RESUMO
BACKGROUND: The long term clinical significance of respiratory infections after lung transplantation remains uncertain. METHODS: In this retrospective single-center cohort study of 441 lung transplant recipients, we formally evaluate the association between respiratory infection and chronic lung allograft dysfunction (CLAD). We furthermore hypothesized that bronchoalveolar lavage fluid (BALF) CXCL9 concentrations are augmented during respiratory infections, and that episodes of infection with elevated BALF CXCL9 are associated with greater CLAD risk. RESULTS: In univariable and multivariable models adjusted for other histopathologic injury patterns, respiratory infection, regardless of the causative organism, was a strong predictor of CLAD development (adjusted HR 1.8 95% CI 1.3-2.6). Elevated BALF CXCL9 concentrations during respiratory infections markedly increased CLAD risk in a dose-response manner. An episode of respiratory infection with CXCL9 concentrations greater than the 25th, 50th, and 75th percentile had adjusted HRs for CLAD of 1.8 (95% CI 1.1-2.8), 2.4 (95% CI 1.4-4.0) and 4.4 (95% CI 2.4-8.0), respectively. CONCLUSIONS: Thus, we demonstrate that respiratory infections, regardless of the causative organism, are strong predictors of CLAD development. We furthermore demonstrate for the first time, the prognostic importance of BALF CXCL9 concentrations during respiratory infections on the risk of subsequent CLAD development.
RESUMO
BACKGROUND: The major limitation to survival after lung transplantation is bronchiolitis obliterative syndrome (BOS). BOS is a chronic inflammatory/immunologic process characterized by fibroproliferation, matrix deposition, and obliteration of the airways. The mechanism(s) that lead to fibro-obliteration of allograft airways have not been fully elucidated. Interleukin-1 receptor antagonist (IL-1Ra) is a naturally occurring antagonist of the pro-inflammatory cytokine IL-1 and has been associated with a number of fibroproliferative diseases. METHODS: We determined whether IL-1Ra, as compared to IL-1beta, IL-10, transforming growth factor (TGF)-beta, and tumor necrosis factor (TNF)-alpha, in the bronchoalveolar lavage fluid (BALF) from lung transplant recipients was associated with BOS. BALF was collected from three groups of patients: BOS (n=22), acute rejection (n=33), and healthy transplant recipients (n=30). RESULTS: IL-1Ra levels were significantly elevated in patients with BOS compared to healthy lung transplant recipients and patients with acute rejection (P<0.001 and P<0.05, respectively). Furthermore, when patients with BOS had their BALF analyzed from their last bronchoscopy before the development of BOS (Future BOS [FBOS] group) (n=20), their levels of IL-1Ra were also significantly elevated compared to healthy lung transplant recipients and patients with acute rejection (P<0.001 and P<0.05, respectively). Importantly, the elevated levels of IL-1Ra in the BOS and FBOS groups were not accompanied by any significant increases in IL-1beta, IL-10, TGF-beta, or TNF-alpha. CONCLUSION: These findings suggest that elevated levels of IL-1Ra may be attenuating IL-1 bioactivity during the pathogenesis of BOS and creating a local environment that favors fibroproliferation and matrix deposition.