By rapid development of genomics, we are now about to understand the genomic variation among individuals. Comprehension of the genome also accelerate understanding of the transcriptome, the whole transcripts present in a cell. To link such genomic information to the pathogenesis of allergic diseases, the clinicians must understand the human genome and classify an allergic disease further into several subtypes based on genomic and molecular information.

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We studied clinical findings in 16 preterm infants and low birth weight infants with gastrointestinal allergy. milk-specific IgE antibody levels were negative in all cases. Distended abdomen were the most common symptoms, and gastrointestinal allergy show several symptoms diarrhea, bloody stool, vomiting, CRP elevation, fever, liver function failure, respiratory failure. Although the most cases were due to cow's milk, a little case was due to breast milk. allergen-specific lymphocyte stimulation test is considered to be most useful for the diagnosis. nutritional change improved symptoms in all cases.
Because Low birth weight infants and preterm infants compared with term newborn, have poor gastrointestinal function to antigen, there should conduct a careful nutritional management.

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Neonatal and infantile gastrointestinal allergy is a syndrome that bloody stool, vomiting appears in neonate and young infant mainly after taking cow's milk formula. It is called food protein-induced enterocolitis syndrome in English. The number of patients is increasing rapidly from 1995. We experienced more than 60 cases of this disease since 2001, though pathophysiology, diagnosis, and treatment is not defined yet. In this article, I discussed this syndrome in the aspect of a pediatric allergologist, and described the future perspective.

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While food-protein induced enteropathy in infancy is a significant cause of lower gastrointestinal bleeding in infants, the precise mechanism of this disease remains unclear. Main pathogenesis of food-protein induced enteropathy is considered as IgE-dependent, IgE-independent, and mixed reactions, where mixed and IgE-independent reactions, including cell-mediated reactions, are considered as the major cause especially in infancy. There are neutrophils, eosinophils, antigen-specific T cells and IgE involved in its pathogenesis together with the prematurity of host defense, digestion, and immunity. Since eosinophilia is a specific feature of this disease, proteinase released from eosinophils may deeply involve in its pathogenesis. Since there is a disease called the neonatal transient eosinophilia enterocolitis (NTEC), which is a very similar disease to food-protein induced enteropathy in infancy but caused without any allergic reactions, we need to further evaluate the pathogenesis of this disease by finding the effector cells in the intestinal inflammation.

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Gastrointestinal symptoms such as vomiting, bloody stool or diarrhea sometimes develop in bottle-fed neonates or younger infants. Althouth IgE antibody for cow's milk is usually negative in these patients, we demonstrated that allergen-specific lymphocyte stimulation test (ALST) for cow's milk protein was positive in most cases, suggesting that the cell-mediated hypersensitivity against cow's milk plays a critical role in the pathogenesis. Thus, we provisionally named the disease early infantile intestinal cow's milk allergy (ICMA). Although κ-casein and α-lactalbumin is regared as less allergenic than αs-casein or β-lactoglobulin in IgE-mediated cow's milk allergy, they showed a potent capacity to activate lymphocytes in ICMA patients. In contrast to IgE-mediated cow's milk allergy, these proteins seem to make a significant contribution to the development of ICMA as major allergens. ICMA develops not only in bottle-fed but also in breast-fed infants. To explore the cause of this problem, we measured ALST for human α-lactalbumin because it is a major component of breast milk and highly homologous to cow's milk α-lactalbumin. Although ALST for human α-lactalbumin was low in most ICMA patients, some showed increased ALST levels comparable to that for cow's milk counterpart. Thus, cross-reactions of lymphocytes to human α-lactalbumin appears to be related to the development of ICMA in breast-fed infants.

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In Japan, the number of reported cases of food protein-induced enterocolitis syndrome (FPIES) has increased dramatically since 1995. IgE is not generally required for the pathogenesis, and the absence of detection of milk-specific IgE antibodies often makes diagnosis difficult. If diagnosis and treatment of FPIES are delayed, ileus and impaired development can occur. Therefore, Japanese Research Group for Neonatal, Infantile Allergic Disorders has established guidelines to enable prompt diagnosis and treatment of FPIES. We will show here our Consensus Recommendations for Diagnosis and Treatment and on-going research data for making definite diagnostic method.

