Altered Functional Connectivity during Mild Transient Respiratory Impairment Induced by a Resistive Load.

Background: Previous neuroimaging studies have identified brain regions related to respiratory motor control and perception. However, little is known about the resting-state functional connectivity (FC) associated with respiratory impairment. We aimed to determine the FC involved in mild respiratory impairment without altering transcutaneous oxygen saturation. Methods: We obtained resting-state functional magnetic resonance imaging data from 36 healthy volunteers during normal respiration and mild respiratory impairment induced by resistive load (effort breathing). ROI-to-ROI and seed-to-voxel analyses were performed using Statistical Parametric Mapping 12 and the CONN toolbox. Results: Compared to normal respiration, effort breathing activated FCs within and between the sensory perceptual area (postcentral gyrus, anterior insular cortex (AInsula), and anterior cingulate cortex) and visual cortex (the visual occipital, occipital pole (OP), and occipital fusiform gyrus). Graph theoretical analysis showed strong centrality in the visual cortex. A significant positive correlation was observed between the dyspnoea score (modified Borg scale) and FC between the left AInsula and right OP. Conclusions: These results suggested that the FCs within the respiratory sensory area via the network hub may be neural mechanisms underlying effort breathing and modified Borg scale scores. These findings may provide new insights into the visual networks that contribute to mild respiratory impairments.

Usefulness of a 4-Grade Novel Mouthpiece Device for Increased Mouth Pressure Reproducing Artificial Difficulty in Breathing.

OBJECTIVE: The use of a novel 4-grade mouthpiece device to reproduce difficulty in breathing was assessed in healthy individuals. METHODS: A double-blind, randomized, crossover-controlled trial was conducted to investigate the efficacy and safety of the device with increasing mouth pressure. The modified Borg (mBorg) scale values, respiratory system resistance at 5 Hz (R5), and forced expiratory volume in one second (FEV1) were assessed while using the device. MATERIALS: The four grades of breathing difficulty device were tested in 32 healthy participants. RESULTS: The 4-grade device linearly worsened the mBorg scale with increasing mouth pressure. The mean R5 (± standard deviation [SD]) with grade I, II, III, and IV devices were 5.6 ± 0.1, 10.3 ± 0.3, 21.5 ± 0.7, and 54.8 ± 2.0 kPa/L/s, respectively. The mean %FEV1 predicted (± SD) were 83.6 ± 15.9% with grade I, 55.3 ± 11.8% with grade II, 32.0 ± 6.1% with grade III, and 15.3 ± 3.2% with the grade IV device. The mBorg scale was positively correlated with R5 (r = 0.79, p < 0.0001) and negatively with %FEV1 predicted (r = -0.81, p < 0.0001). No severe adverse events were reported during the trial. CONCLUSION: We demonstrated that the novel device could effectively reproduce the semi-quantitative artificial difficulty in breathing safely and easily in healthy individuals. These devices could be helpful to understand the mechanisms of difficulty in breathing.

Poor Asthma Control in Schoolchildren May Lead to Lower Lung Function Trajectory from Childhood to Early Adulthood: A Japanese Cohort Study.

Purpose: Although childhood asthma is a risk factor for adult lung function disorders, the correlation between childhood asthma control level and lung function growth remains unclear in Japan. The correlation between childhood asthma control and early adulthood lung function growth was investigated in this study. Patients and Methods: We included 505 children with asthma from the Omuta City Air Pollution-Related Health Damage Cohort Program. The characteristics and lung function of girls and boys aged 6-11 years and 12-17 years were compared between poor and good asthma control groups. Results: Among the 505 children, 214 (42.4%) showed poor asthma control. The mean percentage forced expiratory volume in 1 second predicted for girls and boys aged 6-11 years (80.2% and 79.2%, respectively) and 12-17 years (80.0% and 81.1%, respectively) in the poor control group was significantly lower than those of girls and boys aged 6-11 years (87.9% and 87.3%, respectively) and 12-17 years (88.1% and 87.8%, respectively) in the good control group. However, a linear regression model did not reveal between-group differences in the slopes of lung function growth for both sexes. Girls (24.6%, P < 0.0001) and boys (24.4%, P = 0.0026) in the poor control group had a significantly higher proportion of young adults with obstructive ventilatory patterns than girls (1.4%) and boys (8.1%) in the good control group. Conclusion: Our findings revealed that poor childhood asthma control leaded to lung function disorders, which suggest the importance of early asthma control in school children.

Airway hyperresponsiveness and inflammation in Japanese patients with human immunodeficiency virus 1 infection.

