Japanese guidelines for childhood asthma 2017.

The Japanese Guideline for the Diagnosis and Treatment of Allergic Diseases 2017 (JAGL 2017) includes a minor revision of the Japanese Pediatric Guideline for the Treatment and Management of Asthma 2012 (JPGL 2012) by the Japanese Society of Pediatric Allergy and Clinical Immunology. The section on child asthma in JAGL 2017 provides information on how to diagnose asthma between infancy and adolescence (0-15 years of age). It makes recommendations for best practices in the management of childhood asthma, including management of acute exacerbations and non-pharmacological and pharmacological management. This guideline will be of interest to non-specialist physicians involved in the care of children with asthma. JAGL differs from the Global Initiative for Asthma Guideline in that JAGL emphasizes diagnosis and early intervention of children with asthma at <2 years or 2-5 years of age. The first choice of treatment depends on the severity and frequency of symptoms. Pharmacological management, including step-up or step-down of drugs used for long-term management based on the status of asthma control levels, is easy to understand; thus, this guideline is suitable for the routine medical care of children with asthma. JAGL also recommends using a control test in children, so that the physician aims for complete control by avoiding exacerbating factors and appropriately using anti-inflammatory drugs (for example, inhaled corticosteroids and leukotriene receptor antagonists).

Induction of the Matrix Metalloproteinase 13 Gene in Bronchial Epithelial Cells by Interferon and Identification of its Novel Functional Polymorphism.

Matrix metalloproteinases (MMPs) are a class of extra-cellular and membrane-bound proteases involved in a wide array of physiological and pathological processes including tissue remodeling, inflammation, and cytokine secretion and activation. MMP-13 has been shown to be involved in lung diseases such as acute lung injury, viral infections, and chronic obstructive pulmonary disease; however, the molecular pathogenesis of MMP-13 in these conditions is not well understood. In this study, we investigated the mechanisms and roles of MMP-13 secretion in human small airway epithelial cells (SAECs) and functional polymorphisms of the MMP13 gene. Polyinosinic-polycytidylic acid (poly(I:C)) and interferon ß (IFN-ß) stimulated the secretion of MMP-13 from SAECs by more than several hundred-fold. Stimulation of the secretion by poly(I:C) was abolished by SB304680 (p38 inhibitor), LY294002 (PI3K inhibitor), Janus kinase (JAK) inhibitor I, RNA-activated protein kinase (PKR) inhibitor, and Bay 11-7082 (NF-κB inhibitor), while stimulation by IFN-ß was inhibited by all except Bay 11-7082. These data suggested that the secretion of MMP-13 was mediated through IFN receptor pathways independently of nuclear factor kappa B (NF-κB) and that poly(I:C) stimulated IFN secretion in an NF-κB-dependent manner from SAECs, leading to IFN-stimulated MMP-13 secretion. Chemical MMP-13 inhibitors and MMP-13 small interfering RNA (siRNA) inhibited IFN-stimulated secretion of interferon gamma-inducible protein 10 (IP-10) and regulated on activation, normal T-cell expressed and secreted (RANTES), suggesting that MMP-13 is involved in the secretion of these virus-induced proinflammatory chemokines. We identified a novel functional polymorphism in the promoter region of the MMP13 gene. The MMP13 gene may play important roles in defense mechanisms of airway epithelial cells.

Interleukin-10 and interleukin-5 balance in patients with active asthma, those in remission, and healthy controls.

BACKGROUND: The immunological mechanisms of asthma remission remain unclear although several reports have suggested that balance between T helper (Th) 2 cytokines and regulatory cytokines is related. OBJECTIVE: To study the balance between interleukin (IL) 10 and IL-5 in asthma clinical remission. METHODS: We measured the numbers of IL-5 and IL-10 producing cells in peripheral blood mononuclear cells stimulated with mite antigen obtained from patients with active asthma (group A, n = 18), patients in clinical remission (group R, n = 15) and nonatopic healthy controls (group H, n = 14). RESULTS: The numbers of IL-5 producing cells in groups A and R were significantly higher than in group H. The number of IL-5 producing cells was lower in group R than in group A, although the difference was not statistically significant. The number of IL-10 producing cells was higher in group R than in group A, although again the difference was not statistically significant. There was a significant difference in the number of IL-10 producing cells between groups A and H but not between groups R and H. The ratio of the number of IL-10 to IL-5 producing cells was highest in group H followed by groups R and A, and the differences were statistically significant for each pair of groups. CONCLUSION: Our study suggests that the IL-10/IL-5 balance is related to clinical asthma. The balance differs between patients in clinical remission and healthy controls, suggesting that allergic inflammation may continue even after clinical asthma remission.

Caregiver treatment satisfaction is improved together with children's asthma control: Prospective study for budesonide monotherapy in school-aged children with uncontrolled asthma symptoms.

