Background The INBUILD trial investigated the efficacy and safety of nintedanib versus placebo in patients with progressive fibrosing interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis (IPF). We aimed to establish the effects of nintedanib in subgroups based on ILD diagnosis. Methods The INBUILD trial was a randomised, double-blind, placebo-controlled, parallel group trial done at 153 sites in 15 countries. Participants had an investigator-diagnosed fibrosing ILD other than IPF, with chest imaging features of fibrosis of more than 10% extent on high resolution CT (HRCT), forced vital capacity (FVC) of 45% or more predicted, and diffusing capacity of the lung for carbon monoxide (DLco) of at least 30% and less than 80% predicted. Participants fulfilled protocol-defined criteria for ILD progression in the 24 months before screening, despite management considered appropriate in clinical practice for the individual ILD. Participants were randomly assigned 1:1 by means of a pseudorandom number generator to receive nintedanib 150 mg twice daily or placebo for at least 52 weeks. Participants, investigators, and other personnel involved in the trial and analysis were masked to treatment assignment until after database lock. In this subgroup analysis, we assessed the rate of decline in FVC (mL/year) over 52 weeks in patients who received at least one dose of nintedanib or placebo in five prespecified subgroups based on the ILD diagnoses documented by the investigators: hypersensitivity pneumonitis, autoimmune ILDs, idiopathic non-specific interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, and other ILDs. The trial has been completed and is registered with ClinicalTrials.gov, number NCT02999178.

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 Pulmonary non-tuberculous mycobacterial (NTM) infection is relatively common after lung transplantation, but the effect on mortality remains undetermined. Herein we describe our experience with pulmonary NTM infection after lung transplantation and hypothesized that non-tuberculous mycobacterial infection after lung transplantation would be associated with increased mortality. METHODS We retrospectively evaluated 201 primary lung transplant recipients transplanted between January 2000 and August 2006. Serial bronchoscopies with bronchoalveolar lavage and transbronchial biopsy were performed according to a surveillance protocol and when clinically indicated. The diagnosis NTM infection was established by a positive NTM culture in a bronchoalveolar lavage sample or in at least two separate expectorated sputum samples. NTM infections were further classified as “disease” or “colonization,” based on whether or not NTM infection patients developed symptoms and characteristic radiographic findings. RESULTS Thirty-six (18%) recipients were diagnosed with pulmonary NTM infection at a median of 97 days post-transplantation: 9 were classified as NTM disease and the remaining 27 as NTM colonization cases. Single lung transplant was a significant risk factor for NTM infection (HR 2.25, p = 0.02). NTM colonization was a risk factor for NTM disease (HR 8.39, p = 0.003). NTM infection significantly increased the risk of death after lung transplantation (HR 2.61, p = 0.001) and persisted in multivariate models controlling for single lung transplant and bronchiolitis obliterans syndrome. The increased risk was seen for both NTM colonization and NTM disease. Among the patients who died, non-NTM infection was a more common contributing factor in the cause of death for the NTM infection group (44% vs 12%, p = 0.04). CONCLUSIONS Non-tuberculous mycobacterial infection is common after lung transplantation. NTM colonization and treated acute rejection are risk factors for NTM disease. NTM infection is associated with increased risk of mortality independent of bronchiolitis obliterans syndrome.

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.