Hiatal Hernia and Pulmonary Involvement

Interstitial Lung Disease Clinical Trial

Official title:

Hiatal Hernia and Pulmonary Involvement Related to Subclinical Lung Injury and Fibrosis

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05716022
• Other study ID #: HSR220294
• Status: Active, not recruiting
• Start date: January 5, 2023
• Est. completion date: January 2025

Study information

• Verified date: May 2024
• Source: University of Virginia
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Patients often present with a significant burden of fibrosis upon diagnosis as there is interest in identifying these individuals earlier in their disease course (i.e., "subclinical disease") where targeted treatments and modification of risk factors may curb their progression to fulminant fibrosing ILD. The investigators have investigated with computed tomography (CT) methods such as interstitial lung abnormalities (ILA) and high attenuation areas (HAAs) that may detect early radiological signs of interstitial lung inflammation and scarring and novel modifiable risk factors that contribute to its pathogenesis. Among adults without clinically-diagnosed pulmonary fibrosis, those with a hiatal hernia will have higher levels of pepsin in bronchoalveolar lavage fluid (BALF) compared with adults without a hiatal hernia. Secondarily, examinination on whether there are differences in other reflux contents from BALF including total bile, and peripheral biomarkers related to lung injury and fibrogenesis which include matrix metalloproteinase-7 (MMP-7), vascular cell adhesion molecule 1 (VCAM-1), and cancer antigen 125 (CA-125).

Description:

Fibrosing interstitial lung diseases (ILDs) have significant morbidity and poor overall survival as the investigation of earlier stages of fibrosing ILDs may identify modifiable risk factors and elucidate its pathogenesis. Interstitial lung disease (ILD) constitutes a group of chronic respiratory illnesses that are characterized by repetitive injury to the lung parenchyma that may progress to fibrosis. Fibrosing ILDs, which include idiopathic pulmonary fibrosis (IPF) and other ILD types, can lead to chronic respiratory failure, and poor survival, is the most common indication for lung transplantation. While antifibrotics slow disease progression and may reduce mortality, they carry side effects and are frequently poorly tolerated by patients. Therefore, there is a critical need to identify novel therapeutic targets. Patients often present with a significant burden of fibrosis upon diagnosis as there is interest in identifying these individuals earlier in their disease course (i.e., "subclinical disease") where targeted treatments and modification of risk factors may curb their progression to fulminant fibrosing ILD.

Hiatal hernia and its promotion of gastroesophageal reflux have been implicated as a causal risk factor in pulmonary fibrosis. One potential modifiable risk factor is hiatal hernia and its promotion of gastroesophageal reflux (GER). Gastric materials in the lung induce parenchymal injury and fibrosis in pre-clinical models as GER may be a vehicle of repetitive lung injury that is then followed by aberrant wound healing and eventual fibrosis. Hiatal hernia, which is the protrusion of stomach contents in the thoracic cavity, can promote GER and is more prevalent in adults with pulmonary fibrosis compared with healthy controls and other chronic lung diseases. Further evidence comes from studies in which patients with IPF and other fibrosing ILDs (many of whom had a hiatal hernia) demonstrated elevated levels of pepsin in their bronchoalveolar lavage fluid (BALF), a significant component of reflux and measurable biomarker, compared with healthy controls and is associated with a higher risk of exacerbation. Much of these studies have been case-control and performed in adults with clinically-diagnosed fibrosing ILD which limits causal inferences. It has been hypothesized that fibrosis itself may promote GER due to impaired esophageal sphincter function due to reduced elasticity and more negative intrathoracic pressures. Whether hiatal hernia contributes to subclinical repetitive injury to the lung among adults without clinically-diagnosed ILD is a significant knowledge gap.

Overactivation of the mononuclear phagocyte immune system may contribute to developing fibrosing ILDs and their progression. Single-cell RNA sequencing (scRNA-seq) has accelerated our understanding of fibrosing ILD by identifying biological pathways related to certain cellular populations. Using scRNA-seq, our group and others have demonstrated that overactivation of the mononuclear phagocyte system, a key component of the innate immune system, may be critical in the pathogenesis of IPF with higher populations of monocytes found in the lungs and blood of patients with fibrosis. Higher levels of the absolute monocyte count in the blood are associated with disease progression and worse survival among adults with IPF. The investigators have extended these findings to earlier stages of ILD as higher monocyte counts are associated with more ILA and its progression on CT and a lower forced vital capacity. Notably, adults with ILA have more activated monocytes than those without ILA, suggesting a smoldering activation of innate immunity may prime an individual to developing ILD in combination with other risk factors (i.e., smoking, genetic variants, and hiatal hernia).

Radiologically-detected hiatal hernia is associated with a greater burden of CT interstitial lung abnormalities and worse survival among community-dwelling adults. In a population cohort of U.S. community-dwelling adults, investigators found that the presence of hiatal hernia on CT was associated with more HAAs and their progression over time and more ILA among younger adults. Notably, elevated HAAs on CT were associated with worse survival among those with a hiatal hernia compared with those without a hernia. Our findings suggest that hiatal hernia and its promotion of GER may contribute to subclinical injury and remodeling detected by imaging biomarkers. Whether subclinical abnormalities are detected in the lungs of adults with hiatal hernia remains a major knowledge gap that this study will address by examining BALF contents of adults with hiatal hernia.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 100
• Est. completion date: January 2025
• Est. primary completion date: March 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Able to provide written consent.

2. Clinical diagnosis of hiatal hernia and/or gastroesophageal reflux undergoing pre-operative evaluation for surgical repair at the University of Virginia as part of clinical care.

3. 18 years and above.

