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).

Intermittent and episode-driven use of pranlukast to reduce the frequency of wheezing in atopic children: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Leukotriene receptor antagonist (LTRA) therapy reduces asthma exacerbations in children older than 2 years. However, whether early intervention using LTRA in atopic smaller children aged 1 to 2 years who had experienced episodic wheezing can reduce the frequency of wheezing is unknown. METHODS: A randomized, double-blind, placebo-controlled, multi-center trial of episode-driven intermittent use of pranlukast for 12 months, one of the LTRAs, was conducted by enrolling children who had two, but not more than two, episodes of wheezing prior to entry and were allergen-specific IgE-positive (≥class 2). The primary outcome was increased episodes of wheezing more than once a month for 3 months. RESULTS: Seventy-seven children were randomly assigned to receive pranlukast (n = 37) or placebo (n = 40). The primary outcome occurred in 10 of 36 (28%) of the pranlukast group and 14 of 39 (36%) in the placebo group, which was not significantly different (P = 0.45). Even though the study period was extended to a maximum of >5 years, there was no significant difference in the Kaplan-Meier curves in the occurrence of the primary outcome between the two groups. CONCLUSIONS: These results suggest that intermittent and episode-driven use of pranlukast in small children with a prior history of wheezing and atopic sensitization may not reduce the frequency of wheezing later in life. However, the sample size was too small to make a definitive conclusion. TRIAL REGISTRATION: UMIN000000634.

Effects of sulfur dioxide on the respiratory system of Miyakejima child residents 6 years after returning to the island.

OBJECTIVES: This study investigated the health effects of volcanic gas, mainly sulfur dioxide (SO2), exposure on the children of Miyakejima Island. METHODS: Health checkups were conducted in November from 2006 to 2011. Health effects were evaluated through a self-administered questionnaire on respiratory and irritative symptoms, and spirometry. SO2 was measured continuously from February 2005 onward at six fixed monitoring stations in inhabitable areas. Based on mean SO2 concentration during 3 months before each health checkup, inhabitable areas were classified into three categories: (1) lower (area L); (2) higher (area H-1); and (3) highest (area H-2). RESULTS: Average concentrations (ppb) of SO2 decreased year-by-year and ranged from 11.3 to 2.47 in area L, from 32.2 to 12.2 in area H-1, and from 75.1 to 12.1 in area H-2, respectively. In general, prevalence of respiratory and irritative symptoms was higher in area H-2, and the prevalence decreased year-by-year in all three areas by Cochran-Armitage test for trend. We defined a study population in area L in 2008 as a reference population because we had no unexposed population. Applying a logistic regression model, age-, sex-, and hypersusceptibility-adjusted prevalence odds ratios to the reference population showed clear exposure-dependent increases in some irritative symptoms such as "Irritation and/or pain in throat" and "in eyes," and approximately 30 ppb seemed to be the threshold concentration. Spirometry did not show any significant differences. CONCLUSIONS: Though no pulmonary functions were affected, some subjective symptoms were detected dose-dependently by SO2 exposure concentration in child residents during the 6 years after the eruption.

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.

Effects of ketoprofen for prevention of postoperative cognitive dysfunction in aged rats.

Postoperative cognitive dysfunction is a common geriatric complication that may be associated with increased mortality. Here, we investigated the effects of postoperative analgesia with ketoprofen on cognitive functions in aged animals and compared its effectiveness to morphine. Rats were randomly allocated to one of four groups: isoflurane anesthesia without surgery (group C), isoflurane anesthesia with laparotomy (group IL), and isoflurane anesthesia with laparotomy plus postoperative analgesia with ketoprofen or morphine. There was no difference in postoperative locomotor activity among groups. In group IL, postoperative pain levels assessed by the Rat Grimace Scale significantly increased until 8 h after surgery, which was similarly inhibited by both ketoprofen and morphine. Cognitive function was assessed using radial arm maze testing for 12 consecutive days from postoperative day 3. Results showed that the number of memory errors in group IL were significantly higher than those in goup C. However, both ketoprofen and morphine could attenuate the increase in memory errors following surgery to a similar degree. Conversely, ketoprofen showed no effect on cognitive function in the nonsurgical rats that did not experience pain. Our findings suggest that postoperative analgesia with ketoprofen can prevent the development of surgery-associated memory deficits via its pain-relieving effects.

Preventive effects of multisensory rehabilitation on development of cognitive dysfunction following systemic inflammation in aged rats.

