02 December 2020

BK virus (BKV) is a commonly acquired polyomavirus that, whilst not generally causing problems in healthy individuals, can reactivate in the immunocompromised to cause significant morbidity. The recent publication from Nantes of two kidney transplant patients with reactivation of BKV following COVID-19 infections[1] highlights the careful balance of immunosuppression required to avoid BK viral infections. In this article, we provide a general overview of this virus, the diseases associated with it, and the current status of treatment options. 

The virus
BKV is a ubiquitous polyomavirus, a double-stranded DNA virus belonging to the family Polyomaviridae.[2] It was first reported in 1971 in a patient who developed graft dysfunction 5 months following kidney transplantation[3] and the increasing frequency of BKV disease coincides with the emergence of more effective immunosuppressive treatments.[2, 3] 

BKV is commonly acquired during childhood, being generally asymptomatic or associated with only mild flu-like symptoms.[2, 4, 5] Following the initial infection, the virus establishes latency within renal tubular and uroepithelial cells[5, 6] but can also reside in the liver, lungs, brain, and lymph nodes.[4] 

The seroprevalence rate in children under 5 years old is 50% and in adults is 80-90%.[4-7] BKV can be transmitted by several methods including the faecal-oral route, via the respiratory tract, through blood transfusions and organ transplantation and trans-placentally.[4] In healthy individuals, the virus usually remains latent and generally does not cause any problems[2, 4] but viruria can occur in up to 20% of people.[4, 8] In immunocompromised individuals, however, reactivation is common causing significant morbidity, in particular, BKV-associated nephropathy (BKVAN) in kidney transplant recipients and haemorrhagic cystitis (HC) in haematopoietic stem cell (HSCT) recipients.[2, 4-7] 

Pathogenesis
In kidney transplant recipients, BKV reactivation can occur shortly after immunosuppression and in up to 50% of recipients within the first 3 months. Loss of the transplanted kidney can occur in 30-80% of cases.[3] Data from a US Registry showed that the 3-year graft survival was significantly lowered with BK nephropathy (79% vs. 90%).[3, 8] To prevent this, a reduction in the immunosuppressive therapy is recommended as no other effective treatment is available but this can lead to acute organ rejection.[3, 9]

BKV reactivation can occur in the bladder of kidney transplant patients causing HC that requires bladder irrigation, clot evacuation, blood transfusion, stenting and nephrostomy.[3] 

In HSCT recipients, HC can occur within the first week of transplantation or later during engraftment, generally from Day 10 to 6 months after HSCT, with an incidence ranging from 7 to 70%.[2] Early HC is a consequence of viral reactivation resulting from conditioning toxicity, chemotherapy/radiotherapy, or a combination of these whereas late HC is thought to be due to BKV replication in the urinary tract which has been damaged by previous therapies.[2, 4] High morbidity and mortality is associated with BKV infection in HSCT recipients, particularly when HC is refractory to initial therapies. The infection rate can be as high as 47% and most cases result from BKV reactivation although de novo infection also occurs.[2] 

HC can cause an obstructive syndrome resulting in a tubule-interstitial nephritis or a nephropathy which may lead to renal impairment. Because kidney injury after HSCT is multifactorial and not systematically documented by kidney biopsy, the actual incidence of nephritis after HSCT is unknown.[2] 

Risk factors
Immunosuppression is the major risk factor for post-transplant BKV infection[2, 5], especially tacrolimus- or mycophenolate-based regimens[9]. Other risk factors include donor seropositivity, old age, diabetes, lymphocyte-depleting induction, and ureteral stents.[2, 9] 

The risk of reactivation depends on various factors including kidney injury, ischaemia, drug toxicity, how much virus is present, and the nature of the immune deficit. Temporary BKV viruria occurs in 30–50% of all renal transplant recipients and approximately one-third present with viraemia, but only 1-10% of patients progress to BKVAN.[4]