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In order to clarify relation of nutrition in infants and allergic diseases, we examined allergic disease frequency and pathogenesis mechanism in the breast-feeding infant.
We performed the questionnaire survey to mother at six month after birth, and confirmed the nourishment method and the allergic diseases. In the result, even if exclusive breast-feeding, there was one case which has shown the symptoms of allergic diseases.
The cytokine and the food antigen in breast-milk were examined. TGF-β1 and 2 existed in a high concentration in breast-milk. In breast-milk, food antigens, such as ovalbumin, casein, and gliadin, were detected. A possibility that the cytokine and the food antigen in breast-milk were related to the antigen sensitization and immune tolerance was suggested. At the case who have allergy diseases in spite of exclusive breast-feeding, a possibility that some proteins in breast-milk were acting on endogenous allergen was also suggested.

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To elucidate a role of staphylococcus aureus colonized on the skin in infancy, we performed population based study in Chiba city, in which we examined all the infants who attended regular health check up at 4 months of age for presence and severity of atopic dermatitis and performed skin culture of staphylococcus aureus on the cheeks, then followed them at 18 months and 3 years of age. At 4 months and 18 months of age, frequency of staphylococcal colonization was associated with severity of atopic dermatitis. In addition, staphylococcal colonization in infants without atopic dermatitis was associated with the development of atopic dermatitis in later life. These results suggest that cutaneous colonization with staphylococcus aureus may be involved in not only the increased severity of atopic dermatitis but also the development of the disease in young children. Thus, inhibition of staphylococcus aureus colonization on the skin may be a candidate for prevention of atopic dermatitis in early childhood.

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Several studies have shown an inverse relationship between day care attendance and the development of atopy or serum IgE levels. CD14 is a pattern recognition molecule for bacterial endotoxin and a gene-environmental interaction between the CD14 gene polymorphisms and endotoxin exposure has been shown to affect the development of atopy and allergic diseases. Interleukin 4 receptorα (IL4R) gene is a key gene for IgE production and it has been shown to modify the effect of day care on interferon-γ production in infants. We investigated the interactive relationships between day care attendance and the genetic polymorphisms, and their effect on serum total and specific IgE levels. School children living in a city in Japan participated in this study. Day care attendance in the first 2 years of life (day care) and other possible confounding factors were examined using a questionnaire. We determined total and 8 specific IgE levels in the sera, and genotyped CD14 -550C/T and IL4R Ile50Val. After correction for confounding factors, the interaction between day care and CD14 -550C/T was significant for total IgE and mite-specific IgE, as well as for atopy. The interaction between day care and IL4R Ile50Val was significant for total IgE and mite-specific IgE, but that between CD14-550C/T and IL4R Ile50Val was not significant for any phenotypes. The effect of day care on the total and specific serum IgE levels was affected by genetic backgrounds.

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Frequent upper respiratory infections and exposure to environmental endotoxin during early in life protect infants from subsequent allergic sensitization against airborne antigen and from development of asthma; this phenomenon was referred as to ''Hygiene Hypothesis''. These microbial stimuli shift airborne antigen-specific immune responses towards Th1 through activation of innate immune system. On the other hand, individuals with impaired immune responses against common cold viruses, including respiratory syncytial virus and rhinovirus, or those with impaired responses against bacterial pathogens locally have been shown to have strong risks of subsequent asthma or atopic dermatitis. These local immune responses play critical roles in the development of allergic diseases, and genetic backgrounds of such allergic phenotypes should be further investigated.

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We discussed in this section about of-label usage of pediatric allergic disease at hospital care. Among many of-label medicines continuous inhalation of beta-2 agonists, systemic steroids, and inhaled general anesthesia are important therapy in status asthmatics, however these medicine have of-label problems. It is important to recognize such of-label problems and get approval for using pediatric asthma patients.

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Off-label use in children is common throughout the world and a key issue. Activities resolving these issues have been stepped forward in the U.S. and EU since the 1990s. It have been tried various expedients to achieve the purpose. Because of need for facilitating the development of pediatric trials of therapies for HIV, eventually the following laws were legislated. These are referred to children in whole or in part.
 U.S.: FDA Modernization Act (1997)
  Best Pharmaceuticals for Children Act (2002)
  Pediatric Research Equity Act (2003)
  FDA Amendments Act of 2007
 EU: Paediatric Regulation (2007)
These approaches would promote the pediatric clinical trials and the drug development in the U.S. and EU. We have to work together cooperatively with the U.S. and EU.

