Evaluation of oral immunotherapy efficacy and safety by maintenance dose dependency: A multicenter randomized study.

BACKGROUND: Generally, oral immunotherapy (OIT) aims for daily administration. Recently, the efficacy of treatment with OIT at a low dose has been reported. However, the optimal dose and the evaluation of dose-dependent OIT outcome have not been described. METHODS: A multicenter, parallel, open-labeled, prospective, non-placebo controlled, randomized study enrolled 101 Japanese patients for treatment with OIT. We hypothesized that target dose OIT would induce short-term unresponsiveness (StU) earlier than reduced dose OIT. StU was defined as no response to 6200 mg whole egg, 3400 mg milk, and 2600 mg wheat protein, as evaluated by oral food challenge after 2-week ingestion cessation. To compare the two doses of OIT efficacy, the maximum ingestion doses during the maintenance phase of OIT were divided into 100%-dose or 25%-dose groups against their target StU dose, respectively. A total of 51 patients were assigned to the 100%-dose group [hen's egg (HE) = 26, cow's milk (CM) = 13, wheat = 12] and 50 to the 25%-dose group (HE = 25, CM = 13, wheat = 12). Primary outcome was established by comparing StU at 1 year. Secondary outcome was StU at 2 years and established by comparing allergic symptoms and immunological changes. RESULTS: The year 1 StU rates (%) for the 100%- and 25%-dose groups were 26.9 vs. 20.0 (HE), 7.7 vs. 15.4 (CM), and 50.0 vs. 16.7 (wheat), respectively. The year 2 StU rates were 30.8 vs. 36.0 (HE), 7.7 vs. 23.1 (CM), and 58.3 vs. 58.3 (wheat), respectively. There were no statistically significant differences in StU between years 1 and 2. The total allergic symptom rate in the 25%-dose group was lower than that in the 100%-dose group for egg, milk, and wheat. Antigen-specific IgE levels for egg-white, milk, and wheat decreased at 12 months. CONCLUSIONS: Reduced maintenance dose of egg OIT showed similar therapeutic efficacy to the target dose. However, we were not able to clearly demonstrate the efficacy, particularly for milk and wheat. Reducing the maintenance dose for eggs, milk, and wheat may effectively lower the symptoms associated with their consumption compared to the target OIT dose. Furthermore, aggressive reduction of the maintenance dose might be important for milk and wheat, compared to the 25%-dose OIT. TRIAL REGISTRATION: UMIN000009373, Multicenter Oral Immunotherapy for Hen's Egg, Cow's Milk, and Wheat-Allergic Children at Outpatient Clinic.

Slow low-dose oral immunotherapy: Threshold and immunological change.

BACKGROUND: We examined the feasibility, efficacy and safety of slow low-dose oral immunotherapy (SLOIT) for egg, milk, wheat allergies, with accepted severity-stratified initial and maintenance doses. METHODS: Children with food allergies defined by low-dose oral food challenges (LD-OFCs) to hen's egg (cumulative protein dose up to 983 mg, n = 133), cow's milk (287 mg, n = 50), and wheat (226 mg, n = 45) were recruited. Participants were divided into two groups [SLOIT and control (complete avoidance]) based on their preferences. Participants who selected SLOIT were instructed to take the safe dose daily, with monthly increases, aiming to increase the dose by 10 times in one year. The primary outcome was the proportion of participants who passed the LD-OFCs following 1 year of therapy. RESULTS: The participants in SLOIT group ingested their antigen 92.9% of the therapy's day on average. The proportion of participants who passed LD-OFCs was 35.9% (61/170) in the SLOIT group and 8.7% (4/46) in the control group (P < .001); no large differences were observed among allergens. Among the subjects who failed LD-OFCs, the median change in the total dose in the LD-OFC was 235% (interquartile range: 100%-512%) in the SLOIT group and 100% (42%-235%) in the control group (P < .001). Provoked allergic symptoms were observed in only 0.58% (280/48,486) per programmed intake and approximately 50% of the SLOIT group did not experience any obvious allergic symptoms throughout therapy. CONCLUSIONS: SLOIT showed significant feasibility, efficacy and safety, providing a promising option to manage patients with severe food allergies.

Exercise-induced allergic reactions on desensitization to wheat after rush oral immunotherapy.

