The providing multidisciplinary ILD diagnoses (PROMISE) study - study design of the national registry of Japan facilitating interactive online multidisciplinary discussion diagnosis.

BACKGROUND: Multidisciplinary discussion (MDD), in which physicians, radiologists, and pathologists communicate and diagnose together, has been reported to improve diagnostic accuracy compared to diagnoses made solely by physicians. However, even among experts, diagnostic concordance of MDD is not always good, and some patients may not receive a specific diagnosis due to insufficient findings. A provisional diagnosis based on the ontology with a diagnostic confidence level has recently been proposed. Additionally, we developed an artificial intelligence model to differentiate idiopathic pulmonary fibrosis (IPF) from other chronic interstitial lung diseases (ILD)s, which needs validation in a broader population. METHODS: This prospective nationwide ILD registry has recruited patients with newly diagnosed ILD at the referral respiratory hospitals in Japan and provides rapid MDD diagnoses and treatment recommendations through a central online MDD platform with a 3-year follow-up period. A modified diagnostic ontology is used. If no diagnosis reaches more than 50% certainty, the diagnosis is unclassifiable ILD. If multiple diseases are expected, the diagnosis with a high probability takes precedence. If the confidence levels for the top two possible diagnoses are equal, the diagnosis can be unclassifiable. The registry uses tentative diagnostic criteria for nonspecific interstitial pneumonia with organising pneumonia and smoking-related ILD not otherwise specified as possible new entities. Central MDD diagnosticians review the clinical data, test results, radiology images, and pathological specimens on a dedicated website and conduct MDD diagnoses using online meetings with a cloud-based reporting system. This study aims to (1) provide MDD diagnoses with treatment recommendations; (2) determine the overall ILD rates in Japan; (3) clarify the reasons for unclassifiable ILDs; (4) evaluate possible new disease entities; (5) identify progressive phenotypes and create a clinical prediction model; (6) measure the agreement rate between institutional and central diagnoses in ILD referral and non-referral centres; (7) identify key factors for each specific ILD diagnosis; and (8) create a new disease classification system based on treatment strategies, including the use of antifibrotic drugs. DISCUSSION: This study will provide ILD frequencies, including new entities, using central MDD on dedicated online systems, and develop a machine learning model for ILD diagnosis and prognosis prediction. TRIAL REGISTRATION: UMIN-CTR Clinical Trial Registry (UMIN000040678).

Identification of PANoptosis-related genes for idiopathic pulmonary fibrosis by machine learning and molecular subtype analysis.

Idiopathic pulmonary fibrosis (IPF) is a severe interstitial lung disease characterized by a grim prognosis, in which various forms of cell death are significant contributors to its development. The objective of this study is to explore diagnostic biomarkers and molecular subtypes associated with PANoptosis in IPF, and to develop reliable diagnostic models based on PANoptosis-related mechanisms. The peripheral blood transcriptomic data of IPF from the Gene Expression Omnibus (GEO) database and PANoptosis-related genes from the GeneCards database were utilized to conduct differential gene expression analysis and weighted gene co-expression network analysis (WGCNA), identifying PANoptosis-related differentially expressed genes (PDEGs). We yielded 9 PDEGs and employed machine learning algorithms to identify 3 key diagnostic biomarkers for PANoptosis in IPF: MMP9, FCMR, NIBAN3. Consensus clustering algorithm was applied to recognize two PANoptosis-related subtypes. Cluster 1 exhibited higher abundance of adaptive immune response cells and significant enrichment in DNA damage and repair-related pathways. Cluster 2 exhibited greater prevalence of innate immune response cells and predominant enhancement in pathways related to lipid cholesterol metabolism and vascular remodeling. Diagnostic models were developed with the aid of clinical decision-making and a novel approach to the diagnosis and treatment for IPF.

CXCL10 predicts autoimmune features and a favorable clinical course in patients with IIP: post hoc analysis of a prospective and multicenter cohort study.

