Bronchial asthma is a major cause of chronic morbidity and mortality through the world and the leading cause of absent for daycare and school, number of emergency visit and hospitalization.
Asthma cause recurring episodes of wheezing, breathlessness, chest tightness, and coughing. The pathogenesis of asthma is chronic inflammation and hyper-responsiveness caused by inflammation of airway. Airway become obstructed and air flow is limited by bronchoconstriction, mucus plug and increasing edema of bronchial wall. If such symptoms are repeated, it is relatively easy to diagnose asthma. But infant asthma (defined as asthma <2 years old) is difficult to diagnose. For early intervention, diagnosis can be made if there are 3 or more episodes of wheezing, with or without the presence of respiratory tract infection.
Recently, it was reported that the remodeling of airway occurs with the results of small number of broncho-constriction. For the block of remodeling, correct diagnosis, environmental control and early intervention with anti-inflamatory drugs may needed even in case of infantile asthma.

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[in Japanese]

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[in Japanese]

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[in Japanese]

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[in Japanese]

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[in Japanese]

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Cysteinyl leukotrienes (LTs) are one of the most important chemical mediators in acute and chronic phases of childhood asthma. LTRA is a useful long-term control medicine for intermittent to mild persistent asthma. It is effective as an add-on medicine to ICS in moderate to severe persistent asthma. LTRA may alleviate viral induced-wheezing (asthma) in young children. LTRA is effective for exercise-induced asthma (EIA).
According to accumulating evidences, LTRA is placed as one of the first line medications in intermittent to mild persistent asthma, and one of the preferable choices of add-on drugs in moderate to severe persistent asthma in Japanese Pediatric Guideline for asthma treatment and management (JPGL) 2012.

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Background: The increase in allergic diseases is attributed to a relative lack of microbial stimulation of the infantile gut immune system. There have been attempts to probiotics for the treatment or prevention of atopic dermatitis. Recently a mixture of prebiotic oligosaccharides in atopic risk infants reduced the incidence of AD and increased fecal bifidobacteria. A prebiotic is a non-digestible food ingredient that beneficially affects the host by selectively stimulating the growth of bifidobacteria in the gut. Objective: A randomizedcontrolled trial (RCT) was conducted to confirm the therapeutic effect of kestose fructo-oligo saccharide on AD. Methods: In 34 AD (aged 6 to 36 months) with food allergy, fecal flora and AD severity were analyzed. In preliminary open pilot study, 12 AD infants with the low number of fecal bifidobacteria were received kestose supplements for12 weeks. The RCT of kestose was carried out in 29 AD children with food allergy aged 6 to 46 months (mean 17 months). One to 2 g kestose as active and maltose as placebo were given every day for 12 weeks. Clinical evaluation of AD severity (SCORAD), serum total IgE, specific IgE (Immuno-CAP) and enumeration of bifidobacteria in the feces using realtime PCR were performed at Weeks 0, 6, and 12. Results: Bifidobacteria of feces were decreased in severe AD children. There was a significant correlation between the bifidobacteria count and severity score. In RCT, SCORAD score significantly decreased in active group. Bifidobacteria count of feces were increased in active group in cases with low bifudobacteria. There were no changes in total IgE and specific IgE levels to mite, egg and milk. Conclusion: Although the mechanism of this effect requires further investigation, it appears likely that kestose oligosaccharides modulate altering bowel flora and may also be directly modulate the intestinal permeability.

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Oral food challenge (OFC) is the gold standard for the diagnosis of food allergy. It is performed in many pediatric institutes in Japan, regardless it is specialized to allergy or not. The purpose of OFC is not only an initial diagnosis of food allergy, but is to evaluate the achievement of tolerance. Furthermore, many institutes perform an OFC for the patients to avoid minimum level of allergic food. The standard procedure of an OFC has been established in the guideline. But more evidence should be needed to create the safe and practical diet instruction, especially for the patients with positive food challenge.

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The diagnosis of food allergies is established based on oral challenges, which has been generally acknowledged. However, the advice given in response to the results of challenges has recently been changing in Japan.
The advice given in response to oral challenge results has been changing in order to ensure minimal food avoidance. Thus, the dietary advice given to such patients has changed from strict avoidance to permitting them to consume some foods based on their tolerance levels. In terms of eggs, milk, wheat and soy, we created a chart that lists commercial products in order of their allergen-containing protein concentration. It would help patients to choose food products that were appropriate for them.
Another example, in fish allergies, oral challenges have been increasingly performed in order to identify fish species that patients can eat. When selecting fish for the oral challenge test, we look for allergenic different fish by performing ELISA, using the extracts from about 40 fish species that are commonly eaten in Japan.

