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Background: Maintaining good asthma control minimizes the risk of exacerbations and lung function decline and is a primary goal of asthma management. The Japanese Pediatric Asthma Guidelines (JPGL) employs different classification criteria for control status from other guidelines, stressing a higher level of control. Based on JPGL, we previously developed a caregiver-completed questionnaire for assessing and achieving best asthma control in preschoolers. In this study, we aimed to develop a questionnaire for school-age children and adolescents., Methods: A working questionnaire comprising 14 items for patients and 34 items for caregivers was administered to 362 asthma patients aged 6-15 years and their caregivers. Separately, physicians filled out a questionnaire to determine JPGL-defined control. Logistic regression analysis was performed to construct a model to predict control levels using data from a randomly selected set of completed questionnaires from two-thirds of the subjects. Validation was performed using the remaining questionnaires., Results: A set of 7 questions, encompassing self-assessed control status at the time of the visit and in the past month, and nocturnal/early morning asthma symptoms for patients and frequency of asthma symptoms, dyspnea, rescue beta-agonist use, and asthma hospitalization for caregivers, were selected and the 7-item model showed a good statistical fit with AIC of 110.5. The model has been named the Best Asthma Control Test for School Children and Adolescents (Best ACT-S). Best ACT-S scores differed significantly in the hypothetical direction among the groups of different JPGL-defined control levels, step-up/down treatment decisions, and presence/non-presence of exacerbations in the previous year., Conclusions: The Best ACT-S is a valid questionnaire for children/adolescents aiming for best asthma control., (Copyright © 2023 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Background: Benralizumab is an anti-interleukin-5 receptor α monoclonal antibody approved as an add-on maintenance treatment for patients with uncontrolled severe asthma. Prior Phase 3 studies have evaluated benralizumab in patients aged ≥12 years with severe uncontrolled asthma. The TATE study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), and safety of benralizumab treatment in children., Methods: TATE was an open-label, Phase 3 study of benralizumab in children aged 6-11 years from the United States and Japan (plus participants aged 12-14 years from Japan) with severe eosinophilic asthma. Participants received benralizumab 10/30 mg according to weight (<35/≥35 kg). Primary endpoints included maximum serum concentration (C max ), clearance, half-life (t 1/2 ), and blood eosinophil count. Clearance and t 1/2 were derived from a population PK (popPK) analysis. Safety and tolerability were also assessed., Results: Twenty-eight children aged 6-11 years were included, with an additional two participants from Japan aged 12-14 years also included in the popPK analysis. Mean C max was 1901.2 and 3118.7 ng/mL in the 10 mg/<35 kg and 30 mg/≥35 kg groups, respectively. Clearance was 0.257, and mean t 1/2 was 14.5 days. Near-complete depletion of blood eosinophils was shown across dose/weight groups. Exploratory efficacy analyses found numerical improvements in mean FEV 1 , mean ACQ-IA, patient/clinician global impression of change, and exacerbation rates. Adverse events occurred in 22/28 (78.6%) of participants; none led to discontinuation/death., Conclusion: PK, PD, and safety data support long-term benralizumab in children with severe eosinophilic asthma, and were similar to findings in adolescents and adults., Trial Registration: ClinicalTrials.gov-ID: NCT04305405., (© 2024 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Information on changes in asthma prevalence and the treatment status for asthma is used as basic information for taking medical and administrative measures against asthma. However, this information among adults is relatively limited., Methods: To elucidate changes in the prevalence of asthma and treatment status over time among Japanese adults, health insurance claim data from some health insurance societies covering salaried employees and their dependents were studied longitudinally. Claim data from FY1999 to 2007 were obtained from two health insurance societies, and data from FY 2011 to 2019 were obtained from three different health insurance societies, and changes in standardized asthma prevalence among subjects aged 20-59 years, proportion of asthma patients prescribed ICS, leukotriene receptor antagonist (LTRA), and LABA, and the mean number of acute asthma exacerbations per year were analyzed., Results: The prevalence of asthma increased from 1.6% in 1999 to 3.0% in 2007 and 2.9% in 2011 to 4.6% in 2019. Increased trends in asthma prevalence from 2011 to 2019 were more noticeable in subjects in their 50s than those in their 20s for both sexes. The number of emergency visits related to asthma was 1.5 per year in 1999, which decreased to 0.8 per year in 2019. The proportion of people prescribed all anti-asthma medications (ICS, LTRA, and LABA) increased over time., Conclusions: The prevalence of adult asthma among Japanese salaried employees and their dependents has increased over the last 20 years, suggesting more attention should be paid to the prevention of this disease in adults., (Copyright © 2022 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

The assessment and management of patients with asthma is challenging because of the complexity of the underlying inflammatory mechanisms and heterogeneity of their clinical presentation. Optimizing disease management requires therapy individualization that should rely on reliable biomarkers to unravel the phenotypes and endotypes of asthma. The secretory activity and turnover of eosinophils, as assessed by measuring eosinophil-derived proteins, may provide an accurate and complementary tool that mirrors the eosinophil activation status. Emerging evidence suggests that eosinophil-derived neurotoxin has considerable potential as a precision medicine biomarker. In this review, we explore the suitability of eosinophil-derived neurotoxin as a biomarker in asthma management, with particular emphasis on its clinical significance in the management of both pediatric and adult populations., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Safety and efficacy data for dupilumab beyond 1 year are lacking for patients from Japan with moderate-to-severe asthma., Methods: The TRAVERSE open-label extension (OLE) study (NCT02134028) assessed the safety and efficacy of dupilumab 300 mg every 2 weeks up to 96 weeks in 2282 patients who completed a previous dupilumab asthma study. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Secondary endpoints included annualized severe exacerbation rate and change from parent study baseline in pre-bronchodilator forced expiratory volume in 1 second (FEV 1 ), asthma control, quality of life, and blood eosinophil levels. Anti-drug antibodies (ADA) were evaluated. We report results in 160 (7.8% of exposed population) patients recruited from Japanese centers with non-oral corticosteroid (OCS)-dependent asthma rolled over from two parent studies, and in subgroups with a type 2 inflammatory phenotype., Results: TEAEs were consistent with the parent studies and the known safety profile of dupilumab. One patient permanently discontinued treatment due to TEAEs. Exacerbation rates remained low and were sustained to Week 96, as were improvements in pre-bronchodilator FEV 1 . Rapid, sustained improvements were observed in dupilumab-treated patients who previously received placebo in a parent study, while further improvements in exacerbation rates, asthma control, and asthma-related quality of life were observed in those continuing dupilumab. Blood eosinophil levels decreased progressively while on treatment. Treatment-emergent ADA responses were highest in patients who had previously received placebo. Efficacy results were consistent in patients with a type 2 phenotype., Conclusions: Long-term dupilumab treatment was well tolerated and efficacious in patients with non-OCS-dependent, moderate-to-severe asthma recruited from Japan. (Funded by Sanofi and Regeneron Pharmaceuticals, Inc.; ClinicalTrials.gov identifier, NCT02134028)., (Copyright © 2022 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

