Anna J. Podolanczuk

High attenuation areas on chest computed tomography in community-dwelling adults: the MESA study

Evidence suggests that lung injury, inflammation and extracellular matrix remodelling precede lung fibrosis in interstitial lung disease (ILD). We examined whether a quantitative measure of increased lung attenuation on computed tomography (CT) detects lung injury, inflammation and extracellular matrix remodelling in community-dwelling adults sampled without regard to respiratory symptoms or smoking. We measured high attenuation areas (HAA; percentage of lung voxels between −600 and −250 Hounsfield Units) on cardiac CT scans of adults enrolled in the Multi-Ethnic Study of Atherosclerosis. HAA was associated with higher serum matrix metalloproteinase-7 (mean adjusted difference 6.3% per HAA doubling, 95% CI 1.3–11.5), higher interleukin-6 (mean adjusted difference 8.8%, 95% CI 4.8–13.0), lower forced vital capacity (FVC) (mean adjusted difference −82 mL, 95% CI −119–−44), lower 6-min walk distance (mean adjusted difference −40 m, 95% CI −1–−80), higher odds of interstitial lung abnormalities at 9.5 years (adjusted OR 1.95, 95% CI 1.43–2.65), and higher all cause-mortality rate over 12.2 years (HR 1.58, 95% CI 1.39–1.79). High attenuation areas are associated with biomarkers of inflammation and extracellular matrix remodelling, reduced lung function, interstitial lung abnormalities, and a higher risk of death among community-dwelling adults. Increased lung attenuation on CT may identify subclinical lung injury and inflammation in community-dwelling adults http://ow.ly/97k3300tvKX

Serum Matrix Metalloproteinase-7, Respiratory Symptoms, and Mortality in Community-Dwelling Adults. MESA (Multi-Ethnic Study of Atherosclerosis)

Rationale: Matrix metalloproteinase‐7 (MMP‐7) has been implicated in interstitial lung disease pathobiology and proposed as a diagnostic and prognostic biomarker of idiopathic pulmonary fibrosis. Objectives: To test associations between serum MMP‐7 and lung function, respiratory symptoms, interstitial lung abnormalities (ILA), and all‐cause mortality in community‐dwelling adults sampled without regard to respiratory symptoms or disease. Methods: We measured serum MMP‐7 in 1,227 participants in MESA (Multi‐Ethnic Study of Atherosclerosis) at baseline. The 5‐year outcome data were available for spirometry (n = 697), cough (n = 722), and dyspnea (n = 1,050). The 10‐year outcome data were available for ILA (n = 561) and mortality (n = 1,227). We used linear, logistic, and Cox regression to control for potential confounders. Measurements and Main Results: The mean (±SD) serum MMP‐7 level was 4.3 (±2.5) ng/ml (range, 1.2‐24.1 ng/ml). In adjusted models, each natural log unit increment in serum MMP‐7 was associated with a 3.7% absolute decrement in FVC% (95% confidence interval [CI] = 0.9‐6.6%), a 1.6‐fold increased odds of exertional dyspnea (95% CI = 1.3‐1.9), a 1.5‐fold increased odds of ILAs (95% CI = 1.1‐2.1), and a 2.2‐fold increased all‐cause mortality rate (95% CI = 1.9‐2.5). The associations with ILA and mortality tended to be stronger among never‐smokers (P values for interaction 0.06 and 0.01, respectively). Conclusions: Serum MMP‐7 levels may be a quantitative biomarker of subclinical extracellular matrix remodeling in the lungs of community‐dwelling adults, which may facilitate investigation of subclinical interstitial lung disease.

