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OBJECTIVES: To establish a framework by which experts define disease subsets in systemic sclerosis associated interstitial lung disease (SSc-ILD). METHODS: A conceptual framework for subclinical, clinical and progressive ILD was provided to 83 experts, asking them to use the framework and classify actual SSc-ILD patients. Each patient profile was designed to be classified by at least four experts in terms of severity and risk of progression at baseline; progression was based on 1-year follow-up data. A consensus was reached if ≥75% of experts agreed. Experts provided information on which items were important in determining classification. RESULTS: Forty-four experts (53%) completed the survey. Consensus was achieved on the dimensions of severity (75%, 60 of 80 profiles), risk of progression (71%, 57 of 80 profiles) and progressive ILD (60%, 24 of 40 profiles). For profiles achieving consensus, most were classified as clinical ILD (92%), low risk (54%) and stable (71%). Severity and disease progression overlapped in terms of framework items that were most influential in classifying patients (forced vital capacity, extent of lung involvement on high resolution chest CT [HRCT]); risk of progression was influenced primarily by disease duration. CONCLUSIONS: Using our proposed conceptual framework, international experts were able to achieve a consensus on classifying SSc-ILD patients along the dimensions of disease severity, risk of progression and progression over time. Experts rely on similar items when classifying disease severity and progression: a combination of spirometry and gas exchange and quantitative HRCT.

BackgroundInterstitial 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 questionCan 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 methodsPulmonologists 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.ResultsFifty-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.InterpretationGuidance 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.

Fibrotic interstitial lung disease (ILD) represents a large group of pulmonary disorders that are often progressive and associated with high morbidity and early mortality. Important advancements in the past 10 years have enabled a better understanding, characterisation, and treatment of these diseases. This Series paper summarises the current approach to treatment of fibrotic ILDs, both pharmacological and non-pharmacological, including recent discoveries and practice-changing clinical trials. We further outline controversies and challenges, with discussion of evolving concepts and future research directions.

BackgroundChronic hypersensitivity pneumonitis (CHP) is an immune-mediated interstitial lung disease (ILD) caused by inhalational exposure to environmental antigens, resulting in parenchymal fibrosis. By definition, a diagnosis of CHP assumes a history of antigen exposure, but only half of all patients eventually diagnosed with CHP will have a causative antigen identified. Individual clinician variation in eliciting a history of antigen exposure may affect the frequency and confidence of CHP diagnosis.MethodsA list of potential causative exposures were derived from a systematic review of the literature. A Delphi method was applied to an international panel of ILD experts to obtain consensus regarding technique for the elicitation of exposure to antigens relevant to a diagnosis of CHP. The consensus threshold was set at 80% agreement, and median ≤ 2, interquartile range = 0 on a 5-point Likert scale (1, strongly agree; 2, tend to agree; 3, neither agree nor disagree; 4, disagree; 5, strongly disagree).ResultsIn two rounds, 36/40 experts participated. Experts agreed on 18 exposure items to ask every patient with suspected CHP. Themes included CHP inducing exposures, features that contribute to an exposure's relevance, and quantification of a relevant exposure. Based on the results from the literature review and Delphi process, a CHP exposure assessment instrument was derived. Using cognitive interviews, the instrument was revised by patients with ILD for readability and usability.ConclusionsThis Delphi survey provides items that ILD experts agree are important to ask in all patients presenting with suspected CHP and provides basis for a systematically derived CHP exposure assessment instrument. Clinical utility of this exposure assessment instrument may be affected by different local prevalence patterns of exposures. Ongoing research is required to clinically validate these items and consider their impact in more geographically diverse settings.

