Characteristics of eosinophilic and non-eosinophilic asthma during treatment with inhaled corticosteroids.

OBJECTIVE: Eosinophilic inflammation in the respiratory tract is a hallmark of bronchial asthma. In naïve cases, the inflammatory profile is associated with disease severity and reactivity to inhaled corticosteroids (ICS). Sustained airway eosinophilia has been reported during ICS treatment. However, the immunological characteristics of these cases are not known and it is unclear if this situation contributes to asthma control. This study was performed to determine the answer of these questions. METHODS: To compare phenotypes of eosinophilic and non-eosinophilic asthma (EA and NEA, respectively) under ICS treatment, clinical data were obtained from asthmatic subjects (n = 22) and healthy controls (n = 10), and the leukocyte compositions of induced sputum and peripheral blood were determined. T lymphocyte profiles in systemic blood were assessed by flow cytometry. RESULTS: A higher frequency of emergency room visits was observed in the NEA group, which had a higher neutrophil count relative to the total inflammatory cell population in induced sputum than the EA group (59.5 versus 36.6%; p < 0.01). The fraction of helper T (Th)17 lymphocytes as well as the ratio of Th17 to regulatory T cells (Treg) in the peripheral blood was higher in the NEA than in the EA group (0.24 versus 0.13; p < 0.05). CONCLUSIONS: Th17 were more prevalent than Treg cells in the peripheral blood of NEA patients under ICS treatment, corresponding to neutrophil-dominant airway inflammation and a severe asthmatic phenotype. Thus, an imbalance in Th17/Treg may be associated with the pathogenesis of NEA in patients undergoing ICS treatment.

Cluster analysis identifies characteristic phenotypes of asthma with accelerated lung function decline.

OBJECTIVE: While the majority of individuals with asthma retain normal lung function over time, some exhibit accelerated lung function decline. Preservation of lung function is an important aspect of asthma management. Whether the asthma guidelines can prevent lung function decline remains controversial. This study was performed to determine the distribution of asthmatic subjects with greater lung function decline and to identify characteristic clinical features of such subjects treated in accordance with clinical guidelines by using hierarchical cluster analysis. METHODS: Eighty-six asthmatic subjects without a history of smoking were assessed with respect to eight variables selected from clinical phenotypes by using step-wise multiple regression analysis. Hierarchical cluster analysis using Ward's method generated a dendrogram for estimation of the number of clusters within the population and the differences between them. RESULTS: Three distinct clusters were identified. Cluster 1 (n = 40) comprised women with late-onset asthma. Cluster 2 (n = 17) comprised subjects with early-onset asthma, atopy and long disease duration. Cluster 3 (n = 29) predominantly comprised older men who had late-onset asthma, a lower prevalence of exacerbation and a lower predicted % forced expiratory volume in 1 s (FEV1) at baseline. Subjects in cluster 3 showed a mean decline in FEV1 of 69 mL/year, which was the greatest lung function decline among the three clusters. CONCLUSION: We identified a subgroup of patients with accelerated lung function decline despite appropriate asthma treatment based on guidelines constructed by using subjective symptoms.

Autopsy of Drug-induced Lung Injury with Atypical Diffuse Alveolar Disorder due to Amiodarone: A Case Report.

Amiodarone, a prominent antiarrhythmic drug, may cause lung injury. We herein report the case of an 87-year-old man who had been taking amiodarone for 5 years and was subsequently referred due to respiratory failure. Chest computed tomography revealed multiple consolidations with air bronchograms in both lungs. Despite administering steroid pulse therapy, his respiratory failure worsened, and he died 3 days later. Autopsy revealed hyaline membrane formation and organic formation with fibrin deposition. Drug-induced lung injury caused by amiodarone was confirmed by autopsy. Caution is therefore required when fibrin deposition in the alveolar spaces is observed in such cases, which are prone to suffer a rapid deterioration.

Refractory Eosinophilic Granulomatosis with Polyangiitis Complicated with IgG4-related Disease Showing Different Treatment Responses for Each Organ.

