Fibrosing interstitial lung diseases (ILDs) encompasses a large number of diverse conditions, the prototype being idiopathic pulmonary fibrosis (IPF), characterized by irreversible progression, accounting for loss of lung function, exercise intolerance, and complications especially acute exacerbation and respiratory failure leading to early mortality. A significant proportion of patients with fibrosing ILDs other than IPF will develop a progressive phenotype comparable to IPF. Progression occurs despite conventional treatment which, depending on the underlying condition, may include close monitoring, antigen eviction, glucocorticoids, immunosuppressive therapy, and pulmonary rehabilitation. Progressive pulmonary fibrosis (PPF) has a disease course similar to IPF, with worsening respiratory symptoms, decline in lung function, impairment of quality of life, and premature death. In 2019, a phase III trial demonstrated that treatment with the tyrosine kinase inhibitor nintedanib halves disease progression as measured by a decline in forced vital capacity over one year, and contributed to the validation of the PPF concept. In the 2022 international clinical practice guideline, nintedanib received a conditional recommendation to treat patients with PPF. In 2025, it was demonstrated that the phosphodiesterase 4B inhibitor nerandomilast further reduces disease progression in patients with PPF. Other smaller trials have suggested that pirfenidone may also benefit patients with PPF. Several newer compounds are currently being developed for both IPF and PPF. As a diagnosis of PPF identifies patients with fibrotic disease progression, early identification is warranted for the timely initiation of antifibrotic therapy, consideration of lung transplantation if eligible, and holistic care.

Rationale: Whether change in fibrosis on high-resolution computed tomography is associated with near- and longer-term outcomes in patients with fibrotic interstitial lung disease (fILD) remains unclear. Objectives: We evaluated the association between 1-year change in quantitative fibrosis scores (data-driven textural analysis [DTA]) and subsequent FVC and survival in patients with fILD. Methods: The primary cohort included patients with fILD evaluated from 2017 to 2020 with baseline and 1-year follow-up high-resolution computed tomography and FVC. Associations between DTA change and subsequent FVC were assessed using linear mixed models. Transplant-free survival was assessed using Cox proportional hazards models. The Pulmonary Fibrosis Foundation Patient Registry served as the validation cohort. Measurements and Main Results: The primary cohort included 407 patients (median [interquartile range] age, 70.5 [64.8, 75.9] yr; 214 male). One-year increase in DTA was associated with subsequent FVC decline and transplant-free survival. The largest effect on FVC was observed in patients with low baseline DTA scores, in whom a 5% increase in DTA over 1 year was associated with a change in FVC of -91 ml/yr (95% confidence interval [CI], -117, -65 vs. stable DTA, -49 ml/yr; 95% CI, -69, -29; P = 0.0002). The hazard ratio for transplant-free survival for a 5% increase in DTA over 1 year was 1.45 (95% CI, 1.25, 1.68). The findings were confirmed in the validation cohort. Conclusions: One-year change in DTA score is associated with future disease trajectory and transplant-free survival in patients with fILD. DTA could be a useful trial endpoint, cohort enrichment tool, and metric to incorporate into clinical care.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a complex and heterogeneous disease. Given this, we reasoned that differences in genetic profiles may be associated with unique clinical and radiologic features. Computational image analysis, sometimes referred to as radiomics, provides objective, quantitative assessments of radiologic features in subjects with pulmonary fibrosis. Objectives: To determine if the genetic risk profile of patients with IPF identifies unique computational imaging phenotypes. Methods: Participants with IPF were included in this study if they had genotype data and computed tomography (CT) scans of the chest available for computational image analysis. The extent of lung fibrosis and the likelihood of a usual interstitial pneumonia (UIP) pattern were scored automatically using two separate, previously validated deep learning techniques for CT analysis. UIP pattern was also classified visually by radiologists according to established criteria. Results: Among 329 participants with IPF, MUC5B and ZKSCAN1 were independently associated with the deep learning-based UIP score. None of the common variants were associated with fibrosis extent by computational imaging. We did not find an association between MUC5B or ZKSCAN1 and visually assessed UIP pattern. Conclusions: Select genetic variants are associated with computer-based classification of UIP on CT in this IPF cohort. Analysis of radiologic features using deep learning may enhance our ability to identify important genotype-phenotype associations in fibrotic lung diseases.

