Symptomatic BK virus cystitis in non-renal transplant recipients

Abstract

Background

BK virus is implicated most commonly in causing BK virus-associated nephropathy in renal transplant recipients. However, on rare occasions, it can also produce symptomatic cystitis in other solid organ transplant recipients.

Methods

Retrospective review of 2,149 non-renal solid organ transplant recipients over a 6-year period to evaluate patients for cases of symptomatic BK virus cystitis.

Results

Three patients (two heart transplant recipients and one lung transplant recipient) are reported herein with symptomatic BK virus cystitis. These patients responded to reduced immunosuppressive medication with a reduction in viral load in two instances, and the third patient appeared to have an apparent response to prolonged levofloxacin treatment.

Conclusions

A high index of suspicion should be exercised in non-renal solid organ transplant recipients (particularly heart and lung transplant recipients) who have symptoms consistent with cystitis but have a negative urine bacterial culture.

BK virus (BKV) is a nonenveloped DNA virus of the genus polyomavirus and a member of the Polyomaviridae family (1). BKV seroprevalence reaches 91% by the first 10 years of life (2) and may produce asymptomatic viruria in 6.6% to 15.7% of immunocompetent individuals (3). However, in renal transplant recipients, BKV infection affects the kidney and may result in polyomavirus nephropathy (PVAN) with ultimate graft failure in 46% of the patients affected (4).

BK viruria and viremia in non-renal transplant recipients is far less common. This entity has been described in heart transplant recipients; in two prospective studies, incidence of BK viruria ranged from 20% to 42.8% of recipients, with 10% to 21.4% having viremia (5,6). Moreover, there have been case reports in heart transplant recipients in whom BK virus infection produced PVAN (7–14). In contrast, polyomavirus-associated hemorrhagic cystitis (PVHC) is well described in allogeneic hematopoietic stem cell transplant (HSCT) recipients (15). Surprisingly, three cases of hemorrhagic cystitis secondary to BK virus infection have also been described in lung, liver, and renal solid organ transplant recipients, in both pediatric and adult patients (16–18). Herein, we report a case series of two heart and one lung transplant recipients with the clinical presentation of symptomatic BKV cystitis confirmed by bladder viral cytopathic effects consistent with polyomavirus infection.

Patients and Methods

We reviewed the medical records of non-renal transplant recipients with BKV viruria who reported lower urinary tract symptoms restricted to the bladder (dysuria, frequency, hematuria, and bladder discomfort). Demographic data were collected and recorded on their underlying and comorbid illnesses, transplant procedures, immunosuppressive therapy, urine cytology, urine bacterial cultures, BKV viral loads in the urine and plasma, renal function, cystoscopy findings, and therapeutic interventions. BK viral loads were performed by polymerase chain reaction using the BKV PCR Kit 1.0 (Astra Diagnostics Inc., Mississauga, Ontario) initially, and then the BKV PCR Kit 1.0 (Altona Diagnostics, Toronto, Ontario), in the microbiology laboratory of Mount Sinai Hospital in Toronto, Ontario.

Results

Case 1

A 58-year-old man with a history of idiopathic cardiomyopathy, obstructive sleep apnea, and diabetes mellitus was admitted to the hospital with unstable ventricular tachycardia and congestive heart failure. He progressed to pulseless electrical activity but was resuscitated. He sustained acute kidney injury and was subsequently dialyzed using sustained low-efficiency dialysis. Thereafter, he underwent cardiac transplantation using basiliximab induction. Post-transplant, his condition improved and dialysis was discontinued. However, he continued to have renal insufficiency with a creatinine ranging from 120 to 160 µmol/L. His immunosuppressive therapy consisted of tacrolimus, prednisone, and mycophenolate mofetil.

Twenty-two months post-transplant, the patient developed urinary frequency and urgency with incontinence. He denied fever, flank pain, and macroscopic hematuria. His creatinine remained stable (120 µmol/L). His urinalysis showed no leukocytes, nitrites, or red blood cells. The urine culture had no growth. The patient did undergo cystoscopy and a video urodynamic study that showed a picture of an overactive bladder, but no urine cytology was performed. Fesoterodine therapy was commenced with partial relief of his frequency. Cystoscopy was repeated 4 months later to rule out malignancy when atypical cells were detected in the urine, and urinary frequency persisted. Although cystoscopy showed no evidence of malignancy, bladder irrigation cytology demonstrated viral cytopathic effects consistent with polyomavirus. Urine and plasma viral assays demonstrated BK viral loads of 9.77 × 10¹⁰ copies/mL, and 1.43 × 10⁴ copies/mL, respectively (Table 1). His urine was negative for adenovirus. As a result, his mycophenolate mofetil dose was reduced from 1,080 mg twice daily to 720 mg twice daily. Heart biopsies were conducted every 3 to 6 months to ensure no development of rejection. His BK urine viral load decreased thereafter to 9.11 × 10⁸ copies/mL with a plasma viral load of 2.83 × 10³ copies/mL and some resolution of his symptoms. Nevertheless, BK viruria continued at a reduced viral load, but the patient was asymptomatic.

