Detection and Early Referral of Patients With Interstitial Lung Abnormalities: An Expert Survey Initiative

Background: Interstitial lung abnormalities (ILA) may represent undiagnosed early-stage or subclinical interstitial lung disease (ILD). ILA are often observed incidentally in patients who subsequently develop clinically overt ILD. There is limited information on consensus definitions for, and the appropriate evaluation of, ILA. Early recognition of patients with ILD remains challenging, yet critically important. Expert consensus could inform early recognition and referral. Research Question: Can consensus-based expert recommendations be identified to guide clinicians in the recognition, referral, and follow-up of patients with or at risk of developing early ILDs? Study Design and Methods: Pulmonologists and radiologists with expertise in ILD participated in two iterative rounds of surveys. The surveys aimed to establish consensus regarding ILA reporting, identification of patients with ILA, and identification of populations that might benefit from screening for ILD. Recommended referral criteria and follow-up processes were also addressed. Threshold for consensus was defined a priori as ≥ 75% agreement or disagreement. Results: Fifty-five experts were invited and 44 participated; consensus was reached on 39 of 85 questions. The following clinically important statements achieved consensus: honeycombing and traction bronchiectasis or bronchiolectasis indicate potentially progressive ILD; honeycombing detected during lung cancer screening should be reported as potentially significant (eg, with the Lung CT Screening Reporting and Data System “S-modifier” [Lung-RADS; which indicates clinically significant or potentially significant noncancer findings]), recommending referral to a pulmonologist in the radiology report; high-resolution CT imaging and full pulmonary function tests should be ordered if nondependent subpleural reticulation, traction bronchiectasis, honeycombing, centrilobular ground-glass nodules, or patchy ground-glass opacity are observed on CT imaging; patients with honeycombing or traction bronchiectasis should be referred to a pulmonologist irrespective of diffusion capacity values; and patients with systemic sclerosis should be screened with pulmonary function tests for early-stage ILD. Interpretation: Guidance was established for identifying clinically relevant ILA, subsequent referral, and follow-up. These results lay the foundation for developing practical guidance on managing patients with ILA

Azathioprine response in patients with fibrotic connective tissue disease-associated interstitial lung disease

BACKGROUND: Azathioprine is a commonly prescribed therapy for connective tissue disease-associated interstitial lung disease (CTD-ILD). Combination therapy that included azathioprine was recently shown to increase the risk of death and hospitalization in patients with idiopathic pulmonary fibrosis. Whether azathioprine increases the risk of adverse outcomes in patients with fibrotic CTD-ILD, including those with CTD-associated usual interstitial pneumonia (UIP), remains unknown. METHODS: A retrospective cohort analysis was performed to determine the combined incidence rate of death, transplant and respiratory hospitalization associated with azathioprine exposure. A fibrotic CTD-ILD cohort treated with mycophenolate mofetil served as a comparator group. Incidence rates were compared with an incidence rate ratio (IRR) generated by negative binomial regression. Longitudinal pulmonary function response was then assessed using mixed effects linear regression models. RESULTS: Fifty-four patients were treated with azathioprine and forty-three with mycophenolate. Medication discontinuation due to non-respiratory side effects occurred in 27% and 5% of the azathioprine and mycophenolate cohorts, respectively. The combined incidence rate of adverse outcomes was 0.013 and 0.015 for azathioprine and mycophenolate, respectively (IRR 1.23; 95% CI 0.49-3.12; p=0.66). Similar incidence rates were observed among those with CTD-UIP (IRR 0.83; 95% CI 0.21-3.31; p=0.79). Both groups demonstrated pulmonary function stability over time, with the azathioprine group demonstrating a marginal improvement. CONCLUSIONS: A significant minority of patients could not tolerate azathioprine due to non-respiratory side effects. Of those who did tolerate azathioprine, a similar incidence of adverse outcomes was observed as those treated with mycophenolate. Both therapies were associated with stability in pulmonary function

Genome-Wide Association Study of Susceptibility to Idiopathic Pulmonary Fibrosis

Rationale: Idiopathic pulmonary fibrosis (IPF) is a complex lung disease characterised by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. Genome-wide association studies have reported signals of association implicating multiple pathways including host defence, telomere maintenance, signalling and cell-cell adhesion. Objectives: To improve our understanding of factors that increase IPF susceptibility by identifying previously unreported genetic associations. Methods and measurements: We conducted genome-wide analyses across three independent studies and meta-analysed these results to generate the largest genome-wide association study of IPF to date (2,668 IPF cases and 8,591 controls). We performed replication in two independent studies (1,456 IPF cases and 11,874 controls) and functional analyses (including statistical fine-mapping, investigations into gene expression and testing for enrichment of IPF susceptibility signals in regulatory regions) to determine putatively causal genes. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF. Main results: We identified and replicated three new genome-wide significant (P<5×10−8) signals of association with IPF susceptibility (associated with altered gene expression of KIF15, MAD1L1 and DEPTOR) and confirmed associations at 11 previously reported loci. Polygenic risk score analyses showed that the combined effect of many thousands of as-yet unreported IPF susceptibility variants contribute to IPF susceptibility. Conclusions: The observation that decreased DEPTOR expression associates with increased susceptibility to IPF, supports recent studies demonstrating the importance of mTOR signalling in lung fibrosis. New signals of association implicating KIF15 and MAD1L1 suggest a possible role of mitotic spindle-assembly genes in IPF susceptibility

Coincident molecular auxeticity and negative order parameter in a liquid crystal elastomer

Auxetic materials have negative Poisson's ratios and so expand rather than contract in one or several direction(s) perpendicular to applied extensions. The auxetics community has long sought synthetic molecular auxetics - non-porous, inherently auxetic materials which are simple to fabricate and avoid porosity-related weakening. Here, we report, synthetic molecular auxeticity for a non-porous liquid crystal elastomer. For strains above ~0.8 applied perpendicular to the liquid crystal director, the liquid crystal elastomer becomes auxetic with the maximum negative Poisson's ratio measured to date being -0.74 ± 0.03 - larger than most values seen in naturally occurring molecular auxetics. The emergence of auxeticity coincides with the liquid crystal elastomer backbone adopting a negative order parameter, QB = -0.41 ± 0.01 - further implying negative liquid crystal ordering. The reported behaviours consistently agree with theoretical predictions from Warner and Terentjev liquid crystal elastomer theory. Our results open the door for the design of synthetic molecular auxetics