INTRODUCTION: Despite the growing population of long-term survivors with human immunodeficiency virus 1 (HIV) exhibiting asthma-like features worldwide, the pathogenesis underlying airway hyperresponsiveness (AHR) and airway inflammation remains unclear. We aimed to investigate AHR and airway inflammation in an HIV-infected Japanese population. METHODS: Of 94 Japanese participants, 10 HIV-infected participants with asthma were excluded from the study. We compared the characteristics of HIV-infected (n = 34) and non-HIV-infected participants (n = 50). Eosinophilic, neutrophilic, mixed (eosinophilic and neutrophilic), and paucigranulocytic airway inflammatory phenotypes were classified based on induced sputum characteristics. RESULTS: The prevalence of AHR in HIV-infected participants (32.4%) was significantly higher than that in their non-HIV-infected counterparts (10.0%) (P = 0.0213). The multivariate nominal logistic regression analysis revealed HIV as an independent risk factor for AHR. HIV-infected participants were significantly more likely to have a neutrophilic airway inflammatory phenotype than non-HIV-infected participants (P = 0.0358). Furthermore, HIV-infected participants with AHR demonstrated a significant correlation between AHR levels and the percentage of sputum neutrophils (r = -0.65, P = 0.0316). The percentage of sputum neutrophils was negatively associated with the blood CD4 cell count (r = -0.66, P = 0.0266). CONCLUSIONS: We observed the high prevalence of AHR and neutrophilic airway inflammatory phenotype in Japanese participants with stable HIV infection. Our findings provide insight into the mechanisms of AHR and may facilitate the development of novel treatment for individuals with AHR and HIV infection.

Overweight improves long-term survival in Japanese patients with asthma.

BACKGROUND: Obesity is a risk factor for severe and difficult-to-treat asthma. However, the impact of different physiques on long-term outcomes is poorly understood. We aimed to investigate the correlation between obesity and asthma-associated long-term mortality in Japanese adults. METHODS: From the data on 3146 individuals with air pollution-related respiratory diseases in the Omuta City Air Pollution-Related Health Damage Cohort Program, 697 adult patients with asthma were analyzed. Hazard ratios for long-term all-cause and respiratory disease -related mortality were compared in patients with different physiques using the Cox proportional hazard models. The classification of physiques was based on the WHO obesity criteria. RESULTS: Of the 697 patients, 439 died during the median observation period of 26.3 years. The number (% of total) of underweight, normal-weight, pre-obese, and obese class I-III individuals were 75 (10.8%), 459 (65.9%), 140 (20.1%), and 23 (3.3%), respectively. The Cox proportional hazard model (adjusted hazard ratio [95% confidence interval], P value) showed that pre-obese group had a significantly reduced risk for all-cause (0.65 [0.51 to 0.83], P < 0.05) and respiratory disease (0.55 [0.37 to 0.81], P < 0.05)-related mortality related to normal-weight group. CONCLUSIONS: Our cohort program demonstrated that being slightly overweight may reduce the risk of long-term mortality in patients with asthma. However, the influence of obesity on long-term outcomes remains unclear in asthma, because of the small number of obese patients included in our study. Our findings suggest that interventions, including nutrition and exercises, should be provided to Japanese patients with asthma.

Impact of airflow obstruction on long-term mortality in patients with asthma in Japan.

BACKGROUND: The long-term prognosis of asthma with airflow obstruction is poorly understood in Japan. The aim of this retrospective 26-year study was to investigate the long-term mortality risk of airflow obstruction in asthmatics. METHODS: Using data from the Omuta City Air Pollution-related Health Damage Cohort Program, mortality risk ratios of airflow obstruction in Japanese Individuals were analyzed by Cox proportional hazards models. Airflow obstruction was considered to be present when the forced expiratory volume in 1 sec (FEV1)/forced vital capacity ratio was <0.7 and FEV1 predicted was <80% based on spirometry. RESULTS: Among the 3146 victims with chronic respiratory diseases, 697 with adult asthma were selected. Median follow-up period was 26.3 (range 0.9-40.9) years. The airflow obstruction group (n = 193) showed significantly higher rates of mortality related to respiratory problems (risk ratio [95% confidence interval] 1.51 [1.86-1.93], P = 0.0017) and asthma attacks (1.86 [1.30-2.66], P = 0.0011) than the without airflow obstruction group (n = 504). Airflow obstruction was an independent risk factor for both respiratory-related (1.84 [1.36-2.49], P = 0.0001) and all-cause (1.44 [1.17-1.76], P = 0.0008) mortality after adjustment for age, sex, body mass index, and smoking status. More severe airflow obstruction was significantly associated with poorer prognosis. CONCLUSIONS: This long-term cohort program revealed the impacts of asthma with airflow obstruction as an independent mortality risk. Findings suggest that intervention and prevention of airflow obstruction can reduce long-term mortality in patients with asthma.