Table 1:

Clinical characteristics of patients with symptomatic BKV infection

Characteristics	Case 1	Case 2	Case 3
Age (y), male	58	61	30
Primary diagnosis	Idiopathic cardiomyopathy	Interstitial pneumonia (IP)	Complex cyanotic congenital heart disease
Transplanted organ	Heart	Single left lung	Heart (×2)
Immunosuppression at time of BK cystitis diagnosis	MMF/tacrolimus /prednisone	MMF/cyclosporine Azathioprine	Sirolimus /prednisone
Episodes of rejections	None	Two episodes, treated with methyleprednisone	None
Kidney function pre-transplantation
Creatinine µmol/L	122	66	No available data; transplanted at age 10 years
eGFR mL/min	55	107
Kidney function at time of cystoscopy
Creatinine µmol/L	120	112	181
eGFR mL/min	57	61	40
BK viruria at diagnosis (copies/mL)	9.77 × 1010	3.80 × 106	1.27 × 1010
BK viremia at diagnosis (copies /mL)	1.43 × 104	1.86 × 102	6.35 × 106
Treatment	MMF reduced by 33%	MMF reduced by 25%	Levofloxacin 250 mg daily
Associated bladder carcinoma	No	No	Yes
Status at last available follow-up	Asymptomatic	Died due to CLAD	Asymptomatic

MMF = mycophenolate mofetil; eGFR = estimated glomerular filtration rate; CLAD = chronic lung allograft dysfunction

Case 2

A 61-year-old man underwent a left single lung transplant for interstitial pneumonitis. His comorbid conditions included diabetes mellitus and atrial fibrillation. A cardiac arrest complicated the procedure during the induction of anesthesia. He did require prolonged intubation post-transplant and sustained a right middle cerebral artery stroke in the post-operative period, from which he recovered. His immunosuppressive medications post-transplantation were prednisone, cyclosporine, and azathioprine.

The patient experienced two episodes of cellular rejection for which he received a steroid pulse of 10 mg/kg of methylprednisone at 7 months post-transplantation. Subsequently, 14 months post-transplant, he noted dysuria and frequency with macroscopic hematuria at the end of micturition. His urinalysis revealed no leukocytes or nitrites, but a trace of blood was observed. The urine culture showed no growth of any organisms. Cystoscopy was performed just over 2 years post-transplant, and the bladder cytology demonstrated viral cytopathic effect consistent with polyomavirus effect. No urine testing for adenovirus testing was performed as the urine cytology indicated polyomavirus infection. Urine and plasma BK viral loads were 3.80 × 10⁶ copies/mL and 1.86 × 10² copies/mL, respectively. Because of his symptoms, his mycophenolate mofetil dose was reduced from 720 mg twice daily to 540 mg twice daily. Unfortunately, the patient died due to chronic lung allograft dysfunction and infection while visiting relatives in Ethiopia before further therapeutic manipulations and evaluations could be performed.

Case 3

A 30-year-old man underwent heart transplantation at the age of 10 years for complex cyanotic congenital heart disease. The patient developed graft vascular disease (severe allograft vasculopathy) and subsequently underwent a second heart transplant at 17 years of age. His comorbid conditions included psoriasis, dyslipidemia, migraines, and chronic kidney disease.

After his second heart transplant, the patient had recurrent cytomegalovirus (CMV) reactivations, producing CMV retinitis, for which he was treated with ganciclovir, but he did not respond. Genotype testing verified ganciclovir resistance. Subsequently, he was treated with foscarnet with a good response.

Three years after the second heart transplant, the patient was diagnosed with polymorphic post-transplant lymphoproliferative disorder based on a mesenteric lymph node biopsy. His Epstein–Barr (EBV) virus viral load was 20,805 copies of EBV DNA/mL. He received four cycles of rituximab.

Seven years after the second heart transplant, the patient had recurrent post-transplant lymphoproliferative disorder (PTLD), diagnosed by a jejunal biopsy, and was treated with six cycles of cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone. This was complicated by CMV reactivation that was treated with foscarnet and leflunomide.

