ERS International Congress 2023: highlights from the Interstitial Lung Diseases Assembly.

This article summarises a selection of scientific highlights in the field of interstitial lung diseases (ILDs) presented at the International Congress of the European Respiratory Society in 2023. Translational and clinical studies focused on the whole spectrum of ILDs, from (ultra)rare ILDs to sarcoidosis, ILDs associated with connective tissue disease and idiopathic pulmonary fibrosis. The main topics of the 2023 Congress presentations were improving the diagnostic process of ILDs, better prediction of disease course and investigation of novel treatment options.

Differentiating interstitial lung diseases from other respiratory diseases using electronic nose technology.

INTRODUCTION: Interstitial lung disease (ILD) may be difficult to distinguish from other respiratory diseases due to overlapping clinical presentation. Recognition of ILD is often late, causing delay which has been associated with worse clinical outcome. Electronic nose (eNose) sensor technology profiles volatile organic compounds in exhaled breath and has potential to detect ILD non-invasively. We assessed the accuracy of differentiating breath profiles of patients with ILD from patients with asthma, chronic obstructive pulmonary disease (COPD), and lung cancer using eNose technology. METHODS: Patients with ILD, asthma, COPD, and lung cancer, regardless of stage or treatment, were included in a cross-sectional study in two hospitals. Exhaled breath was analysed using an eNose (SpiroNose) and clinical data were collected. Datasets were split in training and test sets for independent validation of the model. Data were analyzed with partial least squares discriminant and receiver operating characteristic analyses. RESULTS: 161 patients with ILD and 161 patients with asthma (n = 65), COPD (n = 50) or lung cancer (n = 46) were included. Breath profiles of patients with ILD differed from all other diseases with an area under the curve (AUC) of 0.99 (95% CI 0.97-1.00) in the test set. Moreover, breath profiles of patients with ILD could be accurately distinguished from the individual diseases with an AUC of 1.00 (95% CI 1.00-1.00) for asthma, AUC of 0.96 (95% CI 0.90-1.00) for COPD, and AUC of 0.98 (95% CI 0.94-1.00) for lung cancer in test sets. Results were similar after excluding patients who never smoked. CONCLUSIONS: Exhaled breath of patients with ILD can be distinguished accurately from patients with other respiratory diseases using eNose technology. eNose has high potential as an easily accessible point-of-care medical test for identification of ILD amongst patients with respiratory symptoms, and could possibly facilitate earlier referral and diagnosis of patients suspected of ILD.

Methotrexate Polyglutamate Concentrations as a Possible Predictive Marker for Effectiveness of Methotrexate Therapy in Patients with Sarcoidosis: A Pilot Study.

INTRODUCTION: Methotrexate (MTX), a folate antagonist, is often used as second-line treatment in patients with sarcoidosis. Effectiveness of MTX has large inter-patient variability and at present therapeutic drug monitoring (TDM) of MTX is not possible. Upon administration, MTX is actively transported into cells and metabolized to its active forms by adding glutamate residues forming MTXPG(n=1-5) resulting in enhanced cellular retention. In this study we address the question whether different MTXPG(n) concentrations in red blood cells (RBC) of patients with sarcoidosis after 3 months of MTX therapy correlate with response to treatment. METHODS: We retrospectively included patients with sarcoidosis that had started on MTX therapy and from whom blood samples and FDG-PET/CT were available 3 and 6-12 months after MTX initiation, respectively. FDG-uptake was measured by SUVmax in the heart, lungs and thoracic lymph nodes. Changes in SUVmax was used to determine anti-inflammatory response after 6-12 months of MTX therapy. MTXPG(n) concentrations were measured from whole blood RBC using an LC-MS/MS method. Pearson correlation coefficients were calculated to evaluate the relationship between changes in the SUVmax and MTXPG(n) concentrations. RESULTS: We included 42 sarcoidosis patients treated with MTX (15 mg/week); 31 with cardiac sarcoidosis and 11 with pulmonary sarcoidosis. In MTXPG3 and MTXPG4 a significant negative relation between the absolute changes in SUVmax and MTXPG(n) was found r = - 0.312 (n = 42, p = 0.047) for MTXPG3 and r = - 0.336 (n = 42, p = 0.031 for MTXPG4). The other MTXPG(n) did not correlate to changes in SUVmax. CONCLUSION: These results suggest a relation between MTXPG(n) concentrations and the anti-inflammatory effect in patients with sarcoidosis. Further prospective validation is warranted, but if measuring MTXPG concentrations could predict treatment effect of MTX this would be a step in the direction of personalized medicine.

