Toyohiro Hirai

High sensitivity C-reactive protein in asthma

Asthma is characterised by chronic inflammation of the airways, but the relevance of high-sensitivity assays for C-reactive protein (hs-CRP), which are known to be a sensitive marker of low-grade systemic inflammation, has not been fully studied in asthma. The objective was to examine serum hs-CRP levels in patients with asthma and their relationship to clinical characteristics and degree of airway inflammation. Serum hs-CRP levels were cross-sectionally examined in steroid-naive (n = 22) and steroid-inhaling (n = 23) adult patients with asthma and healthy controls (n = 14). All were nonsmokers. Serum hs-CRP levels were significantly increased in steroid-naive patients (mean±sd 1.33±1.48 mg·L−1) compared with controls (0.21±0.30 mg·L−1), but not in patients on inhaled corticosteroid. Among steroid-naive patients, serum hs-CRP levels significantly negatively correlated with indices of pulmonary function (forced expiratory volume in one second/forced vital capacity and forced mid-expiratory flow) and positively with sputum eosinophil count. Among patients on inhaled corticosteroid, hs-CRP levels did not correlate with any indices. In conclusion, an increase in serum C-reactive protein levels measured by high-sensitivity assays may be associated with airflow obstruction and airway inflammation, and may serve as a surrogate marker of airway inflammation in asthma.

CT Scan Findings of Emphysema Predict Mortality in COPD

BACKGROUND Emphysematous change as assessed by CT imaging has been reported to correlate with COPD prognostic factors such as FEV(1) and diffusing capacity of the lung for carbon monoxide (Dlco). However, few studies have assessed the relationship between CT scan assessment and COPD mortality from mild to severe stages of the disease. In this study, we analyzed this relationship in patients with various stages of COPD. METHODS Two hundred and fifty-one outpatients with stable COPD were included in the study. CT scan and pulmonary function tests were performed at study entry in a single institution. The percentage of low attenuation area was measured to quantitatively evaluate emphysematous change with a custom-made software. Prognostic data also were collected, and the median follow-up time was 8 years. RESULTS Of the 251 patients, 79 died, with 40 classified as respiratory deaths not involving lung cancer. Univariate Cox analysis revealed that emphysematous change as assessed by CT scan, lung function, age, or BMI were significantly correlated with mortality. Multivariate analysis revealed that emphysematous change as assessed by CT scan had the best association with mortality. CONCLUSIONS Emphysematous change as assessed by CT scan predicts respiratory mortality in outpatients with various stages of COPD.

Comparison of low attenuation areas on computed tomographic scans between inner and outer segments of the lung in patients with chronic obstructive pulmonary disease: incidence and contribution to lung function

BACKGROUND The low attenuation areas on computed tomographic (CT) scans have been reported to represent emphysematous changes of the lung. However, the regional distribution of emphysema between the inner and outer segments of the lung has not been adequately studied. In this study the regional distribution of low attenuation areas has been compared by quantitative CT analysis and the contribution of the regional distribution to pulmonary function tests evaluated in patients with chronic obstructive pulmonary disease (COPD). METHODS Chest CT images and the results of pulmonary function tests were obtained from 73 patients with COPD. The lung images were divided into inner and outer segments in the upper (cranial), middle, and lower (caudal) sections. The percentage ratio of low attenuation area to corresponding lung area (LAA%) was then calculated. The LAA% of each segment was also compared with the results of pulmonary function tests. RESULTS The mean (SD) LAA% of the inner segment was 39.1 (18.5) compared with 28.1 (13.2) for the outer segment (p<0.0001). Linear and multiple regression analyses revealed that airflow limitation is closely correlated with the inner segment LAA% of the lower lung. In contrast, the carbon monoxide transfer factor is closely correlated with the inner segment LAA% of the upper lung. CONCLUSION Low attenuation areas on CT scans are more often found in the inner segment of the lung than in the outer segment, and the contribution of the inner segment to pulmonary function tests may be greater than the outer segment.

