As the presidential invited lectures, Dr. Junji Yodoi first gave us a lecture on “anti-inflammatory mechanism of redoxisome”. It will be possible to treat allergic diseases by suppressing inflammation in the skin or airway with thioredoxin. Next, Dr. Matyas Sandor presented his data with the title of “Mycobacterial granuloma dynamics : repopulation, reformation and cellular traffic”. The cellular traffic occurs from and into the granulomas. Dendritic cells migrate to lymph nodes and prime T cells with bacterial antigens in the granulomas. Vascular endothelial growth factor (VEGF) is involved in the recruitment of macrophages, which can also produce VEGF. Therefore, VEGF inhibitor may serve as a new treatment for granulomatous inflammatory diseases. Finally, I talked about “full and healthy lives for allergic children-passion, action and connection-, focusing on the importance of passion and collaboration for clinical care and research work.

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Recently, prevalence of food allergy has been drastically increased. Although precise mechanisms for the increase is still to be clarified, the recent hypothesis that epicutaneous sensitization cause food allergy may give a clue to solve the problem. Several birth cohort studies have demonstrated strong association between infantile eczema/atopic dermatitis and food allergy. Recent outbreak of wheat allergy in women who regularly used a cosmetic soap containing hydrolyzed wheat protein is also support the hypothesis. Then, based on the pathogenic understanding, trials of early skin care for neonates and young infants aiming for prevention of atopic dermatitis and food allergy have been attempted and resulted in some hopeful outcomes. Further study will be needed in this frontier field of allergy.

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Fundamental principle for patients with allergic disease is to avoid the exposure to allergen. Elimination diet is the practical method in the case of food allergy. However, immunosuppression to the antigen orally ingested (and absorbed through the intestinal mucosa) has been recognized for a long time in the area of immunology, the concept being established as oral tolerance. In recent years, the information that oral tolerance functions in human model, and that sensitization occurs through the skin with impaired barrier function, came to our knowledge, and a new maneuver, which is quite different from the conventional method, has come into view. Delayed weaning may precipitate food allergy, and the optimal weaning schedule to prevent food allergy should be investigated.

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Epigenetics is the study of mechanisms that change gene functions such as transcription and replication without altering gene sequences. DNA methylation and post-translational modifications of histones are some of the major epigenetic modifications. Epigenetic modifications play a role in the differentiation of immune cells ; therefore, they are assumed to be associated with development of allergic diseases. Moreover, several reports have showed the use of DNA methylation as a biomarker. For instance, the number of regulatory T cells could be estimated by studying stored genomic DNA. Further elucidation of epigenetic involvements in allergic diseases will provide insight into our current understanding of the pathophysiology of these diseases.

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In Japan, non-IgE-mediated gastrointestinal food allergies have increased sharply since around 2000. However, unlike the case of IgE-mediated food allergy, development of diagnostic laboratory tests and our understanding of the immunological mechanisms involved in non-IgE-mediated gastrointestinal food allergies lag. The clinical phenotypes might differ from that of Western countries. Clinicians have sometimes experienced confusion because of differences in the clinical phenotypes from those seen in Western countries. Aiming to solve this problem, we performed clinical research and determined a useful method for dividing patients into 4 clusters with distinctive clinical symptoms. We are confident this method will help in diagnosing and treating these patients.

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Non-immunoglobulin (Ig) E (IgE)-mediated gastrointestinal (GI) allergies are classified according to clinical manifestations such as food protein-induced enterocolitis syndrome (FPIES), food protein-induced allergic proctocolitis (FPIAP), and food protein-induced enteropathy (FPE). However, in infants, since GI allergies may not necessarily fall under these categories, the term “GI allergy in infants” is used to refer to GI allergies in infants in Japan. Although GI allergy in infants is classified on the basis of symptoms, few attempts have been made toward grading it on the basis of severity and demonstrating its relevance. Hence, we propose a severity grading system for GI allergy in infants and compare the clinical features, such as blood test results, endoscopic findings, treatments, and prognoses, between three severity grading. Our results indicate that the most severe grading represents distinct pathophysiology of GI allergy in infants.

