Masashi Mikamo

Colored 3-Dimensional Analyses of Respiratory Resistance and Reactance in COPD and Asthma

Background: The forced oscillation technique (FOT) is a noninvasive method with which to measure respiratory system resistance (Rrs) and reactance (Xrs) at a wide range of frequencies during breathing at rest in a short time. The purpose of this study was to assess the differences in Rrs and Xrs between patients with chronic obstructive pulmonary disease (COPD) and asthma using a new method of FOT with colored 3-dimensional visualization. Methods: Fifty-one patients with stable COPD and 49 patients with controlled or partly controlled asthma were enrolled. Whole-breath or within-breath changes of Rrs and Xrs were measured and compared between the diseases. Results: The colored 3-dimensional images clarified the complex oscillatory properties of the respiratory system. Whole-breath resistance (the difference in Rrs at 5 and 20 Hz) and reactance (Xrs at 5 Hz and resonant frequency), and within-breath changes in reactance (Xrs at 5 Hz and resonant frequency) discriminated between patients with COPD and asthma. In multivariate regression analyses, inspiratory-expiratory differences in Xrs at 5 Hz contributed significantly to the differentiation between COPD and asthma, independent of age, gender, body weight, and pulmonary function. Conclusion: This new method of FOT is useful in the differential diagnosis of COPD and asthma.

Respiratory mechanics measured by forced oscillation technique in combined pulmonary fibrosis and emphysema.

The coexistence of emphysema and pulmonary fibrosis is known as combined pulmonary fibrosis and emphysema (CPFE). The aim of this study was to compare the lung mechanics measured by multi-frequency forced oscillation technique (FOT) among patients with CPFE, interstitial pneumonia (IP), and chronic obstructive pulmonary disease (COPD). FOT and pulmonary function tests were performed in 41 patients with CPFE, 47 with IP, and 86 with COPD. Whole-breath resistance at 20 Hz was significantly lower in patients with CPFE than in those with IP or COPD, irrespective of the severity of airflow limitation. Within-breath analyses of resistance revealed no difference among the 3 groups; however, the difference between inspiratory and expiratory phases of reactance at 5 Hz, which reflects expiratory flow limitation, in patients with CPFE was significantly higher than in those with IP and lower than in those with COPD. In conclusion, both emphysema and fibrosis affect lung mechanics in CPFE, leading to different findings from IP or COPD alone.

Treatment of acute exacerbation of idiopathic pulmonary fibrosis with direct hemoperfusion using a polymyxin B-immobilized fiber column improves survival.

BackgroundAcute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) has an extremely poor prognosis and there is currently no effective treatment for this condition. Direct hemoperfusion with a polymyxin B-immobilized fiber column (PMX-DHP) improves oxygenation, but it is unclear whether treatment of AE-IPF with PMX-DHP affects survival. This study elucidated the effectiveness and safety of PMX-DHP for the treatment of AE-IPF.MethodsThis study included 31 patients with 41 episodes of AE-IPF. All patients received steroids. Of 31, 14 patients (20 episodes) were treated with PMX-DHP. The laboratory and physiological test results after the start of therapy and survival were retrospectively compared between patients treated with and without PMX-DHP.ResultsPatients treated with PMX-DHP had a significantly greater change in PaO2/FiO2 ratio (mean ± SEM, 58.2 ± 22.5 vs. 0.7 ± 13.3, p = 0.034) and a smaller change in white blood cell count (−630 ± 959 /μL vs. 4500 ± 1190 /μL, p = 0.002) after 2 days of treatment than patients treated without PMX-DHP. The 12-month survival rate was significantly higher in patients treated with PMX-DHP (48.2% vs. 5.9%, p = 0.041). PMX-DHP was effective in patients with more severe underlying disease (GAP stages II or III; 12-month survival rate 57.1% with PMX-DHP vs. 0% without PMX-DHP, p = 0.021). Treatment with PMX-DHP was an independent predictor of better prognosis (hazard ratio 0.345, p = 0.037). Mild pulmonary thromboembolism occurred in one patient treated with PMX-DHP.ConclusionsTreatment of AE-IPF with PMX-DHP is tolerable and improves 12-month survival.

Predictors of phase III slope of nitrogen single-breath washout in COPD

The nitrogen (N₂) single-breath washout (SBW) test is a measure of ventilation distribution inhomogeneity and also a small airway function that offers complementary information to spirometry; however, the relevance to the forced oscillation technique (FOT) and pulmonary emphysema in COPD is not fully understood. We hypothesized that pulmonary functions, forced oscillatory parameters, and emphysema extent would contribute independently to the results of the SBW test. In this cross-sectional study we assessed the relationship between the phase III slope (delta N₂) derived from N₂ SBW and these parameters. Spirometry, lung volumes, N₂ SBW, and the broadband frequency FOT were performed in 56 patients with COPD. Emphysema extent was measured by high-resolution computed tomography and scored. In multiple regression analyses, the delta N₂ was independently predicted by forced vital capacity, resonant frequency, and emphysema score (R(2)=0.57, p<0.0001). The degree of ventilation inhomogeneity derived from N₂ SBW is independently predicted by spirometry, lung mechanics, and the degree of emphysema.