Background: Despite advances in diagnosis and management, the interstitial lung disease (ILD) lexicon is plagued by ambiguous and inconsistent terminology that complicates communication and impedes knowledge generation. The objective of this Fleischner Society Consensus Statement was to produce standardized terminology for ILD multidisciplinary diagnoses and major phenotypes. Methods: Interviews with 10 experts were used to identify ILD clinical diagnoses and major phenotypes. The preferred terms for each entity and potential alternatives were identified, alongside the rationale for the preferred term. Entities with more than one potential term were the subject of an online modified Delphi survey posed to the 29 committee members, aiming to achieve consensus. Committee members rated their agreement with the initially preferred term-5 (strongly agree), 4 (agree), 3 (neutral/unsure), 2 (disagree), and 1 (strongly disagree)-with the option to provide additional comments. Median score ⩾4 and interquartile range ⩽1 were considered consensus agreement. Terms not reaching agreement were discussed by video conference, followed by an additional survey that incorporated feedback. Results: From the 60 initial terms, there were two root terms that required upfront consensus before survey initiation (ILD and interstitial pneumonia) and another eight terms that had no alternative suggested by the committee or in the literature. Agreement was met by 47/50 terms (94%) in Round 1 of the survey. The three terms (6%) that did not reach agreement met agreement in Round 2. Conclusions: This document provides standardized recommended terms for ILD multidisciplinary diagnoses and major phenotypes that will facilitate communication among clinicians, researchers, patients, and other stakeholders.

This international multisociety consensus statement, developed by 21 thoracic radiologists and reviewed by four pulmonology experts, aims to standardize chest CT indications, acquisition, and reporting of post–COVID-19 residual CT lung abnormalities.

Background:Suspected interstitial lung disease (ILD) patients may be referred to an ILD-specialist centre or a non-ILD-specialist centre for diagnosis and treatment. Early referral and management of patients at ILD-specialist centres has been shown to improve survival and reduce hospitalisations. The COVID-19 pandemic has affected the ILD patient diagnostic pathway and prompted centres to adapt. This study investigates and contrasts ILD patient pathways in ILD-specialist and non-ILD-specialist centres, focusing on referrals, caseloads, diagnostic tools, multi-disciplinary team (MDT) meeting practices and resource accessibility. Methods:Conducted as a cross-sectional study, a global self-selecting survey ran from September 2022 to January 2023. Participants included ILD specialists and healthcare professionals (HCPs) from ILD-specialist centres and non-ILD-specialist centres. Results:Of 363 unique respondents from 64 countries, 259 were from ILD-specialist centres and 104 from non-ILD-specialist centres. ILD centres had better resource availability, exhibiting higher utilisation of diagnostic tests (median: 12 tests) than non-ILD centres (nine tests) and better access to specialist professions attending MDT meetings (median: six professions at meeting) in specialist centres than non-ILD centres (three professions at meeting). Transitioning to virtual MDT meetings allowed HCPs from other locations to join meetings in nearly 90% of all centres, increasing regular participation in 60% of specialist centres and 72% of non-ILD centres. For treatment of patients, specialist centres had better access to antifibrotic drugs (91%) compared to non-ILD centres (60%). Conclusions:Diagnostic pathways for ILD patients diverged between specialist centres and non-ILD centres. Disparities in resource and specialist availability existed between centres.

Abstract Background Drugs used to treat rheumatic disease are associated with pneumotoxicity (drug-induced lung disease), but little is known about associated risk factors. Aim To determine expert physician-perceived risk factors for developing pneumotoxicity in patients with rheumatologic conditions. Methods A modified international 3-tier Delphi exercise was performed. Tier 1 determined patient and drug variables that physicians perceive to be risk factors. Tier 2 determined degree of risk associated with the Tier-1 derived variables. Tier 3 aimed to internally validate and stratify exemplar cases into risk categories. Results 134 pulmonologists and 49 rheumatologists responded to Tier 1;157 physicians completed all tiers. Perceived risk factors included: drug type; history of previous pneumotoxicity; age; smoking; underlying rheumatic disease type and activity; renal function; pulmonary hypertension; left ventricular failure;presence, nature, severity and progression of pre-existing interstitial lung disease. Tier 2 data stratified these variables into risk profiles e.g. never versus current smoking was perceived as low and high risk respectively. An example of perceived high risk resulting from Tier 3 is a 75-year-old current smoker with high-activity rheumatoid arthritis (RA) with severe, progressive ILD being started on methotrexate. A perceived low risk is a 75-year-old currentsmoker with moderate-activity RA and emphysema with no cardiac or renal disease and no pre-existing ILD being started on rituximab. A risk prediction scoring tool is being developed to be used in validation studies. Conclusion This modified Delphi exercise defined and stratified the perceived risk factors for developing pneumotoxicity. Age, current smoking, high underlying rheumatological disease activity, HRCT definite UIP and honeycombing, severity and progression of pre-existing ILD were perceived to be the highest risk-factors.