Relationship Between Pulmonary Emphysema and Osteoporosis Assessed by CT in Patients With COPD

BACKGROUND Osteoporosis is one of the important systemic features of COPD. Although COPD itself is regarded as one risk factor for osteoporosis, the relationship between the extent of emphysema and reduced bone density is still unclear. Our first aim was therefore to measure vertebral bone density and the percentage of low-attenuation area (LAA%) in the lungs using chest CT scans in COPD patients. Our second aim was to investigate the relationships among CT scan measurements, anthropometric parameters, and pulmonary function. METHODS Chest CT scans and pulmonary function tests were performed in 65 male patients with COPD. Using CT images, the CT scan density of the thoracic and lumbar vertebrae (T4, T7, T10, and L1) and the LAA% were measured quantitatively, and their correlations were analyzed. RESULTS Linear regression analyses revealed that LAA% had a significant negative correlation with bone mineral density (BMD) [r = -0.522]. In addition, multiple regression analysis showed that only LAA% and body mass index (BMI) were predictive of BMD among age, BMI, smoking index, FEV(1), arterial blood gas, and LAA%. CONCLUSIONS The extent of pulmonary emphysema significantly correlated with reduced bone density. Our study suggested that COPD itself could be a risk factor for osteoporosis and that chest CT scanning is useful for the management of COPD as a systemic disease.

Body mass index in male patients with COPD: correlation with low attenuation areas on CT

Background: Chronic obstructive pulmonary disease (COPD) is characterised by the presence of airflow limitation caused by loss of lung elasticity and/or airway narrowing. The pathological hallmark of loss of lung elasticity is emphysema, and airway wall remodelling contributes to the airway narrowing. Using CT, these lesions can be assessed by measuring low attenuation areas (LAA) and airway wall thickness/luminal area, respectively. As previously reported, COPD can be divided into airway dominant, emphysema dominant and mixed phenotypes using CT. In this study, it is postulated that a patient’s physique may be associated with the relative contribution of these lesions to airflow obstruction. Methods: CT was used to evaluate emphysema and airway dimensions in 201 patients with COPD. Emphysema was evaluated using percentage of LAA voxels (LAA%) and airway lesion was estimated by percentage wall area (WA%). Patients were divided into four phenotypes using LAA% and WA%. Results: Body mass index (BMI) was significantly lower in the higher LAA% phenotype (ie, emphysema dominant and mixed phenotypes). BMI correlated with LAA% (ρ = −0.557, p<0.0001) but not with WA%. BMI was significantly lower in the emphysema dominant phenotype than in the airway dominant phenotype, while there was no difference in forced expiratory volume in 1 s %predicted between the two. Conclusion: A low BMI is associated with the presence of emphysema, but not with airway wall thickening, in male smokers who have COPD. These results support the concept of different COPD phenotypes and suggest that there may be different systemic manifestations of these phenotypes.

Impact of Exacerbations on Emphysema Progression in Chronic Obstructive Pulmonary Disease

RATIONALE Low-attenuation areas assessed by computed tomography reflect the extent of pathological emphysema and correlate with airflow limitation and mortality in patients with chronic obstructive pulmonary disease. The cumulative size distribution of low-attenuation area clusters follows a power law characterized by an exponent, D. The values of D reflect the complexity of the terminal airspace geometry and sensitively detect alveolar structural changes. Exacerbations of chronic obstructive pulmonary disease have a negative impact on lung function and prognosis. However, the impact on emphysema progression remains unclear. OBJECTIVES We investigated the relationship between exacerbation and emphysema progression assessed by computed tomography in patients with chronic obstructive pulmonary disease. METHODS Exacerbations were prospectively recorded for 2 years. Annual changes in computed tomography parameters of emphysema were compared between patients with and without a history of exacerbations. MEASUREMENTS AND MAIN RESULTS In patients with exacerbations, increases in the percentage of low-attenuation areas and decreases in D were greater than in patients without exacerbations. To interpret these results, we established a novel simulation model and found that not only enlargement of preexisting low-attenuation areas but also coalescence of adjoining low-attenuation areas due to alveolar wall destruction caused emphysema progression in patients with exacerbations. CONCLUSIONS This is the first longitudinal study to demonstrate that exacerbations are involved in emphysema progression in patients with chronic obstructive pulmonary disease. Emphysema progression should be evaluated as part of the outcomes of exacerbations in the management of chronic obstructive pulmonary disease.

