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.

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Non-specific interstitial pneumonia (NSIP) is an interstitial lung disease that may be idiopathic or secondary to connective tissue disease, toxins or numerous other causes. Idiopathic NSIP is a rare diagnosis and requires exclusion of these other possible causes. Patients typically present in mid-adulthood with dyspnoea, cough and often constitutional symptoms including fever and fatigue. The disease has a female predominance, and more than 50% of patients have never smoked. Physical exam features mild hypoxaemia and inspiratory rales. Pulmonary function tests demonstrate restriction and a low diffusing capacity for carbon monoxide. High-resolution computed tomography abnormalities include predominantly lower lobe subpleural reticular changes, traction bronchiectasis and ground-glass opacities; honeycombing is rarely seen. An evaluation of the underlying pathology is necessary for a firm diagnosis. Histologically, alveolar and interstitial mononuclear cell inflammation and fibrosis are seen in a temporally uniform pattern with preserved underlying alveolar architecture. NSIP must be differentiated from other parenchymal lung diseases including idiopathic pulmonary fibrosis and hypersensitivity pneumonitis. A thorough exposure history and assessment for underlying connective tissue diseases are highly important, as positive findings in these categories would likely denote a case of secondary NSIP. A multidisciplinary discussion that includes pulmonologist(s), radiologist(s) and pathologist(s) assists in reaching a consensus diagnosis and improves diagnostic accuracy. Treatment of idiopathic NSIP, although not well proven, is generally instituted in the form of immunosuppression. Prognosis is favourable compared with idiopathic pulmonary fibrosis, although the diagnosis still carries an attributable mortality. Herein we will summarize the clinical characteristics and management of idiopathic NSIP.

Three prognostically distinct, radiologically defined phenotypes are identified among patients with HP. The importance of pursuing a specific diagnosis (eg, HP vs IPF) among patients with non-honeycomb fibrosis is highlighted. When radiologic honeycombing is present, invasive diagnostic testing directed at determining the diagnosis may be of limited value given a uniformly poor prognosis.

PRM is a novel imaging tool for lung transplant recipients presenting with spirometric decline. Quantifying underlying small airway obstruction via PRM helps further stratify the risk of death in patients with diverse spirometric decline patterns.

Fibrotic diseases display mesenchymal cell (MC) activation with pathologic deposition of matrix proteins such as collagen.Here we investigate the role of mTOR complex 1 (mTORC1) and mTORC2 in regulating MC collagen expression, a hallmark of fibrotic disease. Relative to normal MCs (non-Fib MCs), MCs derived from fibrotic human lung allografts (Fib-MCs) demonstrated increased phosphoinositide-3kinase (PI3K) dependent activation of both mTORC1 and mTORC2, as measured by increased phosphorylation of S6K1 and 4E-BP1 (mTORC1 substrates) and AKT (an mTORC2 substrate). Dual ATP-competitive TORC1/2 inhibitor AZD8055, in contrast to allosteric mTORC1-specific inhibitor rapamycin, strongly inhibited 4E-BP1 phosphorylation and collagen I expression in Fib-MCs. In non-Fib MCs, increased mTORC1 signaling was shown to augment collagen I expression. mTORC1/4E-BP1 pathway was identified as an important driver of collagen I expression in FibMCs in experiments utilizing raptor gene silencing and overexpression of dominant-inhibitory 4E-BP1. Furthermore, siRNA-mediated knockdown of rictor, an mTORC2 partner protein, reduced mTORC1 substrate phosphorylation and collagen expression in Fib-, but not non-Fib MCs, revealing a dependence of mTORC1 signaling on mTORC2 function in activated MCs. Together these studies suggest a novel paradigm where fibrotic activation in MCs increases PI3K dependent mTORC1 and mTORC2 signaling and leads to increased collagen I expression via the mTORC1-dependent 4E-BP1/ eIF4E pathway. These data provide rationale for targeting specific components of mTORC pathways in fibrotic states and underscore the need to further delineate mTORC2 signaling in activated cell states.Tissue fibrosis, marked by mesenchymal cell (MC) 2 infiltration and collagen deposition, continues to be a major cause of organ failure and death both before and after transplantation. Within five years of lung transplantation, 50% of the recipients demonstrate a decline in their lung function termed bronchiolitis obliterans syndrome which arises from progressive airway fibrosis (1, 2). Histologic samples reveal pathologic collagen matrix deposition with interspersed MCs (3). Relentless fibroproliferation is the hallmark of chronic allograft failure across all solid organ transplants, and targeting mechanisms of MC activation and matrix deposition is key to improving long term outcomes.Mammalian target of rapamycin (mTOR), an evolutionarily conserved serine/threonine protein kinase, links multiple upstream signaling cascades to downstream translational activation (4, 5). mTOR forms the catalytic core of two distinct complexes known as mTOR complex 1 (mTORC1) and mTORC2, which are defined by their partner proteins raptor and rictor, respectively (6). mTORC1 promotes cap-dependent mRNA translation via phosphorylation of its effectors S6K1 (ribosomal protein S6 Kinase 1) and 4E-BP1 (eukaryotic initiation factor 4E-binding protein1) (7-11). mTORC2 functions as the major kinase for AKT (12). Constitutive activation of the mTORC1 pathway and incre...

Rationale: After lung transplantation, spirometric values are routinely followed to assess graft function. FEV 1 is used to characterize chronic allograft dysfunction, whereas the course of FVC change has been less acknowledged and rarely used.Objectives: To better understand the temporal relationship and prognostic ability of FEV 1 and FVC decline after lung transplantation.Methods: Serial FEV 1 and FVC values were studied among 205 bilateral lung transplant recipients. Different decline patterns were characterized and evaluated for prognostic value via restricted mean modeling of mortality and times to other pertinent events.Measurements and Main Results: Baseline FEV 1 was achieved earlier than baseline FVC (median, 296 vs. 378 d; P , 0.0001). Decline in FEV 1 or FVC from their respective post-transplant baselines occurred in 85 patients (41%). Fifty-nine of 85 (69%) had an isolated FEV 1 decline, with 80% later meeting the FVC decline criterion. This subsequent FVC decline was associated with worsening FEV 1 and lower median survival. Twenty-five of 85 patients (29%) demonstrated concurrent FEV 1 and FVC decline. Patients with concurrent decline had higher 1-and 5-year mortality rates (1-yr, 53% vs. 18%, P , 0.0001; 5-yr, 61% vs. 48%, P = 0.001).These patients were more likely to have rapid-onset of spirometry decline (P = 0.05) and lower FEV 1 % predicted (P = 0.04) at presentation.Conclusions: FVC decline from its post-transplant baseline provides valuable prognostic information. Concurrent FEV 1 and FVC decline identifies patients with fulminant, rapid deterioration and is the strongest clinical predictor of poor survival. Subsequent FVC decline in patients with an initial isolated FEV 1 decline identifies disease progression and portends poor prognosis.

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