Adenovirus PCR-Positivity in Stool Precedes Intestinal GRAFT Versus HOST Disease After Allogeneic Hematopoietic STEM CELL Transplantation

Introduction
Acute graft versus host disease (aGvHD) is a common (20-50% of all HSCT recipients) and potentially lethal complication after allogeneic hematopoietic stem cell transplantation (HSCT). Risk factors for aGvhD include donor source, preparative regimen and the degree of HLA-mismatching. Currently, there is increasing evidence that (reactivation of) viral infection is a risk factor for aGvHD. We hypothesized that the presence of viruses in the gastrointestinal tract, including AdV, triggers the initiation phase of intestinal GvHD. Therefore we investigated the association between viral PCR-positivity in stool prior to HSCT and the occurrence of intestinal aGvHD.

Methods
We prospectively evaluated 27 consecutive pediatric allogeneic HSCT patients from January ’09 until October ’10. Primary endpoint was the development of intestinal aGvHD diagnosed according to Gluckbergs criteria and confirmed by histopathology. Follow-up ranged from 100 to 376 days or until death. Stool specimens were taken peri-HSCT and analyzed for entero-, -noro-, astro-, -parecho- and adenovirus, by real-time PCR. The association between fecal PCR- positivity and intestinal aGvHD was analyzed using Fisher’s exact tests.

Results
Of the 27 patients that were evaluated, 6 (22%) developed intestinal aGvHD after a median of 64 days (range, 38-74). Four (15%) patients died due to transplant related complications or disease progression/relapse after 22-61 days. All patients with stool specimens positive for AdV (4/27, 15%) developed intestinal aGvHD (versus 2 / 23 (9%) patients without AdV in stool, p=0.001, positive predictive value = 100%, negative predictive value = 91%). Four patients were positive for other viruses but none of these developed aGvHD. Interestingly, one patient became positive for AdV at 327 days post-SCT and developed chronic intestinal GvHD after 476 days. AdV persisted in patient stool for more than 140 days, and preceded systemic infection: AdV was first detected in plasma on day 409 and loads raised from 482 copies/ml to 1.4*10.4 copies/ml on day 500.

Conclusion
AdV in stool prior to HSCT was associated with intestinal acute GvHD. It supports the hypothesis that virally induced tissue damage leads to influx of inflammatory mediators and ultimately activation and influx of activated cytotoxic T-cells involved in GvhD. Currently we perform a prospective follow- up study. These results may impact monitoring and treatment (preventive and curative) guideline/protocols