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BackgroundThe MUC5B promoter variant (rs35705950) and telomere length are linked to pulmonary fibrosis and CT-based qualitative assessments of interstitial abnormalities, but their associations with longitudinal quantitative changes of the lung interstitium among community-dwelling adults are unknown.MethodsWe used data from participants in the Multi-Ethnic Study of Atherosclerosis with high-attenuation areas (HAAs, Examinations 1-6 (2000-2018)) and MUC5B genotype (n=4552) and telomere length (n=4488) assessments. HAA was defined as the per cent of imaged lung with attenuation of -600 to -250 Hounsfield units. We used linear mixed-effects models to examine associations of MUC5B risk allele (T) and telomere length with longitudinal changes in HAAs. Joint models were used to examine associations of longitudinal changes in HAAs with death and interstitial lung disease (ILD).ResultsThe MUC5B risk allele (T) was associated with an absolute change in HAAs of 2.60% (95% CI 0.36% to 4.86%) per 10 years overall. This association was stronger among those with a telomere length below an age-adjusted percentile of 5% (p value for interaction=0.008). A 1% increase in HAAs per year was associated with 7% increase in mortality risk (rate ratio (RR)=1.07, 95% CI 1.02 to 1.12) for overall death and 34% increase in ILD (RR=1.34, 95% CI 1.20 to 1.50). Longer baseline telomere length was cross-sectionally associated with less HAAs from baseline scans, but not with longitudinal changes in HAAs.ConclusionsLongitudinal increases in HAAs were associated with the MUC5B risk allele and a higher risk of death and ILD.

BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive lung disease with few treatment options. N-acetylcysteine (NAC) is a well-tolerated, inexpensive treatment with antioxidant and anti-fibrotic properties. The National Heart, Lung, and Blood Institute (NHLBI)-sponsored PANTHER (Prednisone Azathioprine and NAC therapy in IPF) trial confirmed the harmful effects of immunosuppression in IPF, and did not show a benefit to treatment with NAC. However, a post hoc analysis revealed a potential beneficial effect of NAC in a subgroup of individuals carrying a specific genetic variant, TOLLIP rs3750920 TT genotype, present in about 25% of patients with IPF. Here, we present the design and rationale for the Phase III, multi-center, randomized, double-blind, placebo-controlled Prospective Treatment Efficacy in IPF Using Genotype for NAC Selection (PRECISIONS) clinical trial.MethodsThe PRECISIONS trial will randomize 200 patients with IPF and the TOLLIP rs3750920 TT genotype 1:1 to oral N-acetylcysteine (600 mg tablets taken three times a day) or placebo for a 24-month duration. The primary endpoint is the composite of time to 10% relative decline in forced vital capacity (FVC), first respiratory hospitalization, lung transplantation, or death from any cause. Secondary endpoints include change in patient-reported outcome scores and proportion of participants with treatment-emergent adverse events. Biospecimens, including blood, buccal, and fecal will be collected longitudinally for future research purposes. Study participants will be offered enrollment in a home spirometry substudy, which explores time to 10% relative FVC decline measured at home, and its comparison with study visit FVC.DiscussionThe sentinel observation of a potential pharmacogenetic interaction between NAC and TOLLIP polymorphism highlights the urgent, unmet need for better, molecularly focused, and precise therapeutic strategies in IPF. The PRECISIONS clinical trial is the first study to use molecularly-focused techniques to identify patients with IPF most likely to benefit from treatment. PRECISIONS has the potential to shift the paradigm in how trials in this condition are designed and executed, and is the first step toward personalized medicine for patients with IPF. Trial Registration ClinicalTrials.gov identifier: NCT04300920. Registered March 9, 2020. https://clinicaltrials.gov/ct2/show/NCT04300920.

