ILD cohort

Pulmonary fibrosis (PF) is a general end-stage pathway activated in different forms of ILD, including Idiopathic/Familial Pulmonary Fibrosis (I/FPF), chronic (fibrotic) Hypersensitivity Pneumonitis (cHP), idiopathic non-specific interstitial pneumonia (iNSIP), Connective Tissue Related-ILD (CTD-ILD), and unclassifiable ILD (uILD). PF is characterized by the excessive deposition of extracellular matrix (ECM) in the lungs by activated fibroblasts, leading to irreversible lung function decline, respiratory failure, and eventually death. Patients suffering from progressive pulmonary fibrosis (PPF) might benefit from anti-inflammatory and/or antifibrotic therapy at certain disease stages, which can slow down lung function decline [1,2]. Currently the definition of PPF is based on changes in clinical parameters over time, meaning that at time of diagnosis and initiating therapy loss of pulmonary function due to irreversible fibrosis already has occurred. Consequently, the right (early) timing to start (antifibrotic) treatment is subject of ongoing debate. Early detection of PPF is therefore of utmost importance. More accurate distinction of progressive and non-progressive fibrosis patients and prediction of treatment response is essential for clinical diagnostics, treatment strategies and prognosis.

Next to this, it is important to gain a better understanding of which patients are at risk of developing PPF. Patients with Interstitial Lung Abnormalities (ILAs) can serve as a model for this. ILAs are increasingly recognized as a common finding on Computed Tomography (CT) of the lungs, with an incidence of 4-9% in elderly smokers and 2-7% in non-smokers [3]. ILAs are considered radiologic abnormalities that are characteristic for early-stage ILD, detected without clinical suspicion or symptoms of an ILD. ILAs have been associated with decreased lung capacity [4,5], decreased exercise capacity [6], impaired gas exchange [7,8], genetic variations among FPF and IPF [8,9] and increased all-cause mortality [10]. However, it is unknown which and when ILAs progress to clinically relevant ILD with PPF.

Therefore, P4O2 is building a prospective, non-interventional observational cohort of ILD patients across three arms, at both clinical and pathophysiological levels:

Arm 1: IPF/FPF group (n=150).
Arm 2: Fibrotic ILD group (fILD) at risk for the development of PPF, including cHP, iNSIP, CTD-ILD and uILD (n=150)
Arm 3: ILA group (n=150).

P4O2 parameters:

In all three arms of this cohort, next to biomarker analysis, we will collect the following samples and measurements (as listed below).

These measurements align with the other P4O2 cohorts, including the PARASOL and COPD cohorts which will allow for data analysis over the different cohorts.

The additional measurements include:

Exhaled breath analysis including eNose measurement, PExA analysis, and volatile organic compounds (VOCs) analysis by gas chromatography-mass spectrometry (GC-MS). VOCs have the potential to mirror various metabolic processes locally within the respiratory system and systemically through the blood circulation. VOCs have been utilized as diagnostic, prognostic, and treatment response biomarkers for various respiratory illnesses, including ILD.
Peripheral Blood Mononuclear Cell (PBMC) populations in blood.
HRCT-scan analyses; Novel imaging analyses techniques may be used to stratify the severity of lung involvement and predict outcomes (in kind contribution by imaging partners of P4O2).
External exposome analyses; This includes lifestyle, dietary information (food diaries), and the evaluation of the physical/chemical environment. Previous studies have shown that built environment characteristics, such as ambient air pollution, may be a risk factors for ILD (optional: additional funding will be requested).
Metabolome analyses in urine (optional: additional funding will be requested).
Microbiome analyses in stool and nasal swabs. The gut and respiratory microbiome are important for effective immune response regulation. Analyzing the microbiome in stool and nasal swabs can provide insights into the microbial composition and its potential relationship to ILD. (optional: additional funding will be requested).
Genomics, epigenomics and transcriptome analysis in blood (optional: additional funding will be requested).

Timeline P4O2. Time in months. Made with BioRender. Definition of abbreviations: BAL= bronchoalveolar lavage, HRCT= high-resolution computed tomography, ILA= interstitial lung abnormality, PBMC= peripheral blood mononuclear cells, VOC= volatile organic compound.

Extra measurements and sample collections will be performed at clinical relevant events. Clinical relevant events are defined as follows:

Additional diagnostic measurements e.g., bronchoscopic immunological BAL and/or bronchoscopic lung cryobiopsy/surgical lung biopsy.
Rapid progression of disease outside the fixed time points.
Treatment switch.
Lung transplantation.
Acute exacerbation.
Pulmonary hypertension development.

