Japanese Pediatric Guideline for the Treatment and Management of Asthma (JPGL) is a rare sample in the world, being specialized for children only. Though it is impossible, and not ideal to set up an uniformalized guideline worldwide because of complicated medical situations in each country, comparison of guidelines is a meaningful way to improve ours furthermore. The mainstay of long-term pharmacological management is inhaled corticosteroids (ICS) unexceptionally, though JPGL has put leukotriene receptor antagonists before ICS for children younger than 2 years. The maximal doses of ICS recommended in each GL have been lowered. There are substantial differences in the pharmacological management of asthma exacerbations. Overseas GLs recommend inhaled anti-cholinergic agents and intravenous Mg, and are reluctant to use theophylline, and do not refer to inhaled isoproterenol at all.
To be simple and easy to follow is a fundamental requisite for GL. We need to show more evident attitudes of evidence-based-medicine. In Japan, we could develop GL of highest level in the world.

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In order to investigate the influence of the revised edition of Japanese Pediatric Guideline for the Treatment and Management of Asthma (JPGL) 2005 on the treatment for pediatric asthma patients, we compared the survey for pediatricians in 2006, one year after the publication of JPGL2005, with that in 2005, just before the publication of JPGL2005. A scoring system was introduced to correct some problems that the questionnaires had included, and the survey in 2003 was also referred to.
Regarding the treatment for acute asthma exacerbations, fewer pediatricians selected intravenous xanthines, while the use of systemic steroids increased. Continuous nebulizations of isoproterenol for severe attacks and mechanical ventilations with intratracheal intubations for respiratory failure also increased. Those changes were stronger from 2005 to 2006 than those from 2003 to 2005, clearly indicating the influence of JPGL2005 on the treatment for acute asthma attacks.
As for the controller medications, a decrease in sustained release theophyllines and an increase in inhaled cortico-steroids were observed after the publication of JPGL2005. On the other hand, leukotriene receptor antagonists had already increased before JPGL2005 was published.
This study showed the strong influences of JPGL2005 on asthma treatment in children, although JPGL2005 still has many problems. As well as the further diffusion of JPGL, further improvement is necessary.

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Characterize the pathophysiology of pediatric asthma made rapid progress over the last decade. Its therapeutic strategy also changed to anti-inflammatory therapy for chronic bronchial inflammation. Points that need to be clarify in the next decade are when anti-inflammatory therapy starts in infant asthma, building consensus of asthma control to reach therapeutic destination and developing method to step down anti-inflammatory therapy.
GINA and EPR-3 have changed gradually and describe these points. We are not merely for making copy of guideline abroad but also developing original guideline in consideration of social background.

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[in Japanese]

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Allergic diseases such as atopic asthma are considered multifactorial disorders involved in both genetic and environmental factors. To identify genes conferring susceptibility for allergic diseases, candidate gene approaches and the genome-wide linkage studies have been carried out in different ethnic populations, and several susceptibility genes have been identified. Recent advance of the technology enable us to perform genome-wide association study using hundreds of thousands SNPs to identify susceptibility genes for common diseases, and ORMDL3, CRIM1, and PEX 19 have been identified as new susceptibility genes for asthma. Also, by combining data of microarray analysis and whole genome-wide SNP analysis, global map of the effects of SNPs on gene expression has been created and easy-to-use software is available on the website. These advance in analytical tools and technologies will promote the discovery of the genetic basis of allergic diseases in the future.

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A DNA microarray (also commonly known as DNA chip or GeneChip) is a collection of microscopic DNA spots, commonly representing single genes, arrayed on a solid surface by covalent attachment to a chemical matrix, and allow us to quantify expression levels of multiple genes at one time. The remarkable progress and significant advances in the computer technology and the genetic information facilitated the microarray technology contributing to the progress in the allergy study as an extremely powerful screening tool. The usage was extended over the many divergences such as comprehensive transcriptome profiling of inflammatory cells, the analysis of the signal transduction cascade of inflamed cells, and the analysis of the pathogenesis of allergic diseases. The progress of this methodology realized the comprehensive analysis of the full potentials of different cell types playing some roles in the formation of allergic inflammation, and revealed many unknown cellular functions and interactions between them. It is thought that the microarray technology will play an important role in drawing the total picture of the networks of life activity involving all molecules, proteins and enzymes in an individual (so-called Systems Biology) as well as in the realization of the tailor-made medicine through analyzing disease pathogenesis in different individuals in detail.