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Clinical trials are essential for the evaluation of safety and efficacy of drugs in children. If a drug has been approved in adults without evaluation in children, pediatricians may start to use the drug ''off-labeled''. The Committee on Drugs of the Japan Pediatric Society has been actively involved in solving the off-label use of drugs in children in close corroboration with the Ministry of Health, Labour and Welfare (MHLW). MHLW has started the Study Group on Unapproved Drugs in 2005 and the Study Group on Pediatric Drug Therapy in 2006 to have necessary important pediatric drugs approved rapidly. But these two study groups works on the drugs which have I already been approved in the U.S. and/or E.U., and introduction of stronger regulatory and legal measures similar to the U.S. and the E.U. appears to be necessary for the elimination of approval lags in children. Stronger clinical trial infrastructure is also necessary. Pediatricians have been utilizing sponsor-investigator clinical trials to strengthen clinical trial infrastructure. The MHLW is currently funding 4 children's hospitals to establish a network for pediatric clinical trials. Academia, the regulatory agency and industries must work together for stronger regulatory framework and infrastructure for pediatric drug development in Japan.

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Fraction of exhaled nitric oxide (FeNO) is assumed to be a useful airway inflammation marker in asthmatic patients. We followed up the changes in FeNO values for 60 days in seven children with asthma who hospitalized due to severe asthma attack. The mean FeNO value at hospitalization was 13.5 ppb (8.4∼19.4). Although the mean FeNO level decreased remarkably to 4.9 ppb (2.5∼8.1) after treatment for acute illness, it was in uptrend after leaving hospital. FeNO levels changed to plateau within about 30 days in five out of seven patients, however, further increase of FeNO levels by 20 ppb or more was observed in two remainders. One patient discontinued the drug use including inhaled corticosteroid, the other did not inhale steroid in proper skill. We suppose that regular monitoring of FeNO in asthmatic children may be useful not only for the estimate of airway inflammation, but also in detecting proper drug administration.

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In 2005, we conducted a questionnaire-based evaluation of childhood asthma treatment in Hokuriku district to analyze the current status of the regional medical practice and its potential problems. In the questionnaires, we asked multiple questions including, ages of patients, ages of disease onsets, contents of control medications, if the parents understand precisely the efficacy and the use of medications, current asthma status and quality of life of the patients and the parents, how the parents and the caring physicians evaluate the status of the patients, if the contents of medications changed or the symptoms improved after the initial evaluations. We compared the data obtained from 728 patients who are seen by ''asthma specialists'' and 702 patients who are seen by ''general pediatricians''. There was no difference in the use of control medications between these two groups. There were significant numbers of patients whose asthma symptoms were not controlled well, due to under-evaluation and insufficient medications in both groups. It is important to emphasize the usefulness of JPGL further for the better use of control medications. Development of support materials to enhance effective and easier use of the guideline will help for this purpose.

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Objective and Methods: Using additional data on asthma episodes, activities in school and issues raised by caregivers in Asthma Insights and Reality surveyed in 2005, we sought to describe problems on asthma management practice in child asthma patients and their caregivers.
Results: Participants were 400 children (mean 8.4 years) and their caregivers (mean 39.1 years). At least two unscheduled doctor visits were reported by 68% of patients who has been experienced the event, 84% of patients who experienced school absence repeated same events. Fifteen percent patients (49/318, 5-15 years old) missed to join physical exercise or game at kindergarten/school in the past 1 month. Ninety-one percent of caregivers (337/369) informed teachers about their children's disease. Seventeen percent of caregivers felt teacher had little understanding how to treat asthma patients. Mental/emotional and economic burden in caregivers ware indicated by free comments about issues with asthma.
Conclusions: In Japanese children with asthma, they had limited activities in school life, i.e. frequent school absent and avoiding physical exercise, and caregivers felt mental/emotional and economic burden from asthma. Not to repeat unwanted asthma episodes, keep asthma controlled is essential for both patients and caregivers.

