Recurrent wheeze in infants and young children arises from heterogenous pathophysiology and "endotypes" are still unknown. Currently, phenotyping of the disease has been employed to identify optimal treatment options or to predict outcomes of wheezing. We performed 2 clinical studies on treatment options. First, we tried to prove beneficial outcome by recommendation of Japanese Pediatric Guideline for the treatment and management of asthma (JPGL) compared with that of the international guideline, Global Initiative for Asthma (GINA). For mild asthma JPGL recommends controller treatment with leukotriene receptor antagonists, whereas GINA recommends no controllers. The 2 options were compared in the randomized controlled study and we found that asthma exacerbation rate in JPGL group was significantly lower than in GINA group. Second, we compared clinical effect of inhaled corticosteroid, budesonide, and montelukast in a biomarker-defined phenotype of recurrent wheeze in preschool children. The biomarkers were house dust mite sensitization and an eosinophil marker, EDN. However, we did not find any difference in the clinical effect in the "atopic asthma" type group. Recent clinical studies of early treatment for wheezing children are also reviewed.

"Asthma without good control even with basic treatment in treatment step 4" was defined as refractory asthma in the Japanese pediatric guideline for the treatment and management of asthma 2017. In the management of refractory asthma, it is important to consider factors that affect control, such as a review of diagnosis and a review of adherence and inhalation techniques, and to intervene if necessary. Patients whose control does not improve after the intervention are managed as true severe asthma. The administration of biologics should be considered before introducing oral steroids as an additional treatment in children due to non-negligible side effects such as growth suppression.

Currently, three biologics are available for children: omalizumab, mepolizumab, and dupilumab. Biologics are very powerful treatment option. However, the administration of biologics is highly effective in some cases, but limited in some cases. Biomarkers useful for optimizing the treatment target and treatment method, and evaluation methods after administration is started. The evaluation methods, timing of evaluation, methods for enhancing efficacy, timing of discontinuation, and effects on long-term prognosis after the start of biologic administration are topics for further study.

The long-term management goal of childhood-onset asthma is to suppress airway inflammation, which is a basic condition, and ultimately aim for remission and cure. Anti-inflammatory therapy is a mainstay of the pharmacotherapy, and with its widespread use, zero asthma deaths were achieved in 2017, and the number of patients hospitalized for asthma exacerbation has decreased by 80% in the past two decades. Therefor the major epidemiological prognosis has improved. However, regarding asthma control, it has been reported that 17-25% of asthmatic children have asthma exacerbation weekly and 42-65% have that monthly. In recent years, children with poor asthma control up to around 7 years of age have a low remission rate and an increased risk of diminished pulmonary function as well as chronic obstructive pulmonary disease in adulthood. On the other hand, based on the study that conducted anti-inflammatory therapy according to the severity of pediatric asthma as early intervention treatment, minimizing asthma exacerbation with preventing recurrent wheezing from early in childhood may reduce the risk of deterioration in remission and pulmonary function in adulthood. It is suggested that long-term prognosis may be improved depending on the treatment strategies and treatment practices with anti-inflammatory drugs.

To identify the risk factors of oral food challenge (OFC) -associated anaphylaxis, we performed retrospective analysis of OFCs performed at our hospital between 2005 and 2018. Anaphylaxis occurred in 347 of 9230 patients who underwent OFC. The prevalence of anaphylaxis tended to decrease year by year. The most common food tested by OFC was egg, followed by milk and wheat, and their respective prevalences of anaphylaxis were 3.9%, 6.2% and 6.0%. A short interval between doses, i.e., 15 minutes or less, was most common in the earlier period (up to and including 2012). A longer interval, i.e., more than 30 min, was most common in the later period (after 2012). On the other hand, specific IgE-antibody titers to egg, ovomucoid and milk were significantly higher in the later period than in the earliest period, 2005-2007. In conclusion, the prevalence of OFC-associated anaphylaxis decreased dramatically in recent years, probably due to the longer interval between doses and use of smaller test doses. Meanwhile, more OFCs were performed for patients with high specific IgE titers in recent years than before, hoping to determine the maximum dose at which complete elimination diet would not be necessary. Further investigation is necessary to establish the parameters for safe performance of OFC.