This article covers the salient and updated themes of the Japanese Pediatric Guidelines for the Treatment and Management of Asthma (JPGL) 2020 published by the Japanese Society of Pediatric Allergy and Clinical Immunology. In the 2020 guidelines, five new clinical questions (CQs) have been added to address the 12 CQs regarding the treatment of childhood asthma. "Infant and preschool asthma" is diagnosed when young children (<6 years of age) have three or more episodes of clear expiratory wheezing, which continue for more than 24 h, and symptom improvement can be observed after beta-2 agonist inhalation. In children without clear improvement, diagnostic therapeutic trial for the duration of 1 month with controller treatment can be used. Since long-term management is initiated, the treatment level is adjusted based on the current control status and the management of risk factors, with the provision for holistic care. This underscores the smooth transition of pediatric patients into adult services. There are several differences between the JPGL and the guidelines of other countries. Further evidence is obtained as the utility of the newly proposed management plans should be evaluated in the Japanese population., (Copyright © 2022 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Eosinophilic cationic protein (ECP) is associated with airway inflammation and asthma. However, the clinical value of measuring ECP in childhood asthma is not fully known. We aimed to study the diagnostic performance of serum ECP and other common asthma biomarkers, individually and in combinations., Methods: In a cross-sectional study, 5-16-year-old children with current asthma (CA) (n = 37), transient asthma (TA) (n = 43), (previous history of wheezing/asthma), and healthy children (HC) (n = 86) were investigated for ECP, blood eosinophil count (B-Eos), fractional exhaled nitric oxide (FeNO), and lung function, i.e., spirometry (forced expiratory volume during the first second [FEV1]/forced vital capacity [FVC] ratio)., Results: Both ECP and B-Eos were higher in CA compared to TA (p < 0.01) and HC (p < 0.0001). ECP and B-Eos were also higher in TA compared to HC (p < 0.05 and p < 0.001, respectively). FeNO was higher in CA (p < 0.0001) and TA (p < 0.01) compared to HC but similar between the asthma groups. The FEV1/FVC ratio was lower in CA compared to TA and HC (both p < 0.01) but similar between TA and HC. The best diagnostic performance regarding CA was found for ECP and B-Eos with receiver operating characteristics area under curve (AUC) of 0.801 and 0.810, respectively. The optimal cutoff for ECP (29 μg/L) yielded a sensitivity and specificity of 70.3% and 81.4%. The corresponding AUCs for FeNO and FEV1/FVC were 0.732 and 0.670, respectively. ECP and B-Eos showed the highest AUCs (0.669 and 0.673) for differentiation between CA and TA. Combining ECP with FeNO and FEV1/FVC increased the odds ratio (OR) for having CA from OR 3.97-10.3 for the single biomarkers to OR 20.2 (95% confidence interval: 5.76-68.6)., Conclusion: Our results show that serum ECP is a reliable biomarker in the diagnosis of childhood asthma, with additional value in combination with FeNO and FEV1/FVC, and that ECP can be an alternative to B-Eos., (© 2022 S. Karger AG, Basel.)

The coronavirus disease 2019 (COVID-19) pandemic has had a great influence on medical practice in Japan. In this study, an online questionnaire-based survey was conducted among doctors routinely involved in the treatment of asthma. The questions included in the survey pertained to their thoughts on asthma treatment amidst COVID-19, changes in their clinical approach toward patients with asthma, and the behavioral changes in patients in the pandemic era. The results revealed a significant impact of the pandemic on asthma treatment. Regardless of whether or not they were directly involved in the treatment of patients with COVID-19, the doctors had avoided using nebulizers in outpatient wards/clinics and routine pulmonary function testing. An increase in canceled appointments and inappropriate/non-adherence to treatment among their patients were noticeable. Furthermore, the survey revealed an extensive impact of the pandemic on the doctors engaged in asthma treatment irrespective of the differences in their medical backgrounds., Competing Interests: Conflict of Interest The authors have no conflict of interest., (Copyright © 2021 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: In the LIBERTY ASTHMA QUEST (ClinicalTrials.gov: NCT02414854) study, dupilumab 200 mg and 300 mg every 2 weeks vs matched-volume placebo reduced severe asthma exacerbations and improved lung function (FEV 1 ), asthma control, and quality of life in patients with uncontrolled, moderate-to-severe asthma (N = 1902). Here, we examine the safety and efficacy of dupilumab in the subpopulation of Japanese patients who participated in QUEST (n = 114; 6%)., Methods: Endpoints assessed were annualized severe exacerbation rates and the effect of treatment over the 52-week treatment period on FEV 1 , asthma control, asthma-related quality of life, and markers of type 2 inflammation., Results: In Japanese patients, dupilumab 200 and 300 mg every 2 weeks vs matched placebo reduced severe asthma exacerbation rates by 44% (P = 0.33) and 75% (P = 0.03), respectively, and improved FEV 1 at Week 12 by 0.20 L (P = 0.05) and 0.17 L (P = 0.12). FEV 1 improvements were rapid (by Week 2) and sustained throughout treatment. Significant and/or numerical improvements vs placebo in asthma control and quality of life were also observed throughout treatment. For each endpoint, greater efficacy was observed in patients with elevated baseline levels of type 2 inflammatory biomarkers (blood eosinophils or FeNO). Dupilumab treatment significantly reduced levels of FeNO and total IgE, but not blood eosinophils., Conclusions: In this subanalysis of QUEST, the efficacy and safety of dupilumab in Japanese patients was comparable to that observed in the overall intention-to-treat population, suggesting no variability in efficacy on the basis of Japanese ethnicity. (Funded by Sanofi and Regeneron Pharmaceuticals, Inc.; ClinicalTrials.gov number: NCT02414854)., (Copyright © 2020 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