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Although patients with neonatal and infantile gastrointestinal (GI) allergy (GI allergy) show various GI symptoms, the severity of the disease cannot be properly defined by GI symptoms alone. Recently, fever and the increased serum CRP level were demonstrated to be reproduced by an oral food challenge test. These findings may help estimate the severity of the disease. Among patients with GI allergy, those patients showing fever and high serum CRP levels with undefined GI symptoms (septicemia-like phenotype) should be classified into the most severe disease type because of the seriousness and urgency. Patients with vigorous and prolonged vomiting should be classified into the severe disease type because of a risk of dehydration and hypovolemic shock. Patients manifesting poor weight gain with diarrhea should be classified into the intermediate disease type because of the serious systemic influence causing growth failure. Infants with the severe and intermediate disease type often present a mild increase in the serum CRP levels and abnormal findings in imaging examinations. Patients presenting diarrhea or bloody stool without any systemic symptoms or abnormal laboratory findings are classified into the mild disease type. All patients with GI allergy should be treated properly based on the appropriate grading of the disease severity.

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Gastrointestinal food allergies (GIA) in neonates and infants have several manifestations, including severe consequences like septic shock. Because oral milk (or breast milk) challenge after recovery is the most definitive method of confirming the diagnosis, early diagnosis of GIA is not possible. Gastrointestinal endoscopy (endoscopy) is attracting attention as one of the most reliable forms of examination for diagnosing GIA, but it is still controversial because endoscopic findings are nonspecific in many cases. In this study, we examined usefulness of endoscopy in GIA diagnosis and the correlation between clinical severity of GIA and endoscopic findings. We defined GIA endoscopic findings as “macroscopic findings are nonspecific” and “eosinophil infiltration (20 cells per high power field in two or more biopsy tissues).” The method provided sensitivity of 89% and specificity of 75%. It is especially useful for excluding differential diagnoses, such as inflammatory bowel diseases and primary immunodeficiency diseases. We investigated the correlation between clinical severity and three aspects of endoscopic findings, which are as follows : (1) location, (2) features of macroscopic findings, and (3) the degree of eosinophil infiltration in the colonic mucosa. No correlation was found between the severity of GIA and endoscopic findings. These results suggest that the correlation between the clinical severity of GIA and the number of infiltrated eosinophils or degranulation is not relevant for elucidation of the pathological mechanism of GIA.

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Vomiting, diarrhea, bloody stool, and failure to thrive are the typical symptoms observed in food allergy patients during infancy. Eosinophil infiltration is the common findings especially with patients with bloody stool. “Confirming bloody stool after milk ingestion with eosinophilia” is often considered as an allergic reaction because it is the adverse events after the specific food ingestion induced by immune cells. However, it is not easy to prove the antigen specificity because milk is the only antigen infants can intake during early infancy. Antigen specificity should always be re-evaluated even though the patient is positive for ALST. How are the eosinophils infiltrated? Although the elevation of serum IL-5 or ECP levels sometimes confirmed, it is not easy to prove it as an allergic reaction induced by a specific antigen. Since there is no IgA in early infancy, we consider that eosinophils may be protecting host from pathogens’ invasion instead of IgA. Further investigation is also necessary to find the relationship between eosinophil infiltration and intestinal flora.

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As the first step toward appropriate management of atopic dermatitis (AD) by general pediatricians, it is an essential point to diagnose definitely as it with careful observation and evaluation of cutaneous involvement. When a patient suspected of AD is first seen, it is important to apply his/her cutaneous condition and clinical course to any published criterion, such as the criteria of Hanifin and Rajka or the criteria for AD by the Japanese Dermatological Association. When cutaneous condition becomes uncontrollable or exacerbated during treatment, primary doctor should consult dermatological allergologist and revaluate the complications or current treatment. During follow-up, periodic and objective evaluation of severity of AD is also important with any widely-used severity scoring system. The most validated laboratory test to evaluate the severity of AD is serum TARC (thymus and activation-regulated chemokine) lebel, and peripheral eosinophile count, serum IgE and LDH concentrations are also useful in clinical practice. The most important point is to present overall assesement of AD condition with clinical course and laboratory tests above, which leads AD children to achieve good compliance/adherence to medical treatments.