【Background】

The purpose of this study is to elucidate the clinical course of children with anaphylaxis and to determine the incidence of biphasic reactions in pediatrics.

【Method】

We performed a retrospective analysis of all children admitted for anaphylaxis from our outpatient clinic between 2015 and 2018. Clinical course, including patient characteristics, cause, symptoms, treatment and presence of biphasic allergic response, were collected from medical records.

【Result】

We collected 201 anaphylactic episodes from 129 males and 72 females. The median age was 4 years 3 months. Food was commonly identified as a causative allergen in 158 (78%) of all patients. An adrenaline intramuscular injection was given in 132 cases (66%) as the initial treatment. Biphasic allergic response was observed in 9 cases (4.5%). Logistic regression analysis showed a statistically significant difference between age (p = 0.028) and adrenaline (p = 0.028) as risk factors for the occurrence of biphasic reactions, and the odds ratios (95% confidence intervals) were 1.01 (1.0-1.3) and 0.19 (0.044-0.026).

【Conclusion】

We clarified the incidence of biphasic reactions in children with anaphylaxis. The administration of intramuscular adrenaline may be significant for preventing severe biphasic anaphylaxis.

Objectives: The aim of this study was to evaluate the food allergy prevalence and dietary management of lunch provisions in nursery schools in Fukuoka city over 15 years.

Methods: Once a year, from 2002 to 2016, we administered a questionnaire to ascertain the number of children with food allergies, the prevalence of food allergens diagnosed by pediatricians, and the state of allergen elimination diets provided to all nursery schools in Fukuoka city.

Result: The prevalence of food allergies was 3.8% in 2002 and increased to 5.9% after 2011. The infants with anaphylaxis increased in 96 cases after 2011 from 25 cases of 2002. The rate of food allergies was highest for children less than 1 year old, but the prevalence in 2 to 5-years-old has recently demonstrated a tendency to increase. Major allergens were egg (3.34~4.56%) and cow's milk (1.58~2.16%). Allergies to peanuts increased remarkably from 0.11% to 0.88% between 2002 and 2011. The rate of elimination / substitute foods offered increased from 62.2% to 84.5%. Complete elimination diets was provided at 54.4%.

Conclusions: The prevalence of infants with food allergies and anaphylaxis increased in nursery schools, and providing access to appropriate, safe elimination diets is necessary.

The case is a 4-year-old girl, diagnosed as having asthma. Wheezing was repeated even after the start of a treatment with leukotriene receptor antagonist and inhaled corticosteroid. Therefore, she was received systemic administration of corticosteroids for a long term. The total dose of corticosteroids was more than 1000mg in almost 3 months until she was admitted to our hospital. After hospitalization, the dose of systemic steroid was tapered down to the basal cortisol level, but asthma symptoms were not exacerbated. She has been diagnosed with moderate gastroesophageal reflux (GER) from the result of esophageal pH monitoring, wheezing was improved after start of the therapy of GER. Her adrenal function was not recovered three weeks after administration, and early morning level of cortisol was lower than basal secretion level. It took five months for stop of the oral steroid medicine, and seven months for the complete recovery of the adrenal function.

In infantile asthma, we should be taken to examine carefully of the possibility of differential diagnosis. If we consider the adaptation of long-term glucocorticoid therapy for childhood asthma, be careful of the adverse effects of adrenal function.

Objectives: The present study aimed to elucidate differences in the awareness and knowledge of anaphylaxis management at pre-training (baseline), post-training, and 6 months post-training, according to differences in nursery school attributes and employee characteristics among those who participated in training on initial response to anaphylaxis in children with food allergies.

Methods: We analyzed differences in the "awareness of anaphylaxis management" and "knowledge of EpiPen^®" at baseline according to nursery school attributes and employee characteristics. We also analyzed differences in training effectiveness according to characteristics using the Mann-Whitney U test.