The Japanese Guideline for Childhood Asthma (JGCA) 2020 is a translation of the Japanese Pediatric Guideline for the Treatment and Management of Asthma (JPGL) 2017 into English, which was published by the Japanese Society of Pediatric Allergy and Clinical Immunology. It makes recommendations for best practices in the management of childhood asthma, including management of acute exacerbations and non-pharmacological and pharmacological management. These guidelines will be of interest to non-specialist physicians involved in the care of children with asthma. In JPGL, JPGL2017 is the first evidence-based guidelines updated according to the GRADE system and Minds approach, and it addresses eight clinical questions about the treatment of childhood asthma. In children aged ≤5 years, infant and preschool asthma is diagnosed according to the response to short acting beta2 agonists or the effect of a therapeutic trial during 1 month with controller treatment and worsening after treatment cessation. Long-term management both promotes pharmacological therapy and measures against risk factors that induce exacerbation, better patient education and a partnership with trinity. In addition, long-term management should not be carried out without review but rather be based on a cycle of evaluation, adjustment and treatment. In JPGL2017, the transdermal patch and oral beta2 agonists are positioned as drugs within the concept of "short-term additional treatment" to be used until the symptoms are stabilized when the control state transiently deteriorates., (Copyright © 2020 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Although the guidelines in most countries do not recommend continuous inhalation of l-isoproterenol to treat pediatric patients with acute severe exacerbation of asthma, lower dose of l-isoproterenol has been widely used in Japan. To determine whether the efficacy of low-dose l-isoproterenol was superior to that of salbutamol, we conducted a double-blind, randomized controlled trial., Methods: Hospitalized patients aged 1-17 years were eligible if they had severe asthma exacerbation defined by the modified pulmonary index score (MPIS). Patients were randomly assigned (1:1) to receive inhalation of l-isoproterenol (10 μg/kg/h) or salbutamol (500 μg/kg/h) for 12 hours via a large-volume nebulizer with oxygen. The primary outcome was the change in MPIS from baseline to 3 hours after starting inhalation. Trial registration number UMIN000001991., Results: From December 2009 to October 2013, 83 patients (42 in the l-isoproterenol group and 41 in the salbutamol group) were enrolled into the study. Of these, one patient in the l-isoproterenol group did not receive the study drug and was excluded from the analysis. Compared with salbutamol, l-isoproterenol reduced MPIS more rapidly. Mean (SD) changes in MPIS at 3 hours were -2.9 (2.5) in the l-isoproterenol group and -0.9 (2.3) in the salbutamol group (difference -2.0, 95% confidence interval -3.1 to -0.9; P < 0.001). Adverse events occurred in 1 (2%) and 11 (27%) patients in the l-isoproterenol and salbutamol groups, respectively (P = 0.003). Hypokalemia and tachycardia occurred only in the salbutamol group., Conclusions: Low-dose l-isoproterenol has a more rapid effect with fewer adverse events than salbutamol., (Copyright © 2019 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Airway remodeling is responsible for the progressive decline of lung function in bronchial asthma. Matrix metalloproteinase-2 and fibroblast-to-myofibroblast transition are involved in tissue remodeling. Here we evaluated whether eosinophils play a role in fibroblasts-to-myofibroblasts transition and in the expression of matrix metalloproteinase-2. We co-cultured human eosinophils with human fetal lung fibroblast-1 cells, assessed the expression of remodeling-associated molecules by immunoassays and polymerase-chain reaction, and eosinophils-mediated migration of human fetal lung fibroblast-1 cells using a Boyden chamber. To clarify the participation of matrix metalloproteinase-2 in airway remodeling we administered bone marrow-derived eosinophils by intra-tracheal route to transgenic mice overexpressing the human matrix metalloproteinase-2. The expression of α-smooth muscle actin significantly increased in human fetal lung fibroblast-1 cells co-cultured with human eosinophils compared to controls. There was enhanced expression of matrix metalloproteinase-2 during fibroblast-to-myofibroblast transition. An inhibitor of matrix metalloproteinases blocked eosinophils-associated fibroblast-to-myofibroblast transition and increased migration of fibroblasts. The human matrix metalloproteinase-2 transgenic mice receiving adoptive transfer of mouse eosinophils exhibited increased inflammation and advanced airway remodeling compared to wild type mice. This study demonstrated that eosinophils induce fibroblast-to-myofibroblast transition, secretion of matrix metalloproteinase-2, accelerated migration of fibroblasts, and promote matrix metalloproteinase-2-related airway remodeling. These findings provide a novel mechanistic pathway for eosinophil-associated airway remodeling in bronchial asthma.

Background: To evaluate the long-term safety of subcutaneous immunotherapy with TO-204, a standardized house dust mite (HDM) allergen extracts, we conducted a multicenter, open label clinical trial., Methods: Japanese patients aged 5-65 years were eligible for the study, if they had HDM-induced allergic rhinitis (AR), allergic bronchial asthma (BA), or both. TO-204 was administered in a dose titration scheme, and the maintenance dose was determined according to the predefined criteria. The treatment period was 52 weeks, and patients who were willing to continue the treatment received TO-204 beyond 52 weeks. This clinical trial is registered at the Japan Pharmaceutical Information Center (Japic CTI-121900)., Results: Between July 2012 and May 2015, 44 patients (28 with AR and 16 with allergic BA) were enrolled into the study. All patients were included in the analysis. The duration of treatment ranged from 23 to 142 weeks and the median maintenance dose was 200 Japanese allergy units (JAU). Adverse events occurred in 22 patients (50%). The most common adverse event was local reactions related to the injection sites. Four patients experienced anaphylactic reactions when they were treated with the dose of 500 JAU. Two patients experienced anaphylactic shock with the doses of 1000 JAU at onset. These 6 patients could continue the study with dose reduction., Conclusions: Safety profile of TO-204 was acceptable in Japanese patients with HDM-induced AR or allergic BA. Higher doses should be administered carefully, because the risk of anaphylaxis increased at doses of 500 or 1000 JAU., (Production and hosting by Elsevier B.V.)

