INCREASED SUSCEPTIBILITY TO HERPESVIRUS COMPLICATIONS IN PULMONARY FIBROSIS LUNG TRANSPLANT RECIPIENTS WITH SHORT TELOMERES

Abstract

SESSION TITLE: Late Breaking Pulmonary Fibrosis SESSION TYPE: Original Investigations PRESENTED ON: 10/22/2019 08:45 AM - 09:45 AM PURPOSE: Idiopathic Pulmonary Fibrosis (IPF) is the leading indication for lung transplantation in North America, however transplant survival rates in this population lag behind all other end-stage lung diseases. Herpesvirus infectious complications are common causes of morbidity and mortality among lung transplant recipients (LTRs). We recently demonstrated that a high percentage of IPF lung transplant recipients (IPF-LTRs) have short lymphocyte telomere length (short TL) using flow cytometry and fluorescence in situ hybridization. Cytomegalovirus (CMV) infection continues to be one of the most common opportunistic infections in LTRs and is associated with chronic lung allograft dysfunction (CLAD). Epstein Barr virus (EBV)-associated post-transplant lymphoproliferative disorder (PTLD) is a herpesvirus transplant complication that is associated with significant mortality. METHODS: We performed retrospective outcomes analyses combined with genetic analyses in a single institution LTR cohort. RESULTS: We have shown that IPF-LTRs with short TL have increased susceptibility to CMV viremia and other CMV complications post-transplant, compared to age-matched non-IPF-LTRs (P < 0.01). In addition, we find that IPF-LTRs with short TL demonstrate impaired CMV-specific T cell immunity compared to non-IPF-LTRs. We evaluated a cohort of 611 LTRs at our institution from 2010-2016 for EBV-associated post-transplant lymphoproliferative disorder (PTLD) and found 28 cases of PTLD (4.6% incidence). Of these, 12/28 patients (43%) were IPF-LTRs and IPF was a risk factor associated with PTLD (Odds ratio: 2.9; 95% CI: 1.2-6.9; P<0.02). Kaplan Meier analyses demonstrated a significant decreased freedom from EBV-associated PTLD among IPF-LTRs (P<0.02), as well as decreased survival with PTLD in IPF-LTRs with PTLD (P<0.05). In addition, EBV mismatch (donor+/recipient-), a known risk factor for PTLD, carried an increased risk (Odds ratio: 6.9; 95% CI 2.3-20.9; P<0.001), while other factors such as male sex or age (risk factors for IPF) were not associated with increase risk for PTLD. Using both targeted exome sequencing and whole genome sequencing approaches, we found genetic mutations in either telomere or telomere-maintenance genes associated with the short telomere syndrome among both the CMV cohort and IPF-LTRs with EBV-PTLD. CONCLUSIONS: Together, these data highlight a predominance of short TL among current IPF-LTRs, along with increased susceptibility to herpesvirus complications in IPF-LTRs as manifestations of the short telomere syndrome. The identification of IPF-LTRs at increased risk for herpesvirus complications using telomere length and genome sequencing, may allow the development of clinical strategies to mitigate these post-transplant complications. CLINICAL IMPLICATIONS: Short telomeres are common in IPF LTRs. Stratification of risk for CMV and EBV-PTLD can advance strategies to mitigate adverse clinical outcomes. DISCLOSURES: No relevant relationships by Jonathan Alder, source=Web Response No relevant relationships by Stefanie Hannan, source=Web Response No relevant relationships by Carlo Iasella, source=Web Response No relevant relationships by Ritchie Koshy, source=Web Response No relevant relationships by John McDyer, source=Web Response No relevant relationships by Matthew Morrell, source=Web Response No relevant relationships by Seyed Mehdi Nouraie, source=Web Response No relevant relationships by Joseph Pilewski, source=Web Response No relevant relationships by Iulia Popescu, source=Web Response No relevant relationships by Pablo Sanchez, source=Web Response no disclosure on file for Fernanda Silveira; No relevant relationships by Spencer Winters, source=Web Response