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1.  World Allergy Organization-McMaster University Guidelines for Allergic Disease Prevention (GLAD-P): Probiotics 
Background
Prevalence of allergic diseases in infants, whose parents and siblings do not have allergy, is approximately 10% and reaches 20–30% in those with an allergic first-degree relative. Intestinal microbiota may modulate immunologic and inflammatory systemic responses and, thus, influence development of sensitization and allergy. Probiotics have been reported to modulate immune responses and their supplementation has been proposed as a preventive intervention.
Objective
The World Allergy Organization (WAO) convened a guideline panel to develop evidence-based recommendations about the use of probiotics in the prevention of allergy.
Methods
We identified the most relevant clinical questions and performed a systematic review of randomized controlled trials of probiotics for the prevention of allergy. We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to develop recommendations. We searched for and reviewed the evidence about health effects, patient values and preferences, and resource use (up to November 2014). We followed the GRADE evidence-to-decision framework to develop recommendations.
Results
Currently available evidence does not indicate that probiotic supplementation reduces the risk of developing allergy in children. However, considering all critical outcomes in this context, the WAO guideline panel determined that there is a likely net benefit from using probiotics resulting primarily from prevention of eczema. The WAO guideline panel suggests: a) using probiotics in pregnant women at high risk for having an allergic child; b) using probiotics in women who breastfeed infants at high risk of developing allergy; and c) using probiotics in infants at high risk of developing allergy. All recommendations are conditional and supported by very low quality evidence.
Conclusions
WAO recommendations about probiotic supplementation for prevention of allergy are intended to support parents, clinicians and other health care professionals in their decisions whether to use probiotics in pregnancy and during breastfeeding, and whether to give them to infants.
Electronic supplementary material
The online version of this article (doi:10.1186/s40413-015-0055-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s40413-015-0055-2
PMCID: PMC4307749  PMID: 25628773
Allergy; Prevention; Probiotics; Practice guidelines; GRADE
3.  Precautionary labelling of foods for allergen content: are we ready for a global framework? 
Food allergy appears to be on the rise with the current mainstay of treatment centred on allergen avoidance. Mandatory allergen labelling has improved the safety of food for allergic consumers. However an additional form of voluntary labelling (termed precautionary allergen labelling) has evolved on a wide range of packaged goods, in a bid by manufacturers to minimise risk to customers, and the negative impact on business that might result from exposure to trace amounts of food allergen present during cross-contamination during production. This has resulted in near ubiquitous utilisation of a multitude of different precautionary allergen labels with subsequent confusion amongst many consumers as to their significance. The global nature of food production and manufacturing makes harmonisation of allergen labelling regulations across the world a matter of increasing importance. Addressing inconsistencies across countries with regards to labelling legislation, as well as improvement or even banning of precautionary allergy labelling are both likely to be significant steps forward in improved food safety for allergic families. This article outlines the current status of allergen labelling legislation around the world and reviews the value of current existing precautionary allergen labelling for the allergic consumer. We strongly urge for an international framework to be considered to help roadmap a solution to the weaknesses of the current systems, and discuss the role of legislation in facilitating this.
doi:10.1186/1939-4551-7-10
PMCID: PMC4005619  PMID: 24791183
Allergen labelling; Food allergy; Legislation; Precationary allergen labelling; Anaphylaxis; Allergen avoidance; Mandatory labelling
4.  International consensus on (ICON) anaphylaxis 
ICON: Anaphylaxis provides a unique perspective on the principal evidence-based anaphylaxis guidelines developed and published independently from 2010 through 2014 by four allergy/immunology organizations. These guidelines concur with regard to the clinical features that indicate a likely diagnosis of anaphylaxis -- a life-threatening generalized or systemic allergic or hypersensitivity reaction.
They also concur about prompt initial treatment with intramuscular injection of epinephrine (adrenaline) in the mid-outer thigh, positioning the patient supine (semi-reclining if dyspneic or vomiting), calling for help, and when indicated, providing supplemental oxygen, intravenous fluid resuscitation and cardiopulmonary resuscitation, along with concomitant monitoring of vital signs and oxygenation. Additionally, they concur that H1-antihistamines, H2-antihistamines, and glucocorticoids are not initial medications of choice.
