RATIONALE:Dyspnea is a prominent symptom of fibrotic hypersensitivity pneumonitis (fHP), limiting patients' activity and impairing their quality of life. The University of California San Diego Shortness of Breath questionnaire (UCSD-SOBQ) is a 24-item instrument used to assess dyspnea severity in patients with various respiratory conditions. OBJECTIVES:This study aimed to examine the reliability and responsiveness of the UCSD-SOBQ score, its validity as a measure of dyspnea severity, and its prognostic value in a prospective cohort with fHP. METHODS:We conducted psychometric analyses on UCSD-SOBQ response data and assessed the association between score changes and survival in patients with fHP who completed the UCSD-SOBQ and other HP severity metrics at baseline, 6 and 12 months. We introduce the reliable change index (RCI) and the likely change index (LCI) to assess the statistical significance of within-individual change in UCSD scores. RESULTS:At baseline, internal consistency was high (Cronbach's alpha = 0.97). Significant moderately strong correlations were observed between UCSD-SOBQ scores and percent predicted forced vital capacity (FVC%), r = -0.46, percent predicted diffusing capacity of the lung for carbon monoxide (DLCO%), r = -0.32, and Borg dyspnea scores r = 0.56. UCSD-SOBQ scores were significantly different between the lowest and highest strata of FVC% (64.9 ± 18.9 vs. 36.2 ± 22.9), DLCO% and Borg scores. The threshold for worsening within-individual change in the UCSD-SOBQ score at 95% confidence was 12 points. A 1-point higher baseline UCSD-SOBQ score was associated with a 2% increase in the risk of death or transplant (HR 1.02, 95% CI 1.00, 1.04). CONCLUSIONS:In fHP, the UCSD-SOBQ score is a reliable and valid measure of dyspnea severity, is responsive to change, discriminates patients with differing severities, and is associated with transplant free survival. Additional qualitative data and psychometric analyses could tailor the UCSD-SOBQ to fHP and may further improve its measurement properties.

Background: ​Idiopathic pulmonary fibrosis (IPF) is a rare disease with a poor prognosis. Disease risk involves rare and common genetic variants. However, an inverse association have been described between them. Accordingly, IPF patients with a higher polygenic risk score (PRS) for IPF are less likely to carry rare deleterious variants and vice versa. Here, we evaluate weather PRS of IPF could serve as an additional criterion to patient prioritisation for rare variant discovery. Methods: We identified carriers based on the presence of rare qualifying variants (QVs) in genes linked to monogenic forms of pulmonary fibrosis in 888 IPF patients from the Pulmonary Fibrosis Foundation Patient Registry (PFFPR). Genome-wide association study (GWAS) summary statistics from independent cohorts were used to construct a whole-genome PRS (WG-PRS) using a clumping and thresholding method (C+T) and a Bayesian method (SBayesRC). PRS were also derived from 19 known common sentinel IPF variants (Sentinel-PRS). Logistic regression models were used to evaluate associations between PRS and carrier status. Discriminatory performancewas evaluated using area under the curve (AUC) analysis, and comparisons were made with DeLong’s test. Validation was performed in 472 IPF individuals from the UK PROFILE cohort. Findings: IPF-PRS were strongly associated with the QVs carrier status: Odds Ratio [OR] 0.65 (95% Confidence Interval [CI] 0.53-0.79) for WG-PRSC+T, OR 0.71 (95% CI 0.59-0.86) for WG-PRSSBayesRC, and OR 0.77 (95% CI 0.63-0.94) for Sentinel-PRS. Adding WG-PRS to the patient’s personal clinical history improved the prediction of QVs carriers: AUC=0.62 for the clinical model, AUC=0.68 for WG-PRSC+T (DeLong’s test, p=9.54x10-4) and AUC=0.66 for WG-PRSSBayesRC (DeLong’s test, p=0.02). Adding of IPF-PRS to clinical variables correctly reclassified 22.8% of carriers when using WG-PRSC+T, 20.8% when using Sentinel-PRS, and 16.7% for WG-PRSSBayesRC. WG-PRSSBayesRC and the Sentinel-PRS also demonstrated improved prediction of QVs carriers in telomere-related genes in PROFILE. Interpretation: Incorporating IPF-PRS into a model based on the patient’s clinical history improves the identification of QVs carriers. Although the overall discriminatory power was moderate, these findings raise de the possibility of using WG-PRS as useful criterion for rare variant discovery in patients with IPF and enhance decision-making.