Background: In September 2015, Japan experienced an unusual increase in acute asthma hospitalizations of children that coincided with an enterovirus D68 (EV-D68) epidemic. The objective of this study is to investigate whether EV-D68 had a causal relationship with the spike in asthma hospitalizations., Methods: A nation-wide retrospective survey of asthma hospitalizations of children was performed for the period from January 2010 through October 2015. The Japanese Society of Pediatric Allergy and Clinical Immunology asked its affiliated hospitals to report monthly numbers of hospitalizations, ICU admissions and mechanical ventilations due to acute asthma exacerbation. The data were retrieved from medical databases using predefined search criteria: diagnosis of asthma or asthmatic bronchitis, admission, and age <20 years. Monthly numbers of EV-D68 detection were also obtained from the Infectious Disease Surveillance Center of Japan. A Granger causality test was used to analyze the association of EV-D68 detections for asthma exacerbation., Results: A total of 157 hospitals reported 87,189 asthma hospitalizations, including 477 ICU admissions and 1193 mechanical ventilations, during the survey period of 5 years and 10 months. The numbers of these events increased drastically in September 2015. The Granger causality test verified the association between EV-D68 and asthma hospitalizations/mechanical ventilations. The most-affected age group was 3-6 years old., Conclusions: The spike in pediatric asthma hospitalizations in Japan in September 2015 was found to be associated with the EV-D68 epidemic. Respiratory pathogens can cause "epidemics" of asthma exacerbation. Coordinated surveillance of infectious diseases and asthma may be beneficial for prevention and better control of both illnesses., (Copyright © 2017 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: While Japanese guideline recommends initial control treatment for preschool children with asthma symptoms more than once a month, Western guidelines do not. To determine whether control treatment with montelukast was more effective than as-needed β 2 -agonists in this population, we conducted a randomized controlled trial., Methods: Eligible patients were children aged 1-5 years who had asthma symptoms more than once a month but less than once a week. Patients were randomly assigned in a 1:1 ratio to receive montelukast 4 mg daily for 48 weeks or as-needed β 2 -agonists. The primary endpoint was the number of acute asthma exacerbations before starting step-up treatment with inhaled corticosteroids. This study is registered with the University Hospital Medical Information Network clinical trials registry, number UMIN000002219., Results: From September 2009 to November 2012, 93 patients (47 in the montelukast group and 46 in the no-controller group) were enrolled into the study. All patients were included in the analysis. During the study, 13 patients (28%) in the montelukast group and 23 patients (50%) in the no-controller group had acute exacerbations with the mean numbers of 0.9 and 1.9/year, respectively (P = 0.027). In addition, 10 (21%) and 19 (41%) patients received step-up treatment, respectively. Cumulative incidence of step-up treatment was significantly lower in the montelukast group (hazard ratio 0.45, 95% confidence interval 0.21 to 0.92; P = 0.033)., Conclusions: Montelukast is an effective control treatment for preschool children who had asthma symptoms more than once a month but less than once a week., (Copyright © 2017 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: The use of asthma control guidelines and anti-inflammatory drugs have significantly decreased the number of severe asthma cases including death from asthma. However, there are few prospective cohort studies among pediatric asthma patients in Japan describing the course of asthma symptoms with the treatment taken into consideration., Method: We recruited a total of 851 children diagnosed with asthma through 90 hospitals and clinics in 2004 to 2006. Questionnaires were posted annually to collect data on their asthma symptoms, treatment and environmental exposures. We analyzed the disease course in the first 5 years among the children who were registered at age 4 or younger., Results: The disease course of a total of 641 children, aged 2.8+/-1.1 (mean+/-SD) at registration were analyzed. The proportion of children who had intermittent symptoms increased from 37.6% at registration to 86.5% at 5 years, and the proportion of children with intermittent severity increased from 7.0% to 38.9%, showing a significant decrease in the overall severity. The proportion of children using β 2 stimulants decreased from 87.8% at registration to 53.5% at 5 years, while the use of inhaled cortico-steroids were 41.6% at registration and 38.1% at 5 years., Conclusion: Most of the children with pre-school onset asthma had their symptoms controlled, and had decreased severity over 5 years.

Background: Omalizumab is effective and well-tolerated in children with moderate to severe allergic asthma. However, the effects of long-term treatment with omalizumab in this population haven't been well investigated. The objective of this study is to evaluate the long-term safety, efficacy, pharmacokinetics and pharmacodynamics of omalizumab in children with uncontrolled severe asthma., Methods: Thirty-eight Japanese children (aged 7-16 years) who completed the 24-week treatment core study were included in an uncontrolled extension study, in which treatment with omalizumab continued until the pediatric indication was approved in Japan (ClinicalTrials.gov number: NCT01328886)., Results: Thirty-five patients (92.1%) completed the extension study. The median exposure throughout the core and extension studies was 116.6 weeks (range, 46.9-151.1 weeks). The most common adverse events were nasopharyngitis, influenza, upper respiratory tract infection, and asthma. Serious adverse events developed in 10 patients (26.3%), but resolved completely with additional treatments. Incidence of adverse events didn't increase with extended exposure with omalizumab. Twenty-nine patients (76.3%) achieved completely- or well-controlled asthma compared with 9 patients (23.7%) at the start of the extension study. QOL scores, the rates (per year) of hospitalizations and ER visits were significantly improved compared with the baseline of the core study [39.0 vs 48.0 (median), p < 0.001 for QOL, 1.33 vs 0.16, p < 0.001 for hospitalization, 0.68 vs 0.15, p = 0.002 for ER visits]. Remarkably, the mean total IgE level showed a decreasing trend while exposure to omalizumab remained at steady-state., Conclusions: Long-term treatment with omalizumab is well-tolerated and effective in children with uncontrolled severe allergic asthma. No new safety findings were identified., (Copyright © 2017 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Several guidelines, including the Japanese Pediatric Guideline for the Treatment and Management of Asthma (JPGL), recommend salmeterol/fluticasone combination therapy (SFC) as step 3 to 4 treatment for moderate to severe asthma. However, the optimal step-down approach to SFC remains unclear. In the current study, we examined step-down approaches in asthmatic children whose symptoms had been stabilized by SFC 100/200 μg/day., Methods: This randomized, multicenter, open-label, parallel-group study was conducted over 12 weeks. For step-down therapy, subjects aged 5-15 years were randomly assigned to an SFC group (25/50 μg b.i.d.) or an FP group (100 μg b.i.d.), and treated for 12 weeks. Childhood Asthma Control Test (C-ACT) scores, lung function, and exhaled nitric oxide (FeNO) levels were monitored., Results: Of 131 enrolled subjects, 128 completed the study and were included in the analysis. Decreases in % peak expiratory flow rate and % forced expiratory flow at 50% of vital capacity (V50) were observed in the FP group at each time point. There was a significant difference between the two groups for the change in %V50 from its previous value at each time point. There were no significant changes in FeNO levels (range 15-20 ppb) or C-ACT scores (∼26 points) within or between groups., Conclusions: A high level of asthma control was maintained with both approaches. The use of SFC step-down resulted in somewhat better respiratory function, with no worsening of airway inflammation. However, halving the dose of SFC and switching to FP alone are both optimal step-down approaches., (Copyright © 2016 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Several patient-/caregiver-completed questionnaires have been utilized for the assessment of asthma control. However, due to the diversity in medical/social circumstances, they may not be optimal for use in all countries. The Japanese pediatric asthma guideline (JPGL) aims at higher levels of control compared with other international guidelines, based on a strong social demand for best care. We developed a new control test to help meet that demand., Methods: A 34-item working questionnaire was developed based on input from pediatric asthma specialists and the caregivers of preschool children with asthma. The questionnaire was administered to caregivers of 565 patients aged <6 years who had physician-diagnosed asthma or β2-agonist-responsive recurrent wheeze. Then, 6 questions for assessing JPGL-defined control levels were selected from the 34 questions by stepwise logistic regression methods using randomly selected questionnaires completed by two-thirds of the caregivers. We named that set of questions the Best Asthma Control Test for Preschoolers (Best ACT-P). Validation of Best ACT-P was performed using the remaining completed questionnaires., Results: The 6 questions asked about the frequency/severity of cold-induced wheeze, nighttime awakening, exercise-induced symptoms, and disruption of family life due to asthma in the past 4 weeks and hospitalization in the past 12 months. The 6-item logistic model showed good statistical fit, and the scores for the physicians' ratings of the asthma control differed significantly in the hypothetical direction., Conclusions: Best ACT-P is a valid caregiver-completed questionnaire of asthma control in preschoolers in whom total control needs to be achieved., (© 2015 The Authors. Pediatric Allergy and Immunology Published by John Wiley & Sons Ltd.)

