Elevated Cell Free DNA in Respiratory Viral Infection and Associated Lung Allograft Dysfunction

Abstract

<h3>Purpose</h3> Respiratory viral infection (RVI) is common in lung transplant recipients (LTRs), and a risk for subsequent chronic lung allograft dysfunction (CLAD). Approaches to identify such high risk for post RVI - CLAD are lacking. Our prior research showed viruses thought to be high risk are associated with elevated donor-derived cell-free DNA (%ddcfDNA), a sensitive marker of allograft injury. We hypothesize that high risk RVI are associated with greater allograft injury. We assessed if %ddcfDNA identifies events in which RVI leads to decline in lung function. <h3>Methods</h3> This study included 39 LTRs enrolled in the prospective Genomic Research Alliance for Transplantation with RVI from January 2016 - March 2019 and 1 year of follow up. Serially collected plasma samples were assayed for %ddcfDNA by shotgun sequencing. We defined significant allograft injury as %ddcfDNA values within 7 days of RVI ≥ 1 % (cases) or < 1% (controls). We examined type of RVI, concurrent histopathology, and lung function decline defined as percent change from personal best. <h3>Results</h3> We identified 59 RVI events at a median of 274 days post-transplant (IQR: 142, 425) including 38 controls (%ddcfDNA <1%) and 21 cases (%ddcfDNA ≥ 1%) (medians 0.47% and 3.30%, <i>p < 0.001*</i>). Demographics, personal best FEV₁, and histopathology were not different between cases and controls. At RVI diagnosis, cases showed significantly greater %FEV₁ decline than controls (medians -13.38% and -1.83%, <i>p = 0.006*).</i> Cases also had significantly greater %FEV₁ decline at 90 (medians -7.97% and 0.91%, <i>p = 0.04*</i>) and 365 (medians -20.05% and 1.09%, <i>p = 0.04*</i>) days post RVI. In contrast, no difference in %FEV₁ decline was seen at any timepoint when RVIs were grouped by abnormal (n=17) vs normal (n=27) histopathology. <h3>Conclusion</h3> We found that in subjects experiencing RVI, %ddcfDNA may discriminate between those who will recover their lung function and those who will experience sustained decline, a predictive utility not seen with histopathology or pulmonary function testing.