The shortcomings of qualitative visual assessment have led to the development of computer-based tools to characterise and quantify disease on high-resolution computed tomography (HRCT) in patients with interstitial lung diseases (ILDs). Quantitative CT (QCT) software enables quantification of patterns on HRCT with results that are objective, reproducible, sensitive to change and predictive of disease progression. Applications developed to provide a diagnosis or pattern classification are mainly based on artificial intelligence. Deep learning, which identifies patterns in high-dimensional data and maps them to segmentations or outcomes, can be used to identify the imaging patterns that most accurately predict disease progression. Optimisation of QCT software will require the implementation of protocol standards to generate data of sufficient quality for use in computerised applications and the identification of diagnostic, imaging and physiological features that are robustly associated with mortality for use as anchors in the development of algorithms. Consortia such as the Open Source Imaging Consortium have a key role to play in the collation of imaging and clinical data that can be used to identify digital imaging biomarkers that inform diagnosis, prognosis and response to therapy.

BACKGROUND:The rarity of childhood interstitial lung disease (chILD) makes it challenging to conduct powered trials. In the InPedILD trial, among 39 children and adolescents with fibrosing ILD, there was a numerical benefit of nintedanib versus placebo on change in forced vital capacity (FVC) over 24 weeks (difference in mean change in FVC % predicted of 1.21 [95% confidence interval: -3.40, 5.81]). Nintedanib has shown a consistent effect on FVC across populations of adults with different diagnoses of fibrosing ILD.METHODS:In a Bayesian dynamic borrowing analysis, prespecified before data unblinding, we incorporated data on the effect of nintedanib in adults and the data from the InPedILD trial to estimate the effect of nintedanib on FVC in children and adolescents with fibrosing ILD. The data from adults were represented as a meta-analytic predictive (MAP) prior distribution with mean 1.69 (95% credible interval: 0.49, 3.08). The adult data were weighted according to expert judgment on their relevance to the efficacy of nintedanib in chILD, obtained in a formal elicitation exercise.RESULTS:Combined data from the MAP prior and InPedILD trial analyzed within the Bayesian framework resulted in a median difference between nintedanib and placebo in change in FVC % predicted at Week 24 of 1.63 (95% credible interval: -0.69, 3.40). The posterior probability for superiority of nintedanib versus placebo was 95.5%, reaching the predefined success criterion of at least 90%.CONCLUSION:These findings, together with the safety data from the InPedILD trial, support the use of nintedanib in children and adolescents with fibrosing ILDs.

Background There is no standard definition of respiratory-related hospitalisation, a common end-point in idiopathic pulmonary fibrosis (IPF) clinical trials. As diverse aetiologies and complicating comorbidities can present similarly, external adjudication is sometimes employed to achieve standardisation of these events. Methods An algorithm for respiratory-related hospitalisation was developed through a literature review of IPF clinical trials with respiratory-related hospitalisation as an end-point. Experts reviewed the algorithm until a consensus was reached. The algorithm was validated using data from the phase 3 ISABELA trials (clinicaltrials.gov identifiers NCT03711162 and NCT03733444), by assessing concordance between nonadjudicated, investigator-defined, respiratory-related hospitalisations and those defined by the adjudication committee using the algorithm. Results The algorithm classifies respiratory-related hospitalisation according to cause: extraparenchymal (worsening respiratory symptoms due to left heart failure, volume overload, pulmonary embolism, pneumothorax or trauma); other (respiratory tract infection, right heart failure or exacerbation of COPD); “definite” acute exacerbation of IPF (AEIPF) (worsening respiratory symptoms within 1 month, with radiological or histological evidence of diffuse alveolar damage); or “suspected” AEIPF (as for “definite” AEIPF, but with no radiological or histological evidence of diffuse alveolar damage). Exacerbations (“definite” or “suspected”) with identified triggers (infective, post-procedural or traumatic, drug toxicity- or aspiration-related) are classed as “known AEIPF”; “idiopathic AEIPF” refers to exacerbations with no identified trigger. In the ISABELA programme, there was 94% concordance between investigator- and adjudication committee-determined causes of respiratory-related hospitalisation. Conclusion The algorithm could help to ensure consistency in the reporting of respiratory-related hospitalisation in IPF trials, optimising its utility as an end-point.

