Kaoruko Shimizu

Annual change in pulmonary function and clinical phenotype in chronic obstructive pulmonary disease.

RATIONALE Although the rate of annual decline in FEV1 is one of the most important outcome measures in chronic obstructive pulmonary disease (COPD), little is known about intersubject variability based on clinical phenotypes. OBJECTIVES To examine the intersubject variability in a 5-year observational cohort study, particularly focusing on emphysema severity. METHODS A total of 279 eligible patients with COPD (stages I-IV: 26, 45, 24, and 5%) participated. We conducted a detailed assessment of pulmonary function and computed tomography (CT) at baseline, and performed spirometry every 6 months before and after inhalation of bronchodilator. Smoking status, exacerbation, and pharmacotherapy were carefully monitored. Emphysema severity was evaluated by CT and annual measurements of carbon monoxide transfer coefficient. MEASUREMENTS AND MAIN RESULTS Using mixed effects model analysis, the annual decline in post-bronchodilator FEV1 was -32±24 (SD) ml/yr (n=261). We classified the subjects of less than the 25th percentile as Rapid decliners, the 25th to 75th percentile as Slow decliners, and greater than the 75th percentile as Sustainers (-63±2, -31±1, and -2±1 [SE] ml/yr). Emphysema severity, but not %FEV1, showed significant differences among the three groups. Multiple logistic regression analysis demonstrated that the Rapid decliners were independently associated with emphysema severity assessed either by CT or carbon monoxide transfer coefficient. The Sustainers displayed less emphysema and higher levels of circulating eosinophils. CONCLUSIONS Emphysema severity is independently associated with a rapid annual decline in FEV1 in COPD. Sustainers and Rapid decliners warrant specific attention in clinical practice.

Comparison of airway remodelling assessed by computed tomography in asthma and COPD

BACKGROUND Few studies have directly compared airway remodelling assessed by computed tomography (CT) between asthma and chronic obstructive pulmonary disease (COPD). The present study was conducted to determine whether there are any differences between the two diseases with similar levels of airflow limitation under clinically stable conditions. METHODS Subjects included older male asthmatic patients (n = 19) showing FEV(1)/FVC <70% with smoking history less than 5-pack/year. Age- and sex-matched COPD patients (n = 28) who demonstrated similar airflow limitation as asthmatic patients and age-matched healthy non-smokers (n = 13) were recruited. Using proprietary software, eight airways were selected in the right lung, and wall area percent (WA%) and airway luminal area (Ai) were measured at the mid-portion of the 3rd to 6th generation of each airway. For comparison, the average of eight measurements per generation was recorded. RESULTS FEV(1)% predicted and FEV(1)/FVC was similar between asthma and COPD (82.3 ± 3.3% vs. 77.6 ± 1.8% and 57.7 ± 1.6% vs. 57.9 ± 1.4%). At any generation, WA% was larger and Ai was smaller in asthma, both followed by COPD and then controls. Significant differences were observed between asthma and controls in WA% of the 3rd to 5th generation and Ai of any generation, while no differences were seen between COPD and controls. There were significant differences in Ai of any generation between asthma and COPD. CONCLUSIONS Airway remodelling assessed by CT is more prominent in asthma compared with age- and sex-matched COPD subjects in the 3rd- to 6th generation airways when airflow limitations were similar under stable clinical conditions.

Genetic variants in the mannose receptor gene ( MRC1 ) are associated with asthma in two independent populations

Mannose receptor is a member of the C-type lectin receptor family involved in pathogen molecular pattern recognition and thought to be critical in shaping host immune responses and maintaining homeostasis. The aim of this study was to investigate potential associations of genetic variants in the MRC1 gene with asthma in two independent populations. Seven single-nucleotide polymorphisms (SNPs; rs2477637, rs2253120, rs2477631, rs2477664, rs692527, rs1926736, and rs691005) in the MRC1 gene locus were genotyped and evaluated regarding association with asthma in 870 unrelated Japanese subjects (446 asthmatics, 424 controls). The same markers were validated in 176 unrelated African–American subjects (86 asthmatics, 90 controls). Suggestive evidence of association between five SNPs (rs2477637, rs2253120, rs2477664, rs692527, and rs1926736) and asthma was observed in the analysis of the Japanese population independent of sex, age, smoking status, and atopic status. SNPs rs692527 and rs691005 showed significant association with asthma in the African–American population. Haplotypes containing two linked SNPs (rs692527 and rs1926736) were significantly associated with asthma in both Japanese and African–American populations. Our results suggest that sequence variations in the MRC1 gene are associated with the development of asthma in two independent and ethnically diverse populations.

Genetic variants in mannose receptor gene (MRC1) confer susceptibility to increased risk of sarcoidosis.