Usefulness of Colored 3D Imaging of Respiratory Impedance in Asthma

Purpose Recently, the clinical application of the forced oscillation technique (FOT) has progressed with the spread of commercially available FOT devices, including the impulse oscillation system and MostGraph. We investigated the usefulness of color 3D imaging of respiratory impedance in asthma using MostGraph. Methods Whole-breath and within-breath respiratory system resistance (Rrs) and reactance (Xrs) were measured in 78 patients with asthma. Color 3D images were classified into three patterns: the chronic obstructive pulmonary disease (COPD)-like pattern (high values of Rrs and Xrs with a marked respiratory cycle and frequency dependence), the asthma pattern (moderately high Rrs over the entire frequency and a respiratory cycle with slight Xrs changes), and a normal-like pattern (low Rrs and Xrs with few within-breath changes). The classification was performed by three researchers, who were unaware of the clinical information, and the clinical characteristics were compared among the three groups. Results Color 3D imaging provided a COPD-like pattern in 25 patients, an asthma pattern in 39 patients, and a normal-like pattern in 14 patients. Patients with the COPD-like pattern were predominantly female with a higher body mass index, lower forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC), and higher Rrs and Xrs values (whole-breath and within-breath variation). Those with the normal pattern had higher FEV1 and FVC, and a lower single-breath nitrogen washout slope. There were no differences in asthma control or exhaled nitric oxide levels among the three groups. Conclusions These results suggest that color 3D imaging of respiratory impedance may show asthma phenotypes.

Inspiratory resonant frequency of forced oscillation technique as a predictor of the composite physiologic index in interstitial lung disease

The composite physiologic index (CPI), which is derived from FEV1, FVC, and diffusing capacity, has been developed to predict the extent of fibrosis on high-resolution computed tomography (HRCT). However, the relevance to the forced oscillation technique (FOT) is not fully understood. We hypothesized that FOT would independently predict the CPI in interstitial lung disease (ILD). In this cross-sectional study we assessed the relationship between pulmonary function tests, forced oscillatory parameters, and the degree of fibrosis in ILD. Spirometry, evaluation of diffusing capacity for carbon monoxide, and the broadband frequency FOT were performed in 93 patients with a clinical/HRCT diagnosis of ILD. The CPI was calculated and fibrosis extent was measured by HRCT and scored. Univariate analyses revealed that, of the forced oscillatory parameters, inspiratory resonant frequency best correlated with FVC, FEV1, diffusing capacity, CPI, and fibrosis score. In multiple regression analyses, CPI was independently predicted by inspiratory resonant frequency and fibrosis score (model R(2)=0.405, p<0.0001).

Real-world effect of gastroesophageal reflux disease on cough-related quality of life and disease status in asthma and COPD

BACKGROUND Gastroesophageal reflux disease (GERD) is one of the most common causes of chronic cough and often coexists with asthma or chronic obstructive pulmonary disease (COPD); however, it is unknown whether there are differences in the effect of GERD on these diseases. The purpose of this study was to assess the difference in the effect of GERD on cough-related quality of life and disease status in asthma and COPD in a real-world setting. METHODS Subjects were 132 patients with overall controlled asthma and 102 patients with stable COPD. They completed the frequency scale for symptoms of GERD (FSSG), a validated Japanese questionnaire for GERD, the Leicester Cough Questionnaire (LCQ), and the Asthma Control Test (ACT) or COPD assessment test (CAT) questionnaires. RESULTS We found that 29 (22.0%) patients with asthma and 22 (21.6%) patients with COPD had GERD. There was no difference in the FSSG scale between the diseases. The patients with GERD, regardless of having asthma or COPD, had lower LCQ scores affecting all health domains and lower ACT or higher CAT scores than those without GERD. Overall, the patients with COPD had lower LCQ scores regardless of the presence or absence of GERD. The FSSG scale was negatively correlated with the LCQ total score in asthma and in COPD. In contrast, the FSSG scale was positively correlated with the CAT score but not with the ACT score. CONCLUSIONS Patients with GERD had impaired cough-related quality of life, poor asthma control or more symptoms and impacts of COPD.

