Tetsuro Araki

MUC5B Promoter Polymorphism and Interstitial Lung Abnormalities

BACKGROUND A common promoter polymorphism (rs35705950) in MUC5B, the gene encoding mucin 5B, is associated with idiopathic pulmonary fibrosis. It is not known whether this polymorphism is associated with interstitial lung disease in the general population. METHODS We performed a blinded assessment of interstitial lung abnormalities detected in 2633 participants in the Framingham Heart Study by means of volumetric chest computed tomography (CT). We evaluated the relationship between the abnormalities and the genotype at the rs35705950 locus. RESULTS Of the 2633 chest CT scans that were evaluated, interstitial lung abnormalities were present in 177 (7%). Participants with such abnormalities were more likely to have shortness of breath and chronic cough and reduced measures of total lung and diffusion capacity, as compared with participants without such abnormalities. After adjustment for covariates, for each copy of the minor rs35705950 allele, the odds of interstitial lung abnormalities were 2.8 times greater (95% confidence interval [CI], 2.0 to 3.9; P<0.001), and the odds of definite CT evidence of pulmonary fibrosis were 6.3 times greater (95% CI, 3.1 to 12.7; P<0.001). Although the evidence of an association between the MUC5B genotype and interstitial lung abnormalities was greater among participants who were older than 50 years of age, a history of cigarette smoking did not appear to influence the association. CONCLUSIONS The MUC5B promoter polymorphism was found to be associated with interstitial lung disease in the general population. Although this association was more apparent in older persons, it did not appear to be influenced by cigarette smoking. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00005121.).

Association Between Interstitial Lung Abnormalities and All-Cause Mortality

IMPORTANCE Interstitial lung abnormalities have been associated with lower 6-minute walk distance, diffusion capacity for carbon monoxide, and total lung capacity. However, to our knowledge, an association with mortality has not been previously investigated. OBJECTIVE To investigate whether interstitial lung abnormalities are associated with increased mortality. DESIGN, SETTING, AND POPULATION Prospective cohort studies of 2633 participants from the FHS (Framingham Heart Study; computed tomographic [CT] scans obtained September 2008-March 2011), 5320 from the AGES-Reykjavik Study (Age Gene/Environment Susceptibility; recruited January 2002-February 2006), 2068 from the COPDGene Study (Chronic Obstructive Pulmonary Disease; recruited November 2007-April 2010), and 1670 from ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints; between December 2005-December 2006). EXPOSURES Interstitial lung abnormality status as determined by chest CT evaluation. MAIN OUTCOMES AND MEASURES All-cause mortality over an approximate 3- to 9-year median follow-up time. Cause-of-death information was also examined in the AGES-Reykjavik cohort. RESULTS Interstitial lung abnormalities were present in 177 (7%) of the 2633 participants from FHS, 378 (7%) of 5320 from AGES-Reykjavik, 156 (8%) of 2068 from COPDGene, and in 157 (9%) of 1670 from ECLIPSE. Over median follow-up times of approximately 3 to 9 years, there were more deaths (and a greater absolute rate of mortality) among participants with interstitial lung abnormalities when compared with those who did not have interstitial lung abnormalities in the following cohorts: 7% vs 1% in FHS (6% difference [95% CI, 2% to 10%]), 56% vs 33% in AGES-Reykjavik (23% difference [95% CI, 18% to 28%]), and 11% vs 5% in ECLIPSE (6% difference [95% CI, 1% to 11%]). After adjustment for covariates, interstitial lung abnormalities were associated with a higher risk of death in the FHS (hazard ratio [HR], 2.7 [95% CI, 1.1 to 6.5]; P = .03), AGES-Reykjavik (HR, 1.3 [95% CI, 1.2 to 1.4]; P < .001), COPDGene (HR, 1.8 [95% CI, 1.1 to 2.8]; P = .01), and ECLIPSE (HR, 1.4 [95% CI, 1.1 to 2.0]; P = .02) cohorts. In the AGES-Reykjavik cohort, the higher rate of mortality could be explained by a higher rate of death due to respiratory disease, specifically pulmonary fibrosis. CONCLUSIONS AND RELEVANCE In 4 separate research cohorts, interstitial lung abnormalities were associated with a greater risk of all-cause mortality. The clinical implications of this association require further investigation.

