Infectious Diseases

BK virus (Clinical Condition)

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OVERVIEW: What every practitioner needs to know

Are you sure your patient has BK associated nephropathy (PVAN), ureteral stenosis, or hemorrhagic cystitis? What should you expect to find?

Key symptoms

Nephropathy (PVAN)

  • BK viruria

  • BK viremia

  • Slow asymptomatic rise of serum creatinine

  • Hematuria

  • Fever

  • Laboratory evidence of renal insufficiency

  • Abnormal urinalysis

Ureteral Stenosis

  • Urinary obstruction

  • Elevated serum creatinine

Hemorrhagic cystitis

  • Hematuria

  • Dysuria

  • Urgency

  • Frequency

  • Suprapubic pain

Key physical findings

Nephropathy (PVAN)

  • Hematuria

  • Fever

Ureteral Stenosis

  • Urinary obstruction

Hemorrhagic cystitis

  • Suprapubic pain

How did the patient develop BK associated nephropathy (PVAN), ureteral stenosis, or hemorrhagic cystitis? What was the primary source from which the infection spread?

After asymptomatic BK virus primary infection in childhood of up to 90% of the general population, BK virus establishes lifelong residence in kidney epithelial cells. Although BK viruria can occur in 0-20% of asymptomatic immunocompetent individuals, BK virus associated diseases (nephropathy, ureteral stenosis, hemorrhagic cystitis) are only seen in immunocompromised patients who had renal transplantation or hematopoietic stem cell transplantation.

Basic epidemiology

Nephropathy (PVAN)

  • Prevalence of 1-10% of patients with renal transplantation

  • Occurs a mean of 44 weeks after transplantation

  • Peak occurrence is 24 weeks after transplantation

  • Risk is reduced in patients more than 1 year out from renal transplantation

Ureteral Stenosis

  • Prevalence of 3% in patients with renal transplantation

  • Prevalence ranges from 0.5 to 6% in the general transplantation population

Hemorrhagic cystitis

  • Prevalence of 10-25% of patients with hematopoietic stem cell transplantation

Which individuals are of greater risk of developing disease BK virus associated diseases?

  • Nephropathy (PVAN) occurs most often in renal transplantation patients within 1 year of transplantation. The risk of BK virus reactivation after 1 year is greatly reduced. Late onset BK reactivation in patients more than 1 year from transplant is associated with changes in immunosuppression such as steroid pulse to treat chronic rejection.

  • Hemorrhagic cystitis occurs most often in hematopoietic stem cell transplantation patients around the time of stem cell engraftment.

  • Predisposing factors include:

    • BK virus reactivation is a result of host predisposition, renal system damages, and immunosuppression. Immediately after transplantation, severe immunosuppressive medications, used to protect the transplanted organs, can trigger BK virus reactivation and proliferation in the renal cells.

    • Although the host is not able to completely control BK virus replication, the active replication of the virus can attract immune cells to the renal system. The non-specific immune response can then lyse the infected cells and trigger further renal dysfunction.

    • At engraftment of stem cells, the newly reconstituted immune response can result in an influx of BK virus-specific immune cells and cause further damage by the inflammatory response.

  • Factors associated with increased risk of BK virus reactivation include prior exposure to BK virus, older age of the host, and high anti-BK virus IgG levels prior to transplantation.

Beware: there are other diseases that can mimic BK virus associated diseases:

  • Nephropathy (PVAN): Transplanted kidney rejection can also present with similar symptoms and signs as BK virus associated nephropathy. Biopsy is crucial in deciphering rejection, for which increased immunosuppression is necessary for treatment, from BK virus associated nephropathy, for which decreased immunosuppression is instrumental in halting the viral replication.

  • Hemorrhagic cystitis: In the setting of stem cell transplantation, Hemorrhagic cystitis can also be caused by other viruses, such as adenovirus and CMV. Urine cytology for BK, Adenovirus, and CMV can contain decoy cells, which are enlarged nuclei with single basophilic intranuclear inclusion bodies. Urine can also show tubular casts and other inflammatory cells. Use urine polymerase chain reaction (PCR) to make a diagnosis of the culprit virus.

