Exacerbation rates in Japanese patients with obstructive lung disease: A subanalysis of the prospective, observational NOVELTY study.

BACKGROUND: Although clinical trials including asthma and COPD patients have revealed much about exacerbation frequencies, most studies are limited in that they recruited patients only with a clear diagnosis of one disease or the other, based on conventional diagnostic criteria, which may exclude many real-world patients with mixed symptoms. METHODS: NOVELTY is a global prospective observational study of patients with asthma and/or COPD from real-world practice. In this subanalysis, we compared patient characteristics of obstructive pulmonary diseases between the Japanese population (n = 820) and the overall population excluding Japanese patients (n = 10,406). RESULTS: The Japanese population had fewer exacerbations than the overall population across most of the physician-assessed disease severities and all diagnoses. The difference in exacerbation frequencies was more prominent in patients with COPD and asthma + COPD. The Japanese population was older, had higher former smoking rates, lower BMI, fewer respiratory symptoms, and better health-related quality of life compared with the overall population across all diagnoses. CONCLUSIONS: We clarified differences in patient characteristics among patients with asthma and/or COPD in Japan compared with non-Japanese patients. Importantly, we found that Japanese patients with asthma and/or COPD had significantly fewer exacerbations compared with patients overall. The results from our study may contribute to the development of precision medicine and guidelines specific to Japan.

Examination of Prognostic Factors in Anti-Melanoma Differentiation-Associated Gene 5 Antibody-Positive Dermatomyositis.

OBJECTIVE: This study investigated the prognostic factors of anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis (MDA5-DM). METHODS: This study analysed 34 MDA5-DM cases (20 and 14 in the survival and death groups, respectively) encountered at Kurume University between 2008 and 2021. The clinical, physiological, and computed tomography findings, pulmonary function, and serological results were retrospectively evaluated for each MDA5-DM case during the first visit and throughout the next 12 weeks. RESULTS: In the death group, the mean age of patients was higher (47.6 vs. 61.8 years), while the duration from symptom onset to consultation was shorter (110 vs. 34.9 days). During the first visit, the death group demonstrated a significantly higher serum C-reactive protein (CRP) level (0.52 vs. 1.99) and a significantly lower albumin level (3.23 vs. 2.63) than the survival group; this persisted throughout the next 12 weeks. Poor prognosis was associated with CRP and albumin levels above 0.19 mg/dL and below 2.3 g/dL, respectively, 4 weeks after starting treatment. CONCLUSION: Four weeks after beginning treatment, serum CRP and albumin levels of patients with MDA5-DM can be used to evaluate treatment response and predict prognosis.

The efficacy and safety of additional treatment with short-acting muscarinic antagonist combined with long-acting beta-2 agonist in stable patients with chronic obstructive pulmonary disease: A systematic review and meta-analysis.

BACKGROUND: The rationale for additional treatment with short-acting bronchodilators combined with long-acting bronchodilators for patients with chronic obstructive pulmonary disease (COPD) is not adequately studied. METHODS: We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of a short-acting muscarinic antagonist (SAMA) therapy combined with a long-acting beta-2 agonist (LABA) in patients with stable COPD. Pulmonary function, dyspnea, health-related quality of life, exercise tolerance, physical activity, exacerbations of COPD, and adverse events during regular use were set as outcomes of interest. RESULTS: We included five controlled trials including two sets of publicly available online data without article publications for the meta-analysis. Additional use of SAMA plus LABA showed a significant improvement in the peak response in FEV1 (mean difference (MD) 98.70 mL, p < .00001), transitional dyspnea index score (MD .85, p = .02), and St George's Respiratory Questionnaire score (MD -2.00, p = .008) compared to LABA treatment. There was no significant difference in the risk of exacerbation of COPD (p = .20) and only a slight trend of increased severe adverse events (OR: 2.16, p = .08) and cardiovascular events (OR: 2.38, p = .06). CONCLUSION: Additional treatment with SAMA combined with LABA could be a feasible choice due to its efficacy and safety.

A Cluster of Paragonimiasis with Delayed Diagnosis Due to Difficulty Distinguishing Symptoms from Post-COVID-19 Respiratory Symptoms: A Report of Five Cases.

