Higher Molecular Injury at Diagnosis of Acute Cellular Rejection Increases the Risk of Lung Allograft Failure.

RATIONALE:The association of acute cellular rejection (ACR) with chronic lung allograft dysfunction (CLAD) in lung transplant recipients has primarily been described prior to consensus recommendations incorporating restrictive phenotypes. Further, the association of the degree of molecular allograft injury during ACR with CLAD or death remains undefined. OBJECTIVES:To investigate the association of ACR with the risk of CLAD or death. To further investigate if this risk depends on the degree of molecular allograft injury. METHODS:This multicenter, prospective cohort study included 188 lung transplant recipients. Subjects underwent serial plasma collections for donor-derived cell-free DNA (dd-cfDNA) at prespecified time points and bronchoscopy. Multivariable Cox proportional hazards analysis analyzed the association of ACR with subsequent CLAD or death as well as the association of dd-cfDNA during ACR with risk of CLAD or death. Additional outcomes analyses were performed with episodes of ACR categorized as "high risk" (dd-cfDNA≥1%) and "low risk" (dd-cfDNA<1%). MEASUREMENTS AND MAIN RESULTS:In multivariable analysis, ACR was associated with the composite outcome of CLAD or death (HR=2.07, 95% CI, 1.05-4.10, p=0.036). Elevated dd-cfDNA ≥1% at ACR diagnosis was independently associated with increased risk of CLAD or death (HR 3.32, 95% CI: 1.31 - 8.40, p=0.012). Patients with high risk ACR were at increased risk of CLAD or death (HR 3.13, 95% CI: 1.41 - 6.93, p=0.005) while patients with low-risk status ACR were not. CONCLUSION:Patients with ACR are at higher risk of CLAD or death, however, this may depend on the degree of underlying allograft injury on the molecular level.