Bioactive lipid mediators such as prostaglandins, thromboxanes and leukotrienes play significant roles as modulators in pathogenesis of inflammatory, allergic and neoplastic diseases. These bioactive substances are synthesized through an activation of a series of synthesizing enzymes. The production of these substances is primarily regulated by different distribution of synthesizing enzymes. In addition, new induction of synthesizing enzymes at mRNA levels by external and/or internal stimulation has been elucidated as another important mechanism regulating production of these lipid mediators.

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Detection of food allergen-specific IgE antibodies indicates the diagnosis of food allergy with high sensitivity. On the other hands, false positive detection, where specific IgE antibody is positive in the sera from non-symptomatic patient, is common. For that reason, usage of specific IgE testing in the clinic is limited to estimate the probability of true diagnosis at the given IgE titers (positive predictive value). But if you compare the IgE titers to the related food allergens and consider their cross-reactivity, you may approach to the true diagnosis more easily without oral food challenge. Development of allergen component-specific IgE testing (component-resolved diagnositics) is currently progressed to improve the sensitivity and specificity of the specific IgE testing.

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The oral food challenge test (OFC) is the most reliable diagnostic procedure of the food allergy to confirm presence or absence of symptom provocation after intake suspected foods. The Japanese Society of Pediatric Allergy and Clinical Immunology issued the ‘Japanese Pediatric Guideline for Oral Food Challenge Test in Food Allergy2009’ in 2009 aiming at standardization of test in our country. The OFC is applied for confirm the food allergy in cases; 1) immediate allergy symptom after intake foods, 2) the infants atopic dermatitis having the specific food IgE antibody and 3) tolerance of food allergy. It is important to judge adaptation of test in reference to a medical history or an allergic test value, and perform the OFC that secured safety and accuracy based on the guidelines.

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Food-dependent exercise-induced anaphylaxis (FEIAn) is a relatively rare disease. However, once the diagnosis of FEIAn and the causative food would be determined, the quality of life of the patient must be remarkably improved. For the accurate diagnosis of FEIAn the applying the provocation test should be desirable in all patients except for the severest case.
In April 2009 we proposed the standard protocol of the provocation test of FEIAn in the guideline of oral provocation test for food allergy 2009 from the study group of food allergy in Japan Pediatric Allergy Society. We hope that this standard test would contribute to the accurate diagnosis of FEIAn.

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As food allergy develops in early infancy, enough care for nutrition and maintenance of Quality of Life (QOL) of allergic children and their family is very important. Elimination diet is to be confined to food diagnosed as offending allergen definitely. Taking various kinds of food other than that containing offending allergen is recommended in order to maintain rich diet. Although dietary counselling for food allergic children had been confined to elimination and replacement diet for decades, now it is time to proceed to tailor-made diet aiming at “eating” with minimal elimination diet based on precise diagnosis.
Reducing antigenicity of food makes it possible to take food without allergic symptoms resulting in early outgrow as well as improvement of QOL and safety. Dietary counselling on the basis of the amounts of antigen in food after precise evaluation of one's state of sensitization and oral food challenge test is expected to lead allergic children to early outgrow.

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Reports of efficacy on specific oral tolerance induction are increasing from the specialized institutes in Europe and USA, but there is no standardized method of the oral tolerance induction therapy for persistent food allergy. We think that the indication of the therapy is for the persistent food allergy patients (>6y) with the most severe symptoms so-called “anaphylaxis”. In our hospita1, we doubled the quantity of intakes twice a day over 6-9 days from the equivalent dose of the threshold in admission during the rapid induction phase. We here discuss the indication and methodology from our own experience and the reports on oral tolerance induction for possible standardization of the therapy.

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A placebo-controlled trial of oral immunotherapy in 37 subjects with hen's egg allergy was performed using hypoallergenized hen's egg. Changes in immunological parameters were analyzed before and after the immunotherapy.
In the hypoallergenized hen's egg treated group, tolerance to egg white was induced in 6/23 (26.1%)patients within one month, and in 9/23 (39.1%)within two months. In the placebo group, the percentage of tolerance induction was 9.1%. Immunological analysis demonstrated an elevation of egg specific IgG4, suppressions of both INF-γ and IL-4 expression, and an increase of TGF-β transcription after immunotherapy, suggesting TGF-β might suppress both Th1/Th2 cytokines as a consequence of immunotherapy.
The results of this study implied the importance of clinical trials in combination with immunological analysis to elucidate the mechanism of immunotherapy.