Literature:

1. 1. Flaherty KR, Wells AU, Cottin V, et al. Nintedanib in Progressive Fibrosing Interstitial Lung Diseases. N Engl J Med. 2019;381:1718-1727.
  2. Behr J, Prasse A, Kreuter M, et al. Pirfenidone in patients with progressive fibrotic interstitial lung diseases other than idiopathic pulmonary fibrosis (RELIEF): a double-blind, randomised, placebo-controlled, phase 2b trial. Lancet Respir Med. 2021;S2213-2600:30554-3. Online ahead of print.
  3. Hatabu H, Hunninghake GM, Richeldi L, Brown KK, Wells AU et al. Interstitial lung abnormalities detected incidentally on CT: a Position Paper from the Fleischner Society Lancet Respir Med. 2020;8(7):726-737.
  4. Lederer DJ, Enright PL, Kawut SM, et al. Cigarette smoking is associated with subclinical parenchymal lung disease: the Multi-Ethnic Study of Atherosclerosis (MESA)-lung study. Am J Respir Crit Care Med. 2009; 180:407–414.
  5. Washko GR, Hunninghake GM, Fernandez IE, et al. Lung volumes and emphysema in smokers with interstitial lung abnormalities. N Engl J Med. 2011; 364:897–906.
  6. Doyle TJ, Washko GR, Fernandez IE, et al. Interstitial Lung Abnormalities and Reduced Exercise Capacity. Am J Respir Crit Care Med. 2012; 185(7):756–762.
  7. Tsushima K, Sone S, Yoshikawa S, Yokoyama T, Suzuki T, Kubo K. The radiological patterns of interstitial change at an early phase: over a 4-year follow-up. Respir Med. 2010; 104:1712–1721.
  8. Hunninghake GM, Hatabu H, Okajima Y, et al. MUC5B promoter polymorphism and interstitial lung abnormalities. N Engl J Med. 2013; 368:2192–2200.
  9. Kropski JA, Pritchett JM, Zoz DF, et al. Extensive Phenotyping of Individuals At-risk for Familial Interstitial Pneumonia Reveals Clues to the Pathogenesis of Interstitial Lung Disease. Am J Respir Crit Care Med. 2015; 191(4):417–426.
  10. Putman RK, Hatabu H, Araki T, et al. Association Between Interstitial Lung Abnormalities and All-Cause Mortality. JAMA. 2016; 315(7):672-81.
  11. Wu J, Li X, Zhao M, et al. Early Detection of Urinary Proteome Biomarkers for Effective Early Treatment of Pulmonary Fibrosis in a Rat Model. Proteomics Clin Appl. 2017; 11(11-12).
  12. M. Decaris, M. Rexhepaj, J. Vowinckel, et al. Urine Proteomics Identifies Novel Biomarkers of IPF Disease Progression and Resolution. American Thoracic Society International Conference Abstracts. 2019; A29. EMERGING CONCEPTS IN LUNG FIBROSIS.
  13. Kärkkäinen M, Kettunen HP, Nurmi H, Selander T, Purokivi M, Kaarteenaho R. Comparison of disease progression subgroups in idiopathic pulmonary fibrosis. BMC Pulm Med. 2019; 19(1):228.
  14. Jessen H, Hoyer N, Prior TS, et al. Turnover of type I and III collagen predicts progression of idiopathic pulmonary fibrosis. Respir Res. 2021; 22(1):205.
  15. Stainer A, Faverio P, Busnelli S, et al. Molecular Biomarkers in Idiopathic Pulmonary Fibrosis: State of the Art and Future Directions. Int J Mol Sci. 2021; 22(12):6255.
  16. Lagoutte P, Bettler E, Vadon-Le Goff S, Moali C. Procollagen C-proteinase enhancer-1 (PCPE-1), a potential biomarker and therapeutic target for fibrosis. Matrix Biol Plus. 2021; 11:100062.
  17. Majewski S, Szewczyk K, Żal A, et al. Serial Measurements of Circulating KL-6, SP-D, MMP-7, CA19-9, CA-125, CCL18, and Periostin in Patients with Idiopathic Pulmonary Fibrosis Receiving Antifibrotic Therapy: An Exploratory Study. J Clin Med. 2021 Aug 28;10(17):3864.