BackgroundAdipokines have inflammatory and fibrotic properties that may be critical in interstitial lung disease (ILD). We examined associations of serum adipokine levels with CT imaging-based measures of subclinical ILD and lung function among community-dwelling adults.MethodsA subset of the original Multi-Ethnic Study of Atherosclerosis cohort (n = 1,968) had adiponectin, leptin, and resistin measured during follow-up visits (2002-2005). We used regression models to examine associations of adiponectin, leptin, and resistin levels with (1) high-attenuation areas (HAAs) from CT scans (2004-2005, n = 1,144), (2) interstitial lung abnormalities (ILAs) from CT scans (2010-2012, n = 872), and (3) FVC from spirometry (2004-2006, n = 1,446). We used -(1/HAA2), which we denoted with H, to model HAA as our outcome to meet model assumptions.ResultsHigher adiponectin was associated with lower HAA on CT imaging among adults with a BMI ≥ 25 kg/m2 (P for BMI interaction = .07). Leptin was more strongly associated with ILA among never smokers compared with ever smokers (P for smoking interaction = .004). For every 1-SD increment of log-transformed leptin, the percent predicted FVC was 3.8% lower (95% CI, -5.0 to -2.5). Higher serum resistin levels were associated with greater HAA on CT in a fully adjusted model. For every 1-SD increment of log-transformed resistin there was an increase in H of 14.8 (95% CI, 3.4-26.3).ConclusionsHigher adiponectin levels were associated with lower HAA on CT imaging among adults with a higher BMI. Higher leptin and resistin levels were associated with lower FVC and greater HAA, respectively.

Rationale: Interstitial lung abnormalities (ILAs) are associated with the highest genetic risk locus for idiopathic pulmonary fibrosis (IPF); however, the extent to which there are unique associations among individuals with ILAs or additional overlap with IPF is not known.Objectives: To perform a genome-wide association study (GWAS) of ILAs.Methods: ILAs and a subpleural-predominant subtype were assessed on chest computed tomography (CT) scans in the AGES (Age Gene/Environment Susceptibility), COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease [COPD]), Framingham Heart, ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points), MESA (Multi-Ethnic Study of Atherosclerosis), and SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study) studies. We performed a GWAS of ILAs in each cohort and combined the results using a meta-analysis. We assessed for overlapping associations in independent GWASs of IPF.Measurements and Main Results: Genome-wide genotyping data were available for 1,699 individuals with ILAs and 10,274 control subjects. The MUC5B (mucin 5B) promoter variant rs35705950 was significantly associated with both ILAs (P = 2.6 × 10-27) and subpleural ILAs (P = 1.6 × 10-29). We discovered novel genome-wide associations near IPO11 (rs6886640, P = 3.8 × 10-8) and FCF1P3 (rs73199442, P = 4.8 × 10-8) with ILAs, and near HTRE1 (rs7744971, P = 4.2 × 10-8) with subpleural-predominant ILAs. These novel associations were not associated with IPF. Among 12 previously reported IPF GWAS loci, five (DPP9, DSP, FAM13A, IVD, and MUC5B) were significantly associated (P

Rationale: Several common and rare genetic variants have been associated with idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung. Objectives: To develop an integrated understanding of the rare and common variants located in multiple loci that have been reported to contribute to the risk of disease. Methods: We performed deep targeted resequencing (3.69 Mb of DNA) in cases (n = 3,624) and control subjects (n = 4,442) across genes and regions previously associated with disease. We tested for associations between disease and 1) individual common variants via logistic regression and 2) groups of rare variants via sequence kernel association tests. Measurements and Main Results: Statistically significant common variant association signals occurred in all 10 of the regions chosen based on genome-wide association studies. The strongest risk variant is the MUC5B promoter variant rs35705950, with an odds ratio of 5.45 (95% confidence interval, 4.91-6.06) for one copy of the risk allele and 18.68 (95% confidence interval, 13.34-26.17) for two copies of the risk allele (P = 9.60 × 10-295). In addition to identifying for the first time that rare variation in FAM13A is associated with disease, we confirmed the role of rare variation in the TERT and RTEL1 gene regions in the risk of IPF, and found that the FAM13A and TERT regions have independent common and rare variant signals. Conclusions: A limited number of common and rare variants contribute to the risk of idiopathic pulmonary fibrosis in each of the resequencing regions, and these genetic variants focus on biological mechanisms of host defense and cell senescence.