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Recent studies have shown that tight collaboration between pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) is needed to start an innate immune response to allergens. We have investigated whether polymorphisms of innate immunity genes could associate with the susceptibility and clinical phenotypes of bronchial asthma. Thymic stromal lymphopoietin (TSLP) triggers dendritic cell-mediated T helper (Th) 2 inflammatory responses. We have found that promoter polymorphisms including a gain-of-function variant of the TSLP gene are associated with bronchial asthma susceptibility. IL-18 plays multiple roles in chronic inflammation and in a number of infections and enhances both Th-1- and Th-2-mediated immune responses. We have reported that a functionally relevant IL-18 polymorphism contributes to the disease severity of asthma. The variant affects the level of mRNA expression induced by LPS in human monocytes. Further genetic research will contribute to the development of novel diagnostic, therapeutic, and preventive methods for allergic disease.

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Human respiratory syncytial virus (RSV), a major respiratory viral pathogen, is an enveloped and negative-strand RNA paramyxovirus. Epidemiologic studies show that lower respiratory tract infections caused by RSV is risk factor for both recurrent wheezing and childhood asthma. The pathogenesis of wheezing diseases post-viral infection would be due to (host) Gene-Virus Interaction. The suppressor of cytokines signaling (SOCS) gene family utilizes a feedback loop to inhibit cytokine responses and block the activation of the JAK/STAT signaling pathway. RSV infection up-regulated SOCS1, SOCS3, and CIS mRNA expression in human laryngeal carcinoma cell line, HEp-2 cell. The pathogenesis of wheezing diseases post-viral infection could be declared by the study of SOCS expression in structural cells, such as endothelial, epithelial, smooth muscle, nerve cells, and inflammatory cells within the lung.

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[in Japanese]

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Chlamydophila pneumoniae causes acute human infection which is followed by asthma attack and persistent infection which may increase chronic airway inflammation of asthma. There have been a lot of substantial evidences supporting the association between Chlamydophila pneumoniae infection and asthma. Many researchers reported antibiotics treatment improved asthma symptoms and pulmonary functions in chronic stable asthma. Several reports showed antibiotic treatment favored asthma symptoms and pulmonary functions in acute exacerbation of asthma. We need further evidences for supporting routine antibiotic treatment for asthma patients. At this time, it is better to choose antibiotics, such as macrolides which are effective against Chlamydophila pneumonia when patients need antibitotics.

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The prevalence of allergic disorders has rapidly increased in the industrialized countries including Japan as well as in the developing countries. Recently, an epidemiological survey in Japan showed that the prevalence of Japanese cedar pollinosis has increased from 16.2% to 26.5% of Japanese population over the past ten years. Reasons such as increased allergens, changed food life habits and nutrients, and environmental deterioration, etc. have been suggested to account for the increased prevalence of allergic disorders. One of the explanations is the “hygiene hypothesis”, which postulates that the decrease of opportunity of exposure to immunostimulating microorganisms in the early childhood as a result of cleanliness trends, vaccination and use of antibiotics, caused the increased prevalence of allergic diseases. Neonates are known to be in a Th2-skewed immune balance and need microorganism-stimulation for the development of balanced immunity. Epidemiological and mechanism studies have indicated the association between tuberuculin response and composition of intestinal microflora with the development of allergies. Numerous human studies have shown that tubercle bacilli and probiotic bacteria, such as lactobacilli and bifidobacteria, are potentially beneficial in the prevention and/or treatment of allergic diseases. However, further studies are needed for demonstrating the efficiency of which strain, what intake timing and what dose for targeted subjects.

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There are many unsolved questions in the field of pediatric allergy. Epidemiological study is one of the most important researches to promote our understanding. In this presentation we show some interesting data obtained from our recent epidemiological studies. 1) Prospective study of skin conditions in infancy on regular health check-ups at regional health centers in 3 cities in Japan revealed heterogeneous course of atopic dermatitis and several important risk factors related to development of atopic dermatitis. 2) Study of primary school children on genetic polymorphisms and environmental factors revealed gene-environment interaction related to serum total and mite-specific IgE levels. We would like to stress the importance of large-scale comprehensive cohort studies in Japan in order to understand mechanisms of development of allergic diseases in childhood.

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There is a dramatically increase in the prevalence of allergic diseases, which is now referred as so-called National Disease. To clarify risk factors related with the development of allergic diseases and then to prevent and alleviate allergic diseases is very important issues. It can lead to expand national health and to reduce both medical expenses and costs of social security. Allergic diseases may be primed in the uterus and they develop at the time of infants and younger children, being referred to as allergic march. Pediatricians should take care of this issue, because they just examine infants and younger children.
Performing birth-cohort studies of great precision should be needed to clarify the risk factors native to Japan related with development of allergic diseases. Younger children with higher risk factors may be selected and introduced to primary prevention. In this paper, we presented our data we have recently performed birth cohort study, and discussed the primary prevention of allergic diseases, which should be performed during pregnancy at which fetuses are primed towards allergic status, especially from an epigenetics point of view.