Progressive pulmonary fibrosis (PPF) and interstitial lung abnormalities (ILA) are relatively new concepts in interstitial lung disease (ILD) imaging and clinical management. Recognition of signs of PPF and identification and classification of ILA are important tasks during chest high-resolution CT interpretation to optimize management of patients with ILD and those at risk of developing ILD. However, in professional society guidance, the role of imaging surveillance remains unclear for stable patients with ILD, asymptomatic patients with ILA who are at risk of progression, and asymptomatic patients at risk of developing ILD without imaging abnormalities. In this AJR Expert Panel Narrative Review, we summarize the current knowledge regarding PPF and ILA and describe the range of clinical practice with respect to imaging patients with ILD, those with ILA, and those at risk of developing ILD. In addition, we offer suggestions to help guide surveillance imaging in areas with an absence of published guidelines, where such decisions are currently driven primarily by local pulmonologists' preference.

Abstract Background We sought consensus among practising respiratory physicians on the prediction, identification and monitoring of progression in patients with fibrosing interstitial lung disease (ILD) using a modified Delphi process. Methods Following a literature review, statements on the prediction, identification and monitoring of progression of ILD were developed by a panel of physicians with specialist expertise. Practising respiratory physicians were sent a survey asking them to indicate their level of agreement with these statements on a binary scale or 7-point Likert scale (− 3 to 3), or to select answers from a list. Consensus was considered to be achieved if ≥ 70% of respondents selected the same answer, or, for responses on a Likert scale, the median score was ≤ –2 (disagree/not important) or ≥ 2 (agree/important) with an interquartile range ≤ 1. There were three rounds of the survey. Results Surveys 1, 2 and 3 were completed by 207, 131 and 94 physicians, respectively, between March 2022 and July 2023. Decline in forced vital capacity (FVC), decline in diffusing capacity of the lungs for carbon monoxide, and increased fibrosis on high-resolution computed tomography (HRCT) were ranked as the most important endpoints for determining progression. Consensus was reached that progression on HRCT or a decline in FVC ≥ 10% from baseline is sufficient to determine progression, and that small declines in multiple endpoints indicates progression. Consensus was reached that a histological pattern of usual interstitial pneumonia (UIP) is a risk factor for progression of ILD, but that a biopsy to look for a UIP pattern should not be performed solely for prognostic reasons. Consensus was not reached on the time period over which progression should be defined. There was consensus that appropriate management of ILD depends on the type of ILD, and that ‘despite adequate management’ or ‘despite usual management’ should be included in the definition of progression. Conclusions This modified Delphi process provided consensus statements on the identification of ILD progression that were supported by a broad group of clinicians and may help to inform clinical practice until robust evidence-based guidelines are available.

Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are debilitating diseases associated with divergent histopathological changes in the lungs. At present, due to cost and technical limitations, profiling cell types is not practical in large epidemiology cohorts (n > 1000). Here, we used computational deconvolution to identify cell types in COPD and IPF lungs whose abundances and cell type-specific gene expression are associated with disease diagnosis and severity. We analyzed lung tissue RNA-seq data from 1026 subjects (COPD, n = 465; IPF, n = 213; control, n = 348) from the Lung Tissue Research Consortium. We performed RNA-seq deconvolution, querying thirty-eight discrete cell-type varieties in the lungs. We tested whether deconvoluted cell-type abundance and cell type-specific gene expression were associated with disease severity. The abundance score of twenty cell types significantly differed between IPF and control lungs. In IPF subjects, eleven and nine cell types were significantly associated with forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO), respectively. Aberrant basaloid cells, a rare cells found in fibrotic lungs, were associated with worse FVC and DLCO in IPF subjects, indicating that this aberrant epithelial population increased with disease severity. Alveolar type 1 and vascular endothelial (VE) capillary A were decreased in COPD lungs compared to controls. An increase in macrophages and classical monocytes was associated with lower DLCO in IPF and COPD subjects. In both diseases, lower non-classical monocytes and VE capillary A cells were associated with increased disease severity. Alveolar type 2 cells and alveolar macrophages had the highest number of genes with cell type-specific differential expression by disease severity in COPD and IPF. In IPF, genes implicated in the pathogenesis of IPF, such as matrix metallopeptidase 7, growth differentiation factor 15, and eph receptor B2, were associated with disease severity in a cell type-specific manner. Utilization of RNA-seq deconvolution enabled us to pinpoint cell types present in the lungs that are associated with the severity of COPD and IPF. This knowledge offers valuable insight into the alterations within tissues in more advanced illness, ultimately providing a better understanding of the underlying pathological processes that drive disease progression.

