Hiatal Hernia and Pulmonary Involvement

March 13, 2026 updated by: John Kim, MD, MS, University of Virginia

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

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).

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed 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.

Study Type

Observational

Enrollment (Actual)

14

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Virginia
      • Charlottesville, Virginia, United States, 22908
        • University of Virginia

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

  1. Participants without a clinical diagnosis of pulmonary fibrosis will be recruited from UVA medical center based on the absence of traction bronchiectasis, honeycombing and/or reticular opacities on CT Scan.
  2. Case group will be adults who have a clinical diagnosis of hiatal hernia already scheduled to under surgical repair
  3. Control group will be adults without a CT diagnosis of hiatal hernia who have been scheduled to undergo Bronchoscopy for lung nodule evaluation.

Description

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).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Hiatal Hernia Group
The subject has a history of acid reflux and/or hiatal hernia undergoing surgical repair by thoracic surgery at the University of Virginia.
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.
Diagnostic test: 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.
Control Group
Patients undergoing bronchoscopy for clinical purposes at the University of Virginia endoscopy suite without a clinical diagnosis of hiatal hernia and/or pulmonary fibrosis.
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.
Diagnostic test: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Bronchoalveolar lavage fluid pepsin levels
Time Frame: Baseline
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Serum matrix metalloproteinase-7
Time Frame: Baseline
Serum matrix metalloproteinase-7 will be measured by ELISA assay.
Baseline
Serum CA-125
Time Frame: Baseline
Serum CA-125 will be measured by ELISA assay.
Baseline
Serum vascular cell adhesion molecule-1
Time Frame: Baseline
Serum vascular cell adhesion molecule-1 will be measured by ELISA assay.
Baseline
RNA gene expression
Time Frame: Baseline
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Virginia

Collaborators

American College of Chest Physicians

Investigators

  • Principal Investigator: John Kim, MD, University of Virginia
  • Study Director: Roselove Asare, MA, UVA
  • Study Director: Yousef Althulth, MD, UVA

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 5, 2023

Primary Completion (Actual)

March 31, 2024

Study Completion (Actual)

December 31, 2025

Study Registration Dates

First Submitted

January 18, 2023

First Submitted That Met QC Criteria

January 27, 2023

First Posted (Actual)

February 8, 2023

Study Record Updates

Last Update Posted (Actual)

March 16, 2026

Last Update Submitted That Met QC Criteria

March 13, 2026

Last Verified

March 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • HSR220294

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Will become available 24 months after completion of study upon request to principal investigator.

IPD Sharing Time Frame

Will become available 24 months after completion of study upon request to principal investigator.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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