Rationale:Idiopathic pulmonary fibrosis (IPF) is a rare, chronic, progressive lung disease with high mortality and few treatment options. Using an additive genetic model, genome-wide association studies (GWAS) have identified multiple risk loci highlighting new genes and pathways of interest. Since IPF risk could also be influenced by non-additive effects, we hypothesised that association analyses using alternative genetic models may provide additional mechanistic insight. Objectives:To perform GWAS of IPF susceptibility to detect associations where the underlying effects are consistent with recessive or dominant genetic models. Methods:We performed GWAS of IPF susceptibility, with logistic regression assuming dominant or recessive genetic models, including 5,159 IPF cases, from clinically-curated sources, and 27,459 controls. We functionally annotated independent signals and performed variant-to-gene mapping, applying fine-mapping to define potentially causal variants and genes. We assessed differential expression levels of genes of interest in publicly available single cell RNAseq data and in primary cells derived from IPF donors and controls. Main Results:We identified five genome-wide significant signals, under a recessive model, that had not been reported previously. These included exonic variants in the cell-cycle gene Polyamine-Modulated Factor 1 (PMF1) and in Epsin 3 (EPN3) genes. We also observed evidence of increased PMF1 expression in airway basal cells of IPF patients compared to controls. Conclusions:Using alternative genetic models in IPF susceptibility GWAS identified new signals and genes, providing new insights into IPF pathogenesis and potential future therapies.

Background While prognostic changes in complete blood count (CBC) parameters, such as elevated monocytes and neutrophils, have been studied in idiopathic pulmonary fibrosis (IPF), they are less well characterized in other interstitial lung diseases (ILD). We aimed to comprehensively assess the prognostic value of CBC parameters in various ILDs. Methods This retrospective derivation-validation registry-based study included consecutive ILD patients followed-up at tertiary referral centers that had available CBC and follow-up information. Optimal prognostic CBC cutoffs were determined using Youden’s index. Adjusted multivariate Cox regression analyses were used to assess the relation between CBC components and a composite outcome of lung transplantation or death of any cause. Results The derivation cohort included 369 patients (50.7% males, median age 67, 82.7% non-IPF) with a median follow-up of 20 months. Neutrophil counts >5.6 K/μL and platelets <149 K/μL were associated with worse outcome, although only neutrophil counts were independent predictors. The independent validation cohort of 696 patients (53.9% males, median age 66, 67.1% non-IPF) followed for 60 months, confirmed the prognostic value of neutrophils and platelets in ILD, employing the same cutoffs. In a subgroup analysis, neutrophil counts >5.6 K/μL were prognostic across most ILD categories except in connective tissue diseases (CTD), in both the derivation and validation cohorts. Conclusion A neutrophil count exceeding 5.6 K/μL at the time of ILD diagnosis was validated as an independent biomarker of poor outcomes in ILD, with the exception of CTD-ILD. Additionally, a platelet count below 149 K/μL demonstrated prognostic significance.