BACKGROUND: Interstitial pneumonia with autoimmune features (IPAF), which does not meet any of the criteria for connective tissue diseases (CTD), has been attracting an attention in patients with idiopathic interstitial pneumonia (IIP). However, the biomarkers that reflect the clinical course of these patients have not been fully elucidated. OBJECTIVE: To identify useful serum biomarkers reflecting CTD-related features and favorable prognoses in patients with IIP. METHODS: This was a post hoc analysis of a prospective and multicenter cohort study between 2015 and 2020. Newly diagnosed patients with IIP were consecutively enrolled, and 74 autoimmune features and autoantibodies were comprehensively checked during IIP diagnosis. Serum levels of CXCL10, CXCL1, CCL2, BAFF, angiopoietin-2, and leptin were evaluated at the time of IIP diagnosis. RESULTS: Two hundred twenty-two patients (159 men and 63 women) with IIP were enrolled. The median observation duration was 36 months. The median age was 71 years old, and median %forced vital capacity (FVC) was 84.1% at the time of IIP diagnosis. The proportion of patients who met the classification criteria for IPAF was 11.7%. In patients with high serum CXCL10, changes in both %FVC and %diffusion lung capacity for carbon monoxide at one year were significantly higher than those in patients with low CXCL10 (p = 0.014 and p = 0.009, respectively), whereas these changes were not significant for other chemokines and cytokines. High CXCL10 levels were associated with acute/subacute onset (p < 0.001) and the diagnosis of nonspecific interstitial pneumonia with organizing pneumonia overlap (p = 0.003). High CXCL10 levels were related to a higher classification of IPAF (relative risk for IPAF was 3.320, 95%CI: 1.571-7.019, p = 0.003) and lower classification of progressive pulmonary fibrosis (PPF; relative risk for PPF was 0.309, 95%CI: 0.100-0.953, p = 0.027) compared to those with low CXCL10. Finally, survival was higher in patients with IPF and high CXCL10 (p = 0.044), and high CXCL10 was a significant prognostic factor in multivariate Cox proportional hazards models (hazard ratio 0.368, p = 0.005). CONCLUSIONS: High serum levels of CXCL10 are associated with CTD-related features, the favorable clinical course, and survival in patients with IIP, especially IPF. CLINICAL TRIAL NUMBER: Not applicable.

Novel prediction model of early screening lung adenocarcinoma with pulmonary fibrosis based on haematological index.

BACKGROUND: Lung cancer (LC), a paramount global life-threatening condition causing significant mortality, is most commonly characterized by its subtype, lung adenocarcinoma (LUAD). Concomitant with LC, pulmonary fibrosis (PF) and interstitial lung disease (ILD) contribute to an intricate landscape of respiratory diseases. Idiopathic pulmonary fibrosis (IPF) in association with LC has been explored. However, other fibrotic interrelations remain underrepresented, especially for LUAD-PF and LUAD-ILD. METHODS: We analysed data with statistical analysis from 7,137 healthy individuals, 7,762 LUAD patients, 7,955 ILD patients, and 2,124 complex PF patients collected over ten years. Furthermore, to identify blood indicators related to lung disease and its complications and compare the relationships between different indicators and lung diseases, we successfully applied the naive Bayes model for a biomarker-based prediction of diagnosis and development into complex PF. RESULTS: Males predominantly marked their presence in all categories, save for complex PF where females took precedence. Biomarkers, specifically AGR, MLR, NLR, and PLR emerged as pivotal in discerning lung diseases. A machine-learning-driven predictive model underscored the efficacy of these markers in early detection and diagnosis, with NLR exhibiting unparalleled accuracy. CONCLUSIONS: Our study elucidates the gender disparities in lung diseases and illuminates the profound potential of serum biomarkers, including AGR, MLR, NLR, and PLR in early lung cancer detection. With NLR as a standout, therefore, this study advances the exploration of indicator changes and predictions in patients with pulmonary disease and fibrosis, thereby improving early diagnosis, treatment, survival rate, and patient prognosis.

Integrating cellular experiments, single-cell sequencing, and machine learning to identify endoplasmic reticulum stress biomarkers in idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) presents a severe respiratory challenge with a poor prognosis due to the lack of reliable biomarkers. Recent evidence suggests that Endoplasmic Reticulum Stress (ERS) may be associated with IPF pathogenesis. This study focuses on uncovering ERS-associated biomarkers for IPF. METHODS: Sequencing data from diverse datasets were analyzed, utilizing differential gene expression analysis and Weighted Gene Co-expression Network Analysis (WGCNA). Endoplasmic Reticulum Stress (ERS)-related genes were extracted from the GeneCards database. Hub genes were identified through Protein-Protein Interaction (PPI) analysis. Diagnostic and prognostic models were developed using machine learning algorithms and validated across both training and validation sets. Additionally, techniques such as Cell-type Identification by Estimating Relative Subsets of RNA Transcripts and single-cell RNA sequencing were employed to identify potential IPF-related cells. These findings were further investigated to elucidate their underlying mechanisms through in vitro experiments. RESULTS: Differentially expressed genes, WGCNA-identified blue module genes, and ERS-related genes extracted from the GeneCards database were intersected, and the resulting genes were used to construct diagnostic and prognostic models. Validation using multiple datasets indicated that both the diagnostic and prognostic models possess strong predictive capabilities. PPI analysis highlighted SPP1 as a potential hub gene in IPF. Moreover, M2 macrophages were found in higher quantities in the lung tissue of IPF patients, with a significant increase in SPP1-expressing M2 macrophages compared to the control group. In vitro experiments demonstrated that exogenous SPP1 inhibited the proliferation and migration of M2 macrophages and promoted apoptosis within a certain concentration range. CONCLUSION: This study identifies ERS-related biomarkers in IPF, highlighting SPP1 and M2 macrophages. The resulting diagnostic and prognostic models offer strong predictive capabilities, unveiling new therapeutic avenues.