For self-management of patients at risk of anaphylaxis in community settings, they recommend carrying epinephrine auto-injectors and personalized emergency action plans, as well as follow-up with a physician (ideally an allergy/immunology specialist) to help prevent anaphylaxis recurrences.
ICON: Anaphylaxis describes unmet needs in anaphylaxis, noting that although epinephrine in 1 mg/mL ampules is available worldwide, other essentials, including supplemental oxygen, intravenous fluid resuscitation, and epinephrine auto-injectors are not universally available.
ICON: Anaphylaxis proposes a comprehensive international research agenda that calls for additional prospective studies of anaphylaxis epidemiology, patient risk factors and co-factors, triggers, clinical criteria for diagnosis, randomized controlled trials of therapeutic interventions, and measures to prevent anaphylaxis recurrences. It also calls for facilitation of global collaborations in anaphylaxis research.
In addition to confirming the alignment of major anaphylaxis guidelines, ICON: Anaphylaxis adds value by including summary tables and citing 130 key references. It is published as an information resource about anaphylaxis for worldwide use by healthcare professionals, academics, policy-makers, patients, caregivers, and the public.
doi:10.1186/1939-4551-7-9
PMCID: PMC4038846  PMID: 24920969
Anaphylaxis; Acute systemic allergic reaction; Epinephrine (adrenaline); H1-antihistamines; H2-antihistamines; Glucocorticoids; Food allergy; Venom allergy; Drug allergy; Exercise-induced anaphylaxis; Idiopathic anaphylaxis
5.  A global survey of changing patterns of food allergy burden in children 
While food allergies and eczema are among the most common chronic non-communicable diseases in children in many countries worldwide, quality data on the burden of these diseases is lacking, particularly in developing countries. This 2012 survey was performed to collect information on existing data on the global patterns and prevalence of food allergy by surveying all the national member societies of the World Allergy Organization, and some of their neighbouring countries. Data were collected from 89 countries, including published data, and changes in the health care burden of food allergy. More than half of the countries surveyed (52/89) did not have any data on food allergy prevalence. Only 10% (9/89) of countries had accurate food allergy prevalence data, based on oral food challenges (OFC). The remaining countries (23/89) had data largely based on parent-reporting of a food allergy diagnosis or symptoms, which is recognised to overestimate the prevalence of food allergy. Based on more accurate measures, the prevalence of clinical (OFC proven) food allergy in preschool children in developed countries is now as high as 10%. In large and rapidly emerging societies of Asia, such as China, where there are documented increases in food allergy, the prevalence of OFC-proven food allergy is now around 7% in pre-schoolers, comparable to the reported prevalence in European regions. While food allergy appears to be increasing in both developed and developing countries in the last 10–15 years, there is a lack of quality comparative data. This survey also highlights inequities in paediatric allergy services, availability of adrenaline auto-injectors and standardised National Anaphylaxis Action plans. In conclusion, there remains a need to gather more accurate data on the prevalence of food allergy in many developed and developing countries to better anticipate and address the rising community and health service burden of food allergy.
doi:10.1186/1939-4551-6-21
PMCID: PMC3879010  PMID: 24304599
Food allergy; Allergic disease; Allergy epidemic; Allergy prevention; Food allergens
6.  Thymic Stromal Lymphopoietin Gene Promoter Polymorphisms Are Associated with Susceptibility to Bronchial Asthma 
Thymic stromal lymphopoietin (TSLP) triggers dendritic cell–mediated T helper (Th) 2 inflammatory responses. A single-nucleotide polymorphism (SNP), rs3806933, in the promoter region of the TSLP gene creates a binding site for the transcription factor activating protein (AP)–1. The variant enhances AP-1 binding to the regulatory element, and increases the promoter–reporter activity of TSLP in response to polyinosinic-polycytidylic acid (poly[I:C]) stimulation in normal human bronchial epithelium (NHBE). We investigated whether polymorphisms including the SNP rs3806933 could affect the susceptibility to and clinical phenotypes of bronchial asthma. We selected three representative (i.e., Tag) SNPs and conducted association studies of the TSLP gene, using two independent populations (639 patients with childhood atopic asthma and 838 control subjects, and 641 patients with adult asthma and 376 control subjects, respectively). We further examined the effects of corticosteroids and a long-acting β2-agonist (salmeterol) on the expression levels of the TSLP gene in response to poly(I:C) in NHBE. We found that the promoter polymorphisms rs3806933 and rs2289276 were significantly associated with disease susceptibility in both childhood atopic and adult asthma. The functional SNP rs3806933 was associated with asthma (meta-analysis, P = 0.000056; odds ratio, 1.29; 95% confidence interval, 1.14–1.47). A genotype of rs2289278 was correlated with pulmonary function. Moreover, the induction of TSLP mRNA and protein expression induced by poly(I:C) in NHBE was synergistically impaired by a corticosteroid and salmeterol. TSLP variants are significantly associated with bronchial asthma and pulmonary function. Thus, TSLP may serve as a therapeutic target molecule for combination therapy.
