Development and Progression of Radiologic Abnormalities in Individuals at Risk for Familial Interstitial Lung Disease

Abstract

Rationale: The preclinical natural history of progressive lung fibrosis is poorly understood.Objectives: Our goals were to identify risk factors for interstitial lung abnormalities (ILA) on high-resolution computed tomography (HRCT) scans and to determine progression toward clinical interstitial lung disease (ILD) among subjects in a longitudinal cohort of self-reported unaffected first-degree relatives of patients with familial interstitial pneumonia.Methods: Enrollment evaluation included a health history and exposure questionnaire and HRCT scans, which were categorized by visual assessment as no ILA, early/mild ILA, or extensive ILA. The study endpoint was met when ILA were extensive or when ILD was diagnosed clinically. Among subjects with adequate study time to complete 5-year follow-up HRCT, the proportion with ILD events (endpoint met or radiographic ILA progression) was calculated.Measurements and Main Results: Among 336 subjects, the mean age was 53.1 (SD, 9.9) years. Those with ILA (early/mild [n = 74] or extensive [n = 3]) were older, were more likely to be ever smokers, had shorter peripheral blood mononuclear cell telomeres, and were more likely to carry the MUC5B risk allele. Self-reported occupational or environmental exposures, including aluminum smelting, lead, birds, and mold, were independently associated with ILA. Among 129 subjects with sufficient study time, 25 (19.4%) had an ILD event by 5 years after enrollment; of these, 12 met the study endpoint and another 13 had radiologic progression of ILA. ILD events were more common among those with early/mild ILA at enrollment (63.3% vs. 6.1%; P < 0.0001).Conclusions: Rare and common environmental exposures are independent risk factors for radiologic abnormalities. In 5 years, progression of ILA occurred in most individuals with early ILA detected at enrollment.

Keywords: epidemiology; interstitial; lung diseases; pulmonary fibrosis; telomere.

Figure 1.

Representative high-resolution computed tomography (HRCT) scans showing progressive interstitial lung abnormalities. Images are from a single subject at the time of enrollment and at 5-year follow-up. (A) The upper image is from the enrollment HRCT scan and shows a prone axial image of the lower lungs, demonstrating subtle nondependent reticulation (gray boxes) bilaterally, visually categorized as “early/mild” interstitial lung abnormalities. The lower image was obtained 5 years, 8 months later and shows a prone axial image of the lower lungs, demonstrating an increase in the reticulation in the same areas noted previously (gray boxes). (B) The same enrollment (upper) and follow-up (lower) HRCT scans shown in A, with data-driven textural analysis–measured fibrosis shown in red overlay, demonstrating progression of fibrosis.

Figure 2.

Correlation of data-driven textural analysis (DTA) scores and patient characteristics at enrollment. On the three correlation plots, each dot represents an individual. In the boxplot, dots represent individuals falling outside the range of 1.5 times the interquartile range (also called “upper and lower fences”); the upper whisker represents the maximum observation below the upper fence; the upper line of the box represents the upper quartile (75th percentile); the line inside the box represents the median; the lower line of the box represents the first lower quartile (25th percentile); and the lower whisker represents the lowest observation before the lower fence. HRCT = high-resolution computed tomography; ILA = interstitial lung abnormalities; TRF = telomere restriction fragment.