OVERVIEW: What every clinician needs to know

Pathogen name and classification

  • BK virus is a polyomavirus in the Papovaviridae family. The human polyomaviruses are JC, WU, KI, MW, STL, TS, HPyV6, HPyV7, HPyV9, HPyV12, HPyV13 and Merckel cell carcinoma viruses. BK, JC, TS, and Merckel cell carcinoma viruses are linked to specific human diseases. The other genus in the Papovaridae family is the papillomavirus.

  • BK virus, a human polyomavirus that can cause hemorrhagic cystitis in hematopoietic stem cell transplantation patients and ureteral stenosis and polyomavirus associated nephropathy (PVAN) in renal transplantation patients.

  • BK virus is a small, nonenveloped, double stranded, circular DNA virus.

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  • BK are the initials of a patient who presented with ureteral stenosis several months after renal transplantation.

What is the best treatment?

  • There is currently no effective antiviral therapy for BK virus.

  • Nephropathy

    The best treatment is to reduce immunosuppression. However, this may lead to graft rejection in a renal transplant patient.

    Pre-emptive screening of BK virus in blood and urine after renal transplant are implemented to detect any signs of BK proliferation.

    The goal of treatment is complete clearance of BK virus from plasma.

    BK virus associated nephropathy can result in transplanted graft failure and recurrence of PVAN in the re-transplanted kidney is 12%.

    Cidofovir is an antiviral drug used for cytomegalovirus (CMV) showed inhibition of BK virus activity in vitro. There are case reports of treating PVAN with cidofovir. No randomized or controlled studies were performed. Efficacy is yet to be determined.

    Leflunomide is an immunosuppressive drug approved for use in rheumatoid arthritis. Although used by clinicians and described in case reports, there are no randomized or controlled studies to prove benefit.

    Ciprofloxacin is an antibacterial in the fluoroquinolones class. Case reports describe benefits when used alone or in combination with immunosuppression reduction; however, there are no randomized or controlled studies to prove benefit.

    Intravenous immunoglobulin infusion in kidney transplant patients with BK viremia lowered the viral load in a small case series. Randomized controlled clinical trial is needed to determine efficacy of this therapy.

  • Ureteral stenosis

    The best treatment is to reduce immunosuppression. However, this may lead to graft rejection in a renal transplant patient.

    Surgical intervention is necessary to relief obstruction.

  • Hemorrhagic cystitis

    Control bleeding and supportive care, including bladder irrigation, analgesia, hyperhydration, anti-spasmotics, and transfusion, are the best treatment.

    Reduce immunosuppression if possible.

    Antiviral agents reported in literature include:

    Fluoroquinolones are antibacterial agents that showed in vitro inhibitor of BK virus replication. There are case reports of efficacy in treating hemorrhagic cystitis in hematopoietic stem cell transplant patients. However, there is no randomized or controlled study performed. Recently, a small retrospective study showed prevention of hemorrhagic cystitis when used as prophylaxis in hematopoietic stem cell transplant patients.

    Cidofovir is an antiviral drug used for CMV showed inhibition of BK virus activity in vitro. This has been used by clinicians both intravenously and as bladder instillation. However, small nonrandomized studies showed decreased BK viral load in the urine in less than one-half of the patients.

    Leflunomide is an immunosuppressive drug approved for use in rheumatoid arthritis. Although used by clinicians and described in case reports, there are no randomized or controlled studies to prove benefit.

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How do patients contract this infection, and how do I prevent spread to other patients?

  • Epidemiology

    BK virus is detected in diverse populations worldwide, including geographically isolated regions

    BK virus infects humans starting in early childhood via urine-oral route. Up to 90% of the general adult population is seropositive for BK virus.

    BK virus’ primary infection is asymptomatic, and the virus remains clinically latent in kidney epithelial cells.

    With immunosuppression, such as following stem cell or renal transplantation, BK virus reactivates and proliferates. Although BK virus rarely infects the native kidneys, PVAN can be detected in up to 10% of patients with renal transplantation. Prevalence of BK virus associated ureteral stenosis occurs in up to 3% of renal transplant patients, and BK virus associated hemorrhagic cystitis occurs in 10-25% of patients with hematopoietic stem cell transplantation.