Research priorities for progressive pulmonary fibrosis in the UK.

INTRODUCTION: Health research bodies recommend patient involvement and engagement in research and healthcare planning, although their implementation is not yet widespread. This deficiency extends to progressive pulmonary fibrosis (PPF), where crucial aspects remain unknown, including causal mechanisms, curative treatments and optimal symptom management. This study addresses these gaps by seeking stakeholders' perspectives to guide research and treatment directions. METHOD: A priority-setting partnership was established to explore stakeholders' priorities in the diagnosis, treatment, management and care of PPF, including idiopathic pulmonary fibrosis which is the archetypal PPF. Stakeholders included people living with PPF, their carers, relatives and healthcare professionals involved in their management. RESULTS: Through an online open-ended survey, 2542 responses were collected from 638 stakeholders. Thematic analysis identified 48 specific research questions, which were then cross-referenced with academic literature to pinpoint research gaps. Following the evidence check, 44 unanswered questions were shortlisted by 834 stakeholders in a second online survey. Ultimately, a top 10 priority list was established through consensus.The prioritised research questions include (1) improved diagnosis accuracy and timing, (2) development of new treatments, (3) enhanced accuracy in primary care, (4) optimal timing for drug and non-drug interventions, (5) effective cough treatment, (6) early intervention for PPF, (7) improved survival rates, (8) symptom reduction, (9) impact of interventions on life expectancy and (10) new treatments with reduced side effects. CONCLUSION: Stakeholders' priorities can be summarised into five areas: early diagnosis, drug and non-drug treatments, survival and symptom management. Ideally, these topics should guide funding bodies and health policies.

Utility of the 52-Gene Risk Score to Identify Patients with Idiopathic Pulmonary Fibrosis at Greater Risk of Mortality in the Era of Antifibrotic Therapy.

PURPOSE: We investigated whether a 52-gene signature was associated with transplant-free survival and other clinically meaningful outcomes in patients with idiopathic pulmonary fibrosis (IPF) in the IPF-PRO Registry, which enrolled patients who were and were not taking antifibrotic therapy. METHODS: The 52-gene risk signature was implemented to classify patients as being at "high risk" or "low risk" of disease progression and mortality. Transplant-free survival and other outcomes were compared between patients with a low-risk versus high-risk signature. RESULTS: The 52-gene signature classified 159 patients as at low risk and 86 as at high risk; in these groups, respectively, 56.6% and 51.2% used antifibrotic therapy at enrollment. Among those taking antifibrotic therapy, patients with a low-risk versus high-risk signature were at decreased risk of death, a composite of lung transplant or death, and a composite of decline in DLco % predicted > 15%, lung transplant, or death. Similar results were observed in the overall cohort. CONCLUSIONS: These data suggest that the 52-gene signature can be used in patients with IPF treated with antifibrotic therapy to distinguish patients at higher risk of disease progression and mortality.

Construction of an artificial neural network diagnostic model and investigation of immune cell infiltration characteristics for idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a severe lung condition, and finding better ways to diagnose and treat the disease is crucial for improving patient outcomes. Our study sought to develop an artificial neural network (ANN) model for IPF and determine the immune cell types that differed between the IPF and control groups. METHODS: From the Gene Expression Omnibus (GEO) database, we first obtained IPF microarray datasets. To conduct protein-protein interaction (PPI) networks and enrichment analyses, differentially expressed genes (DEGs) were screened between tissues of patients with IPF and tissues of controls. Afterward, we identified the important feature genes associated with IPF using random forest (RF) analysis, and then constructed and validated a prediction ANN mode. In addition, the proportions of immune cells were quantified using cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) analysis, which was performed on microarray datasets based on gene expression profiling. RESULTS: A total of 11 downregulated and 36 upregulated DEGs were identified. PPI networks and enrichment analyses were carried out; the immune system and extracellular matrix were the subjects of the enrichments. Using RF analysis, the significant feature genes LRRC17, COMP, ASPN, CRTAC1, POSTN, COL3A1, PEBP4, IL13RA2, and CA4 were identified. The nine feature gene scores were integrated into the ANN to develop a diagnostic prediction model. The receiver operating characteristic (ROC) curves demonstrated the strong diagnostic ability of the ANN in predicting IPF in the training and testing sets. An analysis of IPF tissues in comparison to normal tissues revealed a reduction in the infiltration of natural killer cells resting, monocytes, macrophages M0, and neutrophils; conversely, the infiltration of T cells CD4 memory resting, mast cells, and macrophages M0 increased. CONCLUSION: LRRC17, COMP, ASPN, CRTAC1, POSTN, COL3A1, PEBP4, IL13RA2, and CA4 were determined as key feature genes for IPF. The nine feature genes in the ANN model will be extremely important for diagnosing IPF. It may be possible to use differentiated immune cells from IPF samples in comparison to normal samples as targets for immunotherapy in patients with IPF.

