The goal of this observational study is to identify early biomarkers that can predict the development of progressive pulmonary fibrosis (PPF) in participants with interstitial lung diseases (ILDs). The participant population includes adults diagnosed with idiopathic pulmonary fibrosis (IPF), familial pulmonary fibrosis (FPF), other fibrotic ILDs, and interstitial lung abnormalities (ILA). The main questions it aims to answer are: * What biomarkers and risk factors are linked to fibrosis progression or can predict rapid worsening and sudden flare-ups in IPF and FPF patients? * What biomarkers and risk factors can predict the development of a PPF phenotype in different types of ILD? * What biomarkers and risk factors can help identify ILA patients who may develop significant ILD? * What biomarkers and risk factors can predict how well ILD patients will respond to treatment? Researchers will compare the outcomes between participants diagnosed with IPF/FPF, other fibrotic ILDs, and ILA to see if early detection biomarkers differ among these groups. Participants will: * Undergo blood sampling. * Perform lung function tests. * Have CT scans. * Perform breath analysis * Participate in exposome and microbiome analyses. * Complete questionnaires. * A subgroup of participants will be offered bronchoscopy.
Included participants will complete several study visits to collect clinical data and biological samples. Study visits will be performed at baseline, 3, 6, 12, 24, 36, 48 and 60 months, with a 2-month time window for follow-up visits. These time points are aligned with the standard clinical follow-up visits outlined in the ILD Care Path Protocol of Amsterdam UMC.
Study Type
OBSERVATIONAL
Enrollment
450
No intervention so not applicable.
Amsterdam UMC, locatie VUmc
Amsterdam, North Holland, Netherlands
RECRUITINGInflammatory and fibrosis extent assessed by HRCT
High-Resolution Computed Tomography (HRCT) is an advanced imaging technique used to obtain detailed images of the lungs and chest. Unlike standard CT scans, HRCT uses thin slices and special algorithms to produce high-resolution images that provide more precise visualization of lung structures, making it particularly useful for diagnosing and evaluating various lung conditions. The Inflammatory and Fibrosis extent will be analyzed by using artificial intelligence software.
Time frame: A baseline HRCT scan will be performed during screening. Following inclusion in the study, HRCT scans will be repeated annually, starting one year after the initial scan, and continuing each year until the end of follow-up (at 5 years))
Pulmonary function tests (PFTs)- Spirometry volumes
Pulmonary function tests (PFTs) are a group of tests that measure how well your lungs are working. These tests assess lung volume, capacity, rates of flow, and gas exchange. We will look at the following values: 1\. Spirometry Values * Forced Vital Capacity (FVC): The total amount of air exhaled after taking the deepest breath possible. * Forced Expiratory Volume in 1 Second (FEV1): The amount of air forcefully exhaled in one second.
Time frame: It will be measured at baseline, at 3, 6, and 12 months, and every other year till end of follow-up (60months))
Pulmonary function tests (PFTs)- DLCO measurement
Pulmonary function tests (PFTs) are a group of tests that measure how well your lungs are working. These tests assess lung volume, capacity, rates of flow, and gas exchange. We will look at the Diffusion Capacity Tests (DLCO). DLCO: Measures how well oxygen and CO2 are exchanged between the lungs and the blood.
Time frame: It will be measured at baseline, at 3, 6, and 12 months, and every other year till end of follow-up (60months))
Pulmonary function tests (PFTs)- Lungvolume measurement
Pulmonary function tests (PFTs) are a group of tests that measure how well your lungs are working. These tests assess lung volume, capacity, rates of flow, and gas exchange. We will look at the Lung Volumes and Capacities * Total Lung Capacity (TLC): The total volume of air in the lungs after taking the deepest breath. * Residual Volume (RV): The amount of air left in the lungs after a full exhalation. * Functional Residual Capacity (FRC): The amount of air remaining in the lungs after normal exhalation. * Inspiratory Capacity (IC): The maximum amount of air that can be inhaled after a normal exhalation.