The significance of CD163-expressing macrophages in asthma.

BACKGROUND: CD163 is one of the scavenger receptors that are specifically expressed on macrophages and are well known to be upregulated by various inflammatory responses, including chronic obstructive pulmonary disease in airway diseases. OBJECTIVE: To evaluate the CD163 expression in the lungs of patients with fatal asthma and investigated whether CD163 contributes to the pathogenesis in asthma. METHODS: The CD163 expressions in the lungs of patients with fatal asthma (n = 9) and in those of nonasthma control subjects (n = 8) were tested by immunohistochemistry. In mouse models of asthma, airway hyperresponsiveness (AHR) and the numbers of airway inflammatory cells in the bronchoalveolar lavage fluid (BALF) were analyzed in the CD163-deficient mice and the control wild-type mice. RESULTS: The numbers of CD163-positive macrophages in the lung tissues were significantly increased in the all 6 patients with fatal asthma than in the control subjects. In mouse models of asthma, AHR and the numbers of infiltrating leukocytes, such as eosinophils, lymphocytes, neutrophils, and macrophages, in the BALF were significantly decreased in the CD163-deficient mice when compared with control wild-type mice. The concentrations of interferon γ and interleukin 5 in the BALF were significantly decreased in the CD163-deficient mice when compared with those in the control wild-type mice. CONCLUSION: CD163 may play important roles in airway inflammation and AHR in asthma.

Attenuated Airway Eosinophilic Inflammations in IL-38 Knockout Mouse Model.

BACKGROUND: The role of IL-38, a new member of the IL-1 family, in airway eosinophilic inflammatory conditions such as asthma is unclear. To investigate the role of IL-38 in airway eosinophilic inflammation, an IL-38-gene deficient (KO) murine asthma model was analyzed. METHODS: The numbers of eosinophils and neutrophils, and levels of IL-5, IL-13 and IL-17A protein and mRNA in bronchoalveolar lavage fluid (BALF) and lung tissue were compared between wild-type (WT) and IL-38-KO mice after OVA sensitization and challenge. The effects of additional purified recombinant mouse (rm) IL-38 protein were investigated in the IL-38-KO murine asthma model. RESULTS: The IL-38 and IL-5 mRNA in WT mice was significantly higher after OVA challenge than after saline challenge (p<0.05). The number of airway eosinophils in IL-38-KO mice was significantly lower than in WT mice after OVA challenge (p<0.01). BALF analysis confirmed the lower number of airway eosinophils in IL-38-KO mice and showed that this was significantly associated with lower IL-5 protein levels (r=0.92, p<0.0001). However, the additional rm IL-38 protein did not neutralize airway eosinophilia in IL-38-KO mice. CONCLUSION: IL-38 may enhance airway eosinophilic inflammation in asthma through IL-5 induction.

"Frequent exacerbator" is a phenotype of poor prognosis in Japanese patients with chronic obstructive pulmonary disease.

BACKGROUND: The prognosis of Japanese patients with COPD who suffer repeated exacerbations is unclear, although Westerners with such episodes have a poor prognosis. MATERIALS AND METHODS: We conducted a 1-year prospective observational trial involving 90 Japanese patients with COPD: 58 nonexacerbators, 12 infrequent exacerbators, and 20 frequent exacerbators classified on the basis of exacerbation frequency (zero, one, and two or more exacerbations/year), respectively, during the previous year were observed prospectively for 1 year. The characteristics of frequent exacerbators, the frequency of exacerbation, and the period until the first event were then compared among the groups. RESULTS: A total of 78 patients completed the study. Frequent exacerbators had a significantly higher risk of frequent exacerbation in the following year than the case for nonexacerbators (odds ratio [95% confidence interval] 2.94 [1.21-7.17], P=0.0340), but not in comparison with infrequent exacerbators (1.51 [0.49-4.63], P>0.05). The mean annual frequency of exacerbations in the following year was significantly (P=0.0020) higher in the frequent exacerbators (1.4 exacerbations/year) than in the nonexacerbators (0.4), but not in the infrequent exacerbators (0.9, P>0.05). The mean period until the first exacerbation was significantly shorter in the frequent exacerbators than in the infrequent or nonexacerbators (P=0.0012). Independent risk factors for future frequent exacerbation included the presence of gastroesophageal reflux disease, more severe airflow obstruction, and use of inhaled corticosteroids. CONCLUSION: Our present results indicate that Japanese COPD patients suffering frequent exacerbation have a poor prognosis. The characteristics of Japanese and Western COPD patients suffering frequent exacerbation are similar.