Background: Omalizumab has demonstrated clinical benefits in children with moderate to severe allergic asthma. However, no studies have been performed in Japanese asthmatic children. The aim of this study was to evaluate the efficacy including free IgE suppression and safety of omalizumab in Japanese children with severe allergic asthma. The primary objective was to examine whether omalizumab decreases serum free IgE levels to less than 25 ng/ml (target level of suppression)., Methods: Thirty-eight Japanese children (6-15 years) with uncontrolled severe allergic asthma despite inhaled corticosteroids (>200 μg/day fluticasone propionate or equivalent) and two or more controller therapies received add-on treatment with omalizumab in a 24-week, multicenter, uncontrolled, open-label study., Results: The geometric mean serum free IgE level at 24 weeks was 15.6 ng/mL. Compared with baseline, total asthma symptom scores, daily activity scores and nocturnal sleep scores at 24 weeks were significantly improved. The rates of asthma exacerbation and hospitalization due to asthma were reduced by 69.2% and 78.2%, respectively (p < 0.001), versus baseline. Quality-of-life scores were also significantly improved (p < 0.001). In addition, 11 (28.9%) patients reduced the dose of any asthma controller medications. Thirty-six (94.7%) patients experienced at least one adverse event during the treatment period. All adverse events were mild or moderate in severity and no new safety concerns were detected. No patients discontinued the study., Conclusions: In Japanese children with severe allergic asthma, omalizumab decreased free IgE levels to less than 25 ng/mL. Omalizumab improved asthma control and was well-tolerated, as well., (Copyright © 2015 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

The prevalence of allergy to furry animals has been increasing, and allergy to cats, dogs, or both is considered a major risk factor for the development of asthma and rhinitis. An important step forward in the diagnosis of allergy to furry animals has been made with the introduction of molecular-based allergy diagnostics. A workshop on furry animals was convened to provide an up-to-date assessment of our understanding of (1) the exposure and immune response to the major mammalian allergens, (2) the relationship of these responses (particularly those to specific proteins or components) to symptoms, and (3) the relevance of these specific antibody responses to current or future investigation of patients presenting with allergic diseases. In this review research results discussed at the workshop are presented, including the effect of concomitant exposures from other allergens or microorganisms, the significance of the community prevalence of furry animals, molecular-based allergy diagnostics, and a detailed discussion of cat and dog components., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

A new version of the Japanese pediatric guideline for the treatment and management of bronchial asthma was published in Japanese at the end of 2011. The guideline sets the pragmatic goal for clinicians treating childhood asthma as maintaining a "well-controlled level" for an extended period in which the child patient can lead a trouble-free daily life, not forgetting the ultimate goal of obtaining remission and/or cure. Important factors in the attainment of the pragmatic goal are: (i) appropriate use of anti-inflammatory drugs; (ii) elimination of environmental risk factors; and (iii) educational and enlightening activities for the patient and caregivers regarding adequate asthma management in daily life. The well-controlled level refers to a symptom-free state in which no transient coughs, wheezing, dyspnea or other symptoms associated with bronchial asthma are present, even for a short period of time. As was the case in the previous versions of the guideline, asthmatic children younger than 2 years of age are defined as infantile asthma patients. Special attention is paid to these patients in the new guideline: they often have rapid exacerbation and easily present chronic asthmatic conditions after the disease is established., (© 2014 Japan Pediatric Society.)

Background: Few studies have examined the efficacy or safety of a transdermal β(2) agonist as add-on medication to long-term leukotriene receptor antagonist (LTRA) therapy in pediatric asthma patients., Methods: In this randomized, open-label, multicenter clinical trial, children aged 4-12 years on long-term LTRA therapy were treated with tulobuterol patches (1-2mg daily) or oral sustained-release theophylline (usual dose, 4-5mg/kg daily) for 4 weeks. LTRAs were continued throughout the trial. Outcomes included volume of peak expiratory flow (% PEF), fractional exhaled nitric oxide (FeNO), clinical symptoms and adverse events., Results: Thirty-three and 31 patients were treated with tulobuterol patches and theophylline, respectively. % PEF measured in the morning and before bedtime was significantly higher at all times in the treatment period compared with baseline in the tulobuterol patch group (p < 0.001), and was significantly higher in the tulobuterol patch group compared with the theophylline group. FeNO was similar and unchanged from baseline in both groups. There were no drug-related adverse events in either group., Conclusions: These results suggest that short-term use of a transdermal β(2) agonist is an effective therapy for pediatric asthma without inducing airway inflammation in children on long-term LTRA therapy.

Background: It has been suggested that there is a complex interaction between microbiota and various human diseases. Some bacteria have been reported to be involved in the inception and progression of asthma, and others in the protection against asthma. We know very little about the mechanisms by which bacteria do harm or good with regard to asthma. This study investigated whether bacteria exert differential effects on the functions of eosinophils, major effector cells in airway inflammation in asthma., Methods: Eosinophils were purified from healthy adult volunteers by Percoll density gradient centrifugation and negative immunomagnetic bead selection using anti-CD16 microbeads. Three kinds of heat-killed bacteria that have been implicated in asthma, namely Staphylococcus aureus (SA), Haemophilus influenzae (HI) and a Prevotella sp. (PS), were tested for their effects on the secretion of eosinophil-derived neurotoxin (EDN), the generation of superoxides and the production of cytokines/chemokines., Results: SA, but not HI or PS, induced significant EDN release in a dose-dependent manner. Superoxide generation was significantly enhanced by each of the bacterial species, but most strongly by SA, which induced significantly greater TNF-α production by eosinophils than either HI or PS. Conversely, interleukin 10, an anti-inflammatory cytokine, was more strongly induced by HI and PS than by SA., Conclusions: Bacteria exert differential effects on eosinophils. Based on these results, SA may be involved in the exacerbation of, and HI and PS in the inhibition of, eosinophilic inflammation in asthma., (Copyright © 2013 S. Karger AG, Basel.)