Circulating T cells in sarcoidosis have an aberrantly activated phenotype that correlates with disease outcome.

RATIONALE: Disease course in sarcoidosis is highly variable. Bronchoalveolar lavage fluid and mediastinal lymph nodes show accumulation of activated T cells with a T-helper (Th)17.1 signature, which correlates with non-resolving sarcoidosis. We hypothesize that the peripheral blood (PB) T cell phenotype may correlate with outcome. OBJECTIVES: To compare frequencies, phenotypes and function of circulating T cell populations in sarcoidosis patients with healthy controls (HCs) and correlate these parameters with outcome. METHODS: We used multi-color flow cytometry to quantify activation marker expression on PB T cell subsets in treatment-naïve patients and HCs. The disease course was determined after 2-year follow-up. Cytokine production was measured after T cell stimulation in vitro. MEASUREMENTS AND MAIN RESULTS: We observed significant differences between patients and HCs in several T cell populations, including CD8+ and CD4+ T cells, Th1/Th17 subsets, CD4+ T memory stem cells, regulatory T cells (Tregs) and γδ T cells. Decreased frequencies of CD4+ T cells and increased frequencies of Tregs and CD8+ γδ T cells correlated with worse outcome. Naïve CD4+ T cells displayed an activated phenotype with increased CD25 expression in patients with active chronic disease at 2-year follow-up. A distinctive Treg phenotype with increased expression of CD25, CTLA4, CD69, PD-1 and CD95 correlated with chronic sarcoidosis. Upon stimulation, both naïve and memory T cells displayed a different cytokine profile in sarcoidosis compared to HCs. CONCLUSIONS: Circulating T cell subpopulations of sarcoidosis patients display phenotypic abnormalities that correlate with disease outcome, supporting a critical role of aberrant T cell activation in sarcoidosis pathogenesis.

Quality of life in sarcoidosis.

Having sarcoidosis often has a major impact on quality of life of patients and their families. Improving quality of life is prioritized as most important treatment aim by many patients with sarcoidosis, but current evidence and treatment options are limited. In this narrative review, we describe the impact of sarcoidosis on various aspects of daily life, evaluate determinants of health-related quality of life (HRQoL), and provide an overview of the different patient-reported outcome measures to assess HRQoL in sarcoidosis. Moreover, we review the current evidence for pharmacological and non-pharmacological interventions to improve quality of life for people with sarcoidosis.

Pulmonary fibrosis: from pathogenesis to clinical decision-making.

Pulmonary fibrosis (PF) encompasses a spectrum of chronic lung diseases that progressively impact the interstitium, resulting in compromised gas exchange, breathlessness, diminished quality of life (QoL), and ultimately respiratory failure and mortality. Various diseases can cause PF, with their underlying causes primarily affecting the lung interstitium, leading to their referral as interstitial lung diseases (ILDs). The current understanding is that PF arises from abnormal wound healing processes triggered by various factors specific to each disease, leading to excessive inflammation and fibrosis. While significant progress has been made in understanding the molecular mechanisms of PF, its pathogenesis remains elusive. This review provides an in-depth exploration of the latest insights into PF pathophysiology, diagnosis, treatment, and future perspectives.

Design of a phase III, double-blind, randomised, placebo-controlled trial of BI 1015550 in patients with progressive pulmonary fibrosis (FIBRONEER-ILD).