Interstitial lung diseases (ILDs) are a clinically and biologically diverse group of disorders characterized by varying inflammation and fibrosis of the lung parenchyma. Immunosuppressant therapy is commonly used to treat non-idiopathic pulmonary fibrosis (non-IPF) ILD, but treatment response is variable and difficult to predict. Identify and validate molecular endotypes of non-IPF ILD. Twenty plasma proteins associated with inflammation were used to perform latent class analysis (LCA) in two observational non-IPF ILD cohorts (discovery n = 676; validation n = 585). Proteins were measured using a semi-quantitative Olink Explore 3072 platform. The primary outcome was three-year transplant-free survival. Weighted Cox regression was used to assess differential response to mycophenolate or azathioprine in each cohort according to molecular endotype classification. A two-class model best fit both cohorts (p < 0.01), with Class 2 comprising ∼30% of patients. Compared to Class 1, Class 2 was associated with significantly lower three-year transplant-free survival in both discovery (78% vs. 36%, p < 0.001) and validation (83% vs. 46%, p < 0.001) cohorts. Significant interaction between molecular endotype and immunosuppressant exposure was observed in both cohorts (discovery pinteraction=0.022; validation pinteraction=0.019), with survival benefit seen only in Class 2. In pooled analysis, similar trends were observed irrespective of ILD subtype. Pathway analysis supported enrichment of inflammatory signatures in Class 2. In this multicenter observational cohort study, we identified and validated two distinct molecular endotypes of non-IPF ILD with divergent outcomes and response to immunosuppressant therapy. These endotypes could inform precision medicine strategies and clinical trial design in ILD.

RATIONALE:Interstitial lung diseases (ILDs) are a clinically and biologically diverse group of disorders characterized by varying inflammation and fibrosis of the lung parenchyma. Immunosuppressant therapy is commonly used to treat non-idiopathic pulmonary fibrosis (non-IPF) ILD, but treatment response is variable and difficult to predict. OBJECTIVE:Identify and validate molecular endotypes of non-IPF ILD. METHODS:Twenty plasma proteins associated with inflammation were used to perform latent class analysis in 2 observational non-IPF ILD cohorts (discovery n = 676; validation n = 585). Proteins were measured using a semi-quantitative Olink Explore 3072 platform. The primary outcome was 3-year transplant-free survival. Weighted Cox regression was used to assess differential response to mycophenolate or azathioprine in each cohort according to molecular endotype classification. RESULTS:A 2-class model best fit both cohorts (P <0.01), with Class 2 comprising ∼30% of patients. Compared to Class 1, Class 2 was associated with significantly lower 3-year transplant-free survival in both discovery (78% vs 36%, P <0.001) and validation (83% vs 46%, P <0.001) cohorts. Significant interaction between molecular endotype and immunosuppressant exposure was observed in both cohorts (discovery Pinteraction = 0.022; validation Pinteraction = 0.019), with survival benefit seen only in Class 2. In pooled analysis, similar trends were observed irrespective of ILD subtype. Pathway analysis supported enrichment of inflammatory signatures in Class 2. CONCLUSION:In this multicenter observational cohort study, we identified and validated 2 distinct molecular endotypes of non-IPF ILD with divergent outcomes and response to immunosuppressant therapy. These endotypes could inform precision medicine strategies and clinical trial design in ILD.

Rationale:Fibrotic hypersensitivity pneumonitis (fHP) is an antigen-driven, life-threatening interstitial lung disease characterized by heterogeneous radiologic features, clinical outcomes, and treatment responses. Objectives:To identify blood-based fHP endotypes that inform mechanism, prognosis and therapeutic response. Methods:We performed integrative analyses of multi-compartment transcriptomic data derived from whole blood, peripheral blood mononuclear cells, bronchoalveolar lavage, and surgical lung biopsies, alongside circulating plasma proteomics. Multiple clustering algorithms were cross-compared to ensure robustness and reproducibility of endotypes identification. Immune cell composition was inferred using bulk RNA-seq deconvolution and annotated with BAL single-cell RNA-seq. Pathway activities were characterized using Gene Set Enrichment Analysis. Transplant-free survival (TFS) was evaluated for endotype and corticosteroid exposure by Kaplan-Meier methods, with hazard ratios analyzed using multivariable Cox proportional hazards models. Results:Two molecular endotypes, lymphocytic-associated (L-fHP) and non-lymphocytic-associated (N-fHP), were identified and validated. L-fHP showed enrichment of adaptive immune signaling and lymphocyte predominance, whereas N-fHP demonstrated myeloid-cell activation with neutrophil and macrophage predominance. Corticosteroid exposure was associated with worse TFS in L-fHP but not in N-fHP after adjusting for age, sex, and baseline pulmonary function. Compared to L-fHP, N-fHP had poorer baseline pulmonary function, faster 12-month FVC decline, and shorter TFS. N-fHP also exhibited elevated neutrophil-associated markers, including matrix metalloproteinase-9, across paired transcriptomic and proteomic datasets, supporting a neutrophil-driven, cross-compartment disease process. Conclusion:Multi-omic, multi-compartment analysis identifies two reproducible fHP endotypes with distinct clinical outcomes and corticosteroid responses, supporting a precision medicine approach beyond current clinical and radiologic classification.