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Exhaled nitric oxide (eNO) has been identified as a potential indicator of asthmatic airway inflammation. It has become apparent that elevated levels of eNO related to the degree of atopy (e.g., peripheral blood eosinophilia and serum IgE) and airway inflammation (e.g., eosinophils and their markers) in children. Also asthmatic children with elevated levels of eNO suffered from exercise induced asthma. In children with asthma who have not been treated with inhaled corticosteroid (ICS), eNO related with bronchial hyperresponsiveness (BHR).
In our study, eNO was associated with BHR in children. We observed also a weak association between eNO and both BHR and airway obstruction in adolescent. Therefore eNO measurement may be used to prescreen BHR in asthmatic children under 12 years old. On the other hand, eNO measurement was reported useful predictor of failed ICS reduction with asthmatic child.
In asthmatic children, measurement of eNO is simple and time-efficient, and noninvasive and safety tool.

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Chronic airway inflammation is central in the pathophysiology of bronchial asthma. However, clinical markers to evaluate airway inflammation are not available. Sputum cytology can be a useful and non-invasive clinical marker.
By monitoring eosinophils in induced sputum, we can observe the time course of airway eosinophil inflammation not only in acute phase, but also in stable phase after starting controllers such as inhaled corticosteroids, leukotriene antagonists, and long-acting beta agonists. In case of infantile asthma, suction sputum cytology can be obtained to determine the diagnosis and treatment.

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Tools for evaluation which can objectively indicate severity of disease are necessary for a proper diagnosis and treatment of asthma. Especially in children with asthma or wheezing, proper method with non invasiveness, safety and specificity is required. Exhaled breath condensate (EBC) is expected as a safe, comparatively handy, non-invasive method for airway inflammation evaluation. The analysis results of various oxidative-stress markers and eicosanoids, etc. have been reported. We also showed that exhaled LTE₄ levels were increased in all children with mild asthma compared with non-asthmatic controls, and that the EBC LTE₄ levels negatively correlated with methacholine PC₁₅. Clinical application will expand, if the sample collection efficacy and handiness can be improved.

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Airway dysfunction can be appreciated by lung function testing, performing these tests can be difficult in infant. We studied whether breath sound may reflect subtle airway dysfunction in asymptomatic asthmatic children.
We performed sound spectrographic analysis of breath sounds in asymptomatic asthmatic children and found correlations between highest frequency of inspiratory breath sounds (HFI) and lung function in the absence of acute asthmatic symptoms. As a result, higher HFI in asymptomatic asthmatic children indicate small airway obstruction.

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Exercise has been shown as not only exacerbating factor, but also therapeutic method for bronchial asthma. We reviewed literatures on asthma prevalence in athletes, cohort studies regarding exercise and asthma, and exercise therapy of asthma.
The athletes of winter sports, endurance sports, and swimming have high asthma prevalence. The risk of ozone exposure during outdoor sports and chloride gas exposure during indoor swimming for asthma has also been suggested. On the other hand, exercise has been reported to have beneficial effects on cardiorespiratory fitness and to reduce asthma symptoms although no effect on lung function and airway hyperresponsiveness has been observed.
We also discussed about the effect of swimming exercise on asthma control and the relationship between obesity and asthma.

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We have experienced 13 cases of food-induced anaphylactic shock out of 25,574 patients who visited our emergency room between 2003 and 2005. Patients ranged in age from 6 months through to 15 years and about half of them were under 2. Nine patients were male and 4 were female. In 5 of the cases the causative agent was found to be egg, whilst two cases were fish or the remaining cases were believed to be caused variously by peanuts, wheat and a peach. The causes of additional 3 cases were unknown.
Four of the patients, all of whom were male, have repeatedly suffered from anaphylactic shock. The patients aged 1 and 4 had eaten egg by mistake, whereas the 11 and 15 year olds were diagnosed with food-dependent exercise-induced anaphylaxis which they had previously failed to recognize.
In 8 patients, onset of reaction occurred within 10 minutes of ingestion of the causative food substance, making the majority of cases. The time from onset to arrival at hospital is dependent primarily on the distance to hospital, and presentation of symptoms. No patient arrived at hospital within 30 minutes after onset of symptoms, and another 9 arrived within 31-60 minutes.
Considering the time from onset to arrival at hospital, and thus the delayed time before professional medical treatment can be administrated, it is highly advisable for diagnosed sufferers of anaphylactic shock to carry self-injectable epinephrine as a preventative measure. It is also important to recognize food allergy and anaphylactic shock in schools, as well as informing patients and guardians.