Results: The prevalence of nursery school employees with "a feeling of burden when accepting children who carry EpiPen^®" was significantly lower at facilities with nurse (s). Nursery school employees who worked at a facility with children who carry EpiPen^® or who had an experience of participating in training were significantly more knowledgeable. Changes in the level of knowledge were substantial among nursery school employees who worked at a facility without nurse (s) or without children who carry EpiPen^® and among those who had experience participating in training.

Conclusion: The findings of the present study suggest the need to promote the placement of nurses at nursery schools throughout the country and to create a system that supports and facilitates periodic and continuous training for nurses to serve as the key persons for anaphylaxis management. The challenge going forward is to create educational materials that enable nursery school employees to gain the ability to make clinical judgments.

In 2013, the age limit for omalizumab for bronchial asthma was reduced to 6 years old and above, and the age of molecular targeting drugs has arrived in the pediatric allergy area. Currently, three drugs, omalizumab, mepolizumab, and dupilumab, are available in pediatrics for bronchial asthma and one, omalizumab, for chronic urticaria and allergic rhinitis. All the drugs are expensive and must be used properly in appropriate cases. It is important to understand the mechanism of action and characteristics of each drug based on basic knowledge of immunology. In addition, in selecting an appropriate drug, it is essential to consider not only such medical and scientific aspects but also healthcare aspects such as injection pain and administration intervals. There are many other issues to be resolved, such as drug discontinuation criteria, long-term prognosis, and medical economics, and further clinical researches are urgently needed.

Urticaria is one of the most common skin diseases that can basically be diagnosed with visual inspection, but by this reason, one may fall into a pitfall while he is diagnosing and treating a patient as usual. In the Japanese Guidelines for Diagnosis and Treatment of Urticaria 2018, hereditary angioedema, urticaria pigmentosa and cryopyrin-associated periodic fever syndrome have been picked up as urticaria-related hereditary diseases. Furthermore, novel genetic mutations have recently been identified in families with hereditary angioedema with normal activity of C1 inhibitor. In addition, NLRP12-related periodic fever syndrome, PLCG2-related antibody deficiency and immune dysregulation, and NLRC4 abnormalities have been reported as familial cold autoinflammatory syndrome-like diseases. More recently, the causative gene for familial vibratory urticaria/angioedema has also been identified. By deepening knowledge of these hereditary diseases that should be distinguished from urticaria, one can not only make a proper diagnosis of rare diseases in the early stage to prevent serious attacks and complications, but also understand more deeply and widely the pathomechanisms of urticaria and angioedema.

An increasing prevalence of pet allergy has emerged along with a growing number of indoor pets including dogs and cats. In addition to pets, laboratory animals such as mice and hamsters cause allergy. Major allergens of most fur animals, except cats, belong to the lipocalin protein family and show cross-reactivity. Animal allergens, which are mostly secreted in urine and saliva, adhere to hairs and dander, spread into indoor. They are carried to many places by adhering to clothes. In addition, they can float for hours in the indoor air. Sensitization of these allergens is through the respiratory tract, which often results in bronchial asthma and allergic rhinitis. Notably, the bite of experimental animals such as mice, rats, and hamsters, often causes anaphylaxis. Although allergens in bird feathers have not yet been identified, inhalation of bird allergens can cause hypersensitivity pneumonitis. The both allergen components, Can f 1 of the dog and Fel d 1 of the cat, have been shown to aid in diagnosis of allergy to respective animals. Avoidance of allergens is the current best and only treatment for animal allergy, which however is difficult to practice. The development of therapies such as immunotherapy is awaited.

Fungi can be divided into three types based on the environment in which they exist, namely outdoor fungi, indoor fungi, and residential fungi. The major outdoor fungi are Cladosporium and Alternaria, whereas Aspergillus and Penicillium are indoor fungi. It is known that the conidia of these fungi function as aeroallergens, and may correlate with both onset and exacerbation of allergic diseases, such as allergic rhinitis and bronchial asthma. As different fungal allergens have common structures, such as proteases and heat shock proteins, the characteristics of fungal allergens exhibit allergenic cross-reactivity, not only between fungi, but also between other species. As a result of this cross-reactivity, patients who are sensitized to fungi exhibit a higher degree of polysensitization compared with monosensitization. On the other hand, Cla h2 and Alt a1 are fungi-specific allergens. Alt a1 is the major Alternaria allergen. As Alt a1 is comprised of proteins specific to Alternaria, the degree of monosensitization to Alternaria is higher than those of other fungal allergens. Mala S11 and Mala S13 are major allergens in Malassezia, which is a residential fungus, and exhibit antigen cross-reactivity between enzymes from humans. As a result, Malassezia is known to be associated with exacerbation of atopic dermatitis.

