Aspergillus colonization after lung transplantation may increase the risk for bronchiolitis obliterans syndrome (BOS), a disease of small airways. We hypothesized that colonization with small conidia Aspergillus species would be associated with a greater risk of BOS, based upon an increased likelihood of deposition in small airways. We studied adult primary lung recipients from two large centers; 298 recipients at University of California, Los Angeles and 482 recipients at Duke University Medical Center. We grouped Aspergillus species by conidia diameter ≤3.5μm. We assessed the relationship of colonization with outcomes in Cox models. Pre-BOS colonization with small conidia Aspergillus species, but not large, was a risk factor for BOS (P = 0.002, HR 1.44, 95% CI 1.14–1.82), along with acute rejection, single lung, and Pseudomonas. Colonization with small conidia species also associated with risk of death (P = 0.03, HR 1.30, 95% CI 1.03–1.64). Although other virulence traits besides conidia size may be important, we have demonstrated in two large independent cohorts that colonization with small conidia Aspergillus species increases the risk of BOS and death. Prospective evaluation of strategies to prevent Aspergillus colonization of small airways is warranted, with the goal of preserving lung allograft function as long as possible.
Rationale: After lung transplantation, insults to the allograft generally result in one of four histopathologic patterns of injury: (1) acute rejection, (2) lymphocytic bronchiolitis, (3) organizing pneumonia, and (4) diffuse alveolar damage (DAD). We hypothesized that DAD, the most severe form of acute lung injury, would lead to the highest risk of chronic lung allograft dysfunction (CLAD) and that a type I immune response would mediate this process. Objectives: Determine whether DAD is associated with CLAD and explore the potential role of CXCR3/ligand biology. Methods: Transbronchial biopsies from all lung transplant recipients were reviewed. The association between the four injury patterns and subsequent outcomes were evaluated using proportional hazards models with time-dependent covariates. Bronchoalveolar lavage (BAL) concentrations of the CXCR3 ligands (CXCL9/MIG, CXCL10/ IP10, and CXCL11/ITAC) were compared between allograft injury patterns and "healthy" biopsies using linear mixed-effects models. The effect of these chemokine alterations on CLAD risk was assessed using Cox models with serial BAL measurements as time-dependent covariates. Measurements and Main Results: There were 1,585 biopsies from 441 recipients with 62 episodes of DAD. An episode of DAD was associated with increased risk of CLAD (hazard ratio, 3.0; 95% confidence interval, 1.9-4.7) and death (hazard ratio, 2.3; 95% confidence interval, 1.7-3.0). There were marked elevations in BAL CXCR3 ligand concentrations during DAD. Furthermore, prolonged elevation of these chemokines in serial BAL fluid measurements predicted the development of CLAD. Conclusions: DAD is associated with marked increases in the risk of CLAD and death after lung transplantation. This association may be mediated in part by an aberrant type I immune response involving CXCR3/ligands. Keywords: lung transplantation; chronic lung allograft dysfunction; bronchiolitis obliterans syndrome; diffuse alveolar damage; CXC chemokines Lung transplantation has one of the highest mortality rates among solid organ transplants: 48% at 5 years and 71% at 10 years (1). Chronic lung allograft dysfunction (CLAD) is the major factor limiting long-term survival (2). There is accumulating evidence that CLAD has two distinct phenotypes: bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS). These subtypes of CLAD seem to differ in their clinical characteristics and prognosis (3-5). CLAD has traditionally been recognized as BOS with progressive irreversible obstruction on pulmonary function testing (PFT) caused by fibroobliteration of the small airways. Among double lung transplant recipients (LTRs), RAS has recently been identified as another phenotype of CLAD with restriction on PFT caused by fibrosis of the lung parenchyma (4). RAS seems to have significantly higher mortality compared with BOS (3-5). Because there is no known effective treatment for CLAD or its subtypes (BOS and RAS), the identification and avoidance of risk factors are critical.Prior studies ...
Background Community acquired respiratory virus (CARV) infections occur frequently after lung transplantation and may adversely impact outcomes. We hypothesized that while asymptomatic carriage would not increase the risk of chronic lung allograft dysfunction (CLAD) and graft loss, severe infection would. Methods All lung transplant cases between January 2000 and July 2013 performed at our center were reviewed for respiratory viral samples. Each isolation of virus was classified according to clinical level of severity: asymptomatic, symptomatic without pneumonia, and viral pneumonia. Multivariate Cox modeling was employed to assess the impact of CARV isolation on progression to CLAD and graft loss. Results 4408 specimens were collected from 563 total patients with 139 patients producing 324 virus positive specimens in 245 episodes of CARV infection. Overall, the risk of CLAD was elevated by viral infection (HR 1.64, p < 0.01). This risk, however, was due to viral pneumonia alone (HR 3.94, p < 0.01), without significant impact from symptomatic viral infection (HR 0.97, p = 0.94) nor from asymptomatic viral infection (HR 0.99, p = 0.98). The risk of graft loss was not increased by asymptomatic CARV infection (HR 0.74, p = 0.37) nor symptomatic CARV infection (HR 1.39, p = 0.41). Viral pneumonia did, however, significantly increase the risk of graft loss (HR 2.78, p < 0.01). Conclusions With respect to CARV, only viral pneumonia increased the risk of both CLAD and graft loss after lung transplantation. In the absence of pneumonia, respiratory viruses had no impact on measured outcomes.
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