Time frame: It will be measured at baseline, at 3, 6, and 12 months, and every other year till end of follow-up (60months))
Biomarkers related to pulmonary fibrosis will be measured in plasma and serum
Blood will be taken from participants at the 8 different time points. A predefined panel of biomarkers related to pulmonary fibrosis will be measured in serum/plasma, urine, and, if available, bronchoalveolar lavage fluid. Biomarker levels will be correlated with the time to event (i.e., development of rapid progression or acute exacerbation) to identify biomarkers that predict rapid progression or acute exacerbation, as defined by the criteria by Raghu et al., (2022).
Time frame: It will be measured at baseline, at 3, 6, and 12 months, and every other year till end of follow-up (60months))
Peripheral blood mononuclear cell (PBMC) populations in blood
Deep phenotyping of peripheral blood mononuclear cells (PBMCs) and, when available, BAL cells will be performed using flow cytometry, spectral flow, or cyTOF (cytometry by time of flight). A panel of surface and activation markers will define subsets of monocyte and lymphocyte populations. Data will be correlated to the time of the event.
Time frame: It will be measured Will be measured at baseline, at 3, 6 months, 12 months, and every other year till end of follow-up (60months)
Exhaled breath analysis including volatile organic compounds
Exhaled breath analysis involves measurements of volatile organic compounds (VOCs) using gas chromatography-mass spectrometry (GC-MS) and electronic sensor detection of exhaled breath compounds in a non-invasive manner (breathing into a device). For all participants, VOCs will be measured using GC-MS (in house GC mass spectrometer)..
Time frame: It will be measured at baseline, at 3, 6, and 12 months, and every other year till end of follow-up (60months))
Disease-relevant questionnaires: Exposure Questionnaire
During multiple visits, participants will be requested to complete the questionnaires below. The questionnaires that are not completed in the study center will be sent to the participants via email to fill out at home or bring to the clinic next visit. The Exposure questionnaire. Participants will be asked about their exposures and exposure risks. They are requested to answer the questions as completely as possible. The participant is asked about their current occupation and occupation history, as well as any present or past exposures to metals, fibers, chemicals, dust, smoke, fog/mist, gases, fumes, animal- or plant-materials, bacterial, viral or fungi contacts. Additionally, we will inquire about what kind of environment they have been living in and the duration of their residency. Other questions will cover hobbies, pesticide contact, and animal contact. The follow-up questionnaire has fewer questions.
Time frame: Questionnaires will be filled in at baseline, at 6, and 12 months, and every other year till end of follow-up (60months))
Disease-relevant questionnaires: KBILD questionnaire.
During multiple visits, participants will be requested to complete the questionnaires below. The questionnaires that are not completed in the study center will be sent to the participants via email to fill out at home. The King's Brief Interstitial Lung Disease (KBILD) questionnaire is designed to assess the impact of the ILD on the participant's overall well-being and daily life. It can be used to monitor the progression of ILD, evaluate treatment effectiveness, and assess ongoing management. The KBILD questionnaire consists of 15 brief items. For more details, please visit https://www.kbild.com.
Time frame: Questionnaires will be filled in at baseline, at 6, and 12 months, and every other year till end of follow-up (60months))
Disease-relevant questionnaires: Modified Medical Research Council Dyspnea score
During multiple visits, participants will be requested to complete the questionnaires below. The questionnaires that are not completed in the study center will be sent to the participants via email to fill out at home. The mMRC (Modified Medical Research Council) Dyspnea Scale is used to assess the level of baseline functional disability caused by dyspnea. The mMRC dyspnea scale ranges from grade 0 to 4, with 0 indicating minimal dyspnea. This longitudinal data is valuable for understanding the natural progression of ILDs and evaluating the effectiveness of long-term interventions.
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Time frame: Questionnaires will be filled in at baseline, at 6, and 12 months, and every other year till end of follow-up (60months))
Disease-relevant questionnaires: Visual analog scale (VAS)
During multiple visits, participants will be requested to complete the questionnaires below. The questionnaires that are not completed in the study center will be sent to the participants via email to fill out at home. The Visual analog scale (VAS) is a linear scoring method with a scale ranging from 0 to 10. A score of 0 represents no coughing symptoms, while a score of 10 represents the most severe coughing. The participant is asked to mark the severity of the cough on the scale based on self-perception.