    BK virus is detected in the urine of 0-20% of immunocompetent individuals and 10-60% of immunosuppressed individuals.

  • Infection control issues

    Since up to 90% of the general population is seropositive for BK virus, it is assumed that most individuals carry latent virus in the kidneys. Furthermore, diseases caused by BK virus are due to reactivation of the virus, not primary infection. Therefore, no isolation precautions are needed.

What host factors protect against this infection?

  • Most individuals have been infected by BK virus. However, host immune factors may be associated with increased risk of BK virus reactivation.

  • Host factor increasing the risk of developing PVAN in renal transplantation patients include:

    High donor BK virus antibody

    Lack of the HLA-C7 class I allele in both donor and recipient

    Older age

    Male gender

    Diabetes mellitus

    Caucasian ethnicity

  • Host factors increasing the risk of developing hemorrhagic cystitis in hematopoietic stem cell transplantation patients include:

    Allogeneic transplantation

    Occurrence of graft versus host disease

  • Detection of an elevated BK virus-specific cellular immune response in renal transplantation patients with nephropathy correlates with reduced quantities of BK viruria and viremia. Furthermore, humoral immune response is also associated with reduced BK viremia.

  • PVAN and ureteral stenosis occurs in post renal transplantation patients and hemorrhagic cystitis occurs in hematopoietic stem cell transplant patients.

  • Biopsy of the infected renal issue shows detectable viral protein in the tubular epithelium cells with large intranuclear inclusions. Lytic infection of the epithelium cells results in cell detachment. Onset of infection is in the medulla and the distal tubules. Continued BK replication will eventually involve the proximal tubules.

What are the clinical manifestations of infection with this organism?

  • Nephropathy (PVAN)

    Renal transplantation patients can present with fever, hematuria, and renal insufficiency. Onset can range from 6 days to 5 years, with a mean of 10-13 months after transplantation. Nephropathy is commonly only detected in the graft kidney.

    Although rare, nephropathy can be detected in native kidneys of recipients of hematopoietic stem cell transplantation.

  • Ureteral stenosis:

    Renal transplantation patients can present with urinary obstruction and elevated creatinine. Patients may not be able to feel any pain sensation because of the transplantation.

  • Hemorrhagic cystitis:

    Hematopoietic stem cell transplantation patients can present with hematuria, dysuria, urgency, frequency, and suprapubic pain. This most often occurs at engraftment but can be up to months after transplantation. Some patients can also present with graft versus host disease.

What common complications are associated with infection with this pathogen?

  • PVAN can result in the renal graft loss in 20-30% of the patients.

  • Ureteral stenosis can cause renal failure and graft loss.

  • Hemorrhagic cystitis results in uncontrolled bleeding, pain, urinary tract obstruction, and renal failure.

How should I identify the organism?

  • BK virus is both slow to grow and difficult to grow in culture.

  • Detection of BK virus in urine by polymerase chain reaction (PCR) has a positive predictive value of 60% for PVAN in renal transplant recipients. The negative predictive value is 100% if PCR is negative for BK virus. Detection of greater than 107 copies/ml is significant.

  • Detection of BK virus in blood by PCR has a positive predictive value of 53% for PVAN in renal transplantation patients. The negative predictive value is 100% if PCR is negative for BK virus. Detection of greater than 104 copies/ml is significant.

  • BK virus is usually not detected in the blood of patients presenting with ureteral stenosis or hemorrhagic cystitis.

  • Detection of BK virus protein by immunohistochemical staining or DNA by in situ hybridization on renal biopsy tissues is the gold standard. However, because of the focal nature of this disease, the false-negative rate can be as high as 30%.

How does this organism cause disease?

  • BK virus is ubiquitous and infects up to 90% of individuals. The virus resides in the kidney epithelial cells, and asymptomatic reactivation with viral shedding in urine can be detected in 5% of healthy individuals. Reactivation of BK virus in immunosuppressed individuals can result in disease.

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