Pulmonary hyperpolarized noble gas MRI: recent advances and perspectives in clinical application.

The invention of hyperpolarized (HP) noble gas MRI using helium-3 ((3)He) or xenon-129 ((129)Xe) has provided a new method to evaluate lung function. Using HP (3)He or (129)Xe for inhalation into the lung air spaces as an MRI contrast agent significantly increases MR signal and makes pulmonary ventilation imaging feasible. This review focuses on important aspects of pulmonary HP noble gas MRI, including the following: (1) functional imaging types, (2) applications for major pulmonary diseases, (3) safety considerations, and (4) future directions. Although it is still challenging to use pulmonary HP noble gas MRI clinically, the technology offers promise for the investigation of the microstructure and function of the lungs.

Biomarkers of Rheumatoid Arthritis–Associated Interstitial Lung Disease

Interstitial lung disease (ILD) is a relatively common extraarticular manifestation of rheumatoid arthritis (RA) that contributes significantly to disease burden and excess mortality. The purpose of this study was to identify peripheral blood markers of RA‐associated ILD that can facilitate earlier diagnosis and provide insight regarding the pathogenesis of this potentially devastating disease complication.

Imaging characteristics of pathologically proven thymic hyperplasia: identifying features that can differentiate true from lymphoid hyperplasia.

OBJECTIVE The purpose of this article is to investigate the imaging characteristics of pathologically proven thymic hyperplasia and to identify features that can differentiate true hyperplasia from lymphoid hyperplasia. MATERIALS AND METHODS Thirty-one patients (nine men and 22 women; age range, 20-68 years) with pathologically confirmed thymic hyperplasia (18 true and 13 lymphoid) who underwent preoperative CT (n=27), PET/CT (n=5), or MRI (n=6) were studied. The length and thickness of each thymic lobe and the transverse and anterior-posterior diameters and attenuation of the thymus were measured on CT. Thymic morphologic features and heterogeneity on CT and chemical shift on MRI were evaluated. Maximum standardized uptake values were measured on PET. Imaging features between true and lymphoid hyperplasia were compared. RESULTS No significant differences were observed between true and lymphoid hyperplasia in terms of thymic length, thickness, diameters, morphologic features, and other qualitative features (p>0.16). The length, thickness, and diameters of thymic hyperplasia were significantly larger than the mean values of normal glands in the corresponding age group (p<0.001). CT attenuation of lymphoid hyperplasia was significantly higher than that of true hyperplasia among 15 patients with contrast-enhanced CT (median, 47.9 vs 31.4 HU; Wilcoxon p=0.03). The receiver operating characteristic analysis yielded greater than 41.2 HU as the optimal threshold for differentiating lymphoid hyperplasia from true hyperplasia, with 83% sensitivity and 89% specificity. A decrease of signal intensity on opposed-phase images was present in all four cases with in- and opposed-phase imaging. The mean maximum standardized uptake value was 2.66. CONCLUSION CT attenuation of the thymus was significantly higher in lymphoid hyperplasia than in true hyperplasia, with an optimal threshold of greater than 41.2 HU in this cohort of patients with pathologically confirmed thymic hyperplasia.

