Proinflammatory Cytokines as Biomarkers for BOS, Death, or Retransplantation after Lung Transplantation

Abstract

Purpose Chronic Lung Allograft Dysfunction (CLAD) is characterized by airway epithelial damage and fibrosis. The origin and initiation of fibrosis are poorly understood. We hypothesized that immune mediators in bronchoalveolar lavage (BAL) predict bronchiolitis obliterans syndrome (BOS), a form of CLAD, and poor survival. In a multi-center observational study, we investigated the role of proinflammatory cytokines as biomarkers for poor outcome after lung transplant (LTx). Methods In a 24-month, prospective, observational multi-center study, 61 children were recruited between 7/2009 and 4/2013 at 6 US pediatric LTx centers (CTOTC-03; NCT00891865). The immune suppression regimen was standardized across sites. BAL and serum were obtained at specified intervals. The primary composite outcome included: incidence of BOS or its histological manifestation obliterative bronchiolitis (OB), retransplant, or death. Serum and BAL samples were assayed with Luminex panels to detect 78 antigens. Cytokine expression patterns were analyzed, BOS was graded per ISHLT criteria. Univariable linear, repeated measures mixed models were used to model the relationship of each Log10 transformed cytokine with (1) the composite endpoint and (2) BOS or OB without death. Values not adjusted for multiple comparisons. Results 28 children met the composite endpoint vs. 33 remained healthy. With BOS/OB considered alone (n=16), IL23 (p=0.05), EGF (p=0.04), IL31 (p=0.04) and EOX (p=0.02) were significantly increased, whereas IL23 was the only cytokine significantly correlated to the composite endpoint (p=0.02). Conclusion Cytokines IL23, EGF, IL31 and EOX are associated with BOS/OB and linked to airway epithelial cell injury, particularly alveolar type 2 (AT2) cells, suggesting dysregulated repair and chronic inflammation after LTx contribute to BOS. Consistent with other studies that suggest BAL eosinophilia is a major feature of lung allograft rejection, our results found that EOX, a recruiter of eosinophils and Th2 lymphocytes were highly associated with BOS. Finally, IL-23 is pro-inflammatory cytokine linked with chronic inflammation and were significant in both analyses. These data suggest specific inflammatory pathways may be targeted to prevent BOS and improve outcome after LTx in children.