[INVESTIGATION OF SUBCUTANEOUS IMMUNOTHERAPY FOR ALLERGIC RHINITIS IN OUR HOSPITAL FOR THE PAST 17 YEARS].

BACKGROUND: Recently, subcutaneous immunotherapy (SCIT) has not been performed very much in our country. We investigated SCIT for allergic rhinitis in our hospital for the past 17 years. METHODS: Subjects were 188 cases who started SCIT by rush method under hospitalization. We investigated the patient background, laboratory findings, side reactions from their medical records and carried out questionnaire survey about effects and satisfaction to patients and their guardians. RESULTS: The median age at start was 10 years 4 months. Cedar pollen was the most common allergen used in treatment followed by mite, and two or more allergens were used in 85% patients. Five percent of patients dropped out. Medication score decreased significantly after SCIT, and 45% had become free from medication. Systemic adverse reaction was observed in 117 of the 5,954 injections (2%) during the rapid phase and in 10 of the 5,567 injections (0.2%) during the maintenance phase, and all episodes disappeared immediately. Symptom score significantly decreased after SCIT, the effects being similar even after 3 years of cessation of SCIT. CONCLUSION: SCIT was effective for allergic rhinitis in childhood. The effect lasted after treatment cessation for a long term and the patient satisfaction was very high. There are some advantages of SCIT that sublingual immunotherapy does not have. SCIT should be considered as a choice for the treatment of allergic rhinitis in childhood.

Long-term safety of subcutaneous immunotherapy with TO-204 in Japanese patients with house dust mite-induced allergic rhinitis and allergic bronchial asthma: Multicenter, open label clinical trial.

BACKGROUND: To evaluate the long-term safety of subcutaneous immunotherapy with TO-204, a standardized house dust mite (HDM) allergen extracts, we conducted a multicenter, open label clinical trial. METHODS: Japanese patients aged 5-65 years were eligible for the study, if they had HDM-induced allergic rhinitis (AR), allergic bronchial asthma (BA), or both. TO-204 was administered in a dose titration scheme, and the maintenance dose was determined according to the predefined criteria. The treatment period was 52 weeks, and patients who were willing to continue the treatment received TO-204 beyond 52 weeks. This clinical trial is registered at the Japan Pharmaceutical Information Center (Japic CTI-121900). RESULTS: Between July 2012 and May 2015, 44 patients (28 with AR and 16 with allergic BA) were enrolled into the study. All patients were included in the analysis. The duration of treatment ranged from 23 to 142 weeks and the median maintenance dose was 200 Japanese allergy units (JAU). Adverse events occurred in 22 patients (50%). The most common adverse event was local reactions related to the injection sites. Four patients experienced anaphylactic reactions when they were treated with the dose of 500 JAU. Two patients experienced anaphylactic shock with the doses of 1000 JAU at onset. These 6 patients could continue the study with dose reduction. CONCLUSIONS: Safety profile of TO-204 was acceptable in Japanese patients with HDM-induced AR or allergic BA. Higher doses should be administered carefully, because the risk of anaphylaxis increased at doses of 500 or 1000 JAU.

[EVALUATION OF THE EFFECTIVENESS OF SUBCUTANEOUS IMMUNOTHERAPY USING BIRCH POLLEN EXTRACT FOR POLLEN-FOOD ALLERGY SYNDROME].

BACKGROUNDS: Recently, patients with oral allergy syndrome (OAS) to fruits or vegetables caused by pollenfood allergy syndrome (PFAS) have increased nationwide. We examined effectiveness of SCIT using birch pollen extract for PFAS. METHODS: A total of 19 patients (9 male and 10 female) underwent SCIT with birch pollen extract from August 2011 to August 2016. Rush schedule was used for the initial updosing for SCIT in a hospital setting. In maintenance phase, SCIT was administered every 4-8 weeks on an outpatient basis. According to the situation of sensitization, patients underwent SCIT with other extracts at the same time. Oral food challenge (OFC) with fruits and vegetables was performed at baseline and after rush phase. We also investigated about OAS symptoms in maintenance phase. RESULTS: SCIT was remarkably effective in five patients for OAS symptoms just after rush phase, and effective in nine patients. And it was not effective in two patients, and not determined in three patients, but it was confirmed to be effective in four out of these five patients in maintenance phase. There were relapse of OAS symptoms in three patients, then SCIT was remarkably effective or effective in 15 patients (79%) in maintenance phase. No patients dropped off the SCIT protocol. CONCLUSIONS: Generally, PFAS can't be expected to remit naturally. SCIT with birch pollen extract effectively reduces OAS symptoms, and it can be expected as a radical therapy for PFAS.

