A Prospective Multi-Center Study of the Natural History of BK Viremia and Host Immune Response in Children after Allogeneic Hematopoietic Cell Transplant

Introduction BK viremia (BKV) increases the risk of complications after hematopoietic cell transplant (HCT). Most studies are retrospective with no data on the host immune response to BKV. Methods We previously presented 39 children followed prospectively at the Children's Hospital of Philadelphia. We now report a larger prospective validation cohort of 145 consecutive consenting children and young adults transplanted at Cincinnati Children's Hospital with serial blood samples for BKV (PCR; pre-HCT, months 1-4, 8, 12, and 24) and BK serology (IgG ELISA; pre-HCT, months 3 and 12). We also report BK virus-specific T cell function (ELISPOT for interferon gamma (IFNG) release after stimulation with BK VP1 and LTA peptides; month 3). Hemorrhagic cystitis (HC) was defined as at least gross hematuria (chart review) and chronic kidney disease (CKD) as a creatinine glomerular filtration rate persistently 2 ≥8 months post-HCT. Results 145 patients (median age 10 years, interquartile range (IQR) 6-14 years) received HCT (47% bone marrow failure, 28% malignancy, 23% immune deficiency, 2% other) with myeloablative conditioning in 94/145 (65%) and 71/94 (76%) receiving cyclophosphamide. 44/51 (86%) with reduced intensity conditioning received alemtuzumab. Median follow-up was 2.0 years (IQR 0.82-3.8 years) and 51/145 (35%) had acute GVHD, 14/145 (10%) received dialysis, and 36/145 (25%) died of any cause. 53/145 (37%) had quantifiable BKV on >1 sample. HC was diagnosed in 23/145 (16%) a median 32 days after HCT (IQR 22-46 days). The temporal association between BKV and HC was tested by excluding 7 patients with HC before their first monthly sample. We then observed that BKV independently predicted subsequent HC (Hazard Ratio (HR) 3.3, 95% CI 1.01-10.81; P 129/132 (98%) of tested subjects were seropositive for BK IgG pre-HCT but this did not predict later BKV or HC. 24 subjects with BKV in the first 3 months had ELISPOT testing to identify BKV specific T-cell recovery: 12/24 had absent BK-specific T cells (IFNG ELISPOT Conclusion One third of children had BKV, double the number developing HC. Early BKV predicted subsequent HC and HC was associated with later CKD. Patients who developed BK-specific T cells were more likely to clear BKV than those who did not. These data support strategies to identify patients most likely to benefit from cellular or pharmaceutical interventions to reduce the duration and severity of BKV.