doi:10.1165/rcmb.2009-0418OC
PMCID: PMC3159073  PMID: 20656951
asthma; TSLP; bronchial epithelial cells; combination therapy; genetic polymorphisms
7.  492 Nationwide Survey of Immediate Type Food Allergy in Japan 
Background
The food labeling system for food allergens was introduced from April 2002 in Japan. To confirm the effectiveness of the system, we regularly conduct a nationwide food allergy survey every 3 years.
Methods
The survey was conducted in cooperation with over 1000 volunteer allergists in Japan at 2001, 2002, 2005 and 2008. We sent questionnaire to contributing doctors every 3 months based on the past survey system, and contributing doctors were asked to report immediate type food allergy cases seen by those doctors. In this survey, immediate type food allergy was defined as the patients who had developed symptoms due to food allergic reaction within 60 minutes after intake of offending food. The details of questionnaire consisted of age, sex, cause of food allergy, symptoms, CAP system, and type of onset.
Results
A total of 8581 immediate type food allergy cases were reported by the doctors. The most common offending foods were hen's egg (39.0%), milk products (18.0%), wheat (9.4%), fruit (5.3%), crustacean (4.6%), peanuts (3.7%), fish egg, buckwheat and fish (3.6%). The most common clinical symptom was observed on skin (89.7%) followed by respiratory system (29.6%). Interestingly, the causes of food allergy were completely different from infancy (egg, milk, and wheat) to adulthood (wheat, crustacean and fruits). Anaphylactic shock was observed in 10.9% of the total reported cases. The cases of anaphylactic shock were due to hen's egg (27.1%), milk products (21.4%) and wheat (18.1%). Eleven percentages of patients had been hospitalized.
Conclusions
We revealed the current condition of the immediate type food allergy cases seen in Japan recent decade. Based on these data, countermeasures against food allergy are ongoing in collaboration with the Ministry of Health, Labour, and Welfare in Japan in order to improve quality of life of patients.
doi:10.1097/01.WOX.0000411607.27561.ab
PMCID: PMC3512847
8.  496 Cross Sectional Study of 1,822 Pediatric Food Allergy Patients 
The World Allergy Organization Journal  2012;5(Suppl 2):S174-S175.
Background
The aim of this study is to clarify the cross section of pediatric food allergy patients. We investigated the profiles of food allergy (FA) patients seen in our department.
Methods
The number of food allergy patients seen in our department from January to December in 2010 was a total of 1,822 (male: 1207, female: 615, mean age: 5.8 ± 3.8 year). We collected and analyzed the clinical information of these patients from our medical record. We obtained information on the age of FA onset & FA diagnosis, clinical types of FA at the onset, causative food allergens, other allergic complications, and application of oral immunotherapy (OIT).
Results
The average age of FA onset was 8 months, and that of diagnosis was 1 year old, respectively. The most common clinical types of FA at the time of onset were infantile atopic dermatitis (AD) type with food allergy (66.4%) followed by immediate type (30.8%). Food allergens avoided by the patients were the total number of 4,203 items (2.1 items as average). The most common eliminated food was hen's egg (1,245 cases; 29.6%), followed by cow's milk (786 cases; 18.7%), peanut (449 cases; 10.7%), and wheat (407 cases; 9.7%). Food-dependent exercise-induced anaphylaxis (FDEIA) was the total of 18 cases, and the most common causative food for FDEIA was wheat (10 cases) followed by peach (4 cases). One hundred and seventy five cases (9.6%) were currently receiving OIT. Main causative foods under OIT were hen's egg (63 cases), cow's milk (80 cases), and wheat (30 cases). The average starting age of OIT was 7.1 years old. Regarding complications of allergic diseases other than FA, 1119 (61.4%) had atopic dermatitis, and 541 (29.7%) bronchial asthma.