INTRODUCTION:Most research on idiopathic pulmonary fibrosis (IPF) has focused on the interplay among fibroblasts, the immune system and epithelial cells. There is growing evidence that microvascular dysfunction also plays a role in disease progression, but large human translational studies are lacking. In this research, we aim to identify a proteomic signature of microvascular instability and assess the impact of current therapeutics on the microvasculature. METHODS:Olink proteomic data from patients with IPF were obtained from the Pulmonary Fibrosis Foundation Patient Registry (PFF-PR) (n=914) and an independent validation cohort (n=366). Among the PFF-PR, 640 patients also have whole-blood RNA sequencing data available. A subset of 79 microvascular-associated proteins was curated, and their associations with disease severity and transplant-free survival were examined. An adaptive least absolute shrinkage and selection operator was used to generate a novel microvascular risk score. RESULTS:Higher plasma levels of five microvascular-associated proteins (SDC1, MMP10, THBS2, HGF and SERPINA5) were associated with lung function and survival in both cohorts. Whole-blood RNA sequencing of patients with microvascular risk revealed enrichment of immune-mediated processes. Patients with higher microvascular risk who were subsequently put on nintedanib in the following year had significantly better 3-year transplant-free survival compared with patients who did not receive antifibrotic intervention (HR 0.56, 95% CI 0.35 to 0.89, p=0.0142). DISCUSSION:Integrative multi-omics analyses suggest that perturbations to microvascular remodelling contribute to disease severity and progression in IPF. This analysis offers a framework for a precision medicine approach for IPF.

A consensus classification for idiopathic interstitial pneumonias was first published in 2002, providing terminology for clinicians, radiologists and pathologists as well as highlighting that a multidisciplinary approach was best clinical practice. This comprised seven histological patterns that had corresponding idiopathic multidisciplinary diagnoses. This classification was updated in 2013, with the addition of an eighth histological pattern. Since 2013, there have been further advances in our understanding of interstitial pneumonias, in particular relating to idiopathic versus secondary disease, advances in molecular pathology and recognition of progressive pulmonary fibrosis (PPF), which have led to a further update in 2025. This review highlights the changes relevant to pathologists reporting interstitial pneumonias. Major changes include (1) expansion beyond idiopathic interstitial pneumonias to also include secondary causes, (2) subclassification as interstitial (fibrotic vs non-fibrotic) and alveolar filling disorders, (3) expansion to include additional patterns (e.g. bronchiolocentric interstitial pneumonia), (4) improved terminology that better reflects histogenesis and (5) consideration of diagnostic confidence in biopsy evaluation. Pathologists also need to be aware of the advantages and limitations of cryobiopsy interpretation and the importance of reporting features that point towards a secondary cause rather than idiopathic disease. The 2025 classification provides a framework for a methodological approach to reporting biopsies in patients with interstitial pneumonia, which should be used prospectively for both diagnosis and research.