Time frame: Questionnaires will be filled in at baseline, at 6, and 12 months, and every other year till end of follow-up (60months))
Disease-relevant questionnaires: Fatigue Severity Scale (FSS)
During multiple visits, participants will be requested to complete the questionnaires below. The questionnaires that are not completed in the study center will be sent to the participants via email to fill out at home. The Fatigue Severity Scale (FSS) will be used to determine the severity of fatigue in participants. The questionnaire contains nine items and should take approximately 5 minutes to complete. Fatigue is assessed through nine statements that can be scored on a 7-point scale, ranging from 1 (strongly disagree) to 7 (strongly agree). The total score, ranging from 9 to 63, will be divided by 9. A higher score indicated a higher level of fatigue.
Time frame: Questionnaires will be filled in at baseline, at 6, and 12 months, and every other year till end of follow-up (60months))
Genomics analysis in blood.
Increasing evidence suggests that genetic factors play a significant role in the emergence of interstitial lung disease (ILD), particularly within the framework of familial clustering, as seen in cases of familial interstitial pneumonia (FIP)(Borie et al., 2019). DNA and total RNA will be isolated from blood using the RNeasy DNA/RNA Universal kit (Qiagen). RNA will be used for generating the transcriptomic data, while DNA will be dedicated to GWAS analysis and methylome profiling. Whole genome transcriptome analysis will be conducted using state-of-the-art RNA sequencing.
Time frame: Genomics are done once at baseline.
Epigenomics analysis in blood.
Increasing evidence suggests that genetic factors play a significant role in the emergence of interstitial lung disease (ILD), particularly within the framework of familial clustering, as seen in cases of familial interstitial pneumonia (FIP)(Borie et al., 2019). DNA and total RNA will be isolated from blood using the RNeasy DNA/RNA Universal kit (Qiagen). RNA will be used for generating the transcriptomic data, while DNA will be dedicated to GWAS analysis and methylome profiling. Whole genome transcriptome analysis will be conducted using state-of-the-art RNA sequencing.
Time frame: Epigonomics are done at baseline and 1 year after inclusion.
Transcriptome analysis in blood.
Increasing evidence suggests that genetic factors play a significant role in the emergence of interstitial lung disease (ILD), particularly within the framework of familial clustering, as seen in cases of familial interstitial pneumonia (FIP)(Borie et al., 2019). Whole genome transcriptome analysis will be conducted using state-of-the-art RNA sequencing. RNAseq libraries will be generated from poly-A enriched RNA and sequenced on the Illumina Hiseq sequencer. After sequencing, the generated reads will be aligned to the UCSC human hg19 reference genomes using software programs such as the short-read mappers and splice-junction identifier TopHat. Differential gene expression analysis will be performed using the DESeq package. RNAseq offers the advantage of detecting all expressed genes without any "a priori" selection through unlined microarray-based gene expression analysis.
Time frame: Transcriptome is performed at baseline, 6 months and 1 year after inclusion.
Proteome analysis in bronchoalveolar lavage fluid
Biomarkerpanel related to pulmonary fibrosis will be measured in bronchoalveolar lavage fluid. A panel of biomarkers related to pulmonary fibrosis will be measured in BALF. The biomarkers will be determined using a biased approach using the Luminex® Instrument (Austin, USA) and unbiased approach using Olink® (Uppsala, Sweden) techniques. Units of Measure will be concentrations of the different proteins in picograms/mililiters
Time frame: In Group 3, thirty participants will undergo bronchoalveolar lavage at baseline. Additional procedures may be performed during the follow-up period if clinically indicated and will be added to samples. .
Microbiome analyses in stool and nasal swabs.
The gut and respiratory microbiomes play an important role in regulating immune responses. The research study will assess the overall microbial metabolic activity and changes in microbiome composition by analyzing fecal and nasal samples from each participant.
Time frame: Once in first year
Concentration of Biomarkers in Exhaled Particles (Collected via Impaction)
Small droplets, or particles, that arise when small airways close and re-open, are collected from the exhaled air and sampled by impaction (PExA technology). Biomarkers from exhaled air particles, collected through impaction, will be analyzed using proteomics platform assays or Enzyme-Linked Immunosorbent Assay (ELISA). The concentration of specific biomarkers (e.g., proteins, cytokines) will be quantified. Unit of Measure: Concentration (pg/mL or ng/mL).. For more details, visit https://pexa.se/en/.
