Risk Factors of BK Virus Cystitis in Haematopoietic Stem Cell Transplantation-a Retrospective Monocentric Study

Background: BK virus (BKV) is a human polyomavirus. Reactivation occurs during deep immunosuppression as in hematopoietic stem cell transplantation (HSCT) and renal transplantation, leading to hemorrhagic cystitis (HC) and nephropathy respectively. In HSCT, systematic PCR for BKV in urine is positive for 50 to 100% of patients (pts), but only 5 to 40% develop a BKV HC. Thus, BKV PCR is usefull to confirm a diagnostic of BKV HC but not to predict its occurrence. Several risk factors to develop BKV HC have been studied, especially mismatched HLA and haploidentical HSCT.

Objectives: The aim of this retrospective study was to ascertain the risk factors to develop BKV HC.

Methods: A retrospective study was performed by considering data from Grenoble University Hospital in the national retrospective register ProMISe, from the SFGM-TC. The period of the study covered from January 2014 to January 2018. PCR BKV in urine was performed when pts presented hematuria grade 2 or higher with clinical symptoms of cystitis. Viral nucleic acid was extracted from the urine samples with the EasyMag platform (Biomérieux) and the qPCR with BK Virus R-GENE^®kit (ARGENE) on a LightCycler 480 (ROCHE). BKV HC is defined by the association of clinical symptoms of cystitis, haematuria grade 2 or higher and a BKV viruria >7 log10 copies/mL. Univariable and multivariable logistic regression model were used to identify risk factors for BK cystitis.

Results: 188 HSCT were performed during the study period. After exclusion of 13 pts for early mortality (<30 days) and 4 for engraftment failure, 171 pts were finally considered for analysis, from whom 43 (25.1%) developed a BKV HC. The median age of patients presenting with BKV HC was 44 years (23-62) and males represented 67.4 %. Acute leukemia was the most common indication of HSCT (74.4%), followed by myelodysplastic syndromes (9.3%), lymphoma (6.9%), myeloproliferative neoplasms (4.7%) and aplastic anemia (4.7%). In most cases, pts were not in complete response at transplant (51.2%). First autologous or allogenic HSCT had previously been performed for 30.2% of pts. The majority of pts had a transplant with peripheral stem cells as graft source (76.6%), and had a transplant with mismatched HLA (9/10, n=9, 20.9%) or haploidentical donors (n=13, 30.2%). Twenty-nine pts (67.4%) received reduced-intensity conditioning and twenty-two pts (51.2%) received cyclophosphamide post allograft to prevent Graft Versus Host Disease (GVHD). BKV HC prophylaxis relied on hyperhydratation and mesna during the conditioning regimen.

The median time to develop HC was 42 days post-transplantation (30-55) mainly with a grade 3 HC (53.5%). The median viruria was 9 log (9-10). Cidofovir was administered as curative treatment to 20 pts (46.5%) and 25 pts (58%) needed bladder irrigation and forced diuresis. The median level of platelets at diagnosis was 58 G/L (29-123). At diagnosis of BKV HC, 32.6% of pts presented a bacterial cystitis and 62.8% an acute renal failure. Allogenic HSCT was complicated by an acute GVHD in 88.4% of pts and 69.8% were treated by corticosteroids. CMV reactivation was observed in 39.5% of pts, and HHV6 in 18.6%.

In univariate analysis, post-transplant cyclophosphamide (p<0.001), age below 40 years (p<0.001), history of previous auto or allograft (p=0.007), allograft with mismatched HLA (9/10 and haploidentical) (p<0.001), use of peripheral stem cells (p=0.047), engraftment of platelets >100 days (p=0.016), acute GVHD (p=0.007), corticotherapy (p<0.001), co-infection by HHV6 (p=0.006), association to bacterial cystitis (p=0.002), acute renal failure (p=0.009) and platelets below 50G/L (p<0.001) were significantly associated with increased risk of BKV HC.

After logistic regression, the risk factors associated with BKV HC were reduced to: exposition post-transplantation to cyclophosphamide (OR 4.1, 1.5-10.7, p=0.004), age below 40 years (OR 4.1, 1.6-10.9, p=0.004), corticosteroids therapy (OR 3.9, 1.6-9.5, p=0.033), acute renal failure (OR 3.8, 1.5-9.6, p=0.0056), bacterial cystitis (OR 3.3, 1.2-8.7, p=0.0175), and platelets below 50G/L (OR 3.8, 1.382-10.486, p=0.097).

Conclusion: BKV HC was observed in 25.1% of patients. Exposition to cyclophosphamide, young age, corticosteroids therapy and bacterial cystitis are potential risk factors of BKV HC. Surprisingly, young age was not expected as risk factor.