Levofloxacine Prophylaxis Decreases the Incidence of BK Polyoma Virus-Induced Hemorrhagic Cystitis in Patients after Allogeneic Hematopoietic Stem Cell Trans-Plantation
Authors: Ono Yoko , Lache Manja , Jacob Florian , Schneidawind Dominik , Schmitt Anita , Michel Detlef , Mertens Thomas , Döhner Hartmut , Bunjes Donald , Schmitt Michael 
Published: April 2020

Abstract
Objective: BK polyoma virus (BKV) can cause hemorrhagic cystitis (BKV-HC) in patients after allogeneic stem cell transplantation (allo-SCT). Levofloxacine can hamper the proliferation of BKV in patients after kidney transplantation even resulting in less rejections of transplants. We therefore wondered whether the prophylactic use of levofloxacine might also reduce the incidence of BKV-HC in patients after allo-SCT.
Methods: 178 patients undergoing SCT at our institution were included in this study. 72 patients received a BKV-HC prophylaxis with 500 mg/d levofloxacine administered orally till d+50 while 102 patients did not. Patients developing clinical symptoms of cystitis were screened for BKV in the urine by PCR.
Results: 31/102 (30%) patients from the non-prophylaxis group tested positive for BKV after developing clinical symptoms of cystitis. The severity of BKV-HC was classified clinically as follows: grade I (no microhematuria) = 10, grade II (micro-, but no macrohematuria) = 11, grade III (macrohematuria) = 9, and grade IV (intravesicular blood clots) = 1. Patients with BKV-HC grade I were treated symptomatically by oxybutynin. Grade II patients received levofloxacin alone, grade III patients additionally leflunomide. The patient with grade IV BKV-HC received in addition bladder instillations with prostaglandin. BKV-HC was not associated with higher mortality (p=0.77). Differences according to the conditioning regime could be observed: 29 % of patients receiving a radio immune therapy (RIT) developed BKV-HC, vs. 26 % of patients after reduced intensity conditioning (RIC), vs. 19 % of patients after standard or FLAMSA regimen, vs. 7 % of patients after mini-RIT. In contrast, only 12 of 72 patients (17%) with levofloxacin tested positive for BKV in the urine. These patients showed mild or moderate clinical symptoms with microhematuria. Oxybutinin and leflunomide were added and the patients recovered. As for the conditioning, BKV-HC occurred in 4/20 patients after FLAMSA conditioning and 8/36 patients after standard conditioning, but not patients after (mini-)RIT. Of note, the difference between the prophylactic group with a BKV-HC incidence of 17% vs. 30% in the non-prophylaxis group tested significant (p&lt;0.05). We performed T cell assays for 16 HVs and 2 patients who expressed HLA-A2. In 8/16 HVs tested for the VP1p108–116 epitope and in 3/5 HVs tested for the VP1p90–99 epitope BKV specific CD8+ T cells could be detected, two BKV-HC patients had BKV specific T cells for the VP1p108–116 (LLMWEAVTV) epitope and one for the VP1p90–99 (STARIPLPNL) epitope. Addition of levofloxacine to in vitro T cell assays did alter the BKV specific T cell frequency.
Summary: Incidence of BKV-HC depends on the type of conditioning, and can be significantly reduced by levofloxacin prophylaxis. The role of T cell immune response to BKV remains to be elucidated.