High-Attenuation Areas on Chest Computed Tomography and Clinical Respiratory Outcomes in Community-Dwelling Adults

Rationale: Areas of increased lung attenuation visualized by computed tomography are associated with all‐cause mortality in the general population. It is uncertain whether this association is attributable to interstitial lung disease (ILD). Objectives: To determine whether high‐attenuation areas are associated with the risk of ILD hospitalization and mortality in the general population. Methods: We performed a cohort study of 6,808 adults aged 45‐84 years sampled from six communities in the United States. High‐attenuation areas were defined as the percentage of imaged lung volume with attenuation values between −600 and −250 Hounsfield units. An adjudication panel determined ILD hospitalization and death. Measurements and Main Results: After adjudication, 52 participants had a diagnosis of ILD during 75,232 person‐years (median, 12.2 yr) of follow‐up. There were 48 hospitalizations attributable to ILD (crude rate, 6.4 per 10,000 person‐years). Twenty participants died as a result of ILD (crude rate, 2.7 per 10,000 person‐years). High‐attenuation areas were associated with an increased rate of ILD hospitalization (adjusted hazard ratio, 2.6 per 1‐SD increment in high‐attenuation areas; 95% confidence interval, 1.9‐3.5; P < 0.001), a finding that was stronger among men, African Americans, and Hispanics. High‐attenuation areas were also associated with an increased rate of ILD‐specific death (adjusted hazard ratio, 2.3; 95% confidence interval, 1.7‐3.0; P < 0.001). Our findings were consistent among both smokers and nonsmokers. Conclusions: Areas of increased lung attenuation are a novel risk factor for ILD hospitalization and mortality. Measurement of high‐attenuation areas by screening and diagnostic computed tomography may be warranted in at‐risk adults.

Air Pollution and Subclinical Interstitial Lung Disease: The Multi-Ethnic Study of Atherosclerosis (MESA) Air-Lung Study

We studied whether ambient air pollution is associated with interstitial lung abnormalities (ILAs) and high attenuation areas (HAAs), which are qualitative and quantitative measurements of subclinical interstitial lung disease (ILD) on computed tomography (CT). We performed analyses of community-based dwellers enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA) study. We used cohort-specific spatio-temporal models to estimate ambient pollution (fine particulate matter (PM2.5), nitrogen oxides (NOx), nitrogen dioxide (NO2) and ozone (O3)) at each home. A total of 5495 participants underwent serial assessment of HAAs by cardiac CT; 2671 participants were assessed for ILAs using full lung CT at the 10-year follow-up. We used multivariable logistic regression and linear mixed models adjusted for age, sex, ethnicity, education, tobacco use, scanner technology and study site. The odds of ILAs increased 1.77-fold per 40 ppb increment in NOx (95% CI 1.06 to 2.95, p = 0.03). There was an overall trend towards an association between higher exposure to NOx and greater progression of HAAs (0.45% annual increase in HAAs per 40 ppb increment in NOx; 95% CI −0.02 to 0.92, p = 0.06). Associations of ambient fine particulate matter (PM2.5), NOx and NO2 concentrations with progression of HAAs varied by race/ethnicity (p = 0.002, 0.007, 0.04, respectively, for interaction) and were strongest among non-Hispanic white people. We conclude that ambient air pollution exposures were associated with subclinical ILD. Exposure to ambient air pollution was associated with qualitative and quantitative measurements of subclinical ILD http://ow.ly/5OfU30gt2q7

Occupational Exposures and Subclinical Interstitial Lung Disease. The MESA (Multi-Ethnic Study of Atherosclerosis) Air and Lung Studies

Rationale: The impact of a broad range of occupational exposures on subclinical interstitial lung disease (ILD) has not been studied. Objectives: To determine whether occupational exposures to vapors, gas, dust, and fumes (VGDF) are associated with high‐attenuation areas (HAA) and interstitial lung abnormalities (ILA), which are quantitative and qualitative computed tomography (CT)‐based measurements of subclinical ILD, respectively. Methods: We performed analyses of participants enrolled in MESA (Multi‐Ethnic Study of Atherosclerosis), a population‐based cohort aged 45‐84 years at recruitment. HAA was measured at baseline and on serial cardiac CT scans in 5,702 participants. ILA was ascertained in a subset of 2,312 participants who underwent full‐lung CT scanning at 10‐year follow‐up. Occupational exposures were assessed by self‐reported VGDF exposure and by job‐exposure matrix (JEM). Linear mixed models and logistic regression were used to determine whether occupational exposures were associated with log‐transformed HAA and ILA. Models were adjusted for age, sex, race/ethnicity, education, employment status, tobacco use, and scanner technology. Measurements and Main Results: Each JEM score increment in VGDF exposure was associated with 2.64% greater HAA (95% confidence interval [CI], 1.23‐4.19%). Self‐reported vapors/gas exposure was associated with an increased odds of ILA among those currently employed (1.76‐fold; 95% CI, 1.09‐2.84) and those less than 65 years old (1.97‐fold; 95% CI, 1.16‐3.35). There was no consistent evidence that occupational exposures were associated with progression of HAA over the follow‐up period. Conclusions: JEM‐assigned and self‐reported exposures to VGDF were associated with measurements of subclinical ILD in community‐dwelling adults.