Long-term safety, efficacy, pharmacokinetics and pharmacodynamics of omalizumab in children with severe uncontrolled asthma.

BACKGROUND: Omalizumab is effective and well-tolerated in children with moderate to severe allergic asthma. However, the effects of long-term treatment with omalizumab in this population haven't been well investigated. The objective of this study is to evaluate the long-term safety, efficacy, pharmacokinetics and pharmacodynamics of omalizumab in children with uncontrolled severe asthma. METHODS: Thirty-eight Japanese children (aged 7-16 years) who completed the 24-week treatment core study were included in an uncontrolled extension study, in which treatment with omalizumab continued until the pediatric indication was approved in Japan (ClinicalTrials.gov number: NCT01328886). RESULTS: Thirty-five patients (92.1%) completed the extension study. The median exposure throughout the core and extension studies was 116.6 weeks (range, 46.9-151.1 weeks). The most common adverse events were nasopharyngitis, influenza, upper respiratory tract infection, and asthma. Serious adverse events developed in 10 patients (26.3%), but resolved completely with additional treatments. Incidence of adverse events didn't increase with extended exposure with omalizumab. Twenty-nine patients (76.3%) achieved completely- or well-controlled asthma compared with 9 patients (23.7%) at the start of the extension study. QOL scores, the rates (per year) of hospitalizations and ER visits were significantly improved compared with the baseline of the core study [39.0 vs 48.0 (median), p < 0.001 for QOL, 1.33 vs 0.16, p < 0.001 for hospitalization, 0.68 vs 0.15, p = 0.002 for ER visits]. Remarkably, the mean total IgE level showed a decreasing trend while exposure to omalizumab remained at steady-state. CONCLUSIONS: Long-term treatment with omalizumab is well-tolerated and effective in children with uncontrolled severe allergic asthma. No new safety findings were identified.

FOOD-DEPENDENT EXERCISE-INDUCED ANAPHYLAXIS DUE TO INGESTION OF MIKAN (CITRUS UNSHIU).

A 12-year-old girl was referred to our hospital owing to repeated anaphylactic reactions induced by exercise after meals. Food-dependent exercise-induced anaphylaxis (FDEIAn) was suspected. However, sequential tests of typical foods, including egg, milk, soy, and wheat, in combination with exercise, were all negative.The results of the skin prick test (SPT) for Citrus unshiu and specific IgE test for orange and grapefruit were positive. Although no symptoms were noted after an exercise challenge combined with the ingestion of only Citrus unshiu, an anaphylactic reaction was induced by additional acetyl-salicylic acid. From these results, she was diagnosed with FDEIAn due to the ingestion of Citrus unshiu. Because the SPT results for other citrus fruits (including orange, grapefruit, lemon, yuzu, sudachi, ponkan, and iyokan) were all positive, it was suggested that these fruits demonstrate cross-reactivity with each other. Since the girl eliminated citrus fruits from her diet, she has not developed any anaphylactic symptoms. Citrus fruits are not known to cause FDEIAn, but the findings of this case suggest that it is necessary to recognize them as a causative allergen of FDEIAn.

[AN ADULT CASE OF EGG ALLERGY TREATED WITH RUSH ORAL IMMUNOTHERAPY].