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An open long-term extension study was conducted to investigate long-term safety of the budesonide inhalation suspension in infants with bronchial asthma, following an open, randomized, parallel-group study to investigate efficacy and safety of 24-week treatment of the drug. Of the 57 patients who completed the open, randomized, parallel-group study, 54 patients entered this study and all were evaluated for safety. The treatment period was 34 to 144 weeks (mean 102 weeks). The adverse event profile observed in this study was comparable to that in the open, randomized, parallel-group study, i.e., there were no new clinically relevant adverse events and frequency of adverse events did not increase along with the treatment extension. The mean plasma cortisol values were below the baseline of the open, randomized, parallel-group study throughout the treatment period, however, no further decrease was observed and there were no signs or symptoms suggesting adrenal suppression. No effects on growth were observed. Efficacy rate determined by the investigator was 80% or higher through the period of the study. The long-term treatment with budesonide inhalation suspension (maximum 168 weeks including the open, randomized, parallel-group study) in infants with bronchial asthma is suggested to be safe and effective.

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We compared plasma concentrations of disodium cromoglycate (DSCG) between 16 asthmatic children using an ultrasonic nebulizer (NE-U07; n=14) and a compressed air nebulizer (Voyage; n=7) to estimate drug accessibility to the lung. Mean plasma concentration of DSCG at 5 min and 30 min after inhalation, and the mean area under the curve up to 30 min after inhalation in NE-U07 group (7.47ng/ml, 6.00ng/ml, 187.09min · ng/ml) were higher than those in Voyage group (3.17ng/ml, 2.50ng/ml, 78.81min · ng/ml) significantly (p=0.03, p=0.002, p=0.001, respectively). The percentage of patients whose plasma concentrations of DSCG at 5 min after inhalation were exceeded 4ng/ml, the level of which was reported to be more effective to protect asthmatic attacks, was higher in NE-U07 group (86%) than in Voyage group (29%). Moreover, the number of patients who has effective plasma concentrations of DSCG was significantly differed between two types of nebulizers (p=0.05). We estimated that, in asthmatic children, the amount of DSCG accessible to the lung using ultrasonic nebulizers might be more than that using compressed air nebulizers. These results were confirmed by our previous report in healthy adults.

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Objectives: We developed a JPAC questionnaire that can easily determine severity and control status to study its usefulness, in order to ensure that the asthma guideline-based care management is appropriately performed.
Methods: Severity is determined based on 3 questions regarding asthma symptoms, respiratory distress, and impairment of daily activities in the JPAC questionnaire, and control status is determined by adding another 2 questions regarding exercise-induced asthma and the frequency of using a β₂-agonist. Using this questionnaire, the relationship between the JPAC score, severity, and the results of a respiratory functions test was studied in 225 asthma patients aged 5 to 19 who were seen at Shimoshizu Hospital.
Results: There was a significant correlation between increasing severity and a low JPAC score with p<0.0001 in the Jonckheere-Terpstra test.
The mean ± S.D. of the JPAC score at each severity as determined based on the severity and frequency of symptoms were 15±0 for remission, 14.9±0.3 for intermittent asthma, 13.1±1.2 for mild persistent asthma, 9.2±1.0 for moderate persistent asthma, and 7.0±2.4 for severe persistent asthma, and were also consistent with the established control standard of a score of 15 indicatuing complete control, a score of 12-14 indicating good control, and a score of 11 or less indicating poor control.
Analysis of variance showed a significant correlation between JPAC score and the respiratory function tests with p<0.0001 for %FEV_1.0, %MMF, and %V₅₀
Conclusion: JPAC is suited to determine severity and control status in asthma patients, and will help to spread guideline-based care.

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