Interferon-gamma Inducible Chemokine Alterations During Diffuse Alveolar Damage is Associated with Bronchiolitis Obliterans Syndrome after Lung Transplant

Rationale: The development of Bronchiolitis obliterans syndrome (BOS) has been linked to a variety of insults to the lung allograft. We hypothesized that any insult severe enough to cause diffuse alveolar damage (DAD) after lung transplantation would be associated with a high risk of BOS and death. Furthermore, we hypothesized that this association would be mediated by the interferon-gamma inducible chemokines. Objectives: To determine whether episodes of DAD are associated with an increased risk of BOS and death. Methods: Lung transplant recipients received bronchoscopy with broncheoalveolar lavage and transbronchial biopsies at regular intervals as well as during episodes of clinical deterioration. The association between DAD and subsequent outcomes were evaluated using Cox proportional hazards models. In a nested case-control study, the broncheoalveolar lavage fluid (BALF) concentrations of IP10, MIG and ITAC were measured. Chemokine concentrations during episodes of DAD and the effects on subsequent outcomes were evaluated using principal component analysis (PCA). Results: There were 1,608 transbronchial biopsies from 441 recipients with 63 episodes of DAD. DAD was associated with an increased risk of both BOS (HR 3.9 95% CI 2.3-6.3) and death (HR 2.5 95% CI 1.6-3.7). PCA showed increased BALF concentrations of IP10, MIG, and ITAC during episodes of DAD. Furthermore, these chemokine elevations were independent predictors for the development of BOS in multivariable Cox models. Conclusions: Episodes of DAD are associated with a significant increase in the risk of BOS and allograft mortality. This association may be mediated by the interferon-gamma inducible chemokines: IP10, MIG and ITAC