Idiopathic Pulmonary Fibrosis: Review of Current Knowledge.

Idiopathic pulmonary fibrosis (IPF) is a severe and currently incurable disease that is associated with irreversible fibrotic remodeling of the lung parenchyma. Pathological remodeling of the lung leads to damage of the alveolo-capillary barrier. There is a reduction in the diffusing capacity of the lungs for respiratory gases. Later, changes in the mechanical properties of lung tissue occur - their compliance decreases and respiratory work increases. Impaired respiratory gases exchange with restrictive ventilatory failure lead to tissue hypoxia and muscle weakness. Progressive respiratory insufficiency develops. The triggers of fibrotic remodeling of the lung are currently unknown, as are the pathomechanisms that keep this process active. IPF can only be slowed pharmacologically, not reversed. It is therefore very important to start its treatment as soon as possible. Early detection of IPF patients requires a multidisciplinary approach. Diagnosis, treatment initiation, and monitoring in specialized centers offer the best chance of slowing disease progression, enhancing quality of life, and extending patient survival. In addition to antifibrotic therapy, good lifestyle management, maintenance of physical fitness and treatment of associated chronic diseases such as diabetes and cardiac comorbidities are important. Lung transplantation is an option for some patients with IPF. This is a challenging treatment modality, requiring close collaboration with transplant centers and expert selection of suitable candidates, influenced, among other things, by the availability of suitable donor lungs. Our article aims to provide current information about IPF, focusing on its functional consequences and clinical manifestation. We discuss the molecular and cellular mechanisms potentially involved in IPF development, as well as the morphological changes observed in lung biopsies and high-resolution computed tomography (HRCT) images. Finally, we summarize the existing treatment options. Key words: Idiopathic pulmonary fibrosis, Lung biopsy, HRCT, Antifibrotic therapy, Lung transplantation.

Common single nucleotide polymorphisms associated with idiopathic pulmonary fibrosis: a systematic review.

BACKGROUND: Several genetic variants are associated with the risk of idiopathic pulmonary fibrosis (IPF). These have not been systematically reviewed. METHODS: We searched the PubMed, Embase and GWAS Catalog databases for studies indexed between inception and 15 January 2024 describing genetic variants associated with IPF susceptibility. We included studies describing common associated single nucleotide polymorphisms (SNPs). We excluded studies describing rare variants, non-SNP variants and those without an allelic model analysis. We recorded study type, participant characteristics, genotyping methods, IPF diagnostic criteria, the SNPs and the respective genes, odds ratios, and other details. We also searched databases for functions of the identified genes. RESULTS: The primary search retrieved 2697 publications; we included 42 studies. There were nine genome-wide association/linkage studies, while 27 were candidate gene studies. The studies included 22-11 160 IPF subjects. 88 SNPs in 58 genes or loci were found associated with IPF susceptibility. MUC5B rs35705950 was the most studied SNP. Most (n=51) SNPs were in the intronic or intergenic regions; only 11 were coding sequence variants. The SNPs had odds ratios ranging from 0.27 to 7.82 for an association with IPF. Only 22 SNPs had moderate-large effects (OR >1.5 or <0.67). Only 49.1% of the associated genes have a known functional role in IPF; the role of G protein-related signalling and transcriptional regulation (zinc-finger proteins) remain unexplored. CONCLUSION: Several common SNPs in over 50 genes have been found associated with IPF susceptibility. These variants may inform gene panels for future studies (PROSPERO CRD42023408912).

Clinical implications of six-minute walk test in patients with idiopathic pulmonary fibrosis: a retrospective cohort study.