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Appropriate skin care (cleanliness and moisturizing) is required for the treatment of Atopic dermatitis (atopic dermatitis : AD), but the evidence of the way of bathing, proper use of soap and moisturizer is poor. This time, we discussed the appropriate skin care that are believed to be reasonable, based on the domestic and foreign atopic dermatitis guidelines and atopic dermatitis clinic survey intended for Japan Pediatric allergology member (hereinafter AD Survey), and showed the following four points. ①once a day or more of bathing, ②use of soap in a suitable manner, ③reliable application of moisturizer more than twice a day, ④with respect to the application order of the anti-inflammatory agents and moisturizer, teach the easy way to continue, thinking skin condition and coating ease of patients. We expect the accumulation of evidence in the future in Japan.

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A survey on the actual state of treatment for atopic dermatitis (hereinafter “AD actual state survey”) was conducted to examine patients’ (or guardians’) consultation behavior, cooperation between pediatricians and dermatologists, and the relationship between Japanese Society of Allergology-certified specialists (hereinafter “specialists”) and non-specialists. 40% of doctors answered that more than 60% of their AD patients have been examined by the other doctors. More than 60% of pediatricians had experience referring patients to dermatologists and approximately 50% of pediatricians had been introduced patients by a dermatologist. Furthermore, specialists received many introducers from other pediatricians and dermatologists for exacerbation of eczema, other allergies, and patient guidance. Doctors who treated more than 50 AD patients a week also more frequently cooperated with other pediatricians and dermatologists. Experience of cooperation at our clinic suggests that cooperation by doctors may prevent “doctor shopping” and dropout from treatment by patients. Moreover, when symptoms do not improve despite continuing standard treatment for about a month, introduced to a more experienced specialist or dermatologist should be considered. Clear standards for when cooperation should take place in the form of guidelines are awaited going forward.

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Proactive treatment for atopic dermatitis may prevent recurrent disease exacerbations in the maintenance treatment phase. Many Japanese paediatricians are already aware of proactive treatment and have applied it to their patients. We review 6 randomised controlled trials of proactive treatment for paediatric patients with atopic dermatitis. Four trials used 16 to 20 weeks of treatment with topical corticosteroids, and two used 40 to 52 weeks of treatment with tacrolimus ointment. Each trial showed proactive treatment to be effective. Side effects did not significantly increase in the proactive intervention group with proactive treatment compared to placebo. Proactive treatment is a good option even for paediatric atopic dermatitis. It is not yet clear whether it is better to treat with topical corticosteroid or tacrolimus ointment and how safe it is to use proactive treatment for long periods.

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Background : It is crucial to evaluate the state of asthma control for bronchial asthma management in children accurately and objectively. Although the usefulness of questionnaires regarding asthma control has been evaluated, parents are often confused when responding to these questionnaires. Objective : To clarify the recognition among parents of wheezing symptoms in children with a history of wheezing. Subjects and Methods : Questionnaires were issued to 290 parents of children who visited our outpatient clinic at Fukuyama Medical Center and who had a history of wheezing (185 boys, age 6.5±3.8 years). Questionnaire contents concerned recognition of the symptoms of wheezing and asthma according to the Japanese Pediatric Asthma Control Program (JPAC) test. Result : Of the visits to our clinic, 86.2% were routine visits for asthma and 6.5% were observation visits after hospitalization for respiratory syncytial virus bronchiolitis. Furthermore, 62.7% and 75% of parents reported that their child had experienced “wheezing” or “gasping for breath”, respectively. However, 58.3% of parents reported that they did not understand the term “wheezing” and 24.8% of parents had misunderstandings about the term. Conclusion : Recognition of “wheezing” was low among parents of children who had experienced wheezing illnesses. Because is necessary to comprehend and understand symptoms in the long-term management of asthma, a team including a doctor and other medical professionals should provide repeated education to pediatric patients and their parents.