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

  • Serum creatinine - rise in creatinine

  • Urine cytology - decoy cells, with enlarged nucleus containing single basophilic intranuclear inclusion, tubular casts, and inflammatory cells

  • Blood BK PCR - detectable in nephropathy, usually not in hemorrhagic cystitis or ureteral stenosis

  • Urine BK PCR - elevated at levels greater than 107 copies/ml

  • Urinalysis – Increased detection of RBC

Results that confirm the diagnosis

  • Nephropathy: renal biopsy - enlarged intranuclear inclusions and cell detachments, cytopathic changes start at the medulla and distal tubules, and progress to proximal tubules.

  • Hemorrhagic cystitis and ureteral stenosis: elevated urine BK PCR greater than 107 copies/ml, hematuria, adrenal insufficiency.

What imaging studies will be helpful in making or excluding the diagnosis of BK virus associated diseases?

  • Imaging studies are not helpful in making the diagnosis. However, renal ultrasound can be useful to detect obstructions in the ureters.

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

If you decide the patient has BK virus associated diseases what therapies should you initiate immediately?

  • Nephrology

  • Infectious Disease

  • Urology

If possible, reduce immunosuppression.

BK virus proliferation is well controlled by the host cellular immune response. Therefore, currently, the best treatment is reduction in immunosuppression to restore the host cellular immune response.

1. Anti-infective agents

If I am not sure what pathogen is causing the infection, what anti-infective should I order?

There is no empiric therapy for BK virus.

2. Next list other key therapeutic modalities.

  • Nephropathy

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

    • Pre-emptive screening for 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 transplant graft failure; 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; however, no randomized or controlled studies have been performed, and 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 fluoroquinolone class. There are case reports describing benefits when used alone or in combination with immunosuppression reduction; however, there are no randomized or controlled studies to prove benefit.

    • Intravenous infusion of pooled immunoglobulins could decrease BK viral load in the plasma, as demonstrated in a small study of kidney transplant recipients. Randomized controlled studies are needed to determine efficacy.

  • Ureteral stenosis

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

    • Surgical intervention is necessary to relieve obstruction.

  • Hemorrhagic cystitis

    • Control of bleeding and supportive care, including bladder irrigation, analgesia, hyperhydration, and transfusion, are needed.

    • Reduce immunosuppression if possible.

    • Antiviral agents reported in literature include:

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

      • Cidofovir 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.

      • Although leflunomide is used by clinicians and described in case reports, there are no randomized or controlled studies to prove benefit.

Controversial or evolving therapies

There are now several case reports and one retrospective study on the use of hyperbaric oxygen for treatment of BK virus associated disease. Mechanism of this treatment in a viral infection is unclear. True benefit will still need to be better studied.

Since BK cellular immune response can control viral replication, cellular mediated therapy in development may prove to be useful.

What complications could arise as a consequence of BK virus associated diseases?

What should you tell the family about the patient's prognosis?

  • Up to 20-30% of patients with BK virus associated nephropathy can lose the transplanted kidney graft.

  • Hemorrhagic cystitis and ureteral stenosis can progress to renal obstruction and renal failure.

  • Hemorrhagic cystitis can result in uncontrolled bleeding.

  • There is up to a one-third chance of a patient losing the transplanted kidney.

  • Bleeding and renal failure can be reversed with supportive care and surgical measures. If immune reconstitution is feasible to better control BK virus proliferation, then chances are better for complete recovery. In rare instances, patients can die from BK virus associated diseases.

  • BK virus associated nephropathy is associated with transplanted kidney graft loss in 1-10% of patients with nephropathy. Better prognosis for graft survival is correlated with the histological findings of mild viral cytopathic changes with minimal inflammatory infiltrates or fibrosis. A robust BK virus specific cellular immune response is correlated with a decrease in both BK viruria and viremia.

Add what-if scenarios here:

  • In a patient with BK virus associated diseases, what if a rise of BK serology is detected?

    • A rise of BK serology is associated with viral reactivation. This rise in antibodies does not prevent disease.

  • What if a slow rise in creatinine is detected without any symptoms?

    • BK virus associated diseases can be responsible for the decline in renal function, even without any symptoms.

  • What if adenovirus or CMV is detected in the urine of patients with hemorrhagic cystitis?

    • Treatment for CMV or adenovirus should be initiated. Presentation and urine cytology of hemorrhagic cystitis caused by BK, CMV, and Adenoviruses are similar. The only way to distinguish between them is by urine PCR.

  • What if renal biopsy is negative for BK virus?

    • BK virus associated kidney disease is focal. Although biopsy is the gold standard for diagnosis, there is a 30% false-negative rate associated with biopsy.