BACKGROUND: A six-minute walk test (6MWT) is a reproducible, easily performed test, and is widely used to determine functional exercise capacity in patients with idiopathic pulmonary fibrosis (IPF). However, there is currently a paucity of data on the clinical significance of baseline and serial 6-minute walk tests in patients with IPF, especially in Asian patients. OBJECTIVES: We aimed to investigate the clinical significance of serial 6MWT in patients with IPF, especially in Asian patients. DESIGN: This is a single-center retrospective cohort study. METHODS: Clinical data of patients diagnosed with IPF at a tertiary center in Korea were retrospectively analyzed. IPF diagnosis was defined according to the clinical guidelines of the American Thoracic Society (ATS)/European Respiratory Society (ERS)/Japanese Respiratory Society/Latin American Thoracic Association. RESULTS: There were 216 patients diagnosed with IPF from December 2012 to January 2022, of whom 198 had a baseline of 6MWT data. The mean age of the cohort was 66.9 ± 8.6, and 89% were male. The non-survivors showed significantly lower six-minute walk distance (6MWD), minimum saturation of peripheral oxygen (SpO2) during 6MWT, forced vital capacity, and diffusing capacity of the lung for carbon monoxide than survivors at baseline. A multivariate Cox analysis demonstrated that lower minimum SpO2 was independently associated with increased mortality rates (Hazard ratio (HR): 1.081, 95% confidence interval (CI): 1.024-1.142, p = 0.005). Higher mortality rates were also associated with echocardiographic-determined pulmonary hypertension (HR: 2.466, 95% CI: 1.149-5.296, p = 0.021) at diagnosis. Among 144 patients with 6MWT results at 12 months, patients with a decline of 50 m or more in the 6MWD showed poorer overall survival than others (median survival: 45.0 months vs 58.0 months, p < 0.001). CONCLUSIONS: Baseline lower minimum SpO2 during 6MWT was an independent prognostic factor in patients with IPF, and a decline in 6MWD in serial follow-up was also associated with a poorer prognosis. These findings suggest that both baseline 6MWT and follow-up data are important in the prognostication of patients with IPF.

A nitroreductase responsive probe for early diagnosis of pulmonary fibrosis disease.

Idiopathic pulmonary fibrosis (IPF) is a serious interstitial lung disease. However, the definitive diagnosis of IPF is impeded by the limited capabilities of current diagnostic methods, which may fail to capture the optimal timing for treatment. The main goal of this study is to determine the feasibility of a nitroreductase (NTR) responsive probe, 18F-NCRP, for early detection and deterioration monitoring of IPF. 18F-NCRP was obtained with high radiochemical purity (>95 %). BLM-injured mice were established by intratracheal instillation with bleomycin (BLM) and characterized through histological analysis. Longitudinal PET/CT imaging, biodistribution study and in vitro autoradiography were performed. The correlations between the uptake of 18F-NCRP and mean lung density (tested by CT), as well as histopathological characteristics were analyzed. In PET imaging study, 18F-NCRP exhibited promising efficacy in monitoring the progression of IPF, which was earlier than CT. The ratio of uptake in BLM-injured lung to control lung increased from 1.4-fold on D15 to 2.2-fold on D22. Biodistribution data showed a significant lung uptake of 18F-NCRP in BLM-injured mice. There was a strong positive correlation between the 18F-NCRP uptake in the BLM-injured lungs and the histopathological characteristics. Given that, 18F-NCRP PET imaging of NTR, a promising biomarker for investigating the underlying pathogenic mechanism of IPF, is attainable as well as desirable, which might lay the foundation for establishing an NTR-targeted imaging evaluation system of IPF.

Identification and validation of potential biomarkers related to oxidative stress in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial pneumonia with a poor prognosis and a pathogenesis that has not been fully elucidated. Oxidative stress is closely associated with IPF. In this research, we aimed to identify reliable diagnostic biomarkers associated with the oxidative stress through bioinformatics techniques. The gene expression profile data from the GSE70866 dataset was retrieved from the gene expression omnibus (GEO) database. We extracted 437 oxidative stress-related genes (ORGs) from gene set enrichment analysis (GSEA). The GSE141939 dataset was used for single-cell RNA-seq analysis to identify the expression of diagnostic genes in different cell clusters. A total of 10 differentially expressed oxidative stress-related genes (DE-ORGs) were screened. Subsequently, SOD3, CD36, ACOX2, RBM11, CYP1B1, SNCA, and MPO from the 10 DE-ORGs were identified as diagnostic genes based on random forest algorithm with randomized least absolute shrinkage and selection operator (LASSO) regression. A nomogram was constructed to evaluate the risk of disease. The decision curve analysis (DCA) and clinical impact curves indicated that the nomogram based on these seven biomarkers had extraordinary predictive power. Immune cell infiltration analysis results revealed that DE-ORGs were closely related to various immune cells, especially CYP1B1 was in positive correlation with monocytes and negative correlation with macrophages M1. Single-cell RNA-seq analysis showed that CYP1B1 was mainly associated with macrophages, and SNCA was mainly associated with basal cells. CYP1B1 and SNCA were diagnostic genes associated with oxidative stress in IPF.

Key learnings from the INBUILD trial in patients with progressive pulmonary fibrosis.

In a patient with interstitial lung disease (ILD) of known or unknown etiology other than idiopathic pulmonary fibrosis (IPF), progressive pulmonary fibrosis (PPF) is defined by worsening lung fibrosis on high-resolution computed tomography (HRCT), decline in lung function, and/or deterioration in symptoms. The INBUILD trial involved 663 patients with PPF who were randomized to receive nintedanib or placebo. The median exposure to trial medication was approximately 19 months. The INBUILD trial provided valuable learnings about the course of PPF and the efficacy and safety of nintedanib. The relative effect of nintedanib on reducing the rate of forced vital capacity decline was consistent across subgroups based on ILD diagnosis, HRCT pattern, and disease severity at baseline, and between patients who were and were not taking glucocorticoids or disease-modifying anti-rheumatic drugs and/or glucocorticoids at baseline. The adverse events most frequently associated with nintedanib were gastrointestinal, particularly diarrhea, but nintedanib was discontinued in only a minority of cases. The results of the INBUILD trial highlight the importance of prompt detection and treatment of PPF and the utility of nintedanib as a treatment option.