Conclusions
We were able to clarify the cross section of food allergy patients in our department and to obtain the basic data to follow continuous transition of these patients.
doi:10.1097/01.WOX.0000411611.80926.23
PMCID: PMC3512856
9.  436 Ten Years Follow up of Japanese Survey on Immediate Type Food Allergy 
Background
The food labeling system for food allergens was introduced from April 2002 in Japan. To confirm the effectiveness of the system, we regularly conduct a nationwide food allergy survey every 3 years.
Methods
The survey was conducted in cooperation with over 1000 volunteer doctors in Japan at 2001+2002, 2005 and 2008. We have sent questionnaires to contributing doctors every 3 months based on the previous survey system, and contributing doctors were asked to report immediate type food allergy cases seen by those doctors. In this survey, immediate type food allergy was defined as the patients who had developed symptoms due to food allergic reaction within 60 minutes after intake of causative foods. The details of questionnaire consisted of age, sex, cause of food allergy, symptoms, antigen-specific IgE, and type of onset.
Results
A total of 8581 immediate type food allergy cases were reported by the doctors in these surveys. The most common causative foods were hen's egg (39.0%), milk products (18.0%), wheat products (9.4%), fruits (5.3%), crustacean (4.6%), peanuts (3.7%), fish egg, buckwheat and fish (3.6%). The most common clinical symptom was observed on skin (89.7%) followed by respiratory system (29.6%). Interestingly, the causes of food allergy were completely different from infancy (egg, milk, and wheat) to adulthood (wheat, crustacean and fruits). Anaphylactic shock was observed in 10.9% of the total reported cases. The cases of anaphylactic shock were due to hen's egg (27.1%), milk products (21.4%) and wheat (18.1%). Eleven percentages of patients had been hospitalized.
Conclusions
We could clarify the detail of the immediate type food allergy cases seen in Japan for a recent decade. Based on these data, countermeasures against food allergy have been conducted in collaboration with the Ministry of Health, Labour, and Welfare in Japan in order to improve quality of life of patients with food allergy.
doi:10.1097/01.WOX.0000412199.68444.5a
PMCID: PMC3512981
10.  75 Efficacy of Slow Oral Immunotherapy for Cow's Milk Allergy 
The World Allergy Organization Journal  2012;5(Suppl 2):S41-S42.
Background
Efficacy and safety of slow oral immunotherapy (SOIT) is not yet clear, especially regarding tolerance acquisition.
Methods
We recruited 32 cow's milk (CM) allergy confirmed by oral food challenge (OFC). Twenty-five subjects were enrolled as SOIT group, and remaining 7 were as control. The inclusion criteria were as follows; (1) CM allergy without anaphylaxis confirmed by OFC just before the trial, and (2) children >4 years. In SOIT group, they were asked to take small amount of CM at home after the OFC. The initial dose was about 1/4 of the threshold eliciting positive objective symptoms, and it was built up to 200 mL CM depends on the symptoms (build up phase). After reaching 200 mL, they were asked to take 200 mL CM daily until the asymptomatic duration lasting for more than 3m (maintenance phase). The subjects, who completed maintenance phase, underwent OFC to confirm the tolerance acquisition after the cessation of CM ingestion for 2w (confirm-OFC). In control group, they had eliminated CM completely and underwent the confirm-OFC after 9.8 ± 2.9 m (mean ± SD). We investigated the endpoints (adverse reactions, medical treatments, results of confirm-OFC, and laboratory findings), prospectively.
Results
In SOIT group (n = 25) and control group (n = 7), the average age was 6.6y and 4.7y, respectively. The average threshold was 52 mL and 17 mL, and the CM specific IgE was 17.6 Ua/mL/9.9 Ua/mL, respectively. The average period of build up and maintenance phases in SOIT group was 80d (n = 25) and 98d (n = 15), respectively. The frequency of adverse reactions in all of build up (1973d) and maintenance phases (2924d) were 13.5% (mild symptoms)/2.3% (moderate symptoms) and 1.7% (mild)/0.3% (moderate), respectively. No patient had administered adrenaline during SOIT. Fifteen subjects in SOIT and 7 in control underwent the confirm-OFC. In SOIT, 8 subjects (53.3%) passed the confirm-OFC, whereas 2 (28.6%) passed in control. There was no statistically significant difference regarding tolerance acquisition between these 2 groups (P = 0.277).