BACKGROUND: If asthmatic children cannot obtain sufficient control of their disease, not only do they suffer from asthma symptoms, but the daily life activities of their caregivers are also disrupted. We investigated the effectiveness of an inhaled corticosteroid (ICS) for symptom control in previously ICS-untreated school-aged asthmatic children as well as caregiver treatment satisfaction (CTS). METHODS: A multicenter, open-label, single-arm study on 12-week ICS (budesonide Turbuhaler®) monotherapy was undertaken in subjects aged 5-15 years with bronchial asthma not treated with ICS during the previous 3 months. At 0, 4, 8, and 12 weeks after start of ICS administration, Japanese Pediatric Asthma Control Program (JPAC) scores, and CTS scores were summated and lung function measured. At weeks 0 and 12, questionnaires on caregiver anxiety were also assessed. RESULTS: Seventy-five patients were enrolled, and 69 assessed. Ninety percent of subjects had been treated with asthma controller medication except ICS before study enrollment. JPAC score and CTS score were improved significantly at weeks 4, 8, and 12 (p < 0.001). With regard to CTS, more than half of caregivers showed a perfect score at weeks 8 and 12. There was a significant correlation between JPAC score and CTS score. Lung function and caregiver anxiety were also improved, and good compliance with treatment was observed during the intervention. CONCLUSIONS: If treating ICS-untreated school-aged asthmatic children with uncontrolled symptoms, ICS monotherapy can improve CTS along with improving asthma control.

Environmental tobacco exposure is associated with vaccine modified measles in junior high school students.

Vaccine modified measles (VMM) affects individuals with attenuated vaccine induced immunity. An outbreak of measles occurred in a junior high school, starting from an unvaccinated eighth-grade student who developed natural measles and affected a majority of students who were immunized with a low potent strain of measles vaccine (TD97). To determine whether environmental tobacco smoke (ETS) exposure was associated with the development of VMM in this population, a questionnaire was used asking whether students had VMM symptoms during the outbreak and the smoking status of family members. VMM was defined in the study population as occurrence of fever and/or erythema, along with documented history of measles vaccination. A total of 513 students (85.9%) responded. Overall, the presence of in-house smokers did not differ between VMM students (49.3%) and non-VMM students (50.2%). However, in the ninth grade, presence of an in-house smoker was significantly higher in the family of VMM students (54.0%) than in non-VMM students (36.6%) (P = 0.044). Urinary cotinine levels were also measured in selected students (n = 37). Among families with at least one smoker, urinary cotinine levels were significantly higher in VMM students than in non-VMM students (P = 0.032). Furthermore, a multivariable logistic regression analysis showed that a high urinary cotinine level (>10 ng/mg creatinine; 13.5 percentile) was associated with the development of VMM. Our findings suggest that a high level of ETS exposure may be associated with an increased risk of VMM in a population with attenuated vaccine induced immunity against measles.

Japanese pediatric guideline for the treatment and management of bronchial asthma 2012.

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.

Japanese Guideline for Childhood Asthma 2014.

The Japanese Guideline for the Diagnosis and Treatment of Allergic Diseases 2013 (JAGL 2013) describes childhood asthma after the Japanese Pediatric Guideline for the Treatment and Management of Asthma 2012 (JPGL 2012) by the Japanese Society of Pediatric Allergy and Clinical Immunology. JAGL 2013 provides information on diagnosis by age group from infancy to puberty (0-15 years of age), treatment for acute exacerbations, long-term management by anti-inflammatory drugs, daily life guidance, and patient education to allow non-specialist physicians to refer to this guideline for routine medical treatment. JAGL differs from the Global Initiative for Asthma Guideline (GINA) in that JAGL emphasizes early diagnosis and intervention at <2 years and 2-5 years of age. A management method, including step-up or step-down of long-term management drugs based on the status of asthma control levels, as in JAGL, is easy to understand, and thus the Guideline is suitable as a frame of reference for routine medical treatment. JAGL has also introduced treatment and management using a control test on children, recommending that the physician aim at complete control by avoiding exacerbation factors and by appropriate use of anti-inflammatory drugs.

Japanese Guideline for Childhood Asthma 2014.

The Japanese Guideline for the Diagnosis and Treatment of Allergic Diseases 2013 (JAGL 2013) describes childhood asthma after the Japanese Pediatric Guideline for the Treatment and Management of Asthma 2012 (JPGL 2012) by the Japanese Society of Pediatric Allergy and Clinical Immunology. JAGL 2013 provides information on diagnosis by age group from infancy to puberty (0-15 years of age), treatment for acute exacerbations, long-term management by anti-inflammatory drugs, daily life guidance, and patient education to allow non-specialist physicians to refer to this guideline for routine medical treatment. JAGL differs from the Global Initiative for Asthma Guideline (GINA) in that JAGL emphasizes early diagnosis and intervention at <2 years and 2-5 years of age. A management method, including step-up or step-down of long-term management drugs based on the status of asthma control levels, as in JAGL, is easy to understand, and thus the Guideline is suitable as a frame of reference for routine medical treatment. JAGL has also introduced treatment and management using a control test on children, recommending that the physician aim at complete control by avoiding exacerbation factors and by appropriate use of anti-inflammatory drugs.