Cholesterol, lipoproteins and subclinical interstitial lung disease: the MESA study

We investigated associations of plasma lipoproteins with subclinical interstitial lung disease (ILD) by measuring high attenuation areas (HAA: lung voxels between −600 and −250 Hounsfield units) in 6700 adults and serum MMP-7 and SP-A in 1216 adults age 45–84 without clinical cardiovascular disease in Multi-Ethnic Study of Atherosclerosis. In cross-sectional analyses, each SD decrement in high density lipoprotein cholesterol (HDL-C) was associated with a 2.12% HAA increment (95% CI 1.44% to 2.79%), a 3.53% MMP-7 increment (95% CI 0.93% to 6.07%) and a 6.37% SP-A increment (95% CI 1.35% to 11.13%), independent of demographics, smoking and inflammatory biomarkers. These findings support a novel hypothesis that HDL-C might influence subclinical lung injury and extracellular matrix remodelling.

Antacid use and subclinical interstitial lung disease: the MESA study

Idiopathic pulmonary fibrosis (IPF), a prevalent fibrotic idiopathic interstitial lung disease (ILD), is thought to result from recurrent subclinical alveolar epithelial cell (AEC) injury followed by abnormal repair and fibrogenesis [1]. Gastro-oesophageal reflux disease (GORD) has been implicated in AEC injury in IPF [2]. GORD is a prevalent comorbidity in adults with IPF [3], and the gastric enzyme pepsin has been identified in bronchoalveolar lavage fluid of patients with acute IPF exacerbations [4], suggesting a role of micro-aspiration in disease progression. Proton pump inhibitor use is associated with a reduction in subclinical interstitial lung disease http://ow.ly/dbFN30aoRPf

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

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.

Collagen biomarkers and subclinical interstitial lung disease: The Multi-Ethnic Study of Atherosclerosis

BACKGROUND Lung fibrosis is attributed to derangements in extracellular matrix remodeling, a process driven by collagen turnover. We examined the association of two collagen biomarkers, carboxy-terminal telopeptide of collagen type I (ICTP) and amino-terminal propeptide of type III procollagen (PIIINP), with subclinical interstitial lung disease (ILD) in adults. METHODS We performed a cross-sectional analysis of 3244 participants age 45-84 years in the Multi-Ethnic Study of Atherosclerosis. Serum ICTP and PIIINP levels were measured at baseline by radioimmunoassay. Subclinical ILD was defined as high attenuation areas (HAA) in the lung fields on baseline cardiac CT scans. Interstitial lung abnormalities (ILA) were measured in 1082 full-lung CT scans at 9.5 years median follow-up. We used generalized linear models to examine the associations of collagen biomarkers with HAA and ILA. RESULTS Median (IQR) for ICTP was 3.2 μg/L (2.6-3.9 μg/L) and for PIIINP was 5.3 μg/L (4.5-6.2 μg/L). In fully adjusted models, each SD increment in ICTP was associated with a 1.3% increment in HAA (95% CI 0.2-2.4%, p = 0.02) and each SD increment in PIIINP was associated with a 0.96% increment in HAA (95% CI 0.06-1.9%, p = 0.04). There was no association between ICTP or PIIINP and ILA. There was no evidence of effect modification by gender, race, smoking status or eGFR. CONCLUSIONS Higher levels of collagen biomarkers are associated with greater HAA independent of gender, race and smoking status. This suggests that extracellular matrix remodeling may accompany subclinical ILD prior to the onset of clinically evident disease.