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Oral immunotherapy (IT) is forthcoming treatment for food allergy. There are a method of increment by small and small and rush IT in the antigen administration pattern. These IT are associated in varying degrees with side effects such as urticaria, abdominal pain and anaphylaxis. A sublingual IT and IT using hypoallergenic food antigens are recently studied as an oral IT with a few adverse reactions. The oral IT for food allergy is promising treatment. The efficiency has been already approved in many articles on IT for food allergy. The task to be solved is the establishment of safe IT and the clarification of the mechanisms.

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[in Japanese]

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[in Japanese]

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Objective: To conduct a cross-sectional regional surveillance about pediatric asthma control status using the Japanese Pediatric Asthma Control Program (JPAC) questionnaire.
Method: A total of 38 pediatric departments in general hospitals in Aichi prefecture participated in this study, which was performed in November 2008. Patients or parents who visited the hospital as a regular check up were asked to complete JPAC questionnaire. At the same time, the physician in charge judged the severity of a patient's asthma symptoms.
Results: The subjects were 535 boys and 283 girls, aged 7.0 ± 3.7 years (mean ± SD). The total JPAC scores were 15 (perfect control) in 27.5% of subjects; 12-14 (good control) in 47.1% of subjects; and ≤ 11 (loss of control) in 25.4% of subjects. Significant correlations were observed between asthma severity and JPAC scores. However, the JPAC score indicated a loss of symptom control in 44.7% of patients that physicians had diagnosed as mild-persistent and in 71.9% of patients that physicians had diagnosed as moderate-persistent. Inhaled corticosteroids (ICS) and leukotriene receptor antagonists were administered to 52% and 77% of the patients, respectively.
Conclusion: Despite the use of ICS, JPAC scores suggest that asthma symptom control is less adequate than many physicians assess.

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Food protein-induced proctocolitis should be considered as the disease of otherwise healthy infants with blood-streaked stools. Although the diagnostic gold standard is a dietary elimination-challenge test, the diagnosis is often made empirically in infants showing improvements in response to elimination of causative food antigens after exclusion of anal fissures and infectious colitis. However, such empiric diagnosis may often result in overdiagnosis that leads to unnecessary elimination of diets and usage of hypoallergic formula. Recently, pathological diagnostic criteria of food protein-induced proctocolitis employing endoscopic examination have been introduced and widely accepted. We have experienced an otherwise healthy breast-fed 3-month male with bloody mucus stools. Although the infant did not respond to the inappropriate restriction of mother's intake of milk and other considered-to-be causative foods, the mother hesitated to stop breastfeeding. The endoscopic examination of rectum revealed that the infant had eosinophillic proctocolitis, which convinced the mother to stop breastfeeding. The symptoms of the infant were improved with an amino acid-based formula after stopping breastfeeding. In this case, the endoscopic examination was a safe and useful method to make a diagnosis.

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Objective: Development of MicroRint has enabled measurement of airway resistance using the interrupter technique, and this device is expected to be useful for asthma management in children. However, there are no published data on airway resistance values measured with it in healthy Japanese children. We developed prediction equations of Rint values based on age, height, and other factors.
Subjects and Methods: Rint measurement was performed before and after inhalation of bronchodilator in children with bronchial asthma who are symptom free for more than two weeks. The prediction equations from height and age was examined based on the values obtained before inhalation in the cases with less than 10% of change.
Results: Of the subjects, 63 met the inclusion criteria. Their median age was 5.3 years, the median height was 109cm. The approximate linear equation y=-0.0529x+0.9552 was obtained from age, while y=-0.0109x+1.8525 was obtained from height. The correlation was slightly higher for the prediction equation obtained from height (coefficient of determination [r²] for these equations were 0.1656 and 0.2242, respectively).
Conclusion: Rint values have been reported to be highly correlated with height, and the results of the present study were similar tendency to them. Further discussion of prediction equations based on Rint values obtained from healthy children is needed.

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A five year-old boy presented an urticaria induced by cold from the winter in three year-old. He was brought to our hospital because his symptom was getting worse. The diagnosis as a primary acquired cold urticaria was confirmed by positive cold stimulation test and negative results of secondary cause. The plasma histamine levels in the peripheral blood were sampled before and at 5 and 20 minutes after the cold stimulation test. A significant elevation of histamine was observed. Furthermore, efficacy of anti-histamine agent suggests a pivotal role of histamine in this patient, although involvement of other chemical mediators can not be entirely excluded. Here, we present the case because there have been few reports describing the chemical mediators of cold urticaria in childhood. A further examination is necessary with the accumulation of the pediatric cases.

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