INTRODUCTION: Progressive pulmonary fibrosis (PPF) includes any diagnosis of progressive fibrotic interstitial lung disease (ILD) other than idiopathic pulmonary fibrosis (IPF). However, disease progression appears comparable between PPF and IPF, suggesting a similar underlying pathology relating to pulmonary fibrosis. Following positive results in a phase II study in IPF, this phase III study will investigate the efficacy and safety of BI 1015550 in patients with PPF (FIBRONEER-ILD). METHODS AND ANALYSIS: In this phase III, double-blind, placebo-controlled trial, patients are being randomised 1:1:1 to receive BI 1015550 (9 mg or 18 mg) or placebo twice daily over at least 52 weeks, stratified by background nintedanib use. Patients must be diagnosed with pulmonary fibrosis other than IPF that is progressive, based on predefined criteria. Patients must have forced vital capacity (FVC) ≥45% predicted and haemoglobin-corrected diffusing capacity of the lung for carbon monoxide ≥25% predicted. Patients must be receiving nintedanib for at least 12 weeks, or not receiving nintedanib for at least 8 weeks, prior to screening. Patients on stable treatment with permitted immunosuppressives (eg, methotrexate, azathioprine) may continue their treatment throughout the trial. Patients with clinically significant airway obstruction or other pulmonary abnormalities, and those using immunosuppressives that may confound FVC results (cyclophosphamide, tocilizumab, mycophenolate, rituximab) or high-dose steroids will be excluded. The primary endpoint is absolute change from baseline in FVC (mL) at week 52. The key secondary endpoint is time to the first occurrence of any acute ILD exacerbation, hospitalisation for respiratory cause or death, over the duration of the trial. ETHICS AND DISSEMINATION: The trial is being carried out in accordance with the ethical principles of the Declaration of Helsinki, the International Council on Harmonisation Guideline for Good Clinical Practice and other local ethics committees. The study results will be disseminated at scientific congresses and in peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT05321082.

Evaluation of different classification methods using electronic nose data to diagnose sarcoidosis.

Electronic nose (eNose) technology is an emerging diagnostic application, using artificial intelligence to classify human breath patterns. These patterns can be used to diagnose medical conditions. Sarcoidosis is an often difficult to diagnose disease, as no standard procedure or conclusive test exists. An accurate diagnostic model based on eNose data could therefore be helpful in clinical decision-making. The aim of this paper is to evaluate the performance of various dimensionality reduction methods and classifiers in order to design an accurate diagnostic model for sarcoidosis. Various methods of dimensionality reduction and multiple hyperparameter optimised classifiers were tested and cross-validated on a dataset of patients with pulmonary sarcoidosis (n= 224) and other interstitial lung disease (n= 317). Best performing methods were selected to create a model to diagnose patients with sarcoidosis. Nested cross-validation was applied to calculate the overall diagnostic performance. A classification model with feature selection and random forest (RF) classifier showed the highest accuracy. The overall diagnostic performance resulted in an accuracy of 87.1% and area-under-the-curve of 91.2%. After comparing different dimensionality reduction methods and classifiers, a highly accurate model to diagnose a patient with sarcoidosis using eNose data was created. The RF classifier and feature selection showed the best performance. The presented systematic approach could also be applied to other eNose datasets to compare methods and select the optimal diagnostic model.

Design of a phase III, double-blind, randomised, placebo-controlled trial of BI 1015550 in patients with idiopathic pulmonary fibrosis (FIBRONEER-IPF).

IntroductionThere is an unmet need for new treatments for idiopathic pulmonary fibrosis (IPF). The oral preferential phosphodiesterase 4B inhibitor, BI 1015550, prevented a decline in forced vital capacity (FVC) in a phase II study in patients with IPF. This study design describes the subsequent pivotal phase III study of BI 1015550 in patients with IPF (FIBRONEER-IPF). METHODS AND ANALYSIS: In this placebo-controlled, double-blind, phase III trial, patients are being randomised in a 1:1:1 ratio to receive 9 mg or 18 mg of BI 1015550 or placebo two times per day over at least 52 weeks, stratified by use of background antifibrotics (nintedanib/pirfenidone vs neither). The primary endpoint is the absolute change in FVC at week 52. The key secondary endpoint is a composite of time to first acute IPF exacerbation, hospitalisation due to respiratory cause or death over the duration of the trial. ETHICS AND DISSEMINATION: The trial is being carried out in compliance with the ethical principles of the Declaration of Helsinki, in accordance with the International Council on Harmonisation Guideline for Good Clinical Practice and other local ethics committees. The results of the study will be disseminated at scientific congresses and in peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT05321069.