The tulobuterol patch (TP) is a beta(2)-adrenergic agonist with a favorable pharmacokinetic profile used for asthma management in Japan. Because it contains tulobuterol in a molecular, crystallized form that is gradually absorbed percutaneously, TP exerts a prolonged bronchodilator effect exceeding 24 hours. Although it is a well-established treatment for asthma and wheezing, few studies have investigated whether it can reduce or prevent the symptoms associated with upper respiratory tract infections (URTIs) in young children. This study evaluated the effect of TP on the long-term management of asthma in young children. In this 1-year, randomized, multicenter, double-blind, placebo-controlled study, children aged 0.5-3 years old with mild-to-moderate persistent asthma were treated with either TP or placebo patch. The parents/guardians applied the TP or placebo patch to their children after URTI symptoms appeared. Respiratory symptoms were recorded daily during the 1-year observation period. Overall, 86 patients were enrolled and 80 were treated and analyzed in this study. All patients had been treated with anti-inflammatory drugs before enrollment. The time to symptom resolution was significantly shorter (p = 0.001) and the total respiratory symptom score (p = 0.0457) was significantly lower in the TP group than in the placebo group. In young children with mild-to-moderate asthma who had been treated with anti-inflammatory drugs, using the TP soon after the appearance of URTI symptoms led to quicker resolution of respiratory symptoms and lower respiratory symptom scores.

We report a case of 18-old girl with primary ciliary dyskinesia (PCD) who had been diagnosed as asthma. Since birth, she had presented with unexplained productive cough, sputum, rhinorrhea, and stridor with situs solitus. Her familial history was negative for PCD. At 2 years of age, ciliary beat frequency and beat pattern were normal. She was diagnosed as rhinosinusitis, chronic secretory otitis media. At 3 years of age, she was diagnosed as asthma because of wheezing not associated with respiratory infection. Various asthma medications were then administered, including DSCG, inhaled corticosteroids, and salmeterol, but varying responses to the treatment were noted. Spirometry revealed persistent severe small airway obstruction. Beta2 agonist reversibility was recognized by impulse oscillation system, not with FEV1. At age of 18, chest CT disclosed bronchiectasis, and nasal nitric oxide concentration was very low, 98 ppb and a diagnostic approach for PCD was performed. Electron microscopic analysis of nasal cilia demonstrated defects of the outer and inner dynein arms, and the diagnosis of PCD was made. Mutations in DNAH1 and DNAI1 genes were found. The diagnosis of PCD is often difficult in the absence of situs inversus totalis. Recurrent wheeze with chronic rhinosinusitis, chronic otitis media, and brochiectasis may warrant detailed investigations for PCD, especially with nasal NO measurement.

Th2 cytokine IL-5 and CC chemokine eotaxin are thought to be key regulators of eosinophils in bronchial asthma. However, their involvement in children with stable asthma (SA) has not been determined. We investigated the roles of IL-5 and eotaxin in eosinophil degranulation in children with SA. Induced sputum was obtained from 30 SA, 21 allergic rhinitis (AR), and 22 non-atopic healthy control (HC) children. We measured sputum levels of IL-5, eotaxin, and eosinophil indices [percentage eosinophils, eosinophil-derived neurotoxin (EDN), and eosinophil-cationic protein (ECP)]. We also examined correlations of IL-5 and eotaxin with eosinophil indices. Sputum percentage eosinophils and EDN and ECP levels were significantly higher in the SA group than in the HC group, while only the sputum EDN and ECP levels were significantly higher in the AR group than in the HC group. Unexpectedly, sputum levels of IL-5 were not significantly different among the three groups; however, the levels of eotaxin were higher in the SA group when compared to the HC group. No significant correlations were found between IL-5 and percentage eosinophils, EDN, or ECP levels; in contrast, eotaxin levels correlated significantly with percentage eosinophils (R(s) = 0.638; p = 0.0001), EDN (R(s) = 0.522; p = 0.003), and ECP levels (R(s) = 0.630 and p = 0.0002). The elevated levels and good correlations of eotaxin with sputum eosinophil indices, and no elevation or correlation of IL-5 with these indices, suggest that CC chemokine eotaxin may play a more important role in eosinophil degranulation in children with SA.

Abstract The fourth version of the Japanese Pediatric Guidelines for the Treatment and Management of Bronchial Asthma 2008 (JPGL 2008) was published by the Japanese Society of Pediatric Allergy and Clinical Immunology in December 2008. In JPGL 2008, the recommendations were revised on the basis of the JPGL 2005. The JPGL 2008 is different to the Global Initiative for Asthma guideline in that it contains the following items: a classification system of asthma severity; recommendations for long-term management organized by age; a special mention of infantile asthma; and an emphasis on prevention and early intervention. Here we show a summary of the JPGL 2008 revising our previous report concerning JPGL 2005.

Bronchial asthma and allergic rhinitis often co-exist, and rhinitis is a major risk factor for the development of asthma. However, the reported incidence of allergic rhinitis in asthmatic children varies widely. The aim of this study was to elucidate the incidence of allergic rhinitis, the onset age of chronic upper and lower airway symptoms, and the correlation of these two symptoms in asthmatic children. A cohort of 130 consecutive children (ages 2-10) with asthma was evaluated. A questionnaire regarding upper and lower airway symptoms was filled out by the parents. Objective diagnosis of allergic rhinitis was also made on the basis of rhinoscopy, nasal cytology, nasal challenge, and specific serum IgE (CAP-RAST). Persistent nasal symptoms were present in 83.8% of the asthmatic children. The incidence of allergic rhinitis was 77.7% based on the objective findings. The mean onset age of asthma was 2.8 yr, and that of rhinitis was 2.9 yr. Nasal symptoms started as early as the first year of life in 8.9% of the children. In children with comorbid asthma and allergic rhinitis, rhinitis preceded in 33.7%, asthma preceded in 31.7%, and both started in the same year in 26.7%. In 7.9%, rhinitis was asymptomatic. Concomitant exacerbation of the upper and lower airways occurred in 34.6% of the total 130 children. These results demonstrate that allergic rhinitis manifested early in life in the majority of the asthmatic children. Persistent nasal symptoms in infancy may point to subsequent development of asthma and possible early intervention.