A 26-year-old female patient exhibited symptoms associated with egg allergy, which had been present since early childhood. The patient requested the treatment of egg allergy and was admitted to our hospital for rush oral immunotherapy. The threshold was determined by an oral food challenge test, after positive results on a double-blind food challenge test. The patient ingested dry powder of raw egg-white 5 times per day starting with a tenth of the threshold dose (3.0mg), followed by a 1.2-times increase every time. When the amount of powder reached 1g, it was replaced with 8g of scrambled egg, after then subsequent doses were increased 1.5 times every time. The target of one chicken egg (60g) was reached on the 18th day. During treatment, minor allergic symptoms of urticarial and dyspnea were observed on two occasions, but they disappeared after oral administration of antihistamines. The result of an exercise challenge test after ingestion of egg was negative, and no allergic symptoms were observed by the ingestion of processed foods that contained egg. The patient currently receives ongoing maintenance treatment, consisting of the ingestion of one chicken egg per day; no allergic symptoms have been observed during a period of 2 year while receiving this treatment. Rush oral immunotherapy is a treatment option to be considered for adults with food allergy who were not able to acquire immune tolerance during childhood.

THE CASE OF A 14-YEAR-OLD BOY WHO EXPERIENCED ANAPHYLAXIS DUE TO JELLYFISH (MASTIGIAS PAPUA) INGESTION.

We report a case of jellyfish allergy diagnosed via an oral food challenge. A 14-year-old boy had no history of jellyfish stings and had been eating commercially available jellyfish products twice yearly for the past 5-6 years. Five minutes after eating a commercially available boiled jellyfish product (100g), he experienced nausea, wheezing, and erythema and had visited our hospital. We suspected an anaphylactic reaction and treated him with intramuscular adrenaline injection, corticosteroid and antihistamine infusions, volume resuscitation, and salbutamol sulfate inhalation, which resulted in an improvement of the symptoms. One-month later in our hospital, we administered an oral food challenge of the same boiled jellyfish product bought at the same grocery store to the patient. After ingesting 14g of boiled jellyfish, he experienced erythema, wheezing, nausea, and abdominal pain. Several reports have described anaphylaxis caused by the ingestion of jellyfish, but the allergens in jellyfish have not been analyzed. A skin prick test for poly-gamma-glutamic acid (PGA) which is a component of jellyfish stings was negative. This suggests that he was sensitized to some allergen other than PGA via a route different from that of jellyfish sting. Our skin prick test for several kinds of edible jellyfish suggests that allergenicity may be different for different jellyfish.

Omalizumab in Japanese children with severe allergic asthma uncontrolled with standard therapy.

BACKGROUND: Omalizumab has demonstrated clinical benefits in children with moderate to severe allergic asthma. However, no studies have been performed in Japanese asthmatic children. The aim of this study was to evaluate the efficacy including free IgE suppression and safety of omalizumab in Japanese children with severe allergic asthma. The primary objective was to examine whether omalizumab decreases serum free IgE levels to less than 25 ng/ml (target level of suppression). METHODS: Thirty-eight Japanese children (6-15 years) with uncontrolled severe allergic asthma despite inhaled corticosteroids (>200 µg/day fluticasone propionate or equivalent) and two or more controller therapies received add-on treatment with omalizumab in a 24-week, multicenter, uncontrolled, open-label study. RESULTS: The geometric mean serum free IgE level at 24 weeks was 15.6 ng/mL. Compared with baseline, total asthma symptom scores, daily activity scores and nocturnal sleep scores at 24 weeks were significantly improved. The rates of asthma exacerbation and hospitalization due to asthma were reduced by 69.2% and 78.2%, respectively (p < 0.001), versus baseline. Quality-of-life scores were also significantly improved (p < 0.001). In addition, 11 (28.9%) patients reduced the dose of any asthma controller medications. Thirty-six (94.7%) patients experienced at least one adverse event during the treatment period. All adverse events were mild or moderate in severity and no new safety concerns were detected. No patients discontinued the study. CONCLUSIONS: In Japanese children with severe allergic asthma, omalizumab decreased free IgE levels to less than 25 ng/mL. Omalizumab improved asthma control and was well-tolerated, as well.

[A case of eosinophilic esophagogastroenteritis which developed after rush oral immunotherapy for egg allergy].