Paragonimiasis caused by trematodes belonging to the genus Paragonimus is often accompanied by chronic respiratory symptoms such as cough, the accumulation of sputum, hemoptysis, and chest pain. Prolonged symptoms, including respiratory symptoms, after coronavirus disease 2019 infection (COVID-19) are collectively called post-COVID-19 conditions. Paragonimiasis and COVID-19 may cause similar respiratory symptoms. We encountered five cases of paragonimiasis in patients in Japan for whom diagnoses were delayed due to the initial characterization of the respiratory symptoms as a post-COVID-19 condition. The patients had consumed homemade drunken freshwater crabs together. One to three weeks after consuming the crabs, four of the five patients were diagnosed with probable COVID-19. The major symptoms reported included cough, dyspnea, and chest pain. The major imaging findings were pleural effusion, pneumothorax, and nodular lesions of the lung. All the patients were diagnosed with paragonimiasis based on a serum antibody test and peripheral blood eosinophilia (560-15,610 cells/µL) and were treated successfully with 75 mg/kg/day praziquantel for 3 days. Before diagnosing a post-COVID-19 condition, it is necessary to consider whether other diseases, including paragonimiasis, may explain the symptoms. Further, chest radiographic or blood tests should be performed in patients with persistent respiratory symptoms after being infected with COVID-19 to avoid overlooking the possibility of infection.

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.

Triple versus LAMA/LABA combination therapy for patients with COPD: a systematic review and meta-analysis.

BACKGROUND: Recently, the addition of inhaled corticosteroid (ICS) to long-acting muscarinic antagonist (LAMA) and long-acting beta-agonist (LABA) combination therapy has been recommended for patients with COPD who have severe symptoms and a history of exacerbations because it reduces the exacerbations. In addition, a reducing effect on mortality has been shown by this treatment. However, the evidence is mainly based on one large randomized controlled trial IMPACT study, and it remains unclear whether the ICS add-on treatment is beneficial or not. Recently, a large new ETHOS trial has been performed to clarify the ICS add-on effects. Therefore, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety including ETHOS trial. METHODS: We searched relevant randomized control trials (RCTs) and analyzed the exacerbations, quality of life (QOL), dyspnea symptom, lung function and adverse events including pneumonia and mortality, as the outcomes of interest. RESULTS: We identified a total of 6 RCTs in ICS add-on protocol (N = 13,579). ICS/LAMA/LABA treatment (triple therapy) significantly decreased the incidence of exacerbations (rate ratio 0.73, 95% CI 0.64-0.83) and improved the QOL score and trough FEV1 compared to LAMA/LABA. In addition, triple therapy significantly improved the dyspnea score (mean difference 0.33, 95% CI 0.18-0.48) and mortality (odds ratio 0.66, 95% CI 0.50-0.87). However, triple therapy showed a significantly higher incidence of pneumonia (odds ratio 1.52, 95% CI 1.16-2.00). In the ICS-withdrawal protocol including 2 RCTs, triple therapy also showed a significantly better QOL score and higher trough FEV1 than LAMA/LABA. Concerning the trough FEV1, QOL score and dyspnea score in both protocols, the differences were less than the minimal clinically important difference. CONCLUSION: Triple therapy causes a higher incidence of pneumonia but is a more preferable treatment than LAMA/LABA due to the lower incidence of exacerbations, higher trough FEV1 and better QOL score. In addition, triple therapy is also superior to LABA/LAMA due to the lower mortality and better dyspnea score. However, these results should be only applied to patients with symptomatic moderate to severe COPD and a history of exacerbations. CLINICAL TRIAL REGISTRATION: PROSPERO; CRD42020191978.

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.

Using fractional exhaled nitric oxide to guide step-down treatment decisions in patients with asthma: a systematic review and individual patient data meta-analysis.

BACKGROUND: High exhaled nitric oxide fraction (F ENO) levels are associated with greater risk of asthma exacerbation. However, it is not clear how F ENO can be used to guide safe reductions in inhaled corticosteroid (ICS) doses in asthma patients. This study assesses the ability of F ENO to guide ICS reductions. METHODS: Systematic searching of electronic databases identified prospective observational studies and randomised controlled trials which recruited participants with mild-to-moderate asthma aged ≥12 years and measured F ENO before reducing ICS. We performed multilevel mixed-effects logistic regression in relation to acute exacerbations and estimated each participant's exacerbation risk using our logistic regression model. RESULTS: We included data from seven out of eight eligible studies, representing 384 participants. ICS doses were halved in four studies and withdrawn in three studies. A baseline F ENO measurement of ≥50 ppb was associated with increased risk of exacerbations (crude OR 3.14, 95% CI 1.41-7.00, p=0.005; adjusted OR 3.08, 95% CI 1.36-6.98, p=0.007) and corresponded to an estimated exacerbation risk cut-off of 15%. Reducing ICS when estimated exacerbation risk was <15% versus <10% would result in fewer patients remaining on the same ICS dose (40 (10.4%) out of 384 versus 141 (36.7%) out of 384), but similar proportions of patients avoiding exacerbations (222 (91.4%) out of 243, 95% CI 87.1-94.6% versus 311 (90.4%) out of 344, 95% CI 86.8-93.3%). CONCLUSION: In patients with mild-to-moderate asthma, gradual ICS reduction when F ENO is <50 ppb may help decrease ICS use without increasing exacerbations. Future research should aim to validate these findings in larger populations.