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Background: The study of repeated inhalation of nebulized short-acting β₂-agonists is a little in Japan. Neither the inhalation frequency, the dose of the medicine nor the inhalation interval are necessarily clear.
Method: Twenty five patients who visited the outpatient clinic with acute bronchial asthma exacerbations inhaled 1.5 mg of salbutamol. Three 20-minute interval inhalations or less were done to the case of SpO₂ < 97% or score of wheezing ≥ 2.
Results: All patients obtained an enough recovery clinically ( SpO₂ ≥ 97 or score of wheezing ≤ 1 ) and discharged without any side effects such as significant increase of heart rates, arrhythmia, tremor and palpitation. And we experienced the case who had presented a prompt improvement after it had inhaled two times or three times.
Conclusion: Repeated inhalation of nebulized short-acting β₂-agonists was thought to be a very useful treatment for acute bronchial asthma exacerbations. A further effect can be expected by increasing the dose of one inhalation more than the doses of use now. But, it s guessed that practical increase by repeated inhalation is more effective and safer than increasing the dose of one inhalation.

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Objective: We compared the scores of JPAC and C-ACT, two asthma questionnaire surveys that are useful in the management of asthma therapy based on the pediatric asthma guideline, and investigated the correlation between and interchangeability of the two.
Method: We conducted both the C-ACT and JPAC surveys on 4 to 12 year-old asthma patients and their guardians who visited outpatients at 8 national hospital institutions, and the completed questionnaires were collected from 318 cases. We investigated the correlation between the JPAC and C-ACT scores using Pearson's product-moment correlation coefficient and compared the individual items of JPAC and C-ACT using the χ₂ test.
Results: The correlation coefficient of the JPAC and C-ACT scores of the 318 cases was 0.7525, with p<0.0001, indicating a significant correlation. The linear association of the items of exercise-induced asthma and night-sleep disorder between JPAC and C-ACT was p<0.0001, indicating a significant correlation.
Conclusion: Since the two surveys were correlated with high linear regression of y=1.2544x+6.7672 (r=0.7525, p<0.0001), it is clear that, if a C-ACT score of 26 or more is considered as complete control, 20 to 25 as good control, and below 20 as uncontrolled, it is interchangeable with the JPAC score.

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Two patients with hypersensitivity against cow's milk who presented with elevated serum AST, ALT and CRP levels. Neither non-specific IgE level nor cow's milk-specific IgE was not elevated. Since infancy, they had been suffered from recurrent fever and diarrhea. Lymphocyte proliferative responses for α-casein and cow's milk formula were positive. Their symptoms and serum AST, ALT and CRP levels were normalized by changing the fomula from cow's milk to an amino acid fomula.
In conclusion, features of mimicking infantile hepatitis in these cases may be due to type IV hypersensitivity reaction to cow's milk proteins.

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We assessed the efficacy, safety and convenience of salmeterol (SLM)/fluticasone propionate (FP) combination (SFC) in children with asthma. The study was a 4-week crossover design in which each subject received the two treatments, SFC 25/50μg (one inhalation twice daily by pMDI with counter) and SLM 25μg plus FP 50μg (each one inhalation twice daily by DPI) separated by a 2-week washout period. This was followed by an extension phase in which all subjects who completed the crossover treatment received SFC 25/50μg (one inhalation twice daily by pMDI with counter) for 20 weeks. A total of 51 patients were enrolled in the study. The crossover phase efficacy population consisted of 48 patients (32 males and 16 females; mean age, 8.4 years; range, 5 to 14) with mild persistent asthma (11 patients) or moderate persistent asthma (37 patients). The majority (89.6%) used the Aerochamber Plus^® spacer for inhalations of SFC. In the crossover phase, both treatments showed statistically significant improvements from baseline [SFC: 14.6L/min (p=0.0030) , SLM+FP: 17.0L/min (p=0.0003)] in morning PEF and the difference between the treatment groups was not statistically different. In the assessment of convenience, SFC was rated higher compared with SLM+FP. The SFC pMDI with counter was assessed useful to confirm their inhalations of the drug. Fifty patients entered and completed the extension phase. Improved PEF observed at the end of crossover phase was sustained through the extension phase. SFC was safe and well tolerated through the study. [Trial registration: Clinicaltrials. gov Identifier: NCT00448435]

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