Relationship of airway wall thickening to an imbalance between matrix metalloproteinase-9 and its inhibitor in asthma

Background: The balance between matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) may be critical in extracellular matrix remodelling, a characteristic of asthmatic airways. An excess of TIMP-1 over MMP-9 has been associated with chronic airflow obstruction but the mechanisms underlying this association remain unknown. Recent computed tomographic (CT) studies indicate that airway wall thickening is associated with chronic airflow obstruction. Methods: Sputum levels of MMP-9, TIMP-1, and their molar ratio were examined in 26 patients with stable asthma and their relationship with pulmonary function and airway wall thickness, assessed by a validated CT technique which measured wall area corrected by body surface area (WA/BSA), the ratio of WA to outer wall area (WA%), and the absolute wall thickness corrected by √BSA of a segmental bronchus (T/√BSA), was examined. Results: Sputum MMP-9 levels were inversely correlated with WA% and TIMP-1 levels were positively correlated with WA/BSA and T/√BSA. The MMP-9/TIMP-1 molar ratio was inversely correlated with WA% and T/√BSA and positively correlated with post-bronchodilator values of mid-forced expiratory flow and maximum expiratory flow at the quartile of lung volume. Conclusion: Excess TIMP-1 may have a pathogenetic role in airway wall thickening in asthmatic patients which may result in chronic airflow obstruction.

Optimized scanning conditions of high resolution CT in the follow-up of pulmonary emphysema

PURPOSE To address the optimal scanning condition of high resolution computerized tomography from the perspective of minimizing exposed dose. METHOD The influence of the electric current, the slice number, and the slice thickness on precise percent ratio of the low attenuation area to whole lung field (LAA%) of chronic obstructive pulmonary disease patients was examined. The standard conditions were 250 mA, 3 slices, 2 mm slice thickness, and a varied parameter. RESULTS In cases showing an LAA% less than 30, LAA% obtained by < or =150 mA were significantly larger than those by 250 mA. The mean LAA% with 3 and 10 slices were well correlated and the correlation with lung function was similar. The correlation of LAA% with lung function was approximately the same between the 2 and 5 mm slice thicknesses. CONCLUSION The electrical current must be > or =200 mA, and 3 slices and 2 mm slice thickness are appropriate.

Abnormal Swallowing Reflex and COPD Exacerbations

BACKGROUND It is unclear whether an abnormal swallowing reflex affects COPD exacerbations. This study investigated the prevalence of abnormal swallowing reflexes and its relationship with COPD exacerbation prospectively. We also clarified its association with gastroesophageal reflux disease (GERD) and airway bacterial colonization. METHODS Swallowing reflex and serum C-reactive protein (CRP) levels were examined in subjects with stable COPD and in control subjects. Concurrently, GERD symptoms were assessed using a self-reported questionnaire, and sputum bacterial cultures were investigated in the same subjects. Exacerbations were counted prospectively during the following 12 months. RESULTS The study group comprised 67 subjects with COPD and 19 controls. The prevalence of abnormal swallowing reflex was significantly higher in subjects with COPD (22/67) than controls (1/19; P = .02). Among subjects with COPD, the serum CRP level, GERD symptoms, isolation of sputum bacteria, and the frequency of exacerbations were significantly increased in those with abnormal swallowing reflexes compared with controls (2.72 vs 1.04 mg/L, P = .04, for serum CRP level; 6.75 vs 4.10 points, P = .04, for GERD symptoms; 5/11 vs 3/22, P = .04, for the isolation of sputum bacteria; and 2.82 vs 1.56/y, P = .007, for the annual frequency of exacerbations). Multivariable analysis confirmed that abnormal swallowing reflex was significantly associated with frequent exacerbations (>or= 3/y; P = 0.01). CONCLUSIONS Abnormal swallowing reflexes frequently occurred in subjects with COPD and predisposed them to exacerbations. Abnormal swallowing reflexes in COPD might be affected by the comorbidity of GERD, and cause bacterial colonization.

Generation of Alveolar Epithelial Spheroids via Isolated Progenitor Cells from Human Pluripotent Stem Cells

Summary No methods for isolating induced alveolar epithelial progenitor cells (AEPCs) from human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) have been reported. Based on a study of the stepwise induction of alveolar epithelial cells (AECs), we identified carboxypeptidase M (CPM) as a surface marker of NKX2-1+ “ventralized” anterior foregut endoderm cells (VAFECs) in vitro and in fetal human and murine lungs. Using SFTPC-GFP reporter hPSCs and a 3D coculture system with fetal human lung fibroblasts, we showed that CPM+ cells isolated from VAFECs differentiate into AECs, demonstrating that CPM is a marker of AEPCs. Moreover, 3D coculture differentiation of CPM+ cells formed spheroids with lamellar-body-like structures and an increased expression of surfactant proteins compared with 2D differentiation. Methods to induce and isolate AEPCs using CPM and consequently generate alveolar epithelial spheroids would aid human pulmonary disease modeling and regenerative medicine.