Association study of matrix metalloproteinase-12 gene polymorphisms and asthma in a Japanese population.

BACKGROUND: Matrix metalloproteinase 12 gene (MMP12) has been shown to be associated with asthma in a Caucasian population. In this study, we investigate whether single-nucleotide polymorphisms (SNPs) of MMP12 are associated with a risk for asthma in a Japanese population. METHODS: We tested for an association between SNPs in MMP12 and asthma, including its severity, in a Japanese population (630 pediatric and 417 adult patients with atopic asthma and 336 children and 632 adults as controls). The rs652438 A and G variants (N357S) were generated by site-directed mutagenesis and an assay with artificial peptide substrates was used to compare two types of MMP12 activity. The effect of MMP12 inhibition with MMP12-specific small interfering RNA (siRNA) on chemokine secretion from airway epithelial cells was also tested in vitro. RESULTS: N357S showed a p value <0.05 for childhood and combined (adult plus childhood) asthma in the dominant model [odds ratio (OR) 1.60, 95% confidence interval (CI) 1.00-2.56, p = 0.047; OR 1.40, 95% CI 1.04-1.89, p = 0.028, respectively]. This risk variant is associated with asthma severity in adult patients. In the functional assay, the minor-allele enzyme showed significantly lower activity than the major-allele enzyme. MMP12-specific siRNA suppressed IP-10 secretion from airway epithelial cells upon stimulation with IFN-ß. CONCLUSIONS: Our results suggest that MMP12 confers susceptibility to asthma and is associated with asthma severity in a Japanese population. MMP12 may be associated with asthma through inappropriate attraction of leukocytes to the inflamed tissue.

Effects of the tulobuterol patch on the treatment of acute asthma exacerbations in young children.

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.

Effects of the tulobuterol patch on the treatment of acute asthma exacerbations in young children.

The tulobuterol patch (TP) is a beta2-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.

Japanese guideline for adult asthma.

Adult bronchial asthma (hereinafter, asthma) is characterized by chronic airway inflammation, reversible airway narrowing, and airway hyperresponsiveness. Long-standing asthma induces airway remodeling to cause an intractable asthma. The number of patients with asthma has increased, while the number of patients who die from asthma has decreased (1.7 per 100,000 patients in 2009). The aim of asthma treatment is to enable patients with asthma to lead a healthy life without any symptoms. A partnership between physicians and patients is indispensable for appropriate treatment. Long-term management with agents and elimination of causes and risk factors are fundamental to asthma treatment. Four steps in pharmacotherapy differentiate mild to intensive treatments; each step includes an appropriate daily dose of an inhaled corticosteroid (ICS), varying from low to high doses. Long-acting ß(2) agonists (LABA), leukotriene receptor antagonists, and theophylline sustained-release preparation are recommended as concomitant drugs, while anti-IgE antibody therapy is a new choice for the most severe and persistent asthma. Inhaled ß(2) agonists, aminophylline, corticosteroids, adrenaline, oxygen therapy, etc., are used as needed against acute exacerbations. Allergic rhinitis, chronic obstructive pulmonary disease (COPD), aspirin induced asthma, pregnancy, and cough variant asthma are also important factors that need to be considered.

Japanese guideline for childhood asthma.

The Japanese Guideline for the Diagnosis and Treatment of Allergic Diseases 2010 (JAGL 2010) describes childhood asthma based on the Japanese Pediatric Guideline for the Treatment and Management of Asthma 2008 (JPGL 2008) published by the Japanese Society of Pediatric Allergy and Clinical Immunology. JAGL 2010 provides information on diagnosis by age groups from infancy to puberty, treatment for acute exacerbations, long-term management by medication, daily life guidance, and patient education to allow physicians, not specialized in childhood asthma, to refer to this guideline for routine medical treatment. JAGL differs from the Global Initiative for Asthma Guideline (GINA) in that the former emphasizes long-term management of childhood asthma based on asthma severity and early diagnosis and intervention at <2 years and 2-5 years of age. However, a management method, including step-up or step-down of long-term management agents based on the status of asthma symptoms, is easy to understand and thus JAGL is suitable for routine medical treatment. JAGL also introduced treatment and management using a control test for children, recommending treatment and management aimed at complete control through avoiding exacerbation factors and appropriate use of antiinflammatory agents.

Effect of hourly concentration of particulate matter on peak expiratory flow in hospitalized children: a panel study.