Time frame: From moment of inclusion every year untill end of follow-up at 60 months.
Identification of Compounds in Exhaled Particles via Mass Spectrometry (MS)
Small droplets, or particles, that arise when small airways close and re-open, are collected from the exhaled air and sampled by impaction. Exhaled particles will be analyzed using Mass Spectrometry (MS) to identify and quantify specific compounds or molecular signatures. Concentration (μg/mL or relative abundance). For more details, visit https://pexa.se/en/.
Time frame: From moment of inclusion every year untill end of follow-up at 60 months.
Separation and Quantification of Compounds in Exhaled Particles Using Liquid Chromatography (LC) and High-Performance Liquid Chromatography (HPLC)
Small droplets, or particles, that arise when small airways close and re-open, are collected from the exhaled air and sampled by impaction. Liquid Chromatography (LC) and High-Performance Liquid Chromatography (HPLC) will be used to separate and quantify compounds present in exhaled air samples. Unit of Measure: Concentration (ng/mL or μg/mL). For more details, visit https://pexa.se/en/.
Time frame: From moment of inclusion every year untill end of follow-up at 60 months.
Metabolome analyses in blood.
Metabolomics is a rapidly evolving field, and advancements in technology and analytical methods continue to enhance our understanding of the metabolome and its role in human health and disease. By profiling the metabolites present in blood, we can gain insights into metabolic pathways, identify disease signatures, monitor treatment response, and uncover potential therapeutic targets for ILD. IPF is associated with a distinct circulating metabolome (Hesslinger et al., 2019). Blood samples will be collected via venipuncture at ILD centers to profile metabolites associated with idiopathic pulmonary fibrosis (IPF). Specific biomarkers to be assessed include: Amino acids (e.g., glutamine, tryptophan), Lipids (e.g., triglycerides, phospholipids), Organic acids (e.g., lactate, citric acid), Nucleotides (e.g., ATP, uric acid). These metabolites will provide insights into metabolic pathways. Concentration (μmol/L, ng/mL, or similar, as appropriate for each metabolite).
Time frame: Twice in the first year of inclusion; baseline and at 6 months.
Metabolome analyses in urine
Metabolomics is a rapidly evolving field, and advancements in technology and analytical methods continue to enhance our understanding of the metabolome and its role in human health and disease. By profiling the metabolites present in blood, we can gain insights into metabolic pathways, identify disease signatures, monitor treatment response, and uncover potential therapeutic targets for ILD. IPF is associated with a distinct circulating metabolome (Hesslinger et al., 2019). Urine samples will be collected at home and stored at -80ºC in the biobank for metabolome and biomarker analysis. Specific biomarkers to be assessed include: Creatinine, Electrolytes (e.g., sodium, potassium), Organic metabolites (e.g., hippurate, citrate). These biomarkers will help identify metabolic changes related to ILD. Unit of Measure: Concentration (mmol/L, mg/mL, or similar, as appropriate for each metabolite).
Time frame: Twice in the first year of inclusion; baseline and at 6 months.
Personal exposure to environmental pollutants using the Ultrasonic Personal Air Sampler
External exposome factors such as concentrations of ambient air pollution and other environmental pollutants will be quantified. Time-weighted measurements of PM2.5 will be collected using personal samplers.
Time frame: Exposome will be measured twice in first year, dependant on season (for most patients at 6 and 1 year follow-up))
External exposome analyses using Silicon wristbands
These wristbands collect exposome particles from the surrounding air in the participant's living environment. The wristbands will be worn for 4 to 5 days and then stored in a sealed bag to be returned to field workers. External exposome factors such as concentrations of ambient air pollution and other environmental pollutants will be quantified. Time-weighted measurements of PM2.5 will be collected.
Time frame: Exposome will be measured twice in first year, dependant on season (for most patients at 6 and 1 year follow-up))
External exposome analyses using a Sniffer-bike
Sniffer-bike will be placed at the home of the patient and measures external exposome factors such as concentrations of ambient air pollution and other environmental pollutants, these will be quantified. Time-weighted measurements of PM2.5 will be collected using these stationary samplers.
Time frame: Exposome will be measured twice in first year, dependant on season (for most patients at 6 and 1 year follow-up))