Treatment with LABA versus LAMA for stable COPD: a systematic review and meta-analysis.

BACKGROUND: Inhaled bronchodilators including long-acting beta-agonist (LABA) and long-acting muscarinic antagonist (LAMA) play a central role in the treatment of stable chronic obstructive pulmonary disease (COPD). However, it is still unclear whether LABA or LAMA should be used for the initial treatment. Therefore, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of LABA versus LAMA in patients with stable COPD. METHODS: We searched relevant randomized control trials (RCTs) with a period of treatment of at least 12 weeks and analyzed the exacerbations, quality of life, dyspnea score, lung function and adverse events as the outcomes of interest. RESULTS: We carefully excluded unblinded data and identified a total of 19 RCTs (N = 28,211). LAMA significantly decreased the exacerbations compared to LABA (OR 0.85, 95% CI 0.74 to 0.98; P = 0.02). In St George's Respiratory Questionnaire and transitional dyspnoea index score, there were no differences between LABA and LAMA treatment. Compared to LABA, there was a small but significant increase in the trough FEV1 after LAMA treatment (Mean difference 0.02, 95% CI 0.01 to 0.03, P = 0.0006). In the safety components, there was no difference in the serious adverse events between LABA and LAMA. However, LAMA showed a significantly lower incidence of total adverse events compared to LABA (OR 0.92, 95% CI 0.86 to 0.98; P = 0.02). CONCLUSION: Treatment with LAMA in stable COPD provided a significantly lower incidence of exacerbation and non-serious adverse events, and a higher trough FEV1 compared to LABA. TRIAL REGISTRATION: (PROSPERO: CRD42019144764).

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.

Adherence barriers to inhaled medicines in Japanese older patients with asthma evaluated using the "Adherence Starts with Knowledge 20" (ASK-20) questionnaire.

OBJECTIVE: We investigated adherence barriers to inhaled medicines among older compared to younger adults with asthma in Japan. METHODS: Adherence barriers to inhaled medicines were evaluated in 251 Japanese older (n = 138) and younger (n = 113) adults with asthma using the self-reporting "Adherence Starts with Knowledge 20" (ASK-20) questionnaire. RESULTS: There were fewer older adults with poor adherence to inhaled medicines than younger adults. The ASK-20 questionnaire revealed (odds ratio [95% confidence interval]) item Q11 ("My doctor/nurse and I work together to make decisions"; 2.94 [1.31, 6.61]; p < 0.05) as an independent adherence barrier to inhaled medicines among older adults, whereas younger adults reported item Q3 ("My use of alcohol gets in the way of taking my medicines"; 3.91 [1.02 to 15.1]; p < 0.05) and item Q16 ("Taken a medicine more or less often than prescribed? "; 2.31 [1.32 to 4.06]; p < 0.05) as barriers. Older adults with poor adherence identified item Q1 ("I just forget to take my inhaled medicines some of the time"; 4.43 [1.77, 11.1]; p < 0.05) as a barrier, although the total ASK-20 scores and total barrier counts were significantly higher in older (both, p < 0.05) and younger (both, p < 0.05) adults with poor adherence than in those with good adherence. CONCLUSION: Older Japanese patients had better adherence to inhaled medicines than younger patients. Barriers were different between older and younger adults. These results will help personalize education for inhaled medicines in Japanese asthmatics.

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.

Natural regulatory T cells in isolated early responders compared with dual responders with allergic asthma.