What did we find out from the INBUILD trial about progressive lung fibrosis?Lung fibrosis is a rare disease in which the lung tissue becomes scarred and hardened. This makes it more difficult for the lungs to inflate and for the lungs to exchange oxygen with the blood. In some patients, lung fibrosis gets worse over time. This is known as progressive lung fibrosis. In the INBUILD trial, researchers looked at the effects of a drug called nintedanib in patients with progressive lung fibrosis. In this trial, 663 patients were randomly allocated to receive either nintedanib or a placebo and then followed for approximately 19 months. The patients and the researchers did not know which patients were taking the active drug (nintedanib) and which patients were taking placebo. The results showed that the criteria used to find patients with progressive lung fibrosis to take part in the trial successfully identified patients whose disease would continue to worsen. These criteria were based on a decline in the volume (size) of the lungs, worsening symptoms such as shortness of breath, and worsening of changes seen on a scan of the chest. The trial results also showed that nintedanib slowed down loss of lung function and had a similar benefit in patients with different severities of disease at the start of the trial. The most common side-effects of nintedanib were gastrointestinal problems, particularly diarrhea, but most patients given nintedanib were able to cope with these side-effects without needing to stop treatment. Large trials like the INBUILD trial are important for helping us understand how diseases progress and in which patients particular drugs should be used.

Prognostic performance of Krebs von den Lungen-6, surfactant protein A, surfactant protein D levels in the serum and bronchoalveolar lavage fluid in chronic fibrosing interstitial pneumonia: a retrospective study.

BACKGROUND: The serum markers Krebs von den Lungen-6 (KL-6), surfactant protein A (SP-A), and surfactant protein D (SP-D) have been used for the diagnosis, differential diagnosis, and prognosis prediction of interstitial pneumonia. However, the significance of measuring the serum and bronchoalveolar lavage fluid (BALF) KL-6, SP-D, and SP-A levels in predicting the prognosis of chronic fibrosing interstitial pneumonia (CFIP), idiopathic pulmonary fibrosis, and idiopathic nonspecific interstitial pneumonia remains unclear. We aimed to clarify the significance of measuring the serum and BALF KL-6, SP-A, and SP-D levels in predicting the prognosis of patients with CFIP. METHODS: Among 173 patients who were diagnosed with CFIP between September 2008 and February 2021, 39 who underwent bronchoalveolar lavage were included in this study. Among these, patients experiencing an annual decrease in forced vital capacity (FVC) of ≥10% or those facing challenges in undergoing follow-up pulmonary function tests owing to significant deterioration in pulmonary function were categorized as the rapidly progress group. Conversely, individuals with an annual decrease in the FVC of <10% were classified into the slowly progress group. The serum and BALF KL-6, SP-D, and SP-A levels, as well as BALF/serum SP-D and SP-A ratios were compared between the two groups. RESULTS: Among the patients with CFIP, the BALF SP-D level (p=0.0111), BALF SP-A level (p<0.0010), BALF/serum SP-D ratio (p=0.0051), and BALF/serum SP-A ratio (p<0.0010) were significantly lower in the rapidly than in the slowly progress group (p<0.0010). The receiver operating characteristics analysis results demonstrated excellent performance for diagnosing patients with CFIP, with the BALF SP-D level (area under the curve [AUC], 0.7424), BALF SP-A level (AUC, 0.8842), BALF/serum SP-D ratio (AUC, 0.7673), and BALF/serum SP-A ratio (AUC, 0.8556). Moreover, the BALF SP-A level showed a notably superior CFIP diagnostic capability. Survival analysis using the Kaplan-Meier method revealed that patients with a BALF SP-A level of <1500 ng/mL and BALF/serum SP-A ratio of <15.0 had poor prognoses. CONCLUSIONS: Our results suggest that BALF SP-A measurement may be useful for predicting the prognosis in patients with CFIP.

Usefulness of serum transthyretin for prediction of the 1-year outcome in idiopathic pulmonary fibrosis: An evaluation of sarcopenic and nutritional indicators.