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We reported a case of secondary biotin, carnitine and selenium deficiency caused by long-term use of casein hydrolysed formula (New-MA-1^®). The patient was 9 months old girl with Down syndrome. She was suspected as cow’s milk allergy at one month of age because of elevated CRP and positive result of milk allergen-specific lymphocyte stimulation test while being fed with standard formula. She was fed with New-MA-1^® instead of standard formula, and CRP was normalized. She was fed with mainly New-MA-1^®, and ate only low amount of vegetables. Spared hair and erythema of external genitals were evident. Laboratory findings showed elevated urinary 3-hydroxyisovaleric acid, hypocarnitinemia and hyposelenemia. Symptoms and laboratory abnormalities improved after the start of daily oral supplementation of biotin (1 mg), carnitine (200 mg) and selenium (12.5 μg). Although New-MA-1^® is considered to be the only milk for cow’s milk allergy in Japan which contains appropriate amount of carnitine (≥1.2 mg/100 kcal) recommended by CODEX, carnitine is not supplemented and derived from raw material. Thus, carnitine value in New-MA-1^® is not guaranteed. In Japan, clinicians should always consider the possibility of secondary deficiency of nutrients in patients fed only with long-term use of milks for cow’s milk allergy, especially in patients with underlying diseases.

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More than ninety percent of asthmatic children are sensitized to house dust mite (HDM). It is important to eradicate the allergen from their household. We examined if reduction of mite allergen can contribute to sensitization to HDM. Sixteen asthmatics sensitized to HDM aged between four and eleven were recruited. They were assigned alternately into group A or B in order of recruitment. Professional cleaning staff cleaned the household at the first visit. Then in group A the staff visited monthly to advise and help the family clean their households by themselves using the mops offered by the staff. In group B the family cleaned their household as in the same way as usual. The amount of HDM allergen were measured before, just after the first cleaning, and one year after starting intervention. The patients’ total IgE, specific IgE to HDM, Childhood Asthma Control Test (C-ACT) and treatment score for asthma were compared before and after the intervention. The mite allergen in living room in group A was significantly reduced after one year. Specific IgE to HDM were significantly reduced after one year in group A. Other parameters such as C-ACT and treatment score for asthma were not statistically different. The education of cleaning using the mops by professional staff may be effective in keeping reduction of mite allergen and specific IgE to HDM in asthmatic children.

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Eosinophilic gastroenteritis is defined based on histological criteria as marked eosinophilia in the intestine. There are relatively few case reports of eosinophilic gastroenteritis in children. Here, we describe two cases of eosinophilic gastroenteritis in children. Our case reports showed that the clinical course of eosinophil gastroenteritis is various. [Case 1 : A 9-year-old boy] A child was referred to our department with atopic dermatitis at the age of 8 years. At that time, his laboratory data showed peripheral blood hypereosinophilia and high levels of immunoglobulin E. In addition, he had diarrhea and vomiting just after eating eggs. Therefore, we suspected the presence of eosinophilic gastroenteritis and examined his intestine by endoscopy. His colon biopsy specimen revealed an eosinophilic infiltrate. He was treated successfully with antihistamine, leukotriene receptor antagonist, and restrictions on the amount of eggs that he ate. Thereafter, his laboratory data and findings improved. [Case 2 : A 4-year-old boy] A child had been hospitalized with anemia that seemed to be associated with bloody stool, since the age of 1 year. His laboratory data showed peripheral blood hypereosinophilia and detectable eosinophils in the colon membrane, and he therefore started steroid therapy at 3 years of age. Although the bloody stool improved with this treatment, the steroid therapy could not be withdrawn.

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