Topic Importance As interstitial lung abnormalities (ILAs) are increasingly recognized on imaging and in clinical practice, identification and appropriate management are critical. We propose an algorithmic approach to the identification and management of patients with ILAs. Review Findings The radiologist initially identifies chest CT scan findings suggestive of an ILA pattern and excludes findings that are not consistent with ILAs. The next step is to confirm that these findings occupy > 5% of a nondependent lung zone. At this point, the radiologic pattern of ILA is identified. These findings are classified as non-subpleural, subpleural nonfibrotic, and subpleural fibrotic. It is then incumbent on the clinician to ascertain if the patient has symptoms and/or abnormal pulmonary physiology that may be attributable to these radiologic changes. Based on the patient’s symptoms, physiological assessment, and risk factors for interstitial lung disease (ILD), we recommend classifying patients as having ILA, at high risk for developing ILD, probable ILD, or ILD. In patients identified as having ILA, a multidisciplinary discussion should evaluate features that indicate an increased risk of progression. If these features are present, serial monitoring is recommended to be proactive. If the patient does not have imaging or clinical features that indicate an increased risk of progression, then monitoring is recommended to be reactive. If ILD is subsequently diagnosed, the management is disease specific. Summary We anticipate this algorithmic approach will aid clinicians in interpreting the radiologic pattern described as ILA within the clinical context of their patients.

Background: Idiopathic pulmonary fibrosis (IPF) carries significant mortality and unpredictable progression, with limited therapeutic options. Designing trials with patient-meaningful endpoints, enhancing the reliability and interpretability of results, and streamlining the regulatory approval process are of critical importance to advancing clinical care in IPF. Methods: A landmark in-person symposium in June 2023 assembled 43 participants from the US and internationally, including patients with IPF, investigators, and regulatory representatives, to discuss the immediate future of IPF clinical trial endpoints. Patient advocates were central to discussions, which evaluated endpoints according to regulatory standards and the FDA's 'feels, functions, survives' criteria. Results: Three themes emerged: 1) consensus on endpoints mirroring the lived experiences of patients with IPF; 2) consideration of replacing forced vital capacity (FVC) as the primary endpoint, potentially by composite endpoints that include 'feels, functions, survives' measures or FVC as components; 3) support for simplified, user-friendly patient-reported outcomes (PROs) as either components of primary composite endpoints or key secondary endpoints, supplemented by functional tests as secondary endpoints and novel biomarkers as supportive measures (FDA Guidance for Industry (Multiple Endpoints in Clinical Trials) available at: https://www.fda.gov/media/162416/download). Conclusions: This report, detailing the proceedings of this pivotal symposium, suggests a potential turning point in designing future IPF clinical trials more attuned to outcomes meaningful to patients, and documents the collective agreement across multidisciplinary stakeholders on the importance of anchoring IPF trial endpoints on real patient experiences—namely, how they feel, function, and survive. There is considerable optimism that clinical care in IPF will progress through trials focused on patient-centric insights, ultimately guiding transformative treatment strategies to enhance patients' quality of life and survival.

RATIONALE Relatives of patients with familial interstitial pneumonia are at increased risk for pulmonary fibrosis, and develop preclinical pulmonary fibrosis (PrePF). OBJECTIVES We defined the incidence and progression of new onset PrePF; its relationship to survival among first degree relatives of families with familial interstitial pneumonia. METHODS This is a cohort study of family members with familial interstitial pneumonia who were initially screened with a questionnaire and chest HRCT scan, and approximately 4 years later, the evaluation was repeated. 493 asymptomatic first-degree relatives of patients with familial interstitial pneumonia were evaluated at baseline, and 296 (60%) of the original subjects participated in subsequent evaluation. RESULTS The median interval between HRCTs was 3.9 years (IQ range 3.5-4.4). 252 subjects who agreed to repeat evaluation were originally determined not to have PrePF at baseline; 16 developed PrePF. A conservative estimate of the annual incidence of PrePF is 1,023 per 100, 000 person years (95% CI 511-1831). Of 44 subjects with PrePF at baseline, 38.4% subjects had worsening dyspnea compared to 15.4% of those without PrePF (P=0.002). Usual interstitial pneumonia (UIP) by HRCT (P< 0.0002) and baseline quantitative fibrosis score (P<0.001) are also associated with worsening dyspnea. PrePF at the initial screen is associated with decreased survival (P< 0.001). CONCLUSIONS The incidence of PrePF in this at-risk population is at least 100-fold higher than that reported for sporadic idiopathic pulmonary fibrosis (IPF). While PrePF and IPF represent distinct entities, our study demonstrates that PrePF, like IPF, is progressive and associated with decreased survival.