Systemic inflammation can trigger transient or longer-lasting cognitive impairments, particularly in elderly patients. However, its pathogenesis has not been sufficiently clarified. In this study, we explored the potential effects of multisensory rehabilitation on cognitive dysfunction following systemic inflammation using an animal model. Aged male Wister rats were randomly injected intraperitoneally with either saline (control) or lipopolysaccharide (LPS; 5 mg/kg). After injection, both groups of rats were randomly assigned to either of two housing conditions (n = 8 in each condition): a standard cage environment (SC group) or a multisensory early rehabilitation environment (ER group). Cognitive function was examined after 7 days in the assigned environmental condition using a novel object recognition test. In the SC group, the LPS-treated rats showed impaired cognitive function compared with the control animals. These memory deficits were positively correlated with the levels of both tumor necrosis factor (TNF)-α and interleukin (IL)-1ß in the hippocampus. On the other hand, in the LPS-treated ER group, neither cognitive impairment nor an increase in hippocampal levels of both TNF-α and IL-1ß was found. These results imply that early rehabilitation (ER) intervention may be effective in preventing cognitive dysfunction following systemic inflammation via its anti-neuroinflammatory effects.

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.

Efficacy of intravenous immunoglobulin combined with prednisolone following resistance to initial intravenous immunoglobulin treatment of acute Kawasaki disease.

OBJECTIVES: To determine the most effective first-line rescue therapy for intravenous immunoglobulin (IVIG) nonresponders, using IVIG, prednisolone, or both, to prevent coronary artery abnormalities (CAAs). STUDY DESIGN: We retrospectively reviewed the clinical records of 359 consecutive patients with Kawasaki disease who failed to respond to initial IVIG. RESULTS: CAAs up to 1 month after treatment were less common in the IVIG+prednisolone group (15.9%) than in the IVIG group (28.7%, P = .005) and the prednisolone group (30.6%, P = .01). The IVIG+prednisolone group had significantly lower risks of failing to respond to first-line rescue therapy (aOR 0.16, 95% CI 0.09-0.31), CAAs up to 1 month (aOR 0.46, 95% CI 0.27-0.90), and CAAs at 1 month (aOR 0.40, 95% CI 0.18-0.91) than the IVIG group. In the prednisolone and IVIG+prednisolone groups, risk score, day of illness at first-line rescue therapy, prednisolone monotherapy, and resistance to first-line rescue therapy were independent risk factors for CAA. Sex and resistance to first-line rescue therapy were independent risk factors in the IVIG group. CONCLUSIONS: IVIG+prednisolone may be superior to IVIG or prednisolone as first-line rescue therapy in the treatment of IVIG nonresponders. To establish the efficacy of rescue therapy with IVIG+prednisolone following nonresponse to initial IVIG, a prospective randomized trial is warranted.

Visual analog scale as a predictor of GINA-defined asthma control. The SACRA study in Japan.

OBJECTIVE: The assessment of asthma control is pivotal to treatment decisions. A questionnaire that assesses the Global Initiative for Asthma (GINA)-defined control requires four questions. A visual analog scale (VAS) to evaluate asthma control can be simply marked, but its correlation with GINA-defined control has been insufficiently evaluated. The purpose of this study is to evaluate whether VAS levels can predict GINA-defined asthma control with particular emphasis on the distinctions between "partly controlled" and "uncontrolled" and between "partly controlled" and "controlled" asthma, METHODS: A cross-sectional multicenter study was carried out throughout Japan (SACRA) from March to August 2009 among patients with a diagnosis and treatment of asthma. Asthma control was studied using the GINA questionnaire and a VAS measurement of asthma severity. Pulmonary function testing was not carried out, RESULTS: 1910 physicians enrolled 29,518 patients with asthma. 15,051 (51.0%) questionnaires were administered by physicians; patients filled out 14,076 (47.7%) questionnaires themselves. 28,225 (95.6%) of the patients were evaluable. VAS measurement of asthma symptoms was useful in predicting levels of GINA-defined control categories (the area under the receiver operating characteristic curve ranging from 0.704 to 0.837). Patients with "controlled," "partly controlled," and "uncontrolled" asthma were discriminated by VAS levels (1.50, 4.79, and 7.19). Similar results have been obtained with self- and physician-administered questionnaires showing the validity of results. CONCLUSION: Measurement of VAS levels is able to discriminate between patients with "controlled," "partly controlled," and "uncontrolled" asthma. The VAS score could be a simple guide in clinical situations requiring daily or regular evaluation of asthma control.

DNA methylation changes between relapse and remission of minimal change nephrotic syndrome.