Diagnosis
Originally, BKV infection diagnosis was based on rising antibody titres but this proved not to be clinically relevant. Epithelial cells bearing viral inclusions (‘decoy cells’) in urine sediment are present in 40-60% of renal transplant recipients and virus particles can be detected by electron microscopy.[2]

BKV infection following kidney transplantation may gradually progress from viruria to viraemia and then, in 20-40% of viraemic patients, to BKVAN. BKVAN is diagnosed by polymerase chain reaction (PCR)-based plasma and urine viral load analysis with sustained urine viral loads of >7 log10 copies/mL, correlating with the onset of viraemia and a sustained plasma BKV-DNA load of >4 log10 copies/mL being presumptive BKVAN.[4, 10] BKV is initially detected in the urine around 16 weeks and in plasma around 23 weeks, eventually leading to BKVAN around 28 weeks.[4] However, laboratory assays (including quantitative PCR), whilst identifying patients at increased risk, do not provide a definitive BKVAN diagnosis which requires a biopsy to assess the degree of tissue injury. BKVAN is characterised by sub-acute virus-induced tubular injury, inflammation, and progressive nephron damage and by a positive immune-histochemistry staining reaction of SV40 large tumour antigen, a protein encoded in the genomes of polyomaviruses.[2, 4]

Current treatment options
Currently, no approved treatments for renal nephropathy or HC caused by BKV exist and no specific antiviral therapy is available. Management typically consists of reducing immunosuppression with the aim of reconstituting effective BKV immune responses, alleviating discomfort and controlling symptoms.[2, 3, 9]

Ciprofloxacin (a broad spectrum antimicrobial), leflunomide (an immunomodulatory agent) and vidarabine (a purine analogue) all demonstrated some clinical efficacy either in reduction of viruria or improvement in clinical symptoms but there is no strong evidence to support the use of these molecules.[2-4, 9]

Cidofovir, a cytosine derivative of an acyclic nucleotide phosphonate analogue active against various DNA viruses, is commonly used even though efficacy has not been clearly shown and it has significant adverse effects on renal function.[2]

Thus, there is a need for high-quality controlled clinical studies to define the optimal treatment strategies following BKV reactivation. Adoptive cell therapy using ex vivo-expanded BKV-reactive T cells is a novel therapeutic approach that is currently in early clinical development.[2, 3, 6] 

References
1.    Masset, C., et al., Resurgence of BK virus following Covid-19 in kidney transplant recipients. Transpl Infect Dis, 2020: p. e13465.
2.    Saade, A., et al., BK virus infection in allogeneic hematopoietic cell transplantation: an update on pathogenesis, immune responses, diagnosis and treatments. J Infect, 2020.
3.    Muhsin, S. and D. Wojciechowski, BK virus in transplant recipients: current perspectives. Transplant Research and Risk Management 2019. 11: p. 47–58.
4.    Krajewski, W., et al., Pathogenicity of BK virus on the urinary system. Cent European J Urol, 2020. 73(1): p. 94-103.
5.    Favi, E., et al., Incidence, risk factors, and outcome of BK polyomavirus infection after kidney transplantation. World J Clin Cases, 2019. 7(3): p. 270-290.
6.    Ambalathingal, G.R., et al., BK Polyomavirus: Clinical Aspects, Immune Regulation, and Emerging Therapies. Clin Microbiol Rev, 2017. 30(2): p. 503-528.
7.    Sawinski, D. and S. Goral, BK virus infection: an update on diagnosis and treatment. Nephrol Dial Transplant, 2015. 30(2): p. 209-17.
8.    Hirsch, H.H., BK virus: opportunity makes a pathogen. Clin Infect Dis, 2005. 41(3): p. 354-60.
9.    Sawinski, D. and J. Trofe-Clark, BK Virus Nephropathy. Clin J Am Soc Nephrol, 2018. 13(12): p. 1893-1896.
10.    Cesaro, S., et al., ECIL guidelines for the prevention, diagnosis and treatment of BK polyomavirus-associated haemorrhagic cystitis in haematopoietic stem cell transplant recipients. J Antimicrob Chemother, 2018. 73(1): p. 12-21.