A functional genomic model for predicting prognosis in idiopathic pulmonary fibrosis

Background: The course of disease for patients with idiopathic pulmonary fibrosis (IPF) is highly heterogeneous. Prognostic models rely on demographic and clinical characteristics and are not reproducible. Integrating data from genomic analyses may identify novel prognostic models and provide mechanistic insights into IPF. Methods: Total RNA of peripheral blood mononuclear cells was subjected to microarray profiling in a training (45 IPF individuals) and two independent validation cohorts (21 IPF/10 controls, and 75 IPF individuals, respectively). To identify a gene set predictive of IPF prognosis, we incorporated genomic, clinical, and outcome data from the training cohort. Predictor genes were selected if all the following criteria were met: 1) Present in a gene co-expression module from Weighted Gene Co-expression Network Analysis (WGCNA) that correlated with pulmonary function (p 1.5 and false discovery rate (FDR) < 2 %; and 3) Predictive of mortality (p < 0.05) in univariate Cox regression analysis. "Survival risk group prediction" was adopted to construct a functional genomic model that used the IPF prognostic predictor gene set to derive a prognostic index (PI) for each patient into either high or low risk for survival outcomes. Prediction accuracy was assessed with a repeated 10-fold cross-validation algorithm and independently assessed in two validation cohorts through multivariate Cox regression survival analysis. Results: A set of 118 IPF prognostic predictor genes was used to derive the functional genomic model and PI. In the training cohort, high-risk IPF patients predicted by PI had significantly shorter survival compared to those labeled as low-risk patients (log rank p < 0.001). The prediction accuracy was further validated in two independent cohorts (log rank p < 0.001 and 0.002). Functional pathway analysis revealed that the canonical pathways enriched with the IPF prognostic predictor gene set were involved in T-cell biology, including iCOS, T-cell receptor, and CD28 signaling. Conclusions: Using supervised and unsupervised analyses, we identified a set of IPF prognostic predictor genes and derived a functional genomic model that predicted high and low-risk IPF patients with high accuracy. This genomic model may complement current prognostic tools to deliver more personalized care for IPF patients

Longitudinal lung function and gas transfer in individuals with idiopathic pulmonary fibrosis: a genome-wide association study

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an incurable lung disease characterised by progressive scarring leading to alveolar stiffness, reduced lung capacity, and impeded gas transfer. We aimed to identify genetic variants associated with declining lung capacity or declining gas transfer after diagnosis of IPF. METHODS: We did a genome-wide meta-analysis of longitudinal measures of forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLCO) in individuals diagnosed with IPF. Individuals were recruited to three studies between June, 1996, and August, 2017, from across centres in the US, UK, and Spain. Suggestively significant variants were investigated further in an additional independent study (CleanUP-IPF). All four studies diagnosed cases following American Thoracic Society/European Respiratory Society guidelines. Variants were defined as significantly associated if they had a meta-analysis p<5 × 10-8 when meta-analysing across all discovery and follow-up studies, had consistent direction of effects across all four studies, and were nominally significant (p<0·05) in each study. FINDINGS: 1329 individuals with a total of 5216 measures were included in the FVC analysis. 975 individuals with a total of 3361 measures were included in the DLCO analysis. For the discovery genome-wide analyses, 7 611 174 genetic variants were included in the FVC analysis and 7 536 843 in the DLCO analysis. One variant (rs115982800) located in an antisense RNA gene for protein kinase N2 (PKN2) showed a genome-wide significant association with FVC decline (-140 mL/year per risk allele [95% CI -180 to -100]; p=9·14 × 10-12). INTERPRETATION: Our analysis identifies a genetic variant associated with disease progression, which might highlight a new biological mechanism for IPF. We found that PKN2, a Rho and Rac effector protein, is the most likely gene of interest from this analysis. PKN2 inhibitors are currently in development and signify a potential novel therapeutic approach for IPF. FUNDING: Action for Pulmonary Fibrosis, Medical Research Council, Wellcome Trust, and National Institutes of Health National Heart, Lung, and Blood Institute

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

ICAR: endoscopic skull‐base surgery

n/

Antifibrotic therapy for idiopathic pulmonary fibrosis: time to treat

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a dismal prognosis. The average life expectancy of untreated patients with IPF is only 3 to 4 years. Decline in forced vital capacity (FVC) in patients with IPF appears to be almost linear, with patients with well-preserved FVC at baseline experiencing the same rate of decline in FVC as patients with more advanced disease. Two antifibrotic therapies have been approved for the treatment of IPF: nintedanib and pirfenidone. These drugs slow decline in lung function and reduce the risk of acute respiratory deteriorations, which are associated with very high morbidity and mortality. Individual clinical trials have not been powered to show reductions in mortality, but analyses of pooled data from clinical trials, as well as observational studies, suggest that antifibrotic therapies improve life expectancy. Despite this, many individuals with IPF remain untreated. In many cases, this is because the physician perceives that the disease is stable and so does not warrant therapy, or has concerns over the potential side-effects of antifibrotic drugs. There remains a need to educate pulmonologists that IPF is a progressive, irreversible and fatal disease and that prompt treatment is critical to preserving patients’ lung function and improving outcomes. Most individuals can tolerate antifibrotic therapy, and dose adjustment has been shown to be effective at reducing side effects without compromising efficacy. In addition to anti-fibrotic therapies, individuals with IPF benefit from a holistic approach to their care that includes symptom management and supportive care tailored to the needs of the individual. An animation illustrating the themes covered in this article will be available at: http://www.usscicomms.com/respiratory/maher/treatment-of-IPF