How do you contract BK virus associated diseases and how frequent is this disease?

  • BK virus asymptomatic primary infection occurs early in life, with seroprevalence reaching more than 50% at 10 years of age and to up to 90% in adults. BK virus resides in the kidneys. Low levels of replication are asymptomatic and result in BK viruria in 5% of healthy individuals. This prevalence of viruria may vary throughout a person’s lifetime and increases with pregnancy, age, and immune dysfunction.

  • PVAN rarely occurs in the native kidney. The current prevalence of PVAN in renal transplantation patients ranges from 1 to 10%, with a trend of increasing prevalence as newer and more potent immunosuppressive medications are used. PVAN is diagnosed on average 44 weeks after transplantation with a peak around 24 weeks. The risk of developing PVAN decreases significantly by 1 year after transplantation. Incidence of ureteral stenosis in the renal transplant population is approximately 3%, and it is 0.5-6% of the general transplant population. The most prevalent BK associated disease is hemorrhagic cystitis, which occurs in 10-25% of hematopoietic stem cell transplantation patients with a peak at the time of stem cell engraftment.

Incidence

  • PVAN was found to be 0.93% of more than 100 kidney allografts studied in one center.

  • One small study estimated the cumulative incidence of BK virus hemorrhagic cystitis in hematopoietic stem cell transplantation children and adolescents was 0.43.

Mode of spread

  • Primary infection of BK virus occurs early in life. It is unclear how BK is spread. Since it is detected mostly in urine and the kidney, the urine-oral route seems logical.

  • Polyomaviruses are species specific. Therefore, the human polyomavirus BK can only infect humans.

What pathogens are responsible for this disease?

  • BK virus is a human polyomavirus that resides in the kidneys of up to 90% of healthy individuals. Reactivation of the BK virus and the subsequent immune response resulting in cellular destruction causes BK virus associated diseases in immunocompromised patients.

How does BK virus cause disease?

  • BK virus primary infection occurs in childhood. Primary infection is asymptomatic. Seroprevalence of BK virus increases with age starting from infancy after waning of maternal antibodies, reaching more than 50% by 10 years of age and up to 90% in adults. BK virus resides in the kidney epithelial cells. Asymptomatic reactivation resulting in BK viruria occurs in 5% of healthy adults and is usually not associated with nephropathy or hemorrhagic cystitis. BK virus associated diseases are a result of host predisposition, organ damage, and immunosuppression. At the time of transplantation, immunosuppression decreases the host cellular immune response to BK virus, thus, triggering reactivation of the virus. The initial non-specific immune response, along with later BK-specific responses after return of cellular immune function, results in cellular damage and causes organ dysfunction.

What other clinical manifestations may help me to diagnose and manage BK virus associated diseases?

  • Factors influencing immune response are important. These can include family and personal history of immune deficiency diseases and autoimmune disease.

History

  • Immune deficiency

  • Autoimmune disease

  • Other opportunistic infections

  • Risk factors for HIV - Urine BK viral load increases with a decrease of CD4+ T-cell counts in HIV-positive patients.

Physical exam

  • Suprapubic pain

  • Bladder fullness

What other additional laboratory findings may be ordered?

  • BK virus-specific cellular immune response is currently only performed by research laboratories. Measuring such response can provide a prognosis of the diseases to patients.

How can disease BK virus associated diseases be prevented?

  • There are currently no vaccines or approved antiviral medications for BK virus. Therefore, careful monitoring for early detection of BK virus reactivation is the best option.

  • In renal transplantation patients, most centers monitor BK virus by performing PCR of plasma or urine at frequent follow-up intervals up to 2 years following transplant. If reactivation is detected, the immunosuppressive medications can be decreased, when feasible, so that the cellular immune response can increase. BK virus PCR is checked in the blood every 4 weeks until BK virus is completely suppressed. Studies have shown decreased incidence of nephropathy when such early screening for BK viruria and viremia is followed by reduction in immunosuppression. Such monitoring protocols can be considered in hematopoietic stem cell transplantation patients also.

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

(Small study showing reduced BK viral load with IVIG treatment.)

(Commercially available IVIG contain neutralizing antibodies against several serotypes of BK virus.)

DRG CODES and expected length of stay

596.7 - hemorrhagic cystitis

593.3 - ureteral stenosis

589.3 - nephropathy

Length of stay varies depending on comorbidity.

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