Exhaled breath analysis in interstitial lung disease.

PURPOSE OF REVIEW: There is a need for better noninvasive tools to diagnose interstitial lung disease (ILD) and predict disease course. Volatile organic compounds present in exhaled breath contain valuable information on a person's health and may be a novel biomarker in ILD. In this review, we will give an overview of the basic principles of breath analysis, summarize the available evidence in ILD, and discuss future perspectives. RECENT FINDINGS: An increasing number of studies on exhaled breath analysis were performed over the last decade in patients with ILD, using two methods for exhaled breath analysis: gas chromatography-mass spectrometry and electronic nose technology. Most studies showed high accuracy for diagnosis of ILD, but study design and methods widely varied. Studies investigating the potential of electronic nose technology to predict treatment response and disease behavior are ongoing. SUMMARY: The majority of studies using exhaled breath analysis in ILD show promising results for diagnostic purposes, but validation studies are lacking. Larger prospective longitudinal studies using standardized methods are needed to collect the evidence required for developing an approved diagnostic medical test.

Idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive devastating lung disease with substantial morbidity. It is associated with cough, dyspnea and impaired quality of life. If left untreated, IPF has a median survival of 3 years. IPF affects âˆ¼3 million people worldwide, with increasing incidence in older patients. The current concept of pathogenesis is that pulmonary fibrosis results from repetitive injury to the lung epithelium, with fibroblast accumulation, myofibroblast activation, and deposition of matrix. These injuries, in combination with innate and adaptive immune responses, dysregulated wound repair and fibroblast dysfunction, lead to recurring tissue remodeling and self-perpetuating fibrosis as seen in IPF. The diagnostic approach includes the exclusion of other interstitial lung diseases or underlying conditions and depends on a multidisciplinary team-based discussion combining radiological and clinical features and well as in some cases histology. In the last decade, considerable progress has been made in the understanding of IPF clinical management, with the availability of two drugs, pirfenidone and nintedanib, that decrease pulmonary lung function decline. However, current IPF therapies only slow disease progression and prognosis remains poor. Fortunately, there are multiple clinical trials ongoing with potential new therapies targeting different disease pathways. This review provides an overview of IPF epidemiology, current insights in pathophysiology, diagnostic and therapeutic management approaches. Finally, a detailed description of current and evolving therapeutic approaches is also provided.

Ziritaxestat, a Novel Autotaxin Inhibitor, and Lung Function in Idiopathic Pulmonary Fibrosis: The ISABELA 1 and 2 Randomized Clinical Trials.

