DNA in cerebrospinal fluid for diagnosis of progressive multifocal leukoencephalopathy.

Two polyomaviruses, JC virus (JCV) and BK virus (BKV), affect humans. JCV is the causative agent of progressive multifocal leukoencephalopathy (PML), and detection of JCV in the central nervous system (CNS) is a prerequisite for confirmation of the disease. BKV is generally not associated with neurological disease, but involvement of BKV in patients with CNS disorders has been reported. In the present study polyomavirus DNA was detected by a nested PCR at a sensitivity corresponding to the detection of 10 copies of JCV DNA in 10 microliters of cerebrospinal fluid (CSF). CSF samples from 212 patients with neurological symptoms and immunodeficiencies were investigated for the presence of polyomavirus DNA. Of 128 human immunodeficiency virus (HIV)-infected patients, 14 (11%) had JCV DNA in their CSF, and all 14 patients had clinical PML. BKV DNA was detected in one HIV-infected patient with neurological symptoms not compatible with PML. Among 84 HIV-negative patients, 6 (7%) had detectable JCV DNA in their CSF, confirming PML in patients with clinical conditions of T-cell lymphoma, chronic lymphatic leukemia, status postliver transplantation, congenital immunodeficiency, sarcoidosis, and immunodeficiency of unknown origin. The specificity of the PCR was confirmed by a clinical follow-up study which showed full agreement between the detection of JCV DNA in CSF and clinically manifest PML. The described PCR is a rapid, reproducible, and easily performed assay.