Background: Bronchial asthma is often complicated with allergic rhinitis (AR)., Objective: To investigate the relationship between the upper and lower airway diseases in children with asthma, we performed a questionnaire survey at 6 centers in Kinki area in Japan., Methods: A questionnaire was filled out by parents of 333 asthmatic children (0-16 years, median age 7). It included questions concerning nasal symptoms, onset ages of rhinitis and asthma, correlation between nasal symptoms and asthma symptoms, and family history of allergic diseases., Results: One hundred and fifty five (46.5%) subjects answered to have any nasal diseases; 20 with sinusitis, 46 with seasonal AR, and 119 (35.7%) with perennial AR. To further clarify the relationship of asthma and concomitant AR, we focused on patients with perennial AR and compared the clinical characteristics with patients with no nasal diseases. Percentage of non-atopic asthma was significantly lower in patients with comorbid AR than those without. Severity of asthma tended to be milder and family history of perennial AR was more often in the former than the latter group. Interestingly, asthmatic children with comorbid AR were more likely to have cold air-induced asthma exacerbations. In the subjects with comorbid AR, concomitant exacerbation of the upper and lower airways occurred in 38.7%. The median age of onset of asthma and nasal symptoms was 2 and 4 years, respectively. In 43.9% of them, upper airway symptoms started either before or simultaneously with asthma., Conclusion: The attention should be paid to the nasal symptoms in children with asthma, especially they have atopic asthma and positive family history of perennial allergic rhinitis. It is important that an appropriate diagnosis and treatment of nasal symptoms to better control asthma in children.

Bronchial asthma is an inflammatory disorder characterized by recruitment and activation of various inflammatory cells including eosinophils and T cells in the airway mucosa. Oxygen radicals are produced by inflammatory cells in the airways and/or inhaled directly from environmental air. There is ample evidence that oxygen radical production is increased in asthma and is closely related to the pathogenesis and that exogenous oxidants such as cigarette smoke and ozone directly cause asthma exacerbation. The mechanism by which oxygen radicals cause asthma pathology is oxidation or nitration of proteins, lipids, or DNA to cause dysfunction of these molecules. In addition, physiological antioxidant system, which is equipped to protect host from detrimental oxidants, is impaired in asthma, possibly because of inflammation. Thus, the imbalance between oxidant and antioxidant that is called oxidant stress is critical in asthma pathogenesis. Elegant technique to measure oxygen radicals and the footprints of oxidant stress in patients with asthma have been developed and give an important clue to evaluate possible involvement of oxygen radicals in individual pathophysiology. Therapeutic interventions that reduce oxidant stress and enhance antioxidant defense may be useful in the treatment of asthma.

Eosinophils may play an important role in the pathogenesis of airway remodeling in asthma through the production of various fibrogenic cytokines such as transforming growth factor-beta1 (TGF-beta1). Cysteinyl leukotrienes are also suggested to be involved in remodeling with their potential to induce proliferation of airway smooth muscle cells. Since massive eosinophil infiltration and the release of cysteinyl leukotrienes in airway secretions are often seen in asthma, we hypothesized that cysteinyl leukotrienes may be involved in airway remodeling through induction of TGF-beta1 from eosinophils. Peripheral blood eosinophils were cultured with leukotriene D(4) (LTD(4)) and/or interleukin-5 (IL-5) or granulocyte colony-stimulating factor (GM-CSF) for 16 h and gene expression of TGF-beta1 was quantified with real-time PCR. A combination of LTD(4) and IL-5 or LTD(4) and GM-CSF synergistically induced TGF-beta1 expression in eosinophils although stimulation with single factor, LTD(4), IL-5 or GM-CSF did not induce the gene expression. LTD(4) also induced significant gene expression in eosinophils cultured in an intercellular adhesion molecule-1-coated plate. The results suggested that CysLTs stimulate eosinophils to induce TGF-beta1 production in allergic inflammation where IL-5 and GM-CSF are abundant and may be involved in the pathogenesis of airway remodeling., (Copyright 2005 S. Karger AG, Basel.)

Background: Acute asthma exacerbation in children is often caused by respiratory infections. In this study, a coordinated national surveillance system for acute asthma hospitalizations and causative respiratory infections was established. We herein report recent trends in pediatric acute asthma hospitalizations since the COVID‐19 pandemic in Japan. Methods: Thirty‐three sentinel hospitals in Japan registered all of their hospitalized pediatric asthma patients and their causal pathogens. The changes in acute asthma hospitalization in children before and after the onset of the COVID‐19 pandemic and whether or not COVID‐19 caused acute asthma exacerbation were investigated. Results: From fiscal years 2010–2019, the median number of acute asthma hospitalizations per year was 3524 (2462–4570), but in fiscal years 2020, 2021, and 2022, the numbers were 820, 1,001, and 1,026, respectively (the fiscal year in Japan is April to March). This decrease was observed in all age groups with the exception of the 3‐ to 6‐year group. SARS‐CoV‐2 was evaluated in 2094 patients from fiscal years 2020–2022, but the first positive case was not detected until February 2022. Since then, only 36 of them have been identified with SARS‐CoV‐2, none of which required mechanical ventilation. Influenza, RS virus, and human metapneumovirus infections also decreased in FY 2020. In contrast, 24% of patients had not been receiving long‐term control medications before admission despite the severity of bronchial asthma. Conclusion: SARS‐CoV‐2 was hardly detected in children with acute asthma hospitalization during the COVID‐19 pandemic. This result indicated that SARS‐CoV‐2 did not induce acute asthma exacerbation in children. Rather, infection control measures implemented against the pandemic may have consequently reduced other respiratory virus infections and thus acute asthma hospitalizations during this period. However, the fact that many hospitalized patients have not been receiving appropriate long‐term control medications is a major problem that should be addressed. [ABSTRACT FROM AUTHOR]

Background: Childhood asthma is a major risk for low lung function in later adulthood, but what factors in asthma are associated with the poor lung function during childhood is not known. Objective: To identify clinical factors in children with asthma associated with low or declining lung function during the treatment. Methods: We enrolled children with asthma who had been treated throughout three age periods, i.e., 6–9, 10–12, and 13–15 years old, at seven specialized hospitals in Japan. Clinical information and lung function measurements were retrieved from the electronic chart systems. To characterize the lung function trajectories during each age period, we evaluated the forced expiratory volume 1 (FEV1) with % predicted values and individual changes by the slope (S) from linear regression. We defined four trajectory patterns: normal (Group N) and low (Group L), showing %FEV1 ≥80% or <80% throughout all three periods; upward (Group U) and downward (Group D), showing S ≥ 0 or S < 0%. Logistic regression analysis was performed to compare factors associated with the unfavorable (D/L) versus favorable (N/U) groups. Results: Among 273 eligible patients, 197 (72%) were classified into Group N (n = 150)/U (n = 47), while 76 (28%) were in Group D (n = 66)/L (n = 10). A history of poor asthma control, long-acting beta2 agonist use, and a lower height Z-score during 13–15 years were associated with an unfavorable outcome (Group D/L). Conversely, inhaled corticosteroid (ICS) use during 10–12 years and high-dose ICS use during 13–15 years were associated with a favorable outcome (Group N/U). Conclusion: We identified several factors that are associated with unfavorable lung function changes in pediatric asthma. Attention should be paid to the possible relationship between yearly changes in lung function and poor asthma control, use of ICS (and its dose) and use of LABA. [ABSTRACT FROM AUTHOR]

