Immune Response in Hypersensitivity Pneumonitis

CD4 T-cell Immunephenotype in Hypersensitivity Pneumonitis

Hypersensitivity pneumonitis (HP) is an inflammatory lung disease that is caused by exposure of susceptible individuals to organic materials in the environment. It is also known by various names depending on the exposure and some of these names include farmer's lung, pigeon breeder's lung, hot tub lung to name a few. HP can cause lung scarring that impairs breathing and oxygenation. Early detection and avoidance of triggers can stop and reverse the disease but a significant number of patients continue to have active disease requiring treatment in spite of avoiding the trigger. The current choice of therapies is based on clinical experience and not on rigorous clinical trials. Not fully understanding the type of inflammation that is seen in HP and the cells involved in this inflammatory response limits health care providers' ability to choose drugs to study in HP that can stop the inflammation and limit scar formation. The goal of the investigators' study is to better understand the type of cells that are involved in the inflammatory response in the lungs of HP patients and what drives these cells to be active. By better understanding the type of cells and what drives them, health care providers can begin to choose and study drugs that can limit the inflammation and subsequent scarring. The investigators' will recruit HP patients and with their consent perform a scope of the lungs (bronchoscopy) with a limited lung wash to get the inflamed cells out of the lungs to further study them in the lab. The investigators' study will provide us with preliminary results to guide us in performing a more detailed study in the future to better understand the disease.

Study Overview

• Status: Completed
• Conditions: Hypersensitivity Pneumonitis
• Intervention / Treatment: Other: Bronchoscopy with lavage

Detailed Description

Hypersensitivity pneumonitis (HP) is a granulomatous lung disorder triggered by exposure to one of a multitude of organic antigens. Incidence rates of HP vary by geography, season and population studied but it is estimated to be the third most common interstitial lung disease with an estimated prevalence rate in the USA of 420-3000/100,0002. HP accounts for at least 7.5% of ILD related lung transplant. Exposure to an antigen in a susceptible host induces an inflammatory response with the subsequent formation of poorly formed granulomas that impact gas exchange which clinically manifests as shortness of breath, hypoxia and radiographic changes. HP can present acutely, subacutely or chronically depending on the duration of symptoms and radiographic changes. Radiographic manifestations of HP include ground-glass changes, centrilobular nodules, air trapping known as mosaic pattern, fibrosis, emphysema, or more frequently a combination of these. The cornerstone of management is identification and avoidance of the inciting agent which is effective if accomplished early in the disease process.

Although detection and avoidance of possible triggers can attenuate or reverse the disease, a significant number of patients continue to have active and/or progressive disease requiring chronic immunosuppressive therapy. Standard of care for IS therapy is corticosteroids and azathioprine but this is based on clinical experience and not based on randomized clinical trials(ref). The efficacy of this regimen is not known and patients develop persistent or progressive disease in spite of aggressive therapy leading to end stage lung disease necessitating lung transplantation or ending with death. To date, there are no randomized trials for immunosuppressive therapies and no reports of the use of biological agents in HP. The lack of studies is partially due to the lack of a thorough understanding of the immune response in HP especially in patient based studies that focus at the site of disease activity, the lungs.

The immunological response and pathways leading to this response have not been fully investigated especially in humans. The Th17 pathway has been implicated in disease pathogenesis and T-regulatory cell dysfunction has been described although studies in humans are limited. Recent work in sarcoidosis, a granulomatous lung disease, has shown that Th17.1 cells play a potential important role in granuloma immunopathogenesis. Through an R01 mechanism, the investigators are currently investigating the role of T-cell skewing and associated gene expression in sarcoidosis that is associated with progressive disease vs stable disease and the investigators are investigating its impact on disease course.

This gap in knowledge in HP has limited the choice and study of immunomodulatory agents in HP and especially biological agents in the treatment of persistent and progressive disease. To narrow this knowledge gap, the investigators propose conducting a study to investigate the lung CD4+ T-cell immunophenotype and CD4+ T-cell gene expression in HP to enhance the investigators' understanding of the immune response in HP and the pathways involved in the immune response which would enable the investigators to further pursue guided therapeutic trials in subacute and chronic HP.