Galectin-3 Is Associated with Restrictive Lung Disease and Interstitial Lung Abnormalities

RATIONALE Galectin-3 (Gal-3) has been implicated in the development of pulmonary fibrosis in experimental studies, and Gal-3 levels have been found to be elevated in small studies of human pulmonary fibrosis. OBJECTIVES We sought to study whether circulating Gal-3 concentrations are elevated early in the course of pulmonary fibrosis. METHODS We examined 2,596 Framingham Heart Study participants (mean age, 57 yr; 54% women; 14% current smokers) who underwent Gal-3 assessment using plasma samples and pulmonary function testing between 1995 and 1998. Of this sample, 1,148 underwent subsequent volumetric chest computed tomography. MEASUREMENTS AND MAIN RESULTS Higher Gal-3 concentrations were associated with lower lung volumes (1.4% decrease in percentage of predicted FEV1 per 1 SD increase in log Gal-3; 95% confidence interval [CI], 0.8-2.0%; P < 0.001; 1.2% decrease in percentage of predicted FVC; 95% CI, 0.6-1.8%; P < 0.001) and decreased diffusing capacity of the lung for carbon monoxide (2.1% decrease; 95% CI, 1.3-2.9%; P < 0.001). These associations remained significant after multivariable adjustment (P ≤ 0.008 for all). Compared with the lowest quartile, participants in the highest Gal-3 quartile were more than twice as likely to have interstitial lung abnormalities visualized by computed tomography (multivariable-adjusted odds ratio, 2.67; 95% CI, 1.49-4.76; P < 0.001). CONCLUSIONS Elevated Gal-3 concentrations are associated with interstitial lung abnormalities coupled with a restrictive pattern, including decreased lung volumes and altered gas exchange. These findings suggest a potential role for Gal-3 in early stages of pulmonary fibrosis.

Interstitial lung abnormalities in treatment-naïve advanced non-small-cell lung cancer patients are associated with shorter survival

OBJECTIVE Interstitial lung diseases are associated with increased risk of lung cancer. The prevalence of ILA at diagnosis of advanced non-small-cell lung cancer (NSCLC) and its impact on overall survival (OS) remain to be investigated. MATERIALS AND METHOD The study included 120 treatment-naïve stage IV NSCLC patients (53 males, 67 females). ILA was scored on CT prior to any systemic therapy using a 4-point scale [0=no evidence of ILA, 1=equivocal for ILA, 2=suspicious for ILA, 3=ILA] by a sequential reading method previously reported. ILA scores of 2 or 3 indicated the presence of ILA. RESULTS ILA was present in 17 patients (14%) with advanced NSCLC prior to any treatment (score3: n=2, score2: n=15). These 17 patients were significantly older (median age: 69 vs. 63, p=0.04) and had a heavier smoking history (median: 40 vs. 15.5 pack-year, p=0.003) than those with ILA score 0 or 1. Higher ILA scores were associated with shorter OS (p=0.001). Median OS of the 17 patients with ILA was 7.2 months [95%CI: 2.9-9.4] compared to 14.8 months [95%CI: 11.1-18.4] in patients with ILA score 0 or 1 (p=0.002). In a multivariate model, the presence of ILA remained significant for increased risk for death (HR=2.09, p=0.028) after adjusting for first-line systemic therapy (chemotherapy, p<0.001; TKI, p<0.001; each compared to no therapy) and pack years of smoking (p=0.40). CONCLUSION Radiographic ILA was present in 14% of treatment-naïve advanced NSCLC patients. Higher ILA scores were associated with shorter OS, indicating that ILA could be a marker of shorter survival in advanced NSCLC.

Paraseptal emphysema: Prevalence and distribution on CT and association with interstitial lung abnormalities.

