Immune Response in Hypersensitivity Pneumonitis
Condition: Hypersensitivity Pneumonitis
MeSH terms: Pneumonia; Alveolitis, Extrinsic Allergic; Hypersensitivity
Study type: Observational

Summary: 
      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.
    

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.
    

Intervention name(s): Bronchoscopy with lavage
Intervention type(s): Other
Intervention description(s): 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 intervention name(s): blood draw
Observational model: Cohort
Time perspective: Prospective
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