BackgroundMannose receptor (MR) is a member of the C-type lectin receptor family involved in pathogen molecular-pattern recognition and thought to be critical in shaping host immune response. The aim of this study was to investigate potential associations of genetic variants in the MRC1 gene with sarcoidosis.MethodsNine single nucleotide polymorphisms (SNPs), encompassing the MRC1 gene, were genotyped in a total of 605 Japanese consisting of 181 sarcoidosis patients and 424 healthy controls.ResultsSuggestive evidence of association between rs691005 SNP and risk of sarcoidosis was observed independent of sex and age in a recessive model (P = 0.001).ConclusionsThese results suggest that MRC1 is an important candidate gene for sarcoidosis. This is the first study to imply that genetic variants in MRC1, a major member of the C-type lectin, contribute to the development of sarcoidosis.

The CC16 A38G polymorphism is associated with asymptomatic airway hyper-responsiveness and development of late-onset asthma.

BACKGROUND Clara cell secretory protein (CC16) is expressed primarily in the respiratory tract and is a potent anti-inflammatory agent that protects the airway from inflammation. The associations of the A38G polymorphism in this gene with asymptomatic airway hyper-responsiveness (AHR), which is considered a risk factor for future asthma in adults, and the development of adult-onset asthma are unclear. OBJECTIVE To evaluate the association of the CC16 A38G polymorphism with asymptomatic AHR in healthy young adults and the development of adult-onset asthma and the association between plasma CC16 level according to this genotype and asymptomatic AHR. METHODS Nonspecific AHR was measured in 154 asymptomatic, young, healthy adults using a continuous methacholine inhalation method. The cumulative dose values of inhaled methacholine measured at the inflection point at which respiratory conductance started to decrease (Dmin) were used as an index of AHR. Case-control analysis was performed for the association between this polymorphism and the development of asthma in 1,086 unrelated Japanese subjects (504 subjects with asthma and 582 healthy subjects). RESULTS The 38AA + AG genotype was associated with lower Dmin values and lower plasma CC16 levels (P = .012 and .020). There was a significant positive correlation between Dmin values and plasma CC16 levels (P = .012). In the case-control study, the 38AA + AG genotype was significantly associated with late-onset asthma (onset at >40 years; odds ratio, 1.63; P = .016). CONCLUSION These results suggest that the CC16 A38G polymorphism may play a role in asymptomatic AHR and contribute to the development of late-onset asthma.

Lower Leptin/Adiponectin Ratio and Risk of Rapid Lung Function Decline in Chronic Obstructive Pulmonary Disease

RATIONALE The rate of annual change in FEV1 is highly variable among patients with chronic obstructive pulmonary disease (COPD). Reliable blood biomarkers are needed to predict prognosis. OBJECTIVES To explore plasma biomarkers associated with an annual change in FEV1 in patients with COPD. METHODS Plasma samples of 261 subjects, all Japanese, with COPD from the 5-year Hokkaido COPD cohort study were analyzed as a hypothesis-generating cohort, and the results were validated using data of 226 subjects with and 268 subjects without airflow limitation, mainly white, from the 4-year COPD Quantification by Computed Tomography, Biomarkers, and Quality of Life (CBQ) study conducted in Denmark. The plasma samples were measured using Human CardiovascularMAP (Myriad RBM, Austin, TX), which could analyze 50 biomarkers potentially linked with inflammatory, metabolic, and tissue remodeling pathways, and single ELISAs were used to confirm the results. MEASUREMENTS AND MAIN RESULTS Higher plasma adiponectin levels and a lower leptin/adiponectin ratio at enrollment were significantly associated with an annual decline in FEV1 even after controlling for age, sex, height, and body mass index in the Hokkaido COPD cohort study (P = 0.003, P = 0.004, respectively). A lower plasma leptin/adiponectin ratio was also significantly associated with an annual decline in FEV1 in subjects with airflow limitation in the CBQ study (P = 0.014), the patients of which had largely different clinical characteristics compared with the Hokkaido COPD cohort study. There were no significant associations between lung function decline and adipokine levels in subjects without airflow limitation. CONCLUSIONS A lower leptin/adiponectin ratio was associated with lung function decline in patients with COPD in two independent Japanese and Western cohort studies of populations of different ethnicity. Measure of systemic adipokines may provide utility in predicting patients with COPD at higher risk of lung function decline.

Dehydroxymethylepoxyquinomicin (DHMEQ), a novel NF‐kappaB inhibitor, inhibits allergic inflammation and airway remodelling in murine models of asthma

Dehydroxymethylepoxyquinomicin (DHMEQ) is a newly developed compound that inhibits nuclear factor κB activation and is reported to ameliorate animal models of various inflammatory diseases without significant adverse effects. Because nuclear factor κB is a transcription factor that plays a critical role in the pathophysiology of asthma, DHMEQ may be of therapeutic benefit in asthma.