Allergic bronchopulmonary aspergillosis presenting with a pulmonary mass mimicking lung cancer

A 48‐year‐old man with a history of asthma visited our hospital for the investigation of a high density mass at the right hilum. Laboratory data revealed elevated serum carcinoembryonic antigen. A bronchoscopy was performed to rule out lung cancer; however, mucoid impaction was found without malignant or bacterial cells. On the basis of peripheral blood eosinophilia, elevated total serum IgE, and immediate cutaneous reactivity to Aspergillus fumigatus, he was diagnosed with allergic bronchopulmonary aspergillosis. The radiographic findings and serum carcinoembryonic antigen levels improved with corticosteroids. Pulmonary masses are uncommon findings and serum carcinoembryonic antigen may be a useful marker of the disorder.

Impaired cough-related quality of life in patients with controlled asthma with gastroesophageal reflux disease

b Gastroesophageal refluxdisease (GERD) often coexistswith asthma with or without suggestive symptoms. The current asthma guidelines recommend medical management for GERD in patients with symptoms of reflux and poorly controlled asthma, particularly those who have nocturnal symptoms. GERD is a cause of chronic cough not only in the general population but also in patients with asthma despite control of other symptoms on inhaled corticosteroids; however, the latter has not been fully elucidated. In a crosssectional study,we assessed the effect of symptomatic GERDon the cough-related quality of life in patients with controlled asthma. One hundred seventeen patients with controlled asthma who attendedoutpatient clinics at ShizuokaGeneralHospital for routine checkups between December 2009 and September 2010 were enrolled in this study. All patients satisfied the definition of asthma, were receiving inhaled corticosteroids or other medications for asthma for at least 3months, andwere assessed as having totally or well-controlled asthma during the previous 4weeks on the basis of the Asthma Control Test, a validated asthma control questionnaire. Patients were excluded from the study if they (1) had any acute viral infections within at least 1 month before the study; (2) were current smokers; (3) had a smoking history of more than 10 pack-years; (3) had chronic obstructive pulmonary disease; (4) were diagnosed with cough variant asthma; or (5) were receiving proton pump inhibitors. GERD was diagnosed by the Frequency Scale for Symptoms of GERD (FSSG), a validated questionnaire in the Japanese population. The FSSG consists of 12 items, each of which is quantified on a scale ranging from 0 to 4 points, and the cutoff score for GERD is set at 8 points. Cough-related quality of life was assessed by the Leicester Cough Questionnaire (LCQ), which comprises 19 items and 3 domains: physical, psychological, and social. Each item is scored between 1 and 7, with a higher score indicating a better quality of life. The total score ranges from3 to 21. The Japanese version was made by Dr. Niimi A (Kyoto University) and Dr. Ogawa H (Ishikawa-ken Saiseikai Kanazawa Hospital). Statistical analysis was performed by theMann-Whitney U test, the 2 or Fisher’s exact test, and the Spearman rank correlation coefficient. A P value of .05 was considered significant. We found that 22 of 117 (18.8%) patients had GERD, which was diagnosed not by esophagogastroduodenoscopy or pH probe monitoring, but by the FSSG questionnaire. The comparison of characteristics between patients with and without GERD is shown in Table 1. Patientswith GERDhad an impaired quality of life affecting all health domains compared with those without GERD. No signif-

Inhibiting Skp2 E3 Ligase Suppresses Bleomycin-Induced Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor prognosis and no curative therapies. SCF-Skp2 E3 ligase is a target for cancer therapy, but there have been no reports about Skp2 as a target for IPF. Here we demonstrate that Skp2 is a promising therapeutic target for IPF. We examined whether disrupting Skp2 suppressed pulmonary fibrosis in a bleomycin (BLM)-induced mouse model and found that pulmonary fibrosis was significantly suppressed in Skp2-deficient mice compared with controls. The pulmonary accumulation of fibrotic markers such as collagen type 1 and fibronectin in BLM-infused mice was decreased in Skp2-deficient mice. Moreover, the number of bronchoalveolar lavage fluid cells accompanied with pulmonary fibrosis was significantly diminished. Levels of the Skp2 target p27 were significantly decreased by BLM-administration in wild-type mice, but recovered in Skp2−/− mice. In vimentin-positive mesenchymal fibroblasts, the decrease of p27-positive cells and increase of Ki67-positive cells by BLM-administration was suppressed by Skp2-deficency. As these results suggested that inhibiting Skp2 might be effective for BLM-induced pulmonary fibrosis, we next performed a treatment experiment using the Skp2 inhibitor SZL-P1-41. As expected, BLM-induced pulmonary fibrosis was significantly inhibited by SZL-P1-41. Moreover, p27 levels were increased by the SZL-P1-41 treatment, suggesting p27 may be an important Skp2 target for BLM-induced pulmonary fibrosis. Our study suggests that Skp2 is a potential molecular target for human pulmonary fibrosis including IPF.