Incidence of and Risk Factors for Cytomegalovirus (CMV), Epstein Barr Virus (EBV) and Adenovirus (ADV) Reactivation in Pediatric Recipients Post Allogeneic Hematopoietic Stem Cell Transplantation (AlloHCT)

Viral infections are associated with significant morbidity and mortality following AlloHCT. There are no established guidelines for the frequency of viral monitoring and only a few studies in children have analyzed the impact of viremia on AlloHCT related outcomes. In 2008, our center created a standard operating procedure of prospective PCR monitoring for CMV, EBV and ADV prior to AlloHCT and then weekly for 180 days post AlloHCT.

Patients were considered to have viral reactivation if CMV, EBV and ADV copies/ml were ≥600, 1000 and 1000, respectively. Viremia was defined as peri-AlloHCT (d0 - d+14), early viremia (d15 - d+98) and late viremia (d+99 - d+180). From 2008- 2012, 100 consecutive children (median age, 8 yrs; range 0.25-22 yrs; 35F/ 65M) undergoing AlloHSCT for malignant (n=53) and nonmalignant (n=47) disorders, were monitored.  Donor sources included: matched family donor (n= 42, 42%), matched unrelated donors (n=28, 28%) and unrelated cord bloods (n=20, 20%). Patients were conditioned with either myeloablative [MA] (n=43, 43%), reduced toxicity [RT] (n=35, 35%), or reduced intensity [RI] (n=22, 22%) regimens. Additionally, a total of 79 patients (79%) received serotherapy with alemtuzumab (n=48, 48%) or rabbit-Anti-thymocyte globulin [r-ATG] (n=31, 31%).

The incidence of pre-AlloHCT viremia was 8%. The incidence of post-AlloHCT single viremia, multiple viremia and viral disease was 41, 15 and 22% respectively. The incidence of peri-AlloHCT, early and late viremia was CMV: 5%, 22.2% and 6.6%;   EBV: 1%, 9.1% and 1.1%; ADV: 5%, 10.1%, and 6.6%, respectively. Viremia was noted in 36/80 (45%) of patients who received serotherapy vs. 5/20 (25%) who did not receive serotherapy (Chi-square test p=0.1). Days for neutrophil, platelet engraftment, incidence of graft failure and aGVHD were not statistically significant between patients with and without viremia.

We performed  univariate and multivariate analysis for risk factors associated with viremia:  age, sex, donor, stem cell source, graft failure, CMV risk status, alemtuzumab, r-ATG, malignant vs. non-malignant disease, MA vs. RT vs. RI regimens, absolute neutrophil and lymphocyte count at day +30.  Only CMV risk status (p=.0002) and pre-AlloHCT viremia (p= 0.0095) were significant on multivariate analysis. Among patients with viremia vs. those without viremia,  1yr transplant related mortality (TRM) and all-cause mortality was 23.7% vs. 16.7 (p=.4) and 36.8% vs. 18.5% (p=0.04),respectively.

Among patients with viremia vs. without viremia, the median length of initial hospitalization (LOH) vs. LOH in the first 180 days were 44 days  (9-144) vs. 35(19-180) (p=0.02) and 91 days ( 9-165) vs. 59 days (19-180), (p=0.05) respectively. Post-AlloHSCT viremia remains a significant problem and results in a significantly longer LOH. Potentially due to weekly monitoring the TRM was not significantly higher in patients with viremia.