BACKGROUND: Patients with idiopathic pulmonary fibrosis (IPF) often experience sarcopenia and malnutrition. However, this has not been fully examined through longitudinal surveys. This study investigated whether sarcopenia and malnutrition were associated with 1-year outcomes in IPF. METHODS: We evaluated sarcopenia and nutritional status in 64 outpatients with IPF. We assessed the time-to-event for respiratory-related hospitalizations or deaths 12 months after enrollment. Sarcopenia was diagnosed by the criteria of the Asian Working Group for Sarcopenia, 2019. Nutritional status was assessed by serum transthyretin and the Geriatric Nutritional Risk Index (GNRI). RESULTS: The average age was 73.6 ± 7.9 years, and the percent predicted forced vital capacity (FVC) was 81.9 ± 15.7%. Of the 64 patients, 24 (37.5%) had sarcopenia. The median serum transthyretin level and mean GNRI were 23.8 mg/dL and 102, respectively. Eleven patients (17.2%) experienced respiratory-related hospitalization or death within the first year. Cox regression analysis showed that the % predicted diffusion capacity for carbon monoxide, lowest oxygen saturation in the 6-min walk test, serum transthyretin level, and GNRI were significant predictors of 1-year outcomes. The Kaplan-Meier method, which divided the patients into two groups based on a transthyretin level of 22.6 mg/dL, showed a significant difference (P < 0.001, log-rank test). Sarcopenia and the percent predicted FVC did not predict the 1-year outcomes. CONCLUSIONS: This pilot study represents the first longitudinal survey assessing patients with IPF for sarcopenia and malnutrition. Serum transthyretin levels may predict respiratory-related hospitalization or death within 1 year in patients with IPF.

The burden of cough in idiopathic pulmonary fibrosis and other interstitial lung diseases: a systematic evidence synthesis.

BACKGROUND: Cough remains a persistent symptom in patients with idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases (ILDs). To inform future research, treatment and care models, we conducted the first systematic synthesis of evidence on its associated burden. METHODS: A literature search was performed for articles published between January 2010 and October 2023 using databases including Embase, MEDLINE and the Cochrane Library. Studies in patients with IPF and other ILDs reporting cough-related measures were eligible for inclusion. Included studies were categorised based on the types of ILD they examined and their design. Study details, patient characteristics and outcomes were extracted, and the risk of bias was assessed. A narrative synthesis approach was employed to interpret the findings. RESULTS: Sixty-one studies were included: 33 in IPF, 18 in mixed-ILDs, six in connective tissue disease-associated-ILDs and four in sarcoidosis. Across the studies, a range of tools to assess cough and its impact were used. The most frequently used measures of cough were cough severity visual analogue scale (VAS) and objective cough counts, whereas the most frequently used health-related quality of life (HRQoL)/impact measures were the St. George's Respiratory Questionnaire (SGRQ) and Leicester Cough Questionnaire (LCQ). In IPF, studies consistently reported correlations between various cough and HRQoL measures, including between cough VAS scores and objective cough counts, LCQ scores and SGRQ scores. Similar correlations were observed in studies in other ILDs, but data were more limited. Qualitative studies in both IPF and other ILDs consistently highlighted the significant cough-related burden experienced by patients, including disruption of daily activities, fatigue and social embarrassment. Although there were no studies specifically investigating the economic burden of cough, one study in patients with fibrotic ILD found cough severity was associated with workplace productivity loss. CONCLUSIONS: Our study underscores the heterogeneity in assessing cough and its impact in IPF and other ILDs. The findings confirm the negative impact of cough on HRQoL in IPF and suggest a comparable impact in other ILDs. Our synthesis highlights the need for standardised assessment tools, along with dedicated studies, particularly in non-IPF ILDs and on the economic burden of cough.

Real-world safety and effectiveness of pirfenidone and nintedanib in the treatment of idiopathic pulmonary fibrosis: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: Multiple randomized controlled studies have shown that pirfenidone and nintedanib are effective and safe for treating idiopathic pulmonary fibrosis. This study aimed to evaluate their efficacy, safety, and tolerability in a real-world setting. METHODS: We searched PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases for real-world studies published up to March 3, 2023, on pirfenidone and nintedanib for idiopathic pulmonary fibrosis. RESULTS: A total of 74 studies with 23,119 participants were included. After 12 months of treatment, the change from baseline in percent predicted FVC (%FVC) was - 0.75% for pirfenidone and - 1.43% for nintedanib. The change from baseline in percent predicted DLCO (%DCLO) was - 2.32% for pirfenidone and - 3.95% for nintedanib. The incidence of acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) was 12.5% for pirfenidone and 14.4% for nintedanib. The IPF-related mortality rates of pirfenidone and nintedanib were 13.4% and 7.2%, respectively. The all-cause mortality was 20.1% for pirfenidone and 16.6% for nintedanib. In the pirfenidone group, 16.6% of patients discontinued treatment because of adverse events, and in the nintedanib group, 16.2% of patients discontinued treatment because of adverse events. The incidence of adverse events was 56.4% and 69.7% for pirfenidone and nintedanib, respectively. CONCLUSION: The results of this study indicate that pirfenidone and nintedanib are both effective in slowing down the decline of lung function in IPF patients in real-world settings. The incidence of adverse events with pirfenidone is lower than that with nintedanib, but both are below the clinical trial data, and no new major adverse events have been observed. The discontinuation rates due to adverse reactions of the two drugs are consistent with clinical trial data, indicating good tolerability. However, the mortality rates and AE-IPF incidence rates of these two drugs in real-world settings are higher than those in previous clinical trials, with pirfenidone patients showing a higher mortality rate. Further large-sample studies are needed to investigate the risks of these drugs in these aspects. Additionally, we recommend that future real-world studies pay more attention to patients' subjective symptoms and conduct stratified analyses of the efficacy and safety of pirfenidone and nintedanib based on factors such as patients' baseline lung function, comorbidities, and age, in order to provide more personalized medication advice for IPF patients in clinical practice.