BACKGROUND: DNA methylation of gene promoters is associated with transcriptional inactivation. Changes in DNA methylation can lead to differences in gene expression levels and thereby influence disease development. We hypothesized that epigenetics underlies the pathogenesis of minimal change nephrotic syndrome (MCNS). METHODS: Genome-wide DNA methylation changes between relapse and remission in monocytes (n = 6) and naive T helper cells (Th0s) (n = 4) isolated from patients with MCNS were investigated using the microarray-based integrated analysis of methylation by isochizomers (MIAMI) method. We confirmed the MIAMI results using bisulfite-pyrosequencing analysis. Expression analysis was performed using quantitative real-time PCR. RESULTS: Three gene loci (GATA2, PBX4, and NYX) were significantly less methylated in Th0s during relapse than in remission, compared to none in monocytes. In addition, the distance distribution from the regression line of all probes in MIAMI was significantly different between monocytes and Th0s. The mRNA levels of the three genes in Th0s were not significantly different between relapse and remission. CONCLUSIONS: Our results demonstrate that the change in DNA methylation patterns from remission to relapse in MCNS occurs predominantly in Th0s rather than in monocytes and suggest that epigenetic regulation in Th0s underlies the pathogenesis of MCNS.

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.

Efficacy of immunoglobulin plus prednisolone for prevention of coronary artery abnormalities in severe Kawasaki disease (RAISE study): a randomised, open-label, blinded-endpoints trial.

BACKGROUND: Evidence indicates that corticosteroid therapy might be beneficial for the primary treatment of severe Kawasaki disease. We assessed whether addition of prednisolone to intravenous immunoglobulin with aspirin would reduce the incidence of coronary artery abnormalities in patients with severe Kawasaki disease. METHODS: We did a multicentre, prospective, randomised, open-label, blinded-endpoints trial at 74 hospitals in Japan between Sept 29, 2008, and Dec 2, 2010. Patients with severe Kawasaki disease were randomly assigned by a minimisation method to receive either intravenous immunoglobulin (2 g/kg for 24 h and aspirin 30 mg/kg per day) or intravenous immunoglobulin plus prednisolone (the same intravenous immunoglobulin regimen as the intravenous immunoglobulin group plus prednisolone 2 mg/kg per day given over 15 days after concentrations of C-reactive protein normalised). Patients and treating physicians were unmasked to group allocation. The primary endpoint was incidence of coronary artery abnormalities during the study period. Analysis was by intention to treat. This trial is registered with the University Hospital Medical Information Network clinical trials registry, number UMIN000000940. FINDINGS: We randomly assigned 125 patients to the intravenous immunoglobulin plus prednisolone group and 123 to the intravenous immunoglobulin group. Incidence of coronary artery abnormalities was significantly lower in the intravenous immunoglobulin plus prednisolone group than in the intravenous immunoglobulin group during the study period (four patients [3%] vs 28 patients [23%]; risk difference 0·20, 95% CI 0·12-0·28, p<0·0001). Serious adverse events were similar between both groups: two patients had high total cholesterol and one neutropenia in the intravenous immunoglobulin plus prednisolone group, and one had high total cholesterol and another non-occlusive thrombus in the intravenous immunoglobulin group. INTERPRETATION: Addition of prednisolone to the standard regimen of intravenous immunoglobulin improves coronary artery outcomes in patients with severe Kawasaki disease in Japan. Further study of intensified primary treatment for this disease in a mixed ethnic population is warranted. FUNDING: Japanese Ministry of Health, Labour and Welfare.

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.

Japanese guideline for food allergy.

Food allergy is defined as "a phenomenon in which adverse reactions (symptoms in skin, mucosal, digestive, respiratory systems, and anaphylactic reactions) are caused in living body through immunological mechanisms after intake of causative food." Various symptoms of food allergy occur in many organs. Food allergy falls into four general clinical types; 1) neonatal and infantile gastrointestinal allergy, 2) infantile atopic dermatitis associated with food allergy, 3) immediate symptoms (urticaria, anaphylaxis, etc.), and 4) food-dependent exercise-induced anaphylaxis and oral allergy syndrome (i.e., specific forms of immediate-type food allergy). Therapy for food allergy includes treatments of and prophylactic measures against hypersensitivity like anaphylaxis. A fundamental prophylactic measure is the elimination diet. However, elimination diets should be conducted only if they are inevitable because they places a burden on patients. For this purpose, it is highly important that causative foods are accurately identified. Many means to determine the causative foods are available, including history taking, skin prick test, antigen specific IgE antibodies in blood, basophil histamine release test, elimination diet test, oral food challenge test, etc. Of these, the oral food challenge test is the most reliable. However, it should be conducted under the supervision of experienced physicians because it may cause adverse reactions such as anaphylaxis.