Rush oral immunotherapy was provided to a 9 year old boy suffering from egg allergy. The patient reached the goal of one boiled egg daily on day 22 of treatment. He was discharged from the hospital the following day, with the maintenance dose of one whole egg to be taken daily. However, the patient began to experience abdominal pain and vomiting after ingestion of egg approximately one day after discharge. Blood tests revealed a remarkable increase in eosinophils in peripheral blood, and we reduced the patient's intake of egg. The patient's condition did not improve, and he gradually started to lose weight. Maintenance dosing was stopped completely on day 38. An endoscopic biopsy of the mucosa lining from the esophagus to the duodenum was performed on day 45. The results confirmed prominent diffuse eosinophilic infiltration of the entire upper gastrointestinal tract. The patient was finally diagnosed with eosinophil esophagogastroenteritis. While this condition is rare, it should be considered in future cases of persistent gastrointestinal symptoms during food allergy immunotherapy.

Japanese pediatric guideline for the treatment and management of bronchial asthma 2012.

A new version of the Japanese pediatric guideline for the treatment and management of bronchial asthma was published in Japanese at the end of 2011. The guideline sets the pragmatic goal for clinicians treating childhood asthma as maintaining a "well-controlled level" for an extended period in which the child patient can lead a trouble-free daily life, not forgetting the ultimate goal of obtaining remission and/or cure. Important factors in the attainment of the pragmatic goal are: (i) appropriate use of anti-inflammatory drugs; (ii) elimination of environmental risk factors; and (iii) educational and enlightening activities for the patient and caregivers regarding adequate asthma management in daily life. The well-controlled level refers to a symptom-free state in which no transient coughs, wheezing, dyspnea or other symptoms associated with bronchial asthma are present, even for a short period of time. As was the case in the previous versions of the guideline, asthmatic children younger than 2 years of age are defined as infantile asthma patients. Special attention is paid to these patients in the new guideline: they often have rapid exacerbation and easily present chronic asthmatic conditions after the disease is established.

Effects of transdermal tulobuterol in pediatric asthma patients on long-term leukotriene receptor antagonist therapy: results of a randomized, open-label, multicenter clinical trial in Japanese children aged 4-12 years.

BACKGROUND: Few studies have examined the efficacy or safety of a transdermal ß(2) agonist as add-on medication to long-term leukotriene receptor antagonist (LTRA) therapy in pediatric asthma patients. METHODS: In this randomized, open-label, multicenter clinical trial, children aged 4-12 years on long-term LTRA therapy were treated with tulobuterol patches (1-2mg daily) or oral sustained-release theophylline (usual dose, 4-5mg/kg daily) for 4 weeks. LTRAs were continued throughout the trial. Outcomes included volume of peak expiratory flow (% PEF), fractional exhaled nitric oxide (FeNO), clinical symptoms and adverse events. RESULTS: Thirty-three and 31 patients were treated with tulobuterol patches and theophylline, respectively. % PEF measured in the morning and before bedtime was significantly higher at all times in the treatment period compared with baseline in the tulobuterol patch group (p < 0.001), and was significantly higher in the tulobuterol patch group compared with the theophylline group. FeNO was similar and unchanged from baseline in both groups. There were no drug-related adverse events in either group. CONCLUSIONS: These results suggest that short-term use of a transdermal ß(2) agonist is an effective therapy for pediatric asthma without inducing airway inflammation in children on long-term LTRA therapy.

Effects of Transdermal Tulobuterol in Pediatric Asthma Patients on Long-Term Leukotriene Receptor Antagonist Therapy: Results of a Randomized, Open-Label, Multicenter Clinical Trial in Japanese Children Aged 4-12 Years.

