Families-At-risk for Interstitial Lung Disease Study

The interstitial lung diseases (ILDs) are a family of closely related lung conditions characterized by alveolar inflammation, injury, and fibrosis not due to infection or neoplasia. While previously considered to be rare, a recent nationwide study found that idiopathic pulmonary fibrosis (IPF), a fibrotic ILD with a median survival of only 3.8 years, affects nearly 0.5% of older adults in the U.S. While pirfenidone and nintedanib slow the progression of IPF, neither reverses fibrosis nor prevents progression of the disease,and no studies to date have tested interventions that prevent the development of fibrotic ILDs.

The NHLBI has prioritized research focused on the primary prevention of chronic lung diseases, including ILD. The overall goal of this study is to conduct studies preparatory to and requisite for the testing of ILD preventative interventions.

In the current study, the investigators propose to examine the pulmonary histopathology and biology of early subclinical ILD in healthy adults with a first-degree relative with clinically diagnosed ILD. There are two currently accepted computed tomographic (CT)-based phenotypes of subclinical ILD: high attenuation areas (HAAs) and interstitial lung abnormalities (ILA). Investigators from Columbia University Medical Center have previously shown that HAA has strong construct validity as an imaging biomarker of early subclinical alveolar inflammation and fibrosis among community-dwelling adults using the Multi-Ethnic Study of Atherosclerosis (MESA), an ongoing NHLBI-funded prospective cohort study of 6,814 adults age 45 and older at enrollment in 2000-02. Investigators found that greater HAA at baseline was independently associated with reduced lung function and exercise capacity at 5-year follow-up, exertional dyspnea at 10-year follow-up, and elevated serum levels of matrix metalloproteinase-7 (MMP-7) and interleukin-6 (IL-6). ILA is a distinct qualitative and visually-identified early ILD phenotype on CT that has also shown strong construct validity for ILD. Neither HAA nor ILA has been validated histopathologically.

The lipoprotein substudy will examine the role of high density lipoproteins in patients with ILD. Patients with IPF have previously been shown to have low levels of high density lipoprotein (HDL) and high levels of low density lipoprotein (LDL). Investigators have previously shown that high levels of high-density cholesterol (HDL-C) are associated with a reduction in lung injury, inflammation and fibrosis (subclinical ILD) on CT in community-dwelling adults enrolled in the Multi-Ethnic Study of Atherosclerosis. These data are consistent with animal model data showing that treatment with apolipoprotein A-I (ApoA-I; the main component of HDL) attenuates lung fibrosis. Investigators at Columbia University Medical Center are therefore proposing to examine the associations of HDL and its main components (apolipoprotein A-I, apolipoprotein A-II, and paraoxonase-1) with clinical outcomes (FVC decline, death, lung transplantation and respiratory hospitalizations) and serum biomarkers of lung injury, inflammation and remodeling (SP-A, MMP-7, ICAM-1, IL-1, IL-18) in patients with ILD. Investigators will also explore the structure (using quantitative proteomics) and function (using a macrophage efflux assay and paraoxonase-1 activity assay) of HDL particles in adults with ILD and first-degree family members with subclinical ILD.

Obstructive sleep apnea (OSA) is highly prevalent among adults with interstitial lung disease (ILD) and maybe a risk factor based on our previous studies from MESA (https://www.mesa-nhlbi.org/) and other research studies completed at Columbia University Medical Center. Therefore, the investigators will examine the association between OSA and sub-clinical ILD in at-risk adults.

Eligibility Criteria:
Inclusion Criteria: For "At Risk" participants without clinical ILD

* Age 35 years or older, however subjects who are 40 years old and above will undergo HRCT and subjects age 40-65 years old will be eligible to undergo bronchoscopy
* First-degree relative with one of the following clinical diagnoses:
* Idiopathic Pulmonary Fibrosis
* Idiopathic Non-Specific Interstitial Lung Disease (with fibrosis)
* Chronic Hypersensitivity Pneumonitis (with fibrosis)
* Unclassifiable Idiopathic Interstitial Pneumonia (with fibrosis)
* Patients with any ILD characterized by fibrosis on CT chest scan
* Ability to provide informed consent

Inclusion Criteria: For "At Risk Smoker" participants without clinical ILD

* At least 50 years of age
* Smoked at least 1 pack a day for 30 years

Exclusion Criteria: For "At-Risk" participants without clinical ILD

* Known history of interstitial lung disease
* History of illicit drug use within the past year.
* Lower respiratory tract infection in the past 90 days.
* History of chest CT scan in the past year.
* Known history of heart failure or chronic kidney or liver disease.
* Pregnancy or Lactation

Inclusion Criteria: For "Proband" participants with clinical ILD Age 18 years or older

* Has one of the following clinical diagnoses as per ATS guidelines:
* Idiopathic Pulmonary Fibrosis
* Idiopathic Non-Specific Interstitial Lung Disease (with fibrosis)
* Chronic Hypersensitivity Pneumonitis (with fibrosis)
* Unclassifiable Idiopathic Interstitial Pneumonia (with fibrosis)
* Patient with any ILD characterized by fibrosis on CT chest scan
* Ability to provide informed consent

Exclusion Criteria: For "Proband" participants with clinical ILD

* No Living 1st degree relatives.