Recent genetic and genomic advancements have elucidated the complex etiology of idiopathic pulmonary fibrosis (IPF) and other progressive fibrotic interstitial lung diseases (ILDs), emphasizing the contribution of heritable factors. This state-of-the-art review synthesizes evidence on significant genetic contributors to pulmonary fibrosis (PF), including rare genetic variants and common SNPs. The MUC5B promoter variant is unusual, a common SNP that markedly elevates the risk of early and established PF. We address the utility of genetic variation in enhancing understanding of disease pathogenesis and clinical phenotypes, improving disease definitions, and informing prognosis and treatment response. Critical research gaps are highlighted, particularly the underrepresentation of non-European ancestries in PF genetic studies and the exploration of PF phenotypes beyond usual interstitial pneumonia/IPF. We discuss the role of telomere length, often critically short in PF, and its link to progression and mortality, underscoring the genetic complexity involving telomere biology genes (TERT, TERC) and others like SFTPC and MUC5B. In addition, we address the potential of gene-by-environment interactions to modulate disease manifestation, advocating for precision medicine in PF. Insights from gene expression profiling studies and multiomic analyses highlight the promise for understanding disease pathogenesis and offer new approaches to clinical care, therapeutic drug development, and biomarker discovery. Finally, we discuss the ethical, legal, and social implications of genomic research and therapies in PF, stressing the need for sound practices and informed clinical genetic discussions. Looking forward, we advocate for comprehensive genetic testing panels and polygenic risk scores to improve the management of PF and related ILDs across diverse populations. [ABSTRACT FROM AUTHOR]

The article summarizes knowledge on inflammation and fibrosis in interstitial lung disease (ILD), with the relative burden of each in an individual patient gleaned by considering several domains, including clinical history and lung function, imaging, laboratory including bronchoalveolar lavage (BAL), and histopathology. Topics discussed include prediction of disease behavior and first-line treatment decision, inflammation in ILD, and fibrosis in ILD.

The authors discuss studies published in the issue which leverage modern imaging and genomic techniques to put small airways front and center and advance understanding of idiopathic pulmonary fibrosis (IPF). Topics include the usual interstitial pneumonia (UIP) pattern that defines IPF in the appropriate clinical setting, finding on sites affected by IPF, and link between the presence of the MUC5B variant and a reduction of small airway secretory markers and increased mucin and ciliary markers.

Rationale: Fatigue is a common and debilitating symptom for people living with interstitial lung disease (ILD). Studies on fatigue in ILD are limited, and little headway has been made toward developing interventions targeting the alleviation of fatigue. A barrier to progress is a lack of knowledge around the performance characteristics of a patient-reported outcome measure to assess fatigue in patients with ILD. Objectives: To assess the validity and reliability of the Fatigue Severity Scale (FSS) for measuring fatigue in a national cohort of patients with ILD. Methods: FSS scores and several anchors were measured in 1,881 patients from the Pulmonary Fibrosis Foundation Patient Registry. Anchors included the Short Form 6D Health Utility Index (SF-6D) score and a single vitality question from the SF-6D; the University of California, San Diego, Shortness of Breath Questionnaire; FVC; DlcO; and 6-minute-walk distance. Internal consistency reliability, concurrent validity, and known-groups validity were assessed. Structural validity was assessed using confirmatory factor analysis. Measurements and Main Results: The FSS demonstrated high internal consistency (Cronbach's a = 0.96). There were moderate to strong correlations between FSS score and patient-reported anchors (vitality question from the SF-6D [r = 0.55] and University of California, San Diego, Shortness of Breath Questionnaire total score [r = 0.70]) and weak correlations between FSS score and physiological measures (FVC [r= --0.24], percentage predicted Dlco [r= --0.23], and 6-minute-walk distance [r= --0.29]). Higher mean FSS scores, indicating greater fatigue, were observed among patients using supplemental oxygen, those prescribed steroids, and those with lower percentage predicted FVC and percentage predicted Dlco. The confirmatory factor analysis results suggest that the nine questions of the FSS reflect one dimension of fatigue. Conclusions: Fatigue is an important patient-centered outcome in ILD that is poorly correlated with physiological measures of disease severity, including lung function and walk distance. These findings further support the need for a reliable and valid measure of patient-reported fatigue in ILD. The FSS possesses acceptable performance characteristics for assessing fatigue and distinguishing different degrees of fatigue among patients with ILD. [ABSTRACT FROM AUTHOR]

An introduction to articles in the issue is presented which highlight new therapeutic strategies, innovative diagnostic tools, and emerging biomarkers that promise to reshape clinical management of interstitial lung disease (ILD).

The article offers information on a special issue of the Journal focused on interstitial lung disease (ILD), highlighting the advancements in the field over the past decade. Topics include the transformation of understanding in fibrotic lung disease genetics, the approval of therapies for various forms of ILD, and the unmet needs in ILD despite these advancements.