BACKGROUND: Few studies have examined the efficacy or safety of a transdermal ß2 agonist as add-on medicationto long-term leukotriene receptor antagonist (LTRA) therapy in pediatric asthma patients. METHODS: In this randomized, open-label, multicenter clinical trial, children aged 4-12 years on long-term LTRA therapy were treated with tulobuterol patches (1-2 mg daily) or oral sustained-release theophylline (usual dose, 4-5 mg_kg daily) for 4 weeks. LTRAs were continued throughout the trial. Outcomes included volume peak expiratory flow (% PEF), fractional exhaled nitric oxide (FeNO), clinical symptoms and adverse events. RESULTS: Thirty-three and 31 patients were treated with tulobuterol patches and theophylline, respectively. % PEF measured in the morning and before bedtime was significantly higher at all times in the treatment period compared with baseline in the tulobuterol patch group (p < 0.001), and was significantly higher in the tulobuterol patch group compared with the theophylline group. FeNO was similar and unchanged from baseline in both groups. There were no drug-related adverse events in either group. CONCLUSIONS: These results suggest that short-term use of a transdermal ß2 agonist is an effective therapy for pediatric asthma without inducing airway inflammation in children on long-term LTRA therapy.

[Case of 5 year-old boy with anaphylaxis due to erythritol with negative prick test and positive intradermal test].

A 5 year-old boy experienced anaphylaxis after eating a jelly product for diet supplement containing erythritol as a major component. Prick test with the jelly product was negative, but the second oral ingestion of the jelly product at home caused another allergic reaction. Prick test with erythritol was negative even at 300 mg/ml, which was almost the solubility limit. Intradermal test was marginally positive at 0.1 mg/ml, and clearly positive at 1 mg/ml or higher concentration. We found subtle dose-response reaction utilizing basophil activation test, examined with 24 hour incubation at the concentration of 40-4000 µg/ml. At the oral challenge test in the hospital, 3 g of erythritol induced remarkable coughing, urticaria, edema, wheezing and hypoxemia. Erythritol is a natural sugar alcohol, with the molecular weight of 122.12, which is recently being widely used for diet supplements, beverages, or drug medicines due to its properties of calorie-free and good-tasting, with easy-to-use physical characteristics. We now have to recognize erythritol as a candidate for food allergen, and to be careful about negative result of prick test.

The use of complementary and alternative medicine by pediatric food-allergic patients in Japan.

BACKGROUND: In developed countries, increasing food allergy prevalence and concern regarding food allergies have been reported. Although the use of complementary and alternative medicine (CAM) for the treatment of allergic diseases has increased in some Western countries, the actual proportion and patterns of CAM use for pediatric food allergies in Japan are still unknown. METHODS: Fourteen allergy centers in Japan participated in the study using a questionnaire survey regarding the use of CAM by pediatric patients. A diagnosis of food allergy was made at each hospital by pediatric allergists. RESULTS: Surveys were completed by parents/guardians, and data were collected for a total of 962 pediatric food-allergic patients. Overall, 8.4% of the participants used CAM to treat a food allergy. The major CAM therapies used were herbal teas (22.2%), including several Japanese herbal teas, Chinese herbal medicine (18.5%) and lactic acid bacteria (16%). Among the participants using CAM to treat food allergy, 13.6% thought that the CAM being used was very effective, while 11.1% of participants thought that CAM caused some type of side effect. CONCLUSIONS: Our study is the first large-scale national survey regarding the use of CAM in pediatric patients with food allergies in Japan. Unlike in the USA, which has a higher rate of CAM use (17%), approximately 8.4% of food-allergic patients used CAM in Japan. Interestingly, the major types of CAM used in Japan differed from those used in the USA. Cultural differences and food customs may affect the use of CAM.

Effects of the tulobuterol patch on the treatment of acute asthma exacerbations in young children.

The tulobuterol patch (TP) is a beta2-adrenergic agonist with a favorable pharmacokinetic profile used for asthma management in Japan. Because it contains tulobuterol in a molecular, crystallized form that is gradually absorbed percutaneously, TP exerts a prolonged bronchodilator effect exceeding 24 hours. Although it is a well-established treatment for asthma and wheezing, few studies have investigated whether it can reduce or prevent the symptoms associated with upper respiratory tract infections (URTIs) in young children. This study evaluated the effect of TP on the long-term management of asthma in young children. In this 1-year, randomized, multicenter, double-blind, placebo-controlled study, children aged 0.5-3 years old with mild-to-moderate persistent asthma were treated with either TP or placebo patch. The parents/guardians applied the TP or placebo patch to their children after URTI symptoms appeared. Respiratory symptoms were recorded daily during the 1-year observation period. Overall, 86 patients were enrolled and 80 were treated and analyzed in this study. All patients had been treated with anti-inflammatory drugs before enrollment. The time to symptom resolution was significantly shorter (p = 0.001) and the total respiratory symptom score (p = 0.0457) was significantly lower in the TP group than in the placebo group. In young children with mild-to-moderate asthma who had been treated with anti-inflammatory drugs, using the TP soon after the appearance of URTI symptoms led to quicker resolution of respiratory symptoms and lower respiratory symptom scores.