Sinus Computed Tomographic Findings in Adult Smokers and Nonsmokers with Asthma. Analysis of Clinical Indices and Biomarkers

Rationale: When they occur together, sinusitis and asthma are often thought to represent anatomically separate components of the same chronic inflammatory airway disease. Information about the effect of smoking on the interaction between sinusitis and asthma in patients who have both disorders is limited. Objectives: To evaluate the effect of cigarette smoking on the relationship between the presence and severity of sinusitis and selected asthma‐related indices in adults who have asthma. Methods: This study included 127 patients with severe asthma and 79 patients with mild to moderate asthma. Clinical data were obtained from all subjects during a 2‐day stay at Hokkaido University Hospital (Sapporo, Japan). The Lund‐Mackay scoring system was used to assess the anatomic extent and severity of sinusitis as revealed by sinus computed tomographic (CT) images obtained during hospitalization. We examined associations between Lund‐Mackay scores and a variety of asthma‐related indices and levels of biomarkers in blood and sputum. To clarify the effect of smoking on these associations, we conducted separate analyses for nonsmoking (<10 pack‐years; n = 130) and smoking subjects (≥10 pack‐years; n = 76). Measurements and Main Results: In our cohort of adults with asthma, we found significant positive relationships between the presence and severity of sinusitis as assessed by Lund‐Mackay score and the severity of asthma as measured by percent predicted FEV1 or FEV1/FVC for nonsmoking subjects (<10 pack‐years) but not for cigarette smokers (>10 pack‐years). Lund‐Mackay scores correlated with blood and sputum eosinophil counts, serum IgE levels, and fractional exhaled nitric oxide, regardless of smoking status. Lund‐Mackay scores also showed significant positive associations with serum periostin and chemokine C‐C motif ligand 18 levels, regardless of smoking status, whereas a positive association with plasma osteopontin level was seen only for nonsmoking subjects. Conclusions: We found an association between the severity of sinusitis on CT imaging and the severity of concomitant asthma on spirometry for nonsmoking adults but not for smokers. In adults with asthma, CT imaging evidence of severe sinusitis indicates intense Th2‐related inflammation, regardless of smoking status.

Distinct Phenotypes of Cigarette Smokers Identified by Cluster Analysis of Patients with Severe Asthma

RATIONALE Smoking may have multifactorial effects on asthma phenotypes, particularly in severe asthma. Cluster analysis has been applied to explore novel phenotypes, which are not based on any a priori hypotheses. OBJECTIVES To explore novel severe asthma phenotypes by cluster analysis when including cigarette smokers. METHODS We recruited a total of 127 subjects with severe asthma, including 59 current or ex-smokers, from our university hospital and its 29 affiliated hospitals/pulmonary clinics. Twelve clinical variables obtained during a 2-day hospital stay were used for cluster analysis. After clustering using clinical variables, the sputum levels of 14 molecules were measured to biologically characterize the clinical clusters. MEASUREMENTS AND MAIN RESULTS Five clinical clusters were identified, including two characterized by high pack-year exposure to cigarette smoking and low FEV1/FVC. There were marked differences between the two clusters of cigarette smokers. One had high levels of circulating eosinophils, high IgE levels, and a high sinus disease score. The other was characterized by low levels of the same parameters. Sputum analysis revealed increased levels of IL-5 in the former cluster and increased levels of IL-6 and osteopontin in the latter. The other three clusters were similar to those previously reported: young onset/atopic, nonsmoker/less eosinophilic, and female/obese. Key clinical variables were confirmed to be stable and consistent 1 year later. CONCLUSIONS This study reveals two distinct phenotypes of severe asthma in current and former cigarette smokers with potentially different biological pathways contributing to fixed airflow limitation. Clinical trial registered with www.umin.ac.jp (000003254).

Anaplastic transformation of papillary thyroid carcinoma in multiple lung metastases presenting with a malignant pleural effusion: a case report

IntroductionAnaplastic transformation of well-differentiated papillary thyroid carcinoma at distant metastasis sites is rare. To the best of our knowledge, this is the first report of an autopsy case of anaplastic transformation of papillary thyroid carcinoma in multiple lung metastases presenting with a malignant pleural effusion.Case presentationWe report an autopsy case of a 61-year-old Japanese man with anaplastic transformation of papillary thyroid carcinoma with multiple lung metastases presenting with a malignant pleural effusion, which was difficult to diagnose by cytological examination before the autopsy. He presented with a 1-month history of progressive dyspnea, and examination of the left pleural effusion revealed a bloody exudate with an increase in thyroglobulin; however, malignant cells in the pleural fluid were negative for thyroglobulin.ConclusionIt is important to be aware that anaplastic transformation of differentiated thyroid carcinoma could develop in lung metastases and could be a cause of a malignant pleural effusion.