• Study Type: Observational
• Enrollment (Actual): 21

Contacts and Locations

Study Locations

• United States
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Hypersensitivity Pneumonitis patients with confirmed subacute and chronic HP based on compatible radiological and pathological findings will be eligible for recruitment

Description

Inclusion:

1. Adult between the ages of 18 and 80 years old.
2. Non-smoker or previous smoker quit >6months ago.
3. Radiological findings compatible with sub-acute or chronic HP4.
4. Histopathological findings compatible with sub-acute or chronic HP4.
5. Able to understand the consent process and procedures involved in the study.

Exclusion:

1. Unable to understand the consent process or procedures involved in the study.
2. End-stage lung disease defined as predominantly honeycombing on chest CT and/or FVC<60% and/or DLCO <30%.
3. Requiring high oxygen needs >4L.
4. Pregnancy.
5. Treated with a biological agent within the past 6 months.
6. Suspicion of current infection or within the past 3 months.
7. Bleeding disorder or on anti-coagulants other than aspirin.
8. Any co-morbid condition that increases risk of bronchoscopy including but not limited to cardiac disease, uncontrolled hypertension, uncontrolled diabetes and/or morbid obesity.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Patients with subacute or chronic hypersensitivity pneumonitis; Procedures that each subject will undergo include: Chest CT scan to determine extent of disease.; Pulmonary function testing to determine severity of disease.; Bronchoscopy with lavage.; Venipuncture.	Other: Bronchoscopy with lavage; Bronchoscopy will be performed according to standard clinical procedures. Bronchoscopy will be performed under conscious sedation with continuous cardiopulmonary monitoring and the subject's upper airway will be anesthetized with topical lidocaine. The bronchoscope will be passed through the naris or mouth to the upper airway and then into the lower airway. 360cc of sterile saline will be instilled into 2 sub-segments by instilling and aspirating 3 aliquots of 60cc sequentially into each sub-segment. Venipuncture to obtain peripheral blood mononuclear cells (PBMCs) for the proposed assays. Cells collected will be analyzed for various T-cell subsets and gene expression to help determine the type of immune response.; Other Names: blood draw
Healthy Controls; Inclusion: Adult between the ages of 18 and 80 years old.; Non-smoker or previous smoker quit >6months ago.; Able to understand the consent process and procedures involved in the study. Exclusion: Unable to understand the consent process or procedures involved in the study.; Pregnancy.; Suspicion of current infection or within the past 3 months.; Bleeding disorder or on anti-coagulants other than aspirin.; Any co-morbid condition that increases risk of bronchoscopy including but not limited to cardiac disease, uncontrolled hypertension, uncontrolled diabetes and/or morbid obesity.	Other: Bronchoscopy with lavage; Bronchoscopy will be performed according to standard clinical procedures. Bronchoscopy will be performed under conscious sedation with continuous cardiopulmonary monitoring and the subject's upper airway will be anesthetized with topical lidocaine. The bronchoscope will be passed through the naris or mouth to the upper airway and then into the lower airway. 360cc of sterile saline will be instilled into 2 sub-segments by instilling and aspirating 3 aliquots of 60cc sequentially into each sub-segment. Venipuncture to obtain peripheral blood mononuclear cells (PBMCs) for the proposed assays. Cells collected will be analyzed for various T-cell subsets and gene expression to help determine the type of immune response.; Other Names: blood draw

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
T-cell subtypes	T-cell subtypes will be determined by flow cytometry.	outcomes will be assessed after recruitment is complete in 2 years.

Collaborators and Investigators

• Sponsor: Nabeel Hamzeh
• Collaborators: National Jewish Health
• Investigators: Principal Investigator: Nabeel Hamzeh, MD, University of Iowa

Study record dates

Study Major Dates

• Study Start (Actual): November 29, 2018
• Primary Completion (Actual): June 30, 2021
• Study Completion (Actual): March 30, 2022

Study Registration Dates

• First Submitted: February 27, 2019
• First Submitted That Met QC Criteria: March 12, 2019
• First Posted (Actual): March 13, 2019

Study Record Updates

• Last Update Posted (Actual): May 18, 2022
• Last Update Submitted That Met QC Criteria: May 16, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Respiratory Hypersensitivity; Lung Diseases, Interstitial; Hypersensitivity; Pneumonia; Alveolitis, Extrinsic Allergic
• Other Study ID Numbers: 201805937

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No