Effects of the tulobuterol patch on the treatment of acute asthma exacerbations in young children.

The tulobuterol patch (TP) is a beta(2)-adrenergic agonist with a favorable pharmacokinetic profile used for asthma management in Japan. Because it contains tulobuterol in a molecular, crystallized form that is gradually absorbed percutaneously, TP exerts a prolonged bronchodilator effect exceeding 24 hours. Although it is a well-established treatment for asthma and wheezing, few studies have investigated whether it can reduce or prevent the symptoms associated with upper respiratory tract infections (URTIs) in young children. This study evaluated the effect of TP on the long-term management of asthma in young children. In this 1-year, randomized, multicenter, double-blind, placebo-controlled study, children aged 0.5-3 years old with mild-to-moderate persistent asthma were treated with either TP or placebo patch. The parents/guardians applied the TP or placebo patch to their children after URTI symptoms appeared. Respiratory symptoms were recorded daily during the 1-year observation period. Overall, 86 patients were enrolled and 80 were treated and analyzed in this study. All patients had been treated with anti-inflammatory drugs before enrollment. The time to symptom resolution was significantly shorter (p = 0.001) and the total respiratory symptom score (p = 0.0457) was significantly lower in the TP group than in the placebo group. In young children with mild-to-moderate asthma who had been treated with anti-inflammatory drugs, using the TP soon after the appearance of URTI symptoms led to quicker resolution of respiratory symptoms and lower respiratory symptom scores.

[A case of oral allergy syndrome whose symptoms were dramatically improved after rush subcutaneous injection immunotherapy with pollen extracts of birch].

We report a case of oral allergy syndrome, whose symptoms were dramatically improved after rush subcutaneous injection immunotherapy (SCIT) with pollen extracts of birch, ragweed and Japanese cedar. She was diagnosed as allergic rhinitis at 2 years old, and experienced oral allergy syndrome at 5 years old after eating cucumber. Then she had become allergic to wide range of fruits and vegetables. She was introduced to our department for the possible treatment for allergic rhinitis, and underwent rush SCIT at 15 years old. The symptom of single blind oral challenge test of apple up to 30 g, which had been positive before SCIT, turned to negative after the treatment. The threshold of apple measured by open oral challenge test increased from 3 g to more than 50 g. The symptoms to most fruits and vegetables were improved or disappeared. This suggests the possibility that SCIT of birch pollen can be a promising candidate as a radical treatment for pollen-food allergy syndrome.

Case of a 6-year-old boy with anaphylaxis induced by erythritol with positive skin prick test and negative basophil activation test.

Erythritol is widely used as an additive in foods and pharmaceuticals. We present the case of a 6-year-old boy who developed an allergy to erythritol. He showed a positive skin prick test result and a negative basophil activation test result. In cases involving allergens with low molecular weights, the test results should be carefully interpreted.

Japanese pediatric guidelines for the treatment and management of bronchial asthma 2008.

Abstract The fourth version of the Japanese Pediatric Guidelines for the Treatment and Management of Bronchial Asthma 2008 (JPGL 2008) was published by the Japanese Society of Pediatric Allergy and Clinical Immunology in December 2008. In JPGL 2008, the recommendations were revised on the basis of the JPGL 2005. The JPGL 2008 is different to the Global Initiative for Asthma guideline in that it contains the following items: a classification system of asthma severity; recommendations for long-term management organized by age; a special mention of infantile asthma; and an emphasis on prevention and early intervention. Here we show a summary of the JPGL 2008 revising our previous report concerning JPGL 2005.