BACKGROUND: Natural regulatory T (Treg) cells are implicated in the regulation of the inflammatory response in patients with allergic asthma. OBJECTIVES: We sought to determine changes in Treg cell numbers in the airways and peripheral blood of isolated early responder (IER) versus dual responder (DR) subjects with mild allergic asthma before and after allergen challenge. METHODS: Induced sputum was collected from 22 subjects with allergic asthma (10 IERs and 12 DRs) and peripheral blood collected from 8 DRs with allergic asthma at 0, 7, and 24 hours after allergen challenge. Treg cells were identified by using fluorescently labeled antibodies to CD4 and forkhead box protein 3 and enumerated by using flow cytometry. RESULTS: There was a significant increase in the percentage of sputum CD4(+) cells 24 hours after allergen challenge in both IERs and DRs. The percentage of sputum Treg cells significantly decreased 24 hours after challenge in DRs but not IERs. This change was significantly correlated with the magnitude of the late asthmatic response. There was also a significant increase in the absolute number of sputum CD4(+) cells and Treg cells at 24 hours in DRs only. The ratio of the number of Treg cells to CD4(+) cells at 24 hours was significantly smaller in DRs compared with that in IERs. None of the above changes were observed in peripheral blood. CONCLUSIONS: DRs exhibit a diminished percentage of airway Treg cells after allergen challenge that is not observed in IERs and a significantly lower ratio of Treg cells to CD4(+) cells, which might contribute to the development of the late asthmatic response.

The progression of comorbidity in IL-18 transgenic chronic obstructive pulmonary disease mice model.

Patients with severe COPD are known to have comorbidities such as emaciation, cor pulmonale and right heart failure, muscle weakness, hyperlipemia, diabetes mellitus, osteoporosis, muscle atrophy, arterial sclerosis, hypertension, and depression. Therefore, treatment for COPD needs to focus on these comorbidities as well as the lungs. We previously reported a new mouse model of COPD utilizing the human surfactant protein C promoter SP-C to drive the expression of mature mouse IL-18 cDNA; constitutive IL-18 overproduction in the lungs of transgenic (Tg) mice induces severe emphysematous change, dilatation of the right ventricle, and mild pulmonary hypertension with aging. In the present study, we evaluated the progression of comorbidity in our COPD model. In female Tg mice, significant weight loss was observed at 16 weeks and beyond, when compared with control wild-type (WT) mice. This weight loss was suppressed in IL-13-deficient (knockout; KO) Tg mice. Muscle weight and bone mineral density were significantly decreased in aged Tg mice relative to control WT and IL-13 KO Tg mice. The aged Tg mice also showed impaired glucose tolerance. IL-18 and IL-13 may play important roles in the pathogenesis of comorbidity in COPD patients.

Interleukin-18 expression, CD8(+) T cells, and eosinophils in lungs of nonsmokers with fatal asthma.

BACKGROUND: The process of airway inflammation in the lungs of nonsmokers who die of asthma (fatal asthma) has not been reported in detail. OBJECTIVE: To examine nonsmokers who had died of asthma to exclude chronic obstructive pulmonary disease and investigate pulmonary inflammatory cells and the expression of interleukin-18 (IL-18) and its receptor in lung tissues compared with those in patients with well-controlled mild asthma and nonsmokers. METHODS: Lung tissues were obtained at autopsy examination from 12 nonsmokers with fatal asthma, excluding cases of chronic obstructive pulmonary disease, and from 5 nonsmokers with well-controlled mild asthma and 10 nonsmokers who had undergone surgical resection for lung cancer. Pulmonary inflammatory cells were examined and the expression of the proinflammatory cytokine IL-18 and its receptor in the lungs was evaluated. RESULTS: The numbers of eosinophils and lymphocytes, but not basophils or macrophages, were significantly increased in the lungs of patients with fatal asthma compared with the other 2 groups. The lung neutrophil count did not differ significantly between the fatal and mild asthma groups but was significantly higher in the fatal asthma group than in nonsmokers. CD8(+) T cells, but not CD4(+) T cells, were significantly increased in the lungs of the fatal asthma group compared with the other 2 groups. IL-18 protein and IL-18 receptor were strongly expressed in the lungs in the fatal asthma group. CONCLUSION: Caspase-1 inhibitors, anti-IL-18 antibodies, anti-IL-18 receptor antibodies, IL-18 binding protein, or inhibitors of genes downstream of the IL-18 signal transduction pathway may be of clinical benefit for the treatment of patients with severe asthma.

A Case in which Eosinophilic Meningoencephalitis Occurred during Oral Corticosteroid Tapering and after Switching from Anti-IL-5 to Anti-IgE Treatment.