BACKGROUND: Little information is available on the possible association between hourly short-term air pollution and peak expiratory flow (PEF) in asthmatic children. METHODS: PEF was measured twice daily, from October through December, 2000, in 17 children aged 8 to 15 years hospitalized with severe asthma. A total of 1198 PEF measurements were made at 7 a.m. and 1175 at 7 p.m. Measurements were conducted immediately prior to medication under the guidance of trained nurses. PEF changes were estimated in 10-µg/m3 increments of particulate matter with a 50% cut-off aerodynamic diameter of ≤2.5 µm (PM2.5), with adjustment for sex, age, height, and temperature. Lagged-hour exposures of up to 24 hours were examined. RESULTS: Increased 24-hour mean concentration of PM2.5 was associated with a decrease in both morning and evening PEF (-3.0 l/minute; 95%CI: -4.6, -1.4 and -4.4 l/minute; 95%CI: -7.1, -1.7, respectively). In addition, hourly concentrations of PM2.5 and PEF showed a significant association between some lags of PM2.5 and PEF. Effect size was almost -3 l/minute in both morning and evening PEF for an hourly PM2.5 concentration of 10 µg/m3 in several lags. Even after adjustment for other air pollutants, some of the significant associations with PEF remained. CONCLUSION: Among hospitalized children with severe asthma, increased hourly concentration of PM2.5 was associated with a decrease in PEF.

Japanese pediatric guidelines for the treatment and management of bronchial asthma 2008.

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.

Effects of airborne particulate matter on respiratory morbidity in asthmatic children.

BACKGROUND: The effects of airborne particulate matter (PM) are a major human health concern. In this panel study, we evaluated the acute effects of exposure to PM on peak expiratory flow (PEF) and wheezing in children. METHODS: Daily PEF and wheezing were examined in 19 asthmatic children who were hospitalized in a suburban city in Japan for approximately 5 months. The concentrations of PM less than 2.5 mum in diameter (PM(2.5)) were monitored at a monitoring station proximal to the hospital. Moreover, PM(2.5) concentrations inside and outside the hospital were measured using the dust monitor with a laser diode (PM(2.5(LD))). The changes in PEF and wheezing associated with PM concentration were analyzed. RESULTS: The changes in PEF in the morning and evening were significantly associated with increases in the average concentration of indoor PM(2.5(LD)) 24 h prior to measurement (-2.86 L/min [95%CI: -4.12, -1.61] and -3.59 L/min [95%CI: -4.99, -2.20] respectively, for 10-mug/m(3) increases). The change in PEF was also significantly associated with outdoor PM(2.5(LD)) concentrations, but the changes were smaller than those observed for indoor PM(2.5(LD)). Changes in PEF and concentration of stationary-site PM(2.5) were not associated. The prevalence of wheezing in the morning and evening were also significantly associated with indoor PM(2.5(LD)) concentrations (odds ratios = 1.014 [95%CI: 1.006, 1.023] and 1.025 [95%CI: 1.013, 1.038] respectively, for 10-microg/m(3) increases). Wheezing in the evening was significantly associated with outdoor PM(2.5(LD)) concentration. The effects of indoor and outdoor PM(2.5(LD)) remained significant even after adjusting for ambient nitrogen dioxide concentrations. CONCLUSION: Indoor and outdoor PM(2.5(LD)) concentrations were associated with PEF and wheezing among asthmatic children. Indoor PM(2.5(LD)) had a more marked effect than outdoor PM(2.5(LD)) or stationary-site PM(2.5).

[Additive effect of intravenous prednisolone for acute severe asthma in infants and toddlers: a randomized controlled clinical trial].

BACKGROUND: The efficacy of systemic corticosteroids for infants and toddlers with acute severe asthma has been inadequately evaluated. OBJECTIVE: The purpose of this study was to evaluate the additive efficacy of intravenous prednisolone in a randomized controlled study in the management of infants and toddlers with acute severe asthma. METHODS: Sixty-two patients (aged 8 to 70 months) hospitalized with status asthmaticus were studied. They were randomized into two groups. One group received intravenous prednisolone treatment (1 approximately 3 mg/kg/day, 3 days); the other group served as a control. Each group received continuous aminophylline infusion and low-dose continuous isoproterenol inhalation by an Inspiron nebulizer. They were monitored their heart rate, respiratory rate and symptoms (Wood's clinical score). RESULTS: Each group showed rapid improvement in heart rate, respiratory rate and clinical score by low-dose continuous isoproterenol inhalation. There were no significant differences in the time course of these clinical indexes or the duration of aminophylline infusion, continuous isoproterenol inhalation and hospital stay. CONCLUSION: This study failed to confirm the additive benefit of intravenous prednisolone in the management of infants and toddlers with acute severe asthma.