Importance: There is a major need for effective, well-tolerated treatments for idiopathic pulmonary fibrosis (IPF). Objective: To assess the efficacy and safety of the autotaxin inhibitor ziritaxestat in patients with IPF. Design, Setting, and Participants: The 2 identically designed, phase 3, randomized clinical trials, ISABELA 1 and ISABELA 2, were conducted in Africa, Asia-Pacific region, Europe, Latin America, the Middle East, and North America (26 countries). A total of 1306 patients with IPF were randomized (525 patients at 106 sites in ISABELA 1 and 781 patients at 121 sites in ISABELA 2). Enrollment began in November 2018 in both trials and follow-up was completed early due to study termination on April 12, 2021, for ISABELA 1 and on March 30, 2021, for ISABELA 2. Interventions: Patients were randomized 1:1:1 to receive 600 mg of oral ziritaxestat, 200 mg of ziritaxestat, or placebo once daily in addition to local standard of care (pirfenidone, nintedanib, or neither) for at least 52 weeks. Main Outcomes and Measures: The primary outcome was the annual rate of decline for forced vital capacity (FVC) at week 52. The key secondary outcomes were disease progression, time to first respiratory-related hospitalization, and change from baseline in St George's Respiratory Questionnaire total score (range, 0 to 100; higher scores indicate poorer health-related quality of life). Results: At the time of study termination, 525 patients were randomized in ISABELA 1 and 781 patients in ISABELA 2 (mean age: 70.0 [SD, 7.2] years in ISABELA 1 and 69.8 [SD, 7.1] years in ISABELA 2; male: 82.4% and 81.2%, respectively). The trials were terminated early after an independent data and safety monitoring committee concluded that the benefit to risk profile of ziritaxestat no longer supported their continuation. Ziritaxestat did not improve the annual rate of FVC decline vs placebo in either study. In ISABELA 1, the least-squares mean annual rate of FVC decline was -124.6 mL (95% CI, -178.0 to -71.2 mL) with 600 mg of ziritaxestat vs -147.3 mL (95% CI, -199.8 to -94.7 mL) with placebo (between-group difference, 22.7 mL [95% CI, -52.3 to 97.6 mL]), and -173.9 mL (95% CI, -225.7 to -122.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, -26.7 mL [95% CI, -100.5 to 47.1 mL]). In ISABELA 2, the least-squares mean annual rate of FVC decline was -173.8 mL (95% CI, -209.2 to -138.4 mL) with 600 mg of ziritaxestat vs -176.6 mL (95% CI, -211.4 to -141.8 mL) with placebo (between-group difference, 2.8 mL [95% CI, -46.9 to 52.4 mL]) and -174.9 mL (95% CI, -209.5 to -140.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, 1.7 mL [95% CI, -47.4 to 50.8 mL]). There was no benefit with ziritaxestat vs placebo for the key secondary outcomes. In ISABELA 1, all-cause mortality was 8.0% with 600 mg of ziritaxestat, 4.6% with 200 mg of ziritaxestat, and 6.3% with placebo; in ISABELA 2, it was 9.3% with 600 mg of ziritaxestat, 8.5% with 200 mg of ziritaxestat, and 4.7% with placebo. Conclusions and Relevance: Ziritaxestat did not improve clinical outcomes compared with placebo in patients with IPF receiving standard of care treatment with pirfenidone or nintedanib or in those not receiving standard of care treatment. Trial Registration: ClinicalTrials.gov Identifiers: NCT03711162 and NCT03733444.

Role of the internet of medical things in care for patients with interstitial lung disease.

PURPOSE OF REVIEW: Online technologies play an increasing role in facilitating care for patients with interstitial lung disease (ILD). In this review, we will give an overview of different applications of the internet of medical things (IoMT) for patients with ILD. RECENT FINDINGS: Various applications of the IoMT, including teleconsultations, virtual MDTs, digital information, and online peer support, are now used in daily care of patients with ILD. Several studies showed that other IoMT applications, such as online home monitoring and telerehabilitation, seem feasible and reliable, but widespread implementation in clinical practice is lacking. The use of artificial intelligence algorithms and online data clouds in ILD is still in its infancy, but has the potential to improve remote, outpatient clinic, and in-hospital care processes. Further studies in large real-world cohorts to confirm and clinically validate results from previous studies are needed. SUMMARY: We believe that in the near future innovative technologies, facilitated by the IoMT, will further enhance individually targeted treatment for patients with ILD by interlinking and combining data from various sources.

ERS International Congress 2022: highlights from the Interstitial Lung Diseases Assembly.

This article contains a selection of scientific highlights in the field of interstitial lung diseases (ILDs) presented at the hybrid European Respiratory Society International Congress 2022. Early Career Members of Assembly 12 summarise recent advances in translational and clinical research in idiopathic interstitial pneumonias, ILDs of known origin, sarcoidosis and other granulomatous diseases, and rare ILDs. Many studies focused on evaluation of diagnostic and prognostic (bio)markers, and novel pharmacological and nonpharmacological treatment options for different ILDs. In addition, new insights in clinical, physiological and radiological features of various rare ILDs were presented.

Inhaled pirfenidone solution (AP01) for IPF: a randomised, open-label, dose-response trial.