RATIONALE:Whole genome sequencing-estimated telomere length (WGS-TL) correlates with directly measured peripheral blood telomere length. However, raw WGS-TL does not account for normal age-related telomere attrition to identify patients with idiopathic pulmonary fibrosis (IPF) with pathologically short telomeres. OBJECTIVES:Determine utility of age-adjusted WGS-TL to identify adults with telomere-related qualifying variants (TRQV) and whether it associates with survival. METHODS:WGS-TL from two samples of community-dwelling adults (MESA) and cigarette smokers (COPDGene) were used to construct an age-adjusted WGS-TL nomogram (n = 9,940) using linear regression models that regressed on raw WGS-TL and adjusted for chronologic age. Using this nomogram, age-adjusted WGS-TL were generated in IPF cases from the Pulmonary Fibrosis Foundation Patient Registry (PFF-PR) (n = 825) to determine diagnostic performance characteristics for identifying TRQV and survival discrimination. MEASUREMENTS AND MAIN RESULTS:There was a higher proportion of IPF patients from the PFF-PR with abnormally short age-adjusted WGS-TL < 10th percentile (28%) compared to MESA (5%) or COPDGene (10%). Among IPF patients, age-adjusted WGS-TL < 10th percentile outperformed raw WGS-TL < 10th percentile at discriminating TRQV (area under the receiver operating curve 0.66 [95% CI 0.60-0.73] vs. 0.62 [95% CI 0.56-0.69]). At both the shorter age-adjusted and raw WGS-TL thresholds, specificity (0.74-0.99) was higher than sensitivity (0.10-0.58). Age-adjusted WGS-TL below 10th percentile was associated with shorter three-year transplant-free survival (HR 1.35, 95% CI 1.05,1.74) but did not improve survival discrimination over clinical variables alone. CONCLUSION:Age-adjusting WGS-TL enables identification of IPF patients with pathologically short telomeres, modestly improves detection of TRQV, and associates with survival.

BACKGROUND:Interstitial lung abnormalities (ILAs) progress radiologically in many patients and may reflect early interstitial lung disease (ILD). Within idiopathic pulmonary fibrosis and other smoking-related ILDs, there is increasing evidence that aberrant airway biology plays a role in disease development and progression. In this study, we sought to investigate associations between radiologic features of airways disease and progressive ILAs that could provide valuable insights into the management of patients at risk for developing ILD. METHODS:We performed a retrospective study of subjects undergoing low-dose computed tomography (LDCT) for lung cancer screening between January 2016 and August 2022. Adults aged 50-80 years with ≥2 LDCTs performed ≥24 months apart were included. Demographic data, medical history, and LDCTs were collected. LDCTs were qualitatively analyzed for ILAs and features of airways disease by a thoracic radiologist. Data were analyzed using a generalized estimating equation adjusted for age, sex, pack-years of tobacco, and a radiologic usual interstitial pneumonia pattern. RESULTS:Of 482 subjects, 54% (259/482) were female, and 66% (316/482) were Black. Average age was 64 years. The majority of subjects were current smokers (n = 276, 57%). Thirty-one percent (n = 147) had COPD, and 11% had asthma (n = 56). Median time between LDCTs was 51 (39-61) months. There were 85 subjects with ILAs, and of those, 42 (49.4%) had progressive ILAs. Bronchial wall thickening and mosaic attenuation were associated with ILA progression in adjusted models (odds ratio [OR] = 2.61, 95% CI: 1.08-6.23 and OR = 2.51, 95% CI: 1.02-6.17, respectively). CONCLUSIONS:Radiologic features of airways disease, including bronchial wall thickening and mosaic attenuation, were associated with ILA progression in subjects undergoing lung cancer screening.