A 49-year-old man with severe eosinophilic asthma, sinusitis, and esophagitis was admitted with a sudden severe headache. The patient was diagnosed with eosinophilic meningoencephalitis based on frontotemporal abnormalities on brain magnetic resonance imaging and high eosinophil counts in the cerebrospinal fluid. His allergic-disease control levels were poor, requiring regular oral corticosteroid (OCS) use. He was switched from anti-interleukin (IL)-5 to anti-IgE therapy because of worsening urticaria and asthma symptoms during OCS tapering. We suspect this was a case of complex eosinophilic meningoencephalitis caused by the combination of OCS tapering and anti-IL-5 therapy cessation that acquired anti-IgE antibody sensitization based on positive drug-induced lymphocyte stimulation test results.

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.

Positive association between the plasma levels of 5-hydroxyindoleacetic acid and the severity of depression in patients with chronic obstructive pulmonary disease.

BACKGROUND: The role of plasma monoamines in patients with chronic obstructive pulmonary disease (COPD) with depression is unclear. To investigate monoamines in 20 depressed patients with COPD, the plasma concentrations of serotonin, 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid, and 3-methoxy-4-hydroxyphenylglycol (MHPG) were measured and compared with those in 50 non-depressed COPD patients, and also with 23 age- and gender-matched non-smokers and 13 smokers as non-depressed healthy controls. METHODS: Diagnosis of depression was assessed using the Centre for Epidemiologic Studies Depression Scale. Plasma concentrations of monoamines were measured by high-performance liquid chromatography. RESULTS: None of the depressed COPD patients had suicidal ideation. The plasma 5-HIAA level [median, (25% and 75% quartiles)] in depressed COPD patients [6.8 ng/mL, (4.9 and 13.1)] was significantly higher than in non-depressed COPD patients [5.4, (4.2 and 7.5)] (p=0.022) and non-smokers [5.1 (3.8 and 7.2)] (p=0.041), but not smokers [4.7, (4.0 and 6.7)] (p>0.05). The plasma 5-HIAA level (r=0.24, p=0.049) was significantly associated with the severity of depression in patients with COPD. The plasma MHPG level was significantly higher in depressed COPD patients (p=0.043) than in smokers, but was not higher than that in non-depressed COPD patients or non-smokers, although the level of MHPG was not associated with the severity of depression. CONCLUSION: The plasma 5-HIAA level is increased in depressed COPD patients. Plasma monoamines may be a good biomarker for detection of depression in patients with COPD.

Decreased CTLA4(+) and Foxp3(+) CD25(high)CD4(+) cells in induced sputum from patients with mild atopic asthma.

BACKGROUND: Details of the comparisons between airway and peripheral blood regulatory T cells (Tregs) in patients with atopic asthma are still unclear. The objective of this study is to investigate the profiles of both airway and circulating Tregs in atopic asthma. METHODS: We measured the numbers of Tregs and eosinophils in induced sputum and peripheral blood in 28 patients with mild atopic asthma and compared these with numbers in 18 healthy controls. The frequency (%) of Tregs (surface CTLA4+, intracellular Foxp3+, and CTLA4+Foxp3+ on CD25highCD4+ T cells) in sputum and blood was determined by intracellular 5-color flow cytometry. We also correlated the numbers with the level of airway hyperresponsiveness (AHR) in asthmatics. RESULTS: The mean frequencies of cells expressing CTLA4+ (19.4 ± 2.1%, p = 0.075), Foxp3+ (16.4 ± 3.3%, p = 0.001), and CTLA4+Foxp3+ (7.0 ± 1.1%, p = 0.008) in induced sputum from asthmatics were significantly lower than controls (27.2 ± 3.7%, 37.4 ± 4.7%, and 18.2 ± 3.6%, respectively), whereas in peripheral blood, there was no inter-group difference in the frequencies of cells expressing CTLA4+ (7.1 ± 1.5% vs 5.7 ± 1.7%, p > 0.05), Foxp3+ (35.7 ± 3.2% vs 21.1 ± 3.9%, p > 0.05), and CTLA4+Foxp3+ (6.6 ± 1.5% vs 4.2 ± 1.0%, p > 0.05). Moreover, the frequency of CD25highCD4+ cells expressing CTLA4+, but not Foxp3+, in induced sputum was associated with AHR (r = 0.60, p = 0.009) and airway eosinophilic inflammation (r = -0.60, p = 0.008) in asthmatics. CONCLUSIONS: Airway, but not circulating, Tregs are decreased in mild atopic asthmatics, and are negatively correlated to an increase of airway eosinophilic inflammation and AHR.