Rationale: Cough is a key symptom in patients with fibrotic interstitial lung disease (ILD). Objectives: This study evaluated the prevalence, longitudinal change, associations, and prognostic significance of cough severity in patients with fibrotic ILD. Methods: We included consecutive patients with idiopathic pulmonary fibrosis (IPF) and non-IPF fibrotic ILD who completed the 100-mm Cough Severity Visual Analog Scale from the prospective multicenter Canadian Registry for Pulmonary Fibrosis. Baseline cough severity and associations with patient demographics and clinical factors were determined. Relationships between baseline cough severity and health outcomes were evaluated. Measurements and Main Results: Patients with IPF (n = 1,061) had higher median baseline cough severity than those with non-IPF fibrotic ILD (n = 2,825) (24 vs. 20 mm; P < 0.001), with worse cough associated with gastroesophageal reflux disease for both cohorts. Worse cough severity was independently associated with worse health-related quality of life at baseline, larger annualized decline in DlCO, development of disease progression, and reduced transplant-free survival in both IPF and non-IPF fibrotic ILD cohorts. The IPF cohort (2.2 mm; 95% confidence interval, 1.6–2.9 mm) had larger annualized increments in cough severity than the non-IPF fibrotic ILD cohort (1.1 mm; 95% confidence interval, 0.8–1.4 mm; P = 0.004). There was no difference in worsening cough over time comparing those receiving and not receiving ILD-targeted therapy or with and without lung function decline. Conclusions: Cough is common in patients with IPF and non-IPF fibrotic ILD, with increasing cough severity over time irrespective of ILD-targeted therapy. Patient-reported cough severity has prognostic implications on health-related quality of life, disease progression, and survival in fibrotic ILD. [ABSTRACT FROM AUTHOR]

BackgroundAir pollution exposure is associated with acute exacerbation, disease progression, and mortality in patients with idiopathic pulmonary fibrosis (IPF). The objective of this study was to describe the impact of air pollution exposures on disease severity, as well as changes in lung function, in patients with IPF.MethodsUsing home spirometers and symptom diaries, 25 patients with IPF prospectively recorded FVC weekly for up to 40 weeks. Residential addresses were geocoded to estimate weekly mean air pollution exposures for ground-level ozone (O3), nitrogen dioxide (NO2), and particulate matter < 2.5 or 10 μm in aerodynamic diameter (PM2.5 and PM10, respectively). The dependence of weekly clinical measurements on preceding levels of each pollutant was assessed with the use of linear mixed models, yielding beta-coefficients with 95% CIs, using varying lag times.ResultsLower mean FVC % predicted was consistently associated with increased mean exposures to PM10 in the 2 to 5 weeks preceding clinical measurements (range, -0.46 to -0.39 [95% CI, -0.73 to -0.13]; P < .005). Lower mean FVC % predicted over the study period was inversely related to mean levels of NO2 (-0.45 [95% CI, -0.85 to -0.05]; P = .03), PM2.5 (-0.45 [95% CI, -0.84 to -0.07]; P = .02), and PM10 (-0.57 [95% CI, -0.92 to -0.21]; P = .003), averaged over the study. Weekly changes in FVC and changes over 40 weeks were independent of pollution exposures.ConclusionsHigher air pollution exposures were associated with lower lung function, but not changes in lung function, in patients with IPF. Further studies are needed to characterize the mechanisms underlying this relationship.

RationaleCurrent diagnosis of chronic hypersensitivity pneumonitis (cHP) involves considering a combination of clinical, radiological, and pathological information in multidisciplinary team discussions. However, this approach is highly variable with poor agreement between centers.ObjectivesWe aimed to identify diagnostic criteria for cHP that reach consensus among international experts.MethodsA 3-round modified Delphi survey was conducted between April and August 2017. Forty-five experts in interstitial lung disease from 14 countries participated in the online survey. Diagnostic items included in round 1 were generated using expert interviews and literature review. During rounds 1 and 2, experts rated the importance of each diagnostic item on a 5-point Likert scale. The a priori threshold of consensus was ≥ 75% of experts rating a diagnostic item as very important or important. In the third round, experts graded the items that met consensus as important and provided their level of diagnostic confidence for a series of clinical scenarios.Measurements and main resultsConsensus was achieved on 18 of the 40 diagnostic items. Among these, experts gave the highest level of importance to the identification of a causative antigen, time relation between exposure and disease, mosaic attenuation on chest imaging, and poorly formed non-necrotizing granulomas on pathology. In clinical scenarios, the diagnostic confidence of experts in cHP was heightened by the presence of these diagnostic items.ConclusionThis consensus-based approach for the diagnosis of cHP represents a first step towards the development of international guidelines for the diagnosis of cHP.

