Obstructive Sleep Apnea and Subclinical Interstitial Lung Disease in the Multi-Ethnic Study of Atherosclerosis (MESA)

Abstract

Rationale: Obstructive sleep apnea (OSA) has been postulated to contribute to idiopathic pulmonary fibrosis by promoting alveolar epithelial injury via tractional forces and intermittent hypoxia.

Objectives: To determine whether OSA is associated with subclinical interstitial lung disease (ILD) and with biomarkers of alveolar epithelial injury and remodeling.

Methods: We performed cross-sectional analyses of 1,690 community-dwelling adults who underwent 15-channel in-home polysomnography and thoracic computed tomographic imaging in the Multi-Ethnic Study of Atherosclerosis. We measured the obstructive apnea-hypopnea index (oAHI) by polysomnography and high-attenuation areas (HAAs) and interstitial lung abnormalities (ILAs) by computed tomography. Serum matrix metalloproteinase-7 (MMP-7) and surfactant protein-A (SP-A) were measured by ELISA in 99 participants. We used generalized linear models to adjust for potential confounders.

Results: The mean age was 68 years, and the mean forced vital capacity was 97% predicted. The median oAHI was 8.4 events/h, and 32% had an oAHI greater than 15. After adjusting for demographics, smoking, and center, an oAHI greater than 15 was associated with a 4.0% HAA increment (95% confidence interval [CI], 1.4-6.8%; P = 0.003) and 35% increased odds of ILA (95% CI, 13-61%; P = 0.001). However, there was evidence that these associations varied by body mass index (BMI) (P for interaction = 0.08 and 0.04, respectively). Among those with a BMI less than 25 kg/m², an oAHI greater than 15 was associated with a 6.1% HAA increment (95% CI, 0.5-12%; P = 0.03) and 2.3-fold increased odds of ILA (95% CI, 1.3-4.1; P = 0.005). Among those with a BMI greater than 30 kg/m², an oAHI greater than 15 was associated with 1.8-fold greater odds of ILA (95% CI, 1.1-2.9; P = 0.01) but was not associated with HAA. There were no meaningful associations detected among those with a BMI of 25-30 kg/m². Greater oAHI was associated higher serum SP-A and MMP-7 levels, particularly among those with a BMI less than 25 kg/m².

Conclusions: Moderate to severe OSA is associated with subclinical ILD and with evidence of alveolar epithelial injury and extracellular matrix remodeling in community-dwelling adults, an association that is strongest among normal-weight individuals. These findings support the hypothesis that OSA might contribute to early ILD.

Keywords: biomarkers; epidemiologic studies; interstitial lung disease; lung injury; sleep apnea.

Figure 1.

Continuous associations of the obstructive apnea hypopnea index with (A) high-attenuation areas and (B) interstitial lung abnormalities stratified by body mass index (BMI) category. HAA models are adjusted for age, sex, race/ethnicity, smoking status and pack-years, educational attainment, height, glomerular filtration rate, percent emphysema on CT, milliampere dose, total imaged lung volume, and study site. ILA models are adjusted for age, sex, race/ethnicity, smoking status, and pack-years. The thick lines represent the overall adjusted effect estimate; thin lines indicate the 95% confidence bands. Each vertical mark in the rug plot along the x-axis represents one study participant. P values are from generalized additive models and differ somewhat from the P values in Table E2, which are from generalized linear models. AHI = apnea–hypopnea index; CT = computed tomography; HAA = high-attenuation area; ILA = interstitial lung abnormality.