Insect allergens are broadly classified into three categories depending on the route of exposure: 1) by inhalation, 2) by biting, and 3) by contact. Cockroaches are known as representative allergens by inhalation, and Hymenoptera are known as representative allergens by bite. Cockroach antigens are important allergens for bronchial asthma.

Furthermore, Tropomyosin is a pan-allergen, shows cross-reactivity between cockroaches and crustaceans such as shrimp, and arthropods such as house dust mites, and has attracted attention in the fields of food allergy and sublingual immunotherapy.

Hymenoptera venoms contain a variety of allergens and is an important antigen responsible for anaphylaxis. Important toxins are broadly classified into two, honeybee venom and hornet, wasp venom. In honeybees, phospholipase A2 and melittin are the major allergens, and have little common antigenicity with other species of bee venom. On the other hand, the major antigens of the Vespidae family (Vespa genus and Polistes genus) are phospholipase A1 and antigen 5, and the same symptoms may be exhibited even when stung by different kinds of bees. Immunotherapy with bee venom extract has been performed for some time.

Background: Systemic corticosteroids are used mainly in the management of children who suffer from very acute asthma attacks. There is a lack of consensus regarding corticosteroid administration.

Objectives: To evaluate the benefit of systemic corticosteroids for hospitalized acute pediatric asthma.

Methods: Randomized controlled trials about systemic corticosteroids compared to placebo and inhaled steroids in hospitalized acute pediatric asthma were identified, and the results of the selected studies were included in a meta-analysis

Results: Ten trials were included. There were no significant differences between groups in the length of stay or pulmonary function. Neither were there any significant differences of duration of oxygen supply or bronchodilators. Children treated with systemic steroids were less likely to prolong symptoms and relapse after discharge.

Conclusion: Systemic corticosteroids are beneficial to pediatric acute asthma attacks. Further studies examining differing doses and durations of corticosteroids will reveal the most effective therapy.

Background: Systemic corticosteroids are used mainly in the management of children suffering from very acute asthma attacks, but we don't know which regimen is most beneficial.

Objectives: To evaluate different doses or durations of oral steroids for pediatric asthma attack by systematic review.

Methods: Randomized controlled trials about different regimen of oral corticosteroids in acute pediatric asthma were identified and the results of the selected studies were included in a meta-analysis.

Results: We have done a screening and included the nine studies. There were no significant differences between groups in hospitalization or prolong symptoms or side effects. It was difficult to analyze the results of the studies because investigators used a variety of doses and durations of steroids. A complete evaluation wasn't possible because the evaluator didn't include data regarding child patients under two years old in the study.

Conclusion: There were no differences of clinical effect with different regimens (types or doses or durations of oral steroids) for pediatric asthma attack.

A systematic review (SR) was conducted to determine whether intermittent therapy of leukotriene receptor antagonist (LTRA) is useful for episodic viral wheeze in children. Randomized controlled trials (RCTs) were selected to compare the intervention of LTRA and control for the treatment of episodic viral wheeze in children. RCTs in children were selected from a previously published SR of children. Databases (CENTRAL, MEDLINE, and Embase) were searched for RCTs, which were written in English, and were published until December 2017. RCTs reported in Japanese were searched from a database of the Japan Medical Abstracts Society. Four RCTs were selected from a previously published SR, while none of RCT written in English and Japanese were selected from an additional search. These studies included patients with recurrent wheezing or asthma and were investigated the treatment for asthma attacks or wheezing associated with the common cold. LTRA administration did not reduce the risk of wheezing attacks requiring systemic steroids. Therefore, there is not enough evidence to support the recommendation of using LTRA for episodic viral wheeze in children.