The objective of this study was to investigate the reliability, feasibility and analytical impact of home-based measurement of forced vital capacity (FVC) and dyspnoea as clinical endpoints in idiopathic pulmonary fibrosis (IPF).Patients with IPF performed weekly home-based assessment of FVC and dyspnoea using a mobile hand-held spirometer and self-administered dyspnoea questionnaires. Weekly variability in FVC and dyspnoea was estimated, and sample sizes were simulated for a hypothetical 24-week clinical trial using either traditional office-based interval measurement or mobile weekly assessment.In total, 25 patients were enrolled. Mean adherence to weekly assessments over 24 weeks was greater than 90%. Compared with change assessment using baseline and 24-week measurements only, weekly assessment of FVC resulted in enhanced precision and power. For example, a hypothetical 24-week clinical trial with FVC as the primary endpoint would require 951 patients using weekly home spirometry compared with 3840 patients using office spirometry measures at weeks 1 and 24 only. The ability of repeated measures to reduce clinical trial sample size was influenced by the correlation structure of the data.Home monitoring can improve the precision of endpoint assessments, allowing for greater efficiency in clinical trials of therapeutics for IPF.

BackgroundRecent studies have suggested that non-definitive patterns on high-resolution CT (HRCT) scan provide sufficient diagnostic specificity to forgo surgical lung biopsy in the diagnosis of idiopathic pulmonary fibrosis (IPF). The objective of this study was to determine test characteristics of non-definitive HRCT patterns for identifying histopathological usual interstitial pneumonia (UIP).MethodsPatients with biopsy-proven interstitial lung disease (ILD) and non-definitive HRCT scans were identified from two academic ILD centres. Test characteristics for HRCT patterns as predictors of UIP on surgical lung biopsy were derived and validated in independent cohorts.ResultsIn the derivation cohort, 64/385 (17%) had possible UIP pattern on HRCT; 321/385 (83%) had inconsistent with UIP pattern. 113/385 (29%) patients had histopathological UIP pattern in the derivation cohort. Possible UIP pattern had a specificity of 91.2% (95% CI 87.2% to 94.3%) and a positive predictive value (PPV) of 62.5% (95% CI 49.5% to 74.3%) for UIP pattern on surgical lung biopsy. The addition of age, sex and total traction bronchiectasis score improved the PPV. Inconsistent with UIP pattern demonstrated poor PPV (22.7%, 95% CI 18.3% to 27.7%). HRCT pattern specificity was nearly identical in the validation cohort (92.7%, 95% CI 82.4% to 98.0%). The substantially higher prevalence of UIP pattern in the validation cohort improved the PPV of HRCT patterns.ConclusionsA possible UIP pattern on HRCT has high specificity for UIP on surgical lung biopsy, but PPV is highly dependent on underlying prevalence. Adding clinical and radiographic features to possible UIP pattern on HRCT may provide sufficient probability of histopathological UIP across prevalence ranges to change clinical decision-making.

BackgroundThe treatment of chronic hypersensitivity pneumonitis (cHP) often includes systemic oral corticosteroids, but the optimal pharmacologic management remains unclear. The morbidity associated with prednisone has motivated the search for alternative therapies. We aimed to determine the effect of treatment with mycophenolate mofetil (MMF) or azathioprine (AZA) on lung function in patients with cHP.MethodsPatients with cHP treated with either MMF or AZA were retrospectively identified from four interstitial lung disease centers. Change in lung function before and after treatment initiation was analyzed using linear mixed-effects modeling (LMM), adjusting for age, sex, smoking history, and prednisone use.ResultsSeventy patients were included: 51 were treated with MMF and 19 with AZA. Median follow-up after treatment initiation was 11 months. Prior to treatment initiation, FVC and diffusion capacity of the lung for carbon monoxide (Dlco) % predicted were declining at a mean rate of 0.12% (P < .001) and 0.10% (P < .001) per month, respectively. Treatment with either MMF or AZA was not associated with improved FVC (0.5% at 1 year; P = .46) but was associated with a statistically significant improvement in Dlco of 4.2% (P < .001) after 1 year of treatment. Results were similar in the subgroup of patients treated with MMF for 1 year; the FVC increased nonsignificantly by 1.3% (P = .103) and Dlco increased by 3.9% (P < .001).ConclusionsTreatment with MMF or AZA is associated with improvements in Dlco in patients with cHP. Prospective randomized trials are needed to validate their effectiveness for cHP.