OBJECTIVE To investigate the prevalence and distribution of paraseptal emphysema on chest CT images in the Framingham Heart Study (FHS) population, and assess its impact on pulmonary function. Also pursued was the association with interstitial lung abnormalities. MATERIALS AND METHODS We assessed 2633 participants in the FHS for paraseptal emphysema on chest CT. Characteristics of the participants, including age, sex, smoking status, clinical symptoms, and results of pulmonary function tests, were compared between those with and without paraseptal emphysema. The association between paraseptal emphysema and interstitial lung abnormalities was investigated. RESULTS Of the 2633 participants, 86 (3%) had pure paraseptal emphysema (defined as paraseptal emphysema with no other subtypes of emphysema other than paraseptal emphysema or a very few centrilobular emphysema involved) in at least one lung zone. The upper zone of the lungs was almost always involved. Compared to the participants without paraseptal emphysema, those with pure paraseptal emphysema were significantly older, and were more frequently male and smokers (mean 64 years, 71% male, mean 36 pack-years, P<0.001) and had significantly decreased FEV1/FVC% (P=0.002), and diffusion capacity of carbon monoxide (DLCO) (P=0.002). There was a significant association between pure paraseptal emphysema and interstitial lung abnormalities (P<0.001). CONCLUSIONS The prevalence of pure paraseptal emphysema was 3% in the FHS population, predominantly affects the upper lung zone, and contributes to decreased pulmonary function. Cigarette smoking, aging, and male gender were the factors associated with the presence of paraseptal emphysema. Significant association between paraseptal emphysema and interstitial lung abnormalities was observed.

Pulmonary cysts identified on chest CT: are they part of aging change or of clinical significance?

Objective To investigate the prevalence and natural course of pulmonary cysts in a population-based cohort and to describe the CT image characteristics in association with participant demographics and pulmonary functions. Materials and methods Chest CT scans of 2633 participants (mean age 59.2 years; 50% female) of the Framingham Heart Study (FHS) were visually evaluated for the presence of pulmonary cysts and their image characteristics. These findings were correlated with participant demographics and results of pulmonary function tests as well as the presence of emphysema independently detected on CT. The interval change was investigated by comparison with previous CT scans (median interval 6.1 years). Results Pulmonary cysts were seen in 7.6% (95% CI 6.6% to 8.7%; 200/2633). They were not observed in participants younger than 40 years old, and the prevalence increased with age. Multiple cysts (at least five) were seen in 0.9% of all participants. Participants with pulmonary cysts showed significantly lower body mass index (BMI) (p<0.001). Pulmonary cysts were most likely to appear solitary in the peripheral area of the lower lobes and remain unchanged or slightly increase in size over time. Pulmonary cysts showed no significant influence on pulmonary functions (p=0.07–0.6) except for diffusing capacity of the lung for carbon monoxide (DLCO) (p=0.03) and no association with cigarette smoking (p=0.1–0.9) or emphysema (p=0.7). Conclusions Pulmonary cysts identified on chest CT may be a part of the aging changes of the lungs, occurring in asymptomatic individuals older than 40 years, and are associated with decreased BMI and DLCO. Multiple pulmonary cysts may need to be evaluated for the possibility of cystic lung diseases.

Anterior mediastinal masses in the Framingham Heart Study: Prevalence and CT image characteristics

Purpose To investigate the prevalence and CT image characteristics of anterior mediastinal masses in a population-based cohort and their association with the demographics of the participants. Materials and methods Chest CT scans of 2571 Framingham Heart Study participants (mean age 58.9 years, 51% female) were evaluated by two board-certified radiologists with expertise in thoracic imaging for the presence of anterior mediastinal masses, their shape, contour, location, invasion of adjacent structures, fat content, and calcification. For participants with anterior mediastinal masses, a previous cardiac CT scan was reviewed for interval size change of the masses, when available. The demographics of the participants were studied for any association with the presence of anterior mediastinal masses. Results Of 2571, 23 participants (0.9%, 95% CI: 0.6–1.3) had anterior mediastinal masses on CT. The most common CT characteristics were oval shape, lobular contour, and midline location, showing soft tissue density (median 32.1 HU). Fat content was detected in a few cases (9%, 2/23). Six out of eight masses with available prior cardiac CT scans demonstrated an interval growth over a median period of 6.5 years. No risk factors for anterior mediastinal masses were detected among participants’ demographics, including age, sex, BMI, and cigarette smoking. Conclusions The prevalence of anterior mediastinal masses is 0.9% in the Framingham Heart Study. Those masses may increase in size when observed over 5–7 years. Investigation of clinical significance in incidentally found anterior mediastinal masses with a longer period of follow-up would be necessary.