We herein report a 75-year-old woman who presented with dyspnea and purpura. She was diagnosed with eosinophilic granulomatosis with polyangiitis (EGPA) based on axonal damage observed in the left tibial nerve and skin and lung pathologies. Lung pathology showed IgG4-positive plasma cells, considered a complication of IgG4-related disease (IgG4-RD). Computed tomography revealed thickening of the abdominal aorta and a poor contrast area in the left kidney, which was indicative of IgG4-RD. Steroid administration improved the IgG4-RD. However, the EGPA resisted treatment; therefore, immunosuppressive drugs and mepolizumab were administered. Refractory EGPA complicated with IgG4-RD showed different treatment responses for each organ.

A novel prostacyclin agonist protects against airway hyperresponsiveness and remodeling in mice.

Airway remodeling in bronchial asthma results from chronic, persistent airway inflammation. The effects of the reversal of airway remodeling by drug interventions remain to be elucidated. We investigated the effects of ONO-1301, a novel prostacyclin agonist with thromboxane inhibitory activity, on the prevention and reversibility of airway remodeling in an experimental chronic asthma model. Mice sensitized and challenged to ovalbumin (OVA) three times a week for 5 consecutive weeks were administered ONO-1301 or vehicle twice a day from the fourth week of OVA challenges. Twenty-four hours after the final OVA challenge, airway hyperresponsiveness (AHR) was assessed, and bronchoalveolar lavage was performed. Lung specimens were excised for staining to detect goblet-cell metaplasia, airway smooth muscle, and submucosal fibrosis. Mice administered ONO-1301 showed limited increases in AHR compared with mice administered the vehicle. The histological findings of airway remodeling were improved in ONO-1301-treated mice compared with vehicle-treated mice. Presumably, these therapeutic effects of ONO-1301 are attributable to the up-regulation of production of hepatocyte growth factor (HGF) in lung tissue, because the neutralization of HGF by antibodies prevented the effects of ONO-1301 on AHR and airway remodeling. Mice administered ONO-1301 showed similar levels of AHR and airway remodeling as mice administered montelukast, a cysteinyl-leukotriene-1 receptor antagonist, and lower levels were observed in mice administered dexamethasone. These data suggest that ONO-1301 exerts the effect of reversing airway remodeling, at least in part through an elevation of HGF in the lungs, and may be effective as an anti-remodeling drug in the treatment of asthma.

Influence of underweight on asthma control.

BACKGROUND: Although the association between asthma control and body mass index (BMI) has been thoroughly investigated, most of this work has focused on the influence on asthma incidence or the effect of obesity on asthma control. To date, there have been no published studies on the influence of underweight on asthma control. METHODS: The aim of this study was to investigate the influence of underweight, as defined by the Japan Society for the Study of Obesity (JASSO), on asthma control in Japanese asthmatic patients. Using data from questionnaire surveys administered by the Niigata Asthma Treatment Study Group, we compared asthma control, as measured by the Asthma Control Test (ACT), between a normal weight group (18.5kg/m2 =< BMI < 25kg/m2) and an underweight group (BMI < 18.5kg/m2). RESULTS: Of the asthmatic patients who completed the 2008 and 2010 surveys, 1464 and 1260 cases were classified as being in the normal weight group, and 174 and 155 cases were classified as being in the underweight group. The ACT score (median, [interquartile range]) in the underweight group in 2008 (22, [19-24]) and 2010 (23, [19-25]) was significantly lower than that in the normal group in 2008 (23, [20-25]) and in 2010 (24, [21-25]). CONCLUSIONS: This study is the first, large-scale investigation of the influence of underweight on asthma control, and we have confirmed an adverse influence in a clinical setting. A potential mechanism for this interaction was unknown. Further investigation will be required.

Drowning case complicated with a cardiopulmonary arrest and severe ARDS saved with a good neurological outcome by ECMO: A case report.