Background:Idiopathic pulmonary fibrosis (IPF) is a rare, incurable lung disease with a median survival of 3-5 years after diagnosis. Treatment options are limited. Genetic association studies can identify new genes involved in disease that might represent potential new drug targets, and it has been shown that drug targets with support from genetic studies are more likely to be successful in clinical development. Previous genome-wide association studies (GWAS) of IPF susceptibility have identified more than 20 signals implicating genes involved in multiple mechanisms, including telomere dysfunction, cell-cell adhesion, host defence immunity, various signalling pathways and, more recently, mitotic spindle assembly complex. Aim:To leverage new datasets and genotype imputation to discover further genes involved in development of IPF that could yield new pathobiological avenues for exploration and to guide future drug target discovery. Methods:We conducted a GWAS of IPF susceptibility including seven IPF case-control studies comprising 5,159 IPF cases and 27,459 controls of European ancestry, where IPF diagnosis was made by a respiratory clinician according to international guidelines. Genotypes were obtained from Whole Genome Sequencing (WGS) or from array-based imputation to the TOPMed WGS reference panel. New signals were replicated in independent biobanks with IPF defined using Electronic Healthcare Records. Bayesian fine-mapping was performed to identify the most likely causal variant(s) and bioinformatic investigation undertaken to map associated variants to putative causal genes. Results:We identified three novel genetic signals of association with IPF susceptibility. Genes prioritised by functional evidence at these signals included MUC1, which encodes a large transmembrane glycoprotein and known biomarker of lung fibrosis, and NTN4 encoding Netrin-4 whose known roles include angiogenesis. The third signal may map to SLC6A6, a taurine and beta-alanine transporter gene, previously implicated in retinal, cardiac and kidney dysfunction. Conclusion:Our study has identified new associations not previously identified by previous large biobank-based studies thereby highlighting the value of utilising clinically-curated IPF case-control studies, and new genotype imputation. We present new evidence for disease-driving roles of MUC1 and of endothelial cell and vascular changes in IPF.

RATIONALE:Immunosuppression is routinely used for non-idiopathic pulmonary fibrosis (IPF) interstitial lung diseases (ILDs), despite limited trial evidence and unclear impact on long-term outcomes. OBJECTIVES:To evaluate whether mycophenolate or azathioprine improves three-year transplant-free survival and lung function trajectory in fibrotic ILD, including non-IPF idiopathic interstitial pneumonia (IIP), fibrotic hypersensitivity pneumonitis (fHP), and connective-tissue disease (CTD) associated ILD. METHODS:We employed a clone-censor-weighting framework to emulate a randomized controlled trial in this multi-center retrospective study. Each patient was cloned and assigned to immunosuppression initiation within 6 months of enrollment or no initiation strategies, and censored when the assigned strategy deviated from observed treatment. Stabilized inverse probability treatment and censoring weights were used. MEASUREMENTS:The primary endpoint was three-year transplant-free survival assessed with weighted Cox models across treatment strategies. Weighted generalized estimating equations were used to model lung function trajectory. MAIN RESULTS:Among 2,270 included patients, 18% (186/1022) with non-IPF IIP, 30% (162/544) with fHP, and 31% (221/704) with CTD-ILD were initiated on immunosuppression within 6-months. Immunosuppression was not associated with improved survival within any ILD subtype but was associated with worse survival in non-IPF IIP (HR 1.38, 95% CI 1.04-1.84) and fHP (HR 1.62, 95% CI 1.09-2.40). Immunosuppression was not associated with differential lung function trajectory within any ILD subtype. CONCLUSIONS:In this study, immunosuppression initiation showed no evidence of benefit for three-year transplant-free survival or lung function and was associated with higher mortality in select fibrotic ILD subtypes. Prospective randomized controlled trials are needed to inform patient care.

Lung biopsy has traditionally played a fundamental role in addressing diagnostic uncertainty and guiding management of fibrotic interstitial lung disease (fILD). Multiple lung biopsy procedures are available for evaluating fILD, including bronchoscopic techniques such as transbronchial biopsy and transbronchial lung cryobiopsy, as well as surgical lung biopsy, which is now almost exclusively conducted using minimally invasive video-assisted thoracoscopic surgery. The various evolving -considerations for and against lung biopsy have led to substantial ambiguity regarding the optimal timing and choice of biopsy method. The rationale for performing a lung biopsy in fILD is multifaceted, shaped by its potential to enhance diagnostic confidence and inform therapeutic decisions, weighed against procedural risks, and further nuanced by patient values and preferences. The objective of this state-of-the-art document from a multidisciplinary group of experts and patient representatives is to summarize the rationale for and against lung biopsy in the evaluation and management of fILD. Amid ongoing technological innovations, we further emphasize that future research should prioritize the development and validation of minimally invasive and noninvasive modalities that may serve as either alternatives or adjuncts to biopsy in the diagnostic evaluation of fILD.