The 1-min sit-to-stand test as a screening tool to assess exercise-induced oxygen desaturation in normoxemic people with interstitial lung disease.

BACKGROUND: In patients with interstitial lung disease (ILD), exercise-induced desaturation during the 6-min walk test (6MWT), specifically nadir oxygen saturation (nSpO2) of ≤88 % is a negative prognostic marker. As the 6MWT is often impractical for ILD patients, the aim of this study is to compare the 1-min sit-to-stand test (1minSTS) with the 6MWT to detect exercise-induced desaturation. METHODS: Participants were recruited from a tertiary referral clinic with both tests performed on the same day. Utilising Bland-Altman analysis, the relationship between nSpO2 on 1minSTS and 6MWT was determined. An area under the receiver operating characteristic curve (AUC) determined the ability of nSpO2 on 1minSTS test to predict SpO2 ≤88 % on 6MWT. RESULTS: Fifty participants completed the study (idiopathic pulmonary fibrosis n = 24, 48 %; connective tissue disease associated ILD n = 20, 40 %; other ILD n = 6, 12 %). Mean (SD) FVC%pred was 73 ± 16 %, mean DLCO%pred 57 ± 16 % and resting SpO2 99 ± 1 %. The 1minSTS resulted in less exercise-induced oxygen desaturation, with a median IQR nSpO2 of 95 % (89-98) and 93 % (85-96) respectively (p < 0.001). Moderate agreement was determined between the nSpO2 on both tests, with a mean difference of 3.2 % [-14 to +3.0 %]. The 1minSTS test accurately identified participants with nSpO2 ≤88 % on 6MWT (AUC 0.96). Oxygen desaturation ≤94 % during the 1minSTS test provided 100 % sensitivity and 87 % specificity for oxygen desaturation ≤88 % at 6MWT. CONCLUSION: This study demonstrates that exercise-induced oxygen desaturation during the 1minSTS test correlates with oxygen desaturation on 6MWT. The 1minSTS may be a practical screening tool for ILD patients who would benefit from further exercise testing.

Usefulness of Transbronchial Lung Cryobiopsy When Starting Antifibrotic Treatment and Predicting Progressive Fibrosing Interstitial Lung Disease: Descriptive Research.

BACKGROUND: Although transbronchial lung cryobiopsy (TBLC) is widely used in diagnostic algorithms for various interstitial lung diseases (ILDs), its real-world utility in the therapeutic decision-making strategy for ILD patients remains unclear, in particular, when judging the time to start antifibrotic agents. METHODS: We analyzed medical records of 40 consecutive patients with idiopathic or fibrotic hypersensitivity pneumonitis who underwent TBLC. A TBLC-based usual interstitial pneumonia (UIP) score was used to assess three morphologic descriptors: patchy fibrosis, fibroblastic foci, and honeycombing. RESULTS: In our 40 patients with ILD, the most frequent radiological feature was indeterminate for UIP (45.0%). Final diagnosis included idiopathic pulmonary fibrosis (22.5%), fibrotic nonspecific interstitial pneumonia (5.0%), fibrotic hypersensitivity pneumonitis (35.0%), and unclassifiable ILD (37.5%). Linear mixed-effects analysis showed that declines in the slopes of %FVC and %DLCO in patients with TBLC-based UIP "Score ≥ 2" were significantly steeper than those of patients with "Score ≤ 1." During follow-up of patients with Score ≥ 2 (n = 24), more than half of them (n = 17) received an antifibrotic agent, with most patients (n = 13) receiving early administration of the antifibrotic agent within 6 months after the TBLC procedure. CONCLUSIONS: TBLC-based UIP Score ≥ 2 indicated the increased possibility of a progressive fibrosis course that may prove helpful in predicting progressive pulmonary fibrosis/progressive fibrosing ILD even if disease is temporarily stabilized due to anti-inflammatory agents. Patients may benefit from early introduction of antifibrotic agents by treating clinicians.