Background: Allergen-specific immunotherapy is currently the only disease-modifying treatment for allergic asthma, and it has been shown to improve control of asthma while reducing both drug use and asthma exacerbations. However, its effects on lung function—especially its long-term effects—remain controversial. We aimed to identify factors associated with a possible beneficial effect of allergen-specific immunotherapy on lung function in asthma by retrospectively evaluating the long-term changes in lung function in children with asthma who received house dust mite subcutaneous immunotherapy (HDM-SCIT). Methods: We enrolled children with asthma who had undergone HDM-SCIT for more than 1 year. Clinical information and lung function measurements were retrieved from the electronic chart system. To characterize the trajectory of lung function change, we performed linear regression analysis to evaluate the maximal expiratory flow at 50% of the forced vital capacity during two periods: before and during HDM-SCIT. Slopes from a least-squares regression line for the two periods, i.e., S1 before HDM-SCIT and S2 during HDM-SCIT, were compared. The subjects were then classified into two groups: an improving group (Group I) defined as S2 − S1 > 0, and a declining group (Group D) defined as S2 − S1 < 0. The clinical factors at the start of HDM-SCIT were compared between the two groups. Results: A total of 16 patients were analyzed. Eight patients were classified into each of Group I and Group D. The mean ages were 10.5 and 11.8 years, and the mean treatment periods were 4.1 and 3.9 years. Group I had a significantly lower blood eosinophil count and a significantly higher HDM-specific IgE level than Group D. Logistic regression showed a strong relationship between those two markers and the lung function trajectory. Conclusion: Control of the blood eosinophil count in highly HDM-sensitized patients may increase the beneficial effect of HDM-SCIT on lung function. [ABSTRACT FROM AUTHOR]

Eosinophilic inflammation and remodeling of the airways including subepithelial fibrosis and myofibroblast hyperplasia are characteristic pathological findings of bronchial asthma. Epithelial to mesenchymal transition (EMT) plays a critical role in airway remodelling. In this study, we hypothesized that infiltrating eosinophils promote airway remodelling in bronchial asthma. To demonstrate this hypothesis we evaluated the effect of eosinophils on EMT by in vitro and in vivo studies. EMT was assessed in mice that received intra-tracheal instillation of mouse bone marrow derived eosinophils and in human bronchial epithelial cells co-cultured with eosinophils freshly purified from healthy individuals or with eosinophilic leukemia cell lines. Intra-tracheal instillation of eosinophils was associated with enhanced bronchial inflammation and fibrosis and increased lung concentration of growth factors. Mice instilled with eosinophils pre-treated with transforming growth factor(TGF)-β1 siRNA had decreased bronchial wall fibrosis compared to controls. EMT was induced in bronchial epithelial cells co-cultured with human eosinophils and it was associated with increased expression of TGF-β1 and Smad3 phosphorylation in the bronchial epithelial cells. Treatment with anti-TGF-β1 antibody blocked EMT in bronchial epithelial cells. Eosinophils induced EMT in bronchial epithelial cells, suggesting their contribution to the pathogenesis of airway remodelling. [ABSTRACT FROM AUTHOR]

Background: Viral respiratory tract infections play an important role in the inception and exacerbation of asthma. Eosinophils, major effector cells in asthma, often accumulate in the airways during viral infections and are possibly activated by respiratory RNA viruses through Toll-like receptor (TLR) 7. We investigated the effect of a β2-agonist, i.e. procaterol, and a corticosteroid, i.e. budesonide, that are commonly used for viral-induced asthma, on TLR7 ligand-induced activation of eosinophils in vitro. Methods: Purified peripheral blood eosinophils were incubated with procaterol and/or budesonide and stimulated with a TLR7 ligand, i.e. R-837. Expression of CD11b was analyzed by flow cytometry. Superoxide generation was measured via the cytochrome C reduction method. IL-8 in the supernatants was assayed by ELISA. Results: Although procaterol or budesonide alone did not inhibit R-837-induced CD11b expression, combinations of the 2 drugs significantly inhibited CD11b. Likewise, the combinations significantly inhibited O2- generation at low concentrations. Budesonide significantly inhibited R-837-induced IL-8 production in a concentration-dependent manner, and procaterol potentiated inhibition by budesonide although single-agent procaterol had no effect. Conclusion: A combination of procaterol and budesonide inhibits the TLR7-mediated effector function of eosinophils, indicating their possible anti-inflammatory effect for virus-induced asthma. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Eosinophils may play an important role in the pathogenesis of airway remodeling in asthma through the production of various fibrogenic cytokines such as transforming growth factor-β1 (TGF-β1). Cysteinyl leukotrienes are also suggested to be involved in remodeling with their potential to induce proliferation of airway smooth muscle cells. Since massive eosinophil infiltration and the release of cysteinyl leukotrienes in airway secretions are often seen in asthma, we hypothesized that cysteinyl leukotrienes may be involved in airway remodeling through induction of TGF-β1 from eosinophils. Peripheral blood eosinophils were cultured with leukotriene D4 (LTD4) and/or interleukin-5 (IL-5) or granulocyte colony-stimulating factor (GM-CSF) for 16 h and gene expression of TGF-β1 was quantified with real-time PCR. A combination of LTD4 and IL-5 or LTD4 and GM-CSF synergistically induced TGF-β1 expression in eosinophils although stimulation with single factor, LTD4, IL-5 or GM-CSF did not induce the gene expression. LTD4 also induced significant gene expression in eosinophils cultured in an intercellular adhesion molecule-1-coated plate. The results suggested that CysLTs stimulate eosinophils to induce TGF-β1 production in allergic inflammation where IL-5 and GM-CSF are abundant and may be involved in the pathogenesis of airway remodeling. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Presents an overview of several studies on allergic inflammation. Role of eosinophils in the pathogenesis of asthma; Reduction of eosinophil in the lung and peripheral blood by a humanized anti-interleukin-5 monoclonal antibody (SB-240563); Topics presented and discussed at the 14th Annual Workshop on Eosinophils in Allergy and Related Diseases 2001.

Highlights: [•] Inhibition of EMT by montelukast was evaluated. [•] EMT was assessed using a co-culture system of epithelial cells and eosinophils. [•] Montelukast inhibited EMT induced in the co-culture system. [•] Montelukast decreased TGF-β1 production and Smad3 phosphorylation. [•] Eosinophils significantly enhanced CysLTs production but montelukast inhibited it. [Copyright &y& Elsevier]