Exclusion Criteria:

1. Unable to provide written consent.

2. Clinical diagnosis of pulmonary fibrosis.

3. History of hiatal hernia (for control group only).

4. Use of home supplemental oxygen therapy either at rest or exertion.

5. Pregnant Women (will be confirmed as part of standard of care).

Related Conditions & MeSH terms

• Hernia
• Hernia, Hiatal
• Hiatal Hernia
• Interstitial Lung Disease
• Lung Diseases
• Lung Diseases, Interstitial

Intervention

Diagnostic Test:
• Blood Collection
Prior to subject's surgical procedure, blood (about 3 tablespoons (44 mL)) will be collected through a needle in vein for research purposes. The UVA researchers will analyze the biomarkers that are expressed in subject's blood.
• Bronchoscopy
Following blood collection, the subject will undergo the bronchoscopy for research purposes. While in the operating room, a bronchoscope will be inserted through the breathing tube that is already been placed for the surgery. Subject's airways will be examined with the bronchoscope in both lungs. Ten tablespoons (150 mL) of saline solution will be injected into one of subject airways. The fluid will be re-collected by suctioning it back up with the bronchoscope. The fluid will be collected from the bronchscope.

Locations

Country	Name	City	State
United States	University of Virginia	Charlottesville	Virginia

Sponsors (2)

Lead Sponsor	Collaborator
University of Virginia	CHEST Foundation

Country where clinical trial is conducted

United States, 

References & Publications (6)

Kim JS, Axelsson GT, Moll M, Anderson MR, Bernstein EJ, Putman RK, Hida T, Hatabu H, Hoffman EA, Raghu G, Kawut SM, Doyle MF, Tracy R, Launer LJ, Manichaikul A, Rich SS, Lederer DJ, Gudnason V, Hobbs BD, Cho MH, Hunninghake GM, Garcia CK, Gudmundsson G, Barr RG, Podolanczuk AJ. Associations of Monocyte Count and Other Immune Cell Types with Interstitial Lung Abnormalities. Am J Respir Crit Care Med. 2022 Apr 1;205(7):795-805. doi: 10.1164/rccm.202108-1967OC. — View Citation

Kim JS, Kim J, Yin X, Hiura GT, Anderson MR, Hoffman EA, Raghu G, Noth I, Manichaikul A, Rich SS, Smith BM, Podolanczuk AJ, Garcia CK, Barr RG, Prince MR, Oelsner EC. Associations of hiatus hernia with CT-based interstitial lung changes: the MESA Lung Study. Eur Respir J. 2023 Jan 27;61(1):2103173. doi: 10.1183/13993003.03173-2021. Print 2023 Jan. — View Citation

Lee JS, Song JW, Wolters PJ, Elicker BM, King TE Jr, Kim DS, Collard HR. Bronchoalveolar lavage pepsin in acute exacerbation of idiopathic pulmonary fibrosis. Eur Respir J. 2012 Feb;39(2):352-8. doi: 10.1183/09031936.00050911. Epub 2011 Dec 19. — View Citation

Noth I, Zangan SM, Soares RV, Forsythe A, Demchuk C, Takahashi SM, Patel SB, Strek ME, Krishnan JA, Patti MG, Macmahon H. Prevalence of hiatal hernia by blinded multidetector CT in patients with idiopathic pulmonary fibrosis. Eur Respir J. 2012 Feb;39(2):344-51. doi: 10.1183/09031936.00099910. Epub 2011 Jul 7. — View Citation

Scott MKD, Quinn K, Li Q, Carroll R, Warsinske H, Vallania F, Chen S, Carns MA, Aren K, Sun J, Koloms K, Lee J, Baral J, Kropski J, Zhao H, Herzog E, Martinez FJ, Moore BB, Hinchcliff M, Denny J, Kaminski N, Herazo-Maya JD, Shah NH, Khatri P. Increased monocyte count as a cellular biomarker for poor outcomes in fibrotic diseases: a retrospective, multicentre cohort study. Lancet Respir Med. 2019 Jun;7(6):497-508. doi: 10.1016/S2213-2600(18)30508-3. Epub 2019 Mar 29. — View Citation

Wijsenbeek M, Cottin V. Spectrum of Fibrotic Lung Diseases. N Engl J Med. 2020 Sep 3;383(10):958-968. doi: 10.1056/NEJMra2005230. No abstract available. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Bronchoalveolar lavage fluid pepsin levels	Investigators examine whether bronchoalveolar lavage fluid levels of pepsin are significantly different by case (adults with hiatal hernia and/or gastroesophageal reflux undergoing surgical repair) and control status (adults without hiatal hernia). Pepsin levels will be measured by ELISA assay.	Baseline
Secondary	Serum matrix metalloproteinase-7	Serum matrix metalloproteinase-7 will be measured by ELISA assay.	Baseline
Secondary	Serum CA-125	Serum CA-125 will be measured by ELISA assay.	Baseline
Secondary	Serum vascular cell adhesion molecule-1	Serum vascular cell adhesion molecule-1 will be measured by ELISA assay.	Baseline
Secondary	RNA gene expression	Gene set enrichment analysis (GSEA) will be performed with a false-discovery rate of <5%. GSEA uses a priori sets of genes that have been grouped together by their common biological pathway stored in databases. Genes constituting very high and low expression will be determined by using the R package "GOSim" with a cutoff q-value <0.01. Cell Population Mapping will be used, an algorithm in the R package "scBio", to perform cell composition analysis and determine the relative abundance of cell compositions. Reference RNA-seq dataset from healthy donors with an annotated cell type meta data from the Broad Institute Single Cell Portal will be used.	Baseline