INTRODUCTION: Oral pirfenidone reduces lung function decline and mortality in patients with idiopathic pulmonary fibrosis (IPF). Systemic exposure can have significant side effects, including nausea, rash, photosensitivity, weight loss and fatigue. Reduced doses may be suboptimal in slowing disease progression. METHODS: This phase 1b, randomised, open-label, dose-response trial at 25 sites in six countries (Australian New Zealand Clinical Trials Registry (ANZCTR) registration number ACTRN12618001838202) assessed safety, tolerability and efficacy of inhaled pirfenidone (AP01) in IPF. Patients diagnosed within 5 years, with forced vital capacity (FVC) 40%-90% predicted, and intolerant, unwilling or ineligible for oral pirfenidone or nintedanib were randomly assigned 1:1 to nebulised AP01 50 mg once per day or 100 mg two times per day for up to 72 weeks. RESULTS: We present results for week 24, the primary endpoint and week 48 for comparability with published trials of antifibrotics. Week 72 data will be reported as a separate analysis pooled with the ongoing open-label extension study. Ninety-one patients (50 mg once per day: n=46, 100 mg two times per day: n=45) were enrolled from May 2019 to April 2020. The most common treatment-related adverse events (frequency, % of patients) were all mild or moderate and included cough (14, 15.4%), rash (11, 12.1%), nausea (8, 8.8%), throat irritation (5, 5.5%), fatigue (4, 4.4%) and taste disorder, dizziness and dyspnoea (three each, 3.3%). Changes in FVC % predicted over 24 and 48 weeks, respectively, were -2.5 (95% CI -5.3 to 0.4, -88 mL) and -4.9 (-7.5 to -2.3,-188 mL) in the 50 mg once per day and 0.6 (-2.2 to 3.4, 10 mL) and -0.4 (-3.2 to 2.3, -34 mL) in the 100 mg two times per day group. DISCUSSION: Side effects commonly associated with oral pirfenidone in other clinical trials were less frequent with AP01. Mean FVC % predicted remained stable in the 100 mg two times per day group. Further study of AP01 is warranted. TRIAL REGISTRATION NUMBER: ACTRN12618001838202 Australian New Zealand Clinical Trials Registry.

Study protocol of an international patient-led registry in patients with pulmonary fibrosis using online home monitoring: I-FILE.

BACKGROUND: Pulmonary fibrosis (PF) is caused by a heterogeneous group of diseases, with a high inter-individual variability in disease trajectory. Identifying disease progression in patients with PF has impact on clinical management decisions. However, strategies to early identify and predict disease progression for these patients are currently lacking. In this study, we aim to assess long-term FVC change in patients with PF measured with home spirometry, and evaluate the feasibility of a multinational patient-led registry in PF. In addition, we will assess validity of patient-reported outcomes (PROMs) for the different subgroups of patients with PF. METHODS: In this international, prospective, multicenter, observational study, we aim to include 700 patients across seven European countries. Patients will monitor their disease course for a period of two years using an online home monitoring program (I-FILE), which includes home spirometry, pulse oximetry, and PROMs. Results will be directly sent to the hospital via the online application. Patients will be asked to perform daily home spirometry and pulse oximetry in the first three months, followed by once weekly measurements for a period of two years. PROMs will be completed in the online I-FILE application every six months, including the King's brief Interstitial Lung Disease Health Status, The EuroQol five dimensions five-level, Visual Analogue Scales on cough, dyspnea, fatigue and general complaints, Leicester Cough Questionnaire, Fatigue Assessment Scale, Work Productivity and Activity Impairment Questionnaire, Global Rating of Change Scale, and Living with Pulmonary Fibrosis questionnaire. DISCUSSION: This study will provide much needed insights in disease trajectories of the different subgroups of patients with PF. Simultaneously, the I-FILE study will yield valuable information on the use and feasibility of home-based data collection. This international patient-led registry will facilitate trans-border collaboration to further optimize care and research for patients with PF. TRIAL REGISTRATION: The study was registered on the 12th of March 2020 in the International Clinical Trial Registry, www. CLINICALTRIALS: gov ; Identifier: NCT04304898.