Cardiopulmonary arrest (CPA) due to drowning has an extremely high mortality rate, and very few cases have good neurological outcomes. Severe respiratory failure can occur even after resuscitation. A 66 year old woman with a history of refractory epilepsy had a CPA due to drowning. Approximately 20 min after drowning, she was resuscitated and transported to the hospital, and extracorporeal membrane oxygenation (ECMO) was introduced on day two due to continued severe respiratory failure caused by acute respiratory distress syndrome (ARDS). After the introduction of ECMO, her respiratory status gradually improved and ECMO was discontinued on day 12. Approximately 6 months after drowning, she visited our hospital for a follow-up with a cerebral performance category of 1. Since cases of CPA due to drowning with a short drowning time or hypothermia are expected to have good neurological outcomes, the introduction of ECMO should be considered as a treatment for ARDS after resuscitation.

Diffusion magnetic resonance tractography-based evaluation of commissural fiber abnormalities in a heparan sulfate endosulfatase-deficient mouse brain.

During brain development, neural circuits are formed through cellular differentiation, cell migration, axon guidance, and synaptogenic processes by the coordinated actions of many genes. Abnormalities in neural development, especially connectivity defects, can result in psychiatric disorders, such as schizophrenia and autism. Recent advances in diffusion tensor imaging have enabled us to examine the brain's macroscopic nerve trajectories. In this study, we investigated the abnormalities of the commissural fibers that connect the left and right cerebral hemispheres in mice lacking heparan sulfate 6-O endosulfatases, Sulf1 and Sulf2 (Sulf1/2), which are extracellular enzymes that remove 6-O sulfate from heparan sulfate and thereby modulate the function of axon guidance factors. We previously demonstrated that Sulf1/2 double knockout (DKO) mouse embryos harbored defects in their corticospinal tract and that some of these DKO mice experienced corpus callosum agenesis. However, abnormalities of the commissural fibers in the adult DKO brain have not been systematically assessed. In this study, we investigated commissural fiber abnormalities in these mice by the combined use of radiological and histological analyses. First, we acquired diffusion-weighted images and three-dimensional-T2 weighted images of adult brains using a 9.4 T animal magnetic resonance imaging system and found that Sulf1/2 DKO mice had a smaller corpus callosum and dorsal hippocampal commissure. Next, we performed myelin staining and anterograde tracing, revealing that the dorsal hippocampal commissure was elongated in a rostral direction. These results suggest that Sulf1/2 play an important role in the formation of commissural tracts and that diffusion tensor imaging associated with microscopic analysis is a powerful tool to clarify nerve tract abnormalities.

A single injection of a sustained-release prostacyclin analog (ONO-1301MS) suppresses airway inflammation and remodeling in a chronic house dust mite-induced asthma model.

ONO-1301, a novel prostacyclin agonist with thromboxane A2 synthase inhibitory activity, is a useful agent for ameliorating airway allergic inflammation; however, its short-action feature implies a requirement for the frequent administration of this drug. Therefore, we investigated the effects of ONO-1301-loaded poly (d,l-lactic-co-glycolic acid) microspheres (ONO-1301MS; to release ONO-1301 for 3 weeks) on the airway inflammation and remodeling in chronic house dust mite (HDM)-induced model. Balb/c mice were exposed to an HDM extract intranasally for 5 days/week for 5 consecutive weeks. The mice received a single subcutaneous injection of ONO-1301MS or vehicle after 3 weeks of HDM exposure, followed by 2 additional weeks of HDM exposure. Forty-eight hours after the last HDM exposure, airway hyperresponsiveness to methacholine was assessed and bronchoalveolar lavage was performed. Lung specimens were excised and stained to check for goblet cell metaplasia, airway smooth muscle hypertrophy, and submucosal fibrosis. Mice receiving ONO-1301MS showed significantly lower airway hyperresponsiveness, airway eosinophilia, and induced T helper 2 cytokine production compared with mice receiving the vehicle. Histological findings such as goblet cell metaplasia, airway smooth muscle hypertrophy, and submucosal fibrosis were decreased in ONO-1301MS-treated mice compared with vehicle-treated mice. A single administration of ONO-1301MS achieved sustained elevation of its circulating level for 3 weeks. These data suggest that a single administration of ONO-1301MS may suppress airway hyperresponsiveness, airway allergic inflammation, and development of airway remodeling in chronic HDM-induced asthma model. This agent may be effective as an anti-inflammatory and remodeling drug in the practical treatment of asthma.