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]

Rationale: A visual analog scale (VAS) is a simple and easily administered tool for measuring the impact of disease; however, little is known about the use of a dyspnea VAS in interstitial lung disease (ILD). Objectives: To validate the use of a dyspnea VAS in a large and heterogeneous cohort of patients with fibrotic ILD, including its minimal clinically important difference (MCID), responsiveness to change, and prognostic significance. Methods: Patients with fibrotic ILD were identified from a large prospective registry. The validity of a 100-mm dyspnea VAS was assessed by testing its correlation in change score with other measures of ILD severity, including the University of California San Diego Shortness of Breath Questionnaire, the King's Brief Interstitial Lung Disease quality of life questionnaire Breathlessness and Activities Domain, the European Quality of Life VAS, forced vital capacity, and diffusing capacity of the lung for carbon monoxide. The responsiveness of the dyspnea VAS was qualitatively confirmed on the basis of there being an observable difference in the change in dyspnea VAS across tertiles of change in anchor variables. The MCID in dyspnea VAS was calculated using both anchor (linear regression) and distribution (one-half standard deviation) approaches, with anchors including the above variables that had a correlation with dyspnea VAS (|r| ≥ 0.30). The association of dyspnea VAS with time to death or transplant was determined. Results: The cohort included 826 patients with fibrotic ILD, including 127 patients with follow-up measurements at 6 months. The mean baseline dyspnea VAS was 53 ± 24 mm. Dyspnea VAS change scores were moderately correlated with the University of California San Diego Shortness of Breath Questionnaire (|r| = 0.55) and the King's Brief Interstitial Lung Disease quality of life questionnaire Breathlessness and Activities Domain (|r| = 0.44) and weakly correlated with the European Quality of Life VAS (|r| = 0.19), forced vital capacity percent predicted (|r| = 0.21), and diffusing capacity of the lung for carbon monoxide percent predicted (|r| = 0.05). The MCID was 2.7 to 4.5 using the more reliable anchor-based methods and 12.0 based on distribution-based methods. Dyspnea VAS was associated with time to death or transplant in unadjusted models and after adjustment for age and sex (hazard ratios, 1.16 and 1.15, respectively; P < 0.05 for both). Conclusions: This study provides support for the use of the dyspnea VAS in patients with fibrotic ILD, with an estimated anchor-based MCID of 5 mm. [ABSTRACT FROM AUTHOR]

The objective of this study was to develop a diagnostic model that allows for a highly specific diagnosis of chronic hypersensitivity pneumonitis using clinical and radiological variables alone. Chronic hypersensitivity pneumonitis and other interstitial lung disease cases were retrospectively identified from a longitudinal database. High-resolution CT scans were blindly scored for radiographic features (eg, ground-glass opacity, mosaic perfusion) as well as the radiologist's diagnostic impression. Candidate models were developed then evaluated using clinical and radiographic variables and assessed by the cross-validated C-statistic. Forty-four chronic hypersensitivity pneumonitis and eighty other interstitial lung disease cases were identified. Two models were selected based on their statistical performance, clinical applicability and face validity. Key model variables included age, down feather and/or bird exposure, radiographic presence of ground-glass opacity and mosaic perfusion and moderate or high confidence in the radiographic impression of chronic hypersensitivity pneumonitis. Models were internally validated with good performance, and cut-off values were established that resulted in high specificity for a diagnosis of chronic hypersensitivity pneumonitis.

Idiopathic pulmonary fibrosis is a diffuse parenchymal lung disease of unknown cause. The natural history of disease can vary considerably, making it difficult to predict the clinical trajectory for an individual patient. Accurate prognostication is desirable for clinical management as well as for cohort enrichment in clinical trials of therapeutics. Clinical and biomarker models of disease behavior have been developed to improve prognostication in idiopathic pulmonary fibrosis, with moderate predictive capabilities. Integrated prediction models that combine both clinical and biomarker variables will improve prognostication for patients and improved cohort enrichment strategies for clinical trials. This goal may be best achieved through collaborative patient registries with prospectively collected biological samples that allow for characterization of disease behavior in idiopathic pulmonary fibrosis.