Lung function trajectory in progressive fibrosing interstitial lung disease

Proposed criteria for progressive fibrosing interstitial lung disease (PF-ILD) have been linked to increased mortality risk, but lung function trajectory after satisfying individual criterion remains unknown. Because survival is rarely employed as the primary endpoint in therapeutic trials, identifying PF-ILD criteria that best predict subsequent change in forced vital capacity (FVC) could improve clinical trial design. A retrospective, multi-center longitudinal cohort analysis was performed in consecutive patients with fibrotic connective tissue disease-associated ILD (CTD-ILD), chronic hypersensitivity pneumonitis and idiopathic interstitial pneumonia at three US centers (test cohort) and one UK center (validation cohort). One-year change in FVC after satisfying proposed PF-ILD criteria was estimated using joint modeling. Subgroup analyses were performed to determine whether results varied across key subgroups. One thousand two hundred twenty-seven patients were included, with CTD-ILD predominating. Six of nine PF-ILD criteria were associated with differential one-year change in FVC, with radiologic progression of fibrosis, alone and in combination with other features, associated with the largest subsequent decline in FVC. Findings varied significantly by ILD subtype, with CTD-ILD demonstrating little change in FVC after satisfying most PF-ILD criteria, while other ILDs showed significantly larger changes. Findings did not vary after stratification by radiologic pattern or exposure to immunosuppressant therapy. Near-term change in FVC after satisfying proposed PF-ILD criteria was heterogeneous depending on the criterion assessed and was strongly influenced by ILD subtype. These findings may inform future clinical trial design and suggest ILD subtype should be taken into consideration when applying PF-ILD criteria

“ERS/ATS Task Force onUndifferentiated Forms of CTD-ILD”. An official European RespiratorySociety/American Thoracic Society research statement: interstitial pneumonia withautoimmunefeatures

Many patients with an idiopathic interstitial pneumonia (IIP) have clinical features that suggest an underlying autoimmune process but do not meet established criteria for a connective tissue disease (CTD). Researchers have proposed differing criteria and terms to describe these patients, and lack of consensus over nomenclature and classification limits the ability to conduct prospective studies of a uniform cohort.The "European Respiratory Society/American Thoracic Society Task Force on Undifferentiated Forms of Connective Tissue Disease-associated Interstitial Lung Disease" was formed to create consensus regarding the nomenclature and classification criteria for patients with IIP and features of autoimmunity.The task force proposes the term "interstitial pneumonia with autoimmune features" (IPAF) and offers classification criteria organised around the presence of a combination of features from three domains: a clinical domain consisting of specific extra-thoracic features, a serologic domain consisting of specific autoantibodies, and a morphologic domain consisting of specific chest imaging, histopathologic or pulmonary physiologic features.A designation of IPAF should be used to identify individuals with IIP and features suggestive of, but not definitive for, a CTD. With IPAF, a sound platform has been provided from which to launch the requisite future research investigations of a more uniform cohort

Blood transcriptomic predicts progression of pulmonary fibrosis and associates natural killer cells.

Rationale: Disease activity in idiopathic pulmonary fibrosis (IPF) remains highly variable, poorly understood, and difficult to predict. Objective: To identify a predictor using short-term longitudinal changes in gene-expression that forecasts future forced vital capacity (FVC) decline and to characterize involved pathways and cell types. Methods: Seventy-four patients from Correlating Outcomes with biochemical Markers to Estimate Time-progression in IPF (COMET) cohort were dichotomized as progressors (≥10% FVC decline) or stable. Blood gene-expression changes within individuals were calculated between baseline and 4 months, and regressed with future FVC status, allowing determination of expression variations, sample size, and statistical power. Pathway analyses were conducted to predict downstream effects and identify new targets. An FVC-predictor for progression was constructed in COMET and validated using independent cohorts. Peripheral blood mononuclear single-cell RNA-seq (PBMC scRNA-seq) data from healthy controls were used as references to characterize cell type compositions from bulk PBMC RNA-seq data that were associated with FVC decline. Results: The longitudinal model reduced gene-expression variations within stable and progressor groups, resulting in increased statistical power when compared to a cross-sectional model. The FVC-predictor for progression anticipated patients with future FVC decline with 78% sensitivity and 86% specificity across independent IPF cohorts. Pattern recognition receptor pathways and mTOR pathways were down- and up-regulated, respectively. Cellular deconvolution using scRNA-seq data identified natural killer (NK) cells as significantly correlated with progression. Conclusions: Serial transcriptomic change predicts future FVC decline. Analysis of cell types involved in the progressor signature supports the novel involvement of NK cells in IPF progression

Proceedings of the American College of Rheumatology/Association of Physicians of Great Britain and Ireland Connective Tissue Disease-Associated Interstitial Lung Disease Summit: A multidisciplinary approach to address challenges and opportunities

Interstitial lung disease (ILD), a group of diffuse parenchymal lung disorders classified together based on specific clinical, radiologic, and histopathologic features, is often associated with significant morbidity and mortality and is a common manifestation in connective tissue disease (CTD). ILD often arises within the context of a specific exposure or is associated with an underlying CTD. The CTDs are a spectrum of systemic autoimmune disorders with significant clinical heterogeneity characterized by immune-mediated organ dysfunction, and the lung is a frequent target. All CTD patients are at risk of developing ILD, and those with systemic sclerosis (SSc), polymyositis/dermatomyositis (PM/DM), and rheumatoid arthritis (RA) are at particularly high risk. ILD may develop at any point in the natural history of CTD, is most frequently identified in the setting of an established CTD, and may also be the first clinically apparent manifestation of occult CTD. Determining whether a patient has a diagnosis of CTD-associated ILD is important, as this knowledge may impact treatment decisions, guide surveillance for other concomitant clinical features, and help with assessment of prognosis