Conclusions
This study suggests that SOIT for about 1/2 year induces desensitization effectively for CM allergy without severe adverse reactions. Further and longer study would be required to prove accelerated tolerance acquisition by SOIT.
doi:10.1097/01.WOX.0000411820.08764.3a
PMCID: PMC3513047
11.  429 Natural History of Food Allergy in Childhood -3 Years' Follow up of Pediatric Food Allergy Patients 
Background
Food allergy (FA) is prevalent among children however natural history of FA is not fully clarified.
Methods
We sought to investigate the natural course of childhood FA. To follow up the transition of same patients, we collected clinical records of patients with 3 years’ interval from 2008 to 2010. Four hundred ninety-one patients (male 321 and female 170) were recruited to this study.
Results
The onset of FA was at the age of 5 months ± 1 year 3 month (mean ± SD). The clinical type at the onset was with infantile atopic eczema (84.1%), and followed by immediate reactions without eczema (14.9%). The initial diagnosis age was 10 months ± 1 year 4 months, and the first visit to our department was 1 year 11 month ± 2 years 5 months. Current age of the patients was 7 years 5 months ± 2 years 11 months, and 444 patients (90.4%) had experienced immediate reactions. The number of eliminated foods decreased from 2.4 ± 1.5 items/patient (n = 1191) to 1.9 ± 1.6 items/patient (n = 926) in 3 years. The ratio of stopping elimination of major allergens was 35.9% (121/337 patients) for hen's egg, 25.6% (52/203 patients) for cow's milk and 47.8% (44/92 patients) for wheat. Fourteen patients (2.9%) had developed new food allergies, and 2 of them had experienced anaphylaxis by tree nuts. Newly diagnosed allergens were only 0.1 ± 0.3 items/patient (n = 32), and nuts (n = 6) and peanut (n = 5) were the most frequent. Seventy-nine patients (16.1%) had developed complete remission of FA in 3 years, and 21.5% of them (17 patients) had never developed immediate reactions.
Conclusions
Most of pediatric FA started during infancy with atopic eczema, and developing tolerance is expected with aging. In some patients, persistent FA is troublesome for school age children.
doi:10.1097/01.WOX.0000412192.55876.a1
PMCID: PMC3513182
12.  World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) Guidelines 
doi:10.1097/WOX.0b013e3181defeb9
PMCID: PMC3488907  PMID: 23268426
Cow milk allergy; oral food challenge; epidemiology; DBPCFC; amino acid formula; hydrolyzed milk formula; hydrolyzed rice formula; hydrolyzed soy formula; skin prick test; specific IgE; OIT; SOTI; GRADE
13.  Large scale genotyping study for asthma in the Japanese population 
BMC Research Notes  2009;2:54.
Background
Asthma is a complex phenotype that is influenced by both genetic and environmental factors. Genome-wide linkage and association studies have been performed to identify susceptibility genes for asthma. These studies identified new genes and pathways implicated in this disease, many of which were previously unknown.
Objective
To perform a large-scale genotyping study to identify asthma-susceptibility genes in the Japanese population.
Methods
We performed a large-scale, three-stage association study on 288 atopic asthmatics and 1032 controls, by using multiplex PCR-Invader assay methods at 82,935 single nucleotide polymorphisms (SNPs) (1st stage). SNPs that were strongly associated with asthma were further genotyped in samples from asthmatic families (216 families, 762 members, 2nd stage), 541 independent patients, and 744 controls (3rd stage).
Results
SNPs located in the 5' region of PEX19 (rs2820421) were significantly associated with P < 0.05 through the 1st to the 3rd stage analyses; however, the P values did not reach statistically significant levels (combined, P = 3.8 × 10-5; statistically significant levels with Bonferroni correction, P = 6.57 × 10-7). SNPs on HPCAL1 (rs3771140) and on IL18R1 (rs3213733) were associated with asthma in the 1st and 2nd stage analyses, but the associations were not observed in the 3rd stage analysis.
Conclusion
No association attained genome-wide significance, but several loci for possible association emerged. Future studies are required to validate these results for the prevention and treatment of asthma.
doi:10.1186/1756-0500-2-54
PMCID: PMC2674055  PMID: 19335888

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