Ten years after the second heart transplant, the patient noticed increased urinary frequency and terminal dysuria. He had a number of urine cultures, none of which showed any evidence of infection. His urinalysis showed no leukocytes, nitrites, or red blood cells. A computed tomography scan demonstrated bladder wall thickening along the left aspect of the bladder including the region of the trigone. Mild left hydroureter and hydronephrosis were present. Subsequently, cystoscopy did show irritation of the left ureteric vesical junction.

Biopsy of urinary bladder showed high grade intra-urothelial neoplasia (carcinoma in situ) with viral cytopathic effects consistent with polyomavirus. He had no other apparent risk factors for this cancer. The urine and plasma BKV viral load were 1.27 × 10¹⁰ and 6.35 × 10⁶ copies of DNA/mL, respectively. His immunosuppressive medications were sirolimus 1 mg daily, and prednisone 10 mg daily.

The patient underwent transurethral resection of his bladder tumour. Pathological examination of the resected tumour once more showed viral cytopathic effect consistent with polyomavirus in the tissue. He was subsequently treated with 12 Bacillus Calmette–Guérin (BCG) instillations in his bladder. The patient was also treated with levofloxacin 250 mg daily for BKV infection over a period of 53 months. BK viral load in the serum improved to a range of 1.60 × 10⁴ copies/mL to 9.95 × 10⁴ copies/mL. In addition, his symptoms of urinary frequency and terminal dysuria abated over this time. Thereafter, multiple cystoscopies found no evidence of recurrence. The patient was lost to follow-up, as he moved out of the country.

Discussion

Herein, we have described the unusual presentation of symptomatic BK virus cystitis in two heart transplant recipients and one lung transplant recipient. These cases occurred over a 6-year period during which 2,149 solid organ transplants were performed excluding all renal transplants. Polyomavirus hemorrhagic cystitis was present in the lung transplant recipient, while one of the heart transplant patients had BKV-related high grade intra-urothelial neoplasia (carcinoma in situ). BKV has also been associated with urothelial malignancies (19). Indeed, BKV DNA has been shown to be integrated into the cellular genome of urothelial carcinoma (20). The BKV genome elaborates an early protein, large T antigen, that may be oncogenic and promote a causal role for BKV in the development of urothelial carcinoma (21). Clinicians should have a high index of suspicion for BKV-related infection in non-renal solid organ transplant recipients with symptomatic cystitis who have no bacteria isolated in their urine cultures.

The diagnosis of BKV-related cystitis is based on the exclusion of bacterial bladder infection and detection of BKV by polymerase chain reaction in urine. Cystitis should be verified by cystoscopy of the bladder. Moreover, cystoscopy is also effective in ruling out the presence of BKV-induced urothelial cancer. All of our patients underwent cystoscopy to rule out malignancies, and bladder cytology detected the cytopathic changes related to BK virus.

The mainstay of therapy for polyomavirus-associated nephropathy is reduction in immunosuppression (22). Combined reduction in mycophenolate mofetil and the calcineurin inhibitor can be attempted initially to reverse polyomavirus-associated nephropathy (23–25). Subsequently, further immunosuppression reduction may be accomplished by discontinuing mycophenolate mofetil and a further reduction in calcineurin inhibitor immunosuppression (26). Thus, two of our patients experienced improvement in their symptoms of cystitis, with no further decline in renal function with reduction in mycophenolate mofetil. Another therapeutic option for those patients unresponsive to reductions in immunosuppression is leflunomide therapy (27). Leflunomide inhibits protein kinase activity and pyrimidine synthesis, thus reducing the production of BKV protein and DNA (2). Fluroquinolones, are inhibitors of DNA topoisomerase II (28) and possess activity against polyomaviruses in vitro (29). Levofloxacin is more active than ciprofloxacin against BKV (30) and attains higher urinary concentrations than ciprofloxacin (31) while only being administered once daily. Levofloxacin, however, failed to prevent BK viruria in a randomized trial in renal transplant recipients (32) and only produced a modest reduction in the treatment of viremia (33). Although our intervention was undertaken before the publication of these studies, we believe that the more prolonged course of treatment employed may have proven beneficial.

In conclusion, although infrequent based on the number of solid organ transplants performed at our institution a high index of suspicion should be exercised in non-renal solid organ transplant recipients (particularly heart and lung transplant recipients) who have symptoms consistent with cystitis but have a negative urine bacterial culture. Urine BKV, as well as blood BKV viral loads, should be performed. Subsequently, if there is evidence of BKV viruria, performing a cystoscopy to assess the bladder for inflammation related to BKV and rule out the presence of cancer would be prudent. Finally, reduction in immunosuppression should be undertaken initially to relieve bladder symptoms and prevent the development of further complications such as urothelial cancer.

Competing Interests:

The authors have nothing to disclose.

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Funding:

No funding was received for this work.

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This article has been peer reviewed.