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Food-dependent exercise-induced anaphylaxis (FEIAn) is a relatively rare disease. It is classified into a special form of food allergy. Neither a food-intake alone nor exercise alone induces anaphylaxis. And it is only elicited by a certain food-intake followed by exercise under some conditions. Besides of some progresses, the pathophysiology and the epidemiology of FEIAn remain unclear.
From our study in Japanese students the frequency of FEIAn was 0.0085%. And male was predominant to female in this age group. The most frequent causative food in Japan is wheat. The antigenic analysis revealed that most adult onset patients with wheat-dependent exercise-induced anaphylaxis (WDEIA) had antibodies against omega-5 gliadin (80%) and high molecular weight glutenin (<20%) . Now, specific IgE antibody to ω-5 gliadin is commercially available and useful for the screening of the adult-onset but not the child-onset WDEIA.
Recently, hydrolysed wheat proteins present in cosmetics were reported to induce WDEIA in mainly adult female from Japan and France. It took some times to present the symptoms. Serum CAP-FEIA IgE antibodies to wheat and gluten were positive, however, ω-5 gliadin antibody was negative. Antigenic analysis with immunoblotting showed the smear pattern. It is quite interesting that the route of the sensitization is skin. These cases have presented us other aspects of the pathophysiology of FEIAn. In addition, we have experienced the more number of patients with severe food allergy treated with oral immunotherapy the more number of FEIAn patients even after achieving a remission.
Recently, the prostaglandin E (PGE) drug was shown to be effective for preventing the onset of FEIAn in some cases. Therefore, PGE might be a protecting factor. Aspirin is known as one of risk factors, which demonstrated to increase an uptake of antigens from gastrointestinal tract and to suppress PGE production in FEIAn.
Finally, to avoid serious outcomes and unnecessary restriction, we believe it is important to enlighten FEIAn to not only physicians, but also school nurses and teachers.

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Japanese cedar pollen (JCP) pollinosis is a significant burden in early spring for a large number of people in Japan. Onset of the disease was initially considered to be the second or third decade of life but recent epidemiological studies show that the disease starts early in childhood. Current pharmacological remedies only partially alleviate symptoms, not the disease itself. Allergen specific immunotherapy for allergic rhinitis and asthma has been shown to provide good clinical efficacy and some disease-modifying effects. We performed rush immunotherapy (RIT) for patients with severe JCP. The RIT allows a fast increment of allergen doses and confer allergen-specific, rapid protection from the disease. Thirty six patients with JCP pollinosis was treated with RIT at Mie National Hospital. Severity based on Japanese guideline for allergic rhinitis was very severe in all the patients in pre-RIT season. In 2011 season when the pollen count was very high, about half of the patients had no symptom and in the other half severity was mild except for one patient whose severity was moderate. Medication score was significantly lower in post-RIT 2011 season than in pre-RIT seasons. Allergen-induced basophil activation utilizing CD203c expression was significantly reduced and JCP-specific IgG4 levels were significantly elevated after RIT. The major drawback of the RIT, however, was high rate of allergic reactions caused by allergen injections, all had local reactions and 16.7% had generalized urticaria 8.3% had respiratory symptoms. No patients experienced anaphylactic shock. Although RIT for JCP is highly efficacious and may have disease-modifying effect, relatively high rate of side effects restricts the application only to severe patients.

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In infants and young children, early intervention for asthma, including both environment improvement and medication, is important for preventing disease onset and progress of airway remodeling. Environment improvements include reducing allergen exposure, avoiding tobacco smoke and preventing virus infections. Early intervention with medication has three different stages. Primary prevention is defined as prevention of asthma onset before allergic sensitization. Palivizumab, a humanized monoclonal antibody against respiratory syncytial virus (RSV), reduces hospitalization for RSV infection and possibly reduces asthma development. Secondary prevention is defined as interventions after allergic sensitization. Suplatast tosilate, a Th2 cytokine inhibitor, decreased the incidence of asthma and prolonged the time to onset of wheezing when used for infants and young children with food allergy. Ternary prevention is a treatment to prevent disease progression after asthma onset. In preschool children, both inhaled corticosteroids and cysteinyl-leukotriene receptor antagonists are recommended for use as first-line treatments for asthma and recurrent wheezing.

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It is well known that RSV is the most frequent cause of bronchiolitis and pneumonia in infants requiring hospitalization worldwide. Also, RSV is the major etiologic agent of epidemic wheezing in infants. It has been suggested that severe RSV infection in infants might lead to the development of recurrent wheezing and/or bronchial asthma. Sigurs et al. reported that the relationship between severe RSV bronchiolitis in infancy and later development of asthma and allergy sensitization is still observed in children aged up to 18 years.
It has been speculated that there are two pathways by which RSV infection induces childhood asthma: (1) a direct effect on airways, and (2) an indirect effect on the immune system. In natural infections, airway epithelial cells are the primary sites for RSV invasion, and RSV replication induces cytokine/chemokine gene expression networks in a coordinated manner. Airway damage/remodeling continues over a prolonged period, because airways are still immature in infants. Also, RSV infection affects the immune system by acting on lymphocytes, which may indirectly induce allergic asthma.
Most infants with so-called asthma might have had recurrent viral wheeze. One of the most consistent findings in clinical studies of asthma is that allergy and viral infections synergistically increase the risk of acute exacerbations. Interestingly, it has been suggested that there are several phenotypes of early childhood recurrent wheezing disease. Clearer phenotype definitions both of early childhood viral disease and of subsequent recurrent wheezing disorders are required.

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[in Japanese]

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Viral infection induces both development and exacerbations of bronchial asthma. Previous reports and our recent report showed that the major causes of development and exacerbations of childhood asthma are rhino and respiratory syncytial (RS) viruses. Rhinovirus infection is a major cause of acute exacerbations of asthma in both adult and children. Recent report showed that the most significant risk factor for the development of preschool childhood wheezing is the occurrence of symptomatic rhinovirus illnesses during infancy. On the other hand, RS virus is a leading cause of serious lower respiratory tract infection in infants, including acute bronchiolitis. RS virus infection also exacerbates recurrent wheezing attacks in patients with established asthma. A number of case-control studies appear to have established at least a statistical connection between RS virus infection in infancy and the development of recurrent wheezing and asthma in young children. In later life, it appears unlikely to be a cause of atopic asthma. In this review, the pathophysiology of development and exacerbations of childhood asthma induced by rhino- and RS-virus infection will be discussed.

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