BACKGROUND: The effect of oral immunotherapy (OIT) on wheat allergy is promising in terms of the potential to obtain desensitization; however, the frequency of exercise-induced allergic reactions on desensitization (EIARDs) and the associated risk factors remain to be determined. METHODS: Twenty-five patients underwent rush OIT for wheat allergy, and 21 achieved the full-dose intake of wheat products (5 g of wheat protein). Exercise-provocation tests were repeatedly performed after the ingestion of a full-dose wheat product. The time-course of the levels of the specific IgEs (sIgE) to wheat extract, total gliadin, deamidated gliadin, recombinant gliadin components (α/ß-, γ- and ω-5-), and glutenin (high and low molecular weight) components was analyzed using ImmunoCAP® , ELISA, or IgE immunoblotting. RESULTS: Fourteen patients (66.7%) were diagnosed as EIARD+, which remained 5 years after rush OIT in 11 patients (52.4%). There were no differences in the clinical backgrounds of the EIARD+ and EIARD- patients. However, EIARD+ patients showed significantly higher sIgE levels to all gliadin and glutenin components than EIARD- patients before OIT. The sIgE levels to each component decreased equally after 1 and 2 years of OIT. On IgE immunoblotting, sera from all patients reacted to the multiple gluten bands, and some reacted to the water-soluble bands. The intensity of all IgE-reactive bands also became equally lighter after OIT. CONCLUSIONS: EIARDs were frequently observed and remained for a long period after successful OIT for wheat allergy. None of the specific wheat components were found to contribute to EIARDs.

Additive effect of Lactobacillus acidophilus L-92 on children with atopic dermatitis concomitant with food allergy.

BACKGROUND: Atopic dermatitis (AD) in infants is often related to food allergies (FA). The beneficial effects of lactic acid bacteria towards allergic diseases have been reported, but there are few reports on their effect and preferable dosages on AD in young children with concomitant FA. OBJECTIVE: To examine additional effects of two different dose of paraprobiotic Lactobacillus acidophilus L-92 (L-92) on the clinical treatment in young children afflicted by AD with diagnosed or suspected FA. METHODS: Fifty-nine AD young children from 10 months to 3 years old, with FA or who had not started to ingest specific food(s) because of high specific IgE levels, were recruited and randomly allocated into L-92 group (daily intake of 20 mg L-92/day) and placebo group. Participants were given test sample with conventional treatment for AD over a 24-week period. The severity of eczema was evaluated using SCORing Atopic Dermatitis (SCORAD) index before intervention, and at 4, 12, and 24 weeks after intervention. RESULTS: After 24 weeks of intervention, a significant decrease in SCORAD was observed only in the L-92 group when compared with the baseline values. Significant decreases in thymus and activation-regulated chemokine (TARC) and total IgE were also detected 24 weeks after intake in the L-92 group compared with the placebo group. CONCLUSION: It was suggested that intake of sufficient amounts of L-92 works as an adjunctive treatment of young children afflicted by AD with diagnosed or suspected FA.

[THE CLINICAL CHARACTERISTICS OF PEANUT ALLERGY AND THE DIAGNOSTIC ACCURACY OF THE SPECIFIC IgE TO Ara h 2].

BACKGROUND: This study aimed to evaluate the clinical accuracy of specific IgE (sIgE) to Ara h 2 in the diagnosis of peanut allergy (PA). We also investigated the prevalence of complications with other nut allergies in PA patients. METHODS: The Ara h 2-sIgE titer was examined in patients with positive results for sIgE to peanut from April 2014 to March 2015. The presence or absence of PA was diagnosed based on an oral food challenge or a convincing clinical history. The characteristics of 217 patients (including 90 PA patients) were retrospectively evaluated. RESULTS: At ≥0.35UA/mL, Ara h 2 showed 85.6% sensitivity in the diagnosis of PA. At the clinically-designated positive cut-off value (≥4.0UA/mL), the positive predictive value was 93.1% and the specificity was 96.9%. However, the Ara h 2-sIgE levels were not correlated with the threshold dose or the severity of the symptoms that were provoked in the peanut challenge (n=42). Nine (10%) of the PA patients also had allergies to other tree nuts. CONCLUSION: The re-evaluation of the clinically-designated positive Ara h 2-sIgE cut-off value revealed that the cut-off value was appropriate. The differential diagnosis of tree nut allergies was suggested to be important in PA patients.

Surveillance of the use of adrenaline auto-injectors in Japanese children.

BACKGROUND: The appropriate usage of an adrenaline auto-injector (AAI, Epipen®) is a key aspect of patient and social education in the management of anaphylaxis. However, although AAIs are being prescribed increasingly frequently, there are few reports on their actual use. METHODS: The Anaphylaxis Working Group of the Japanese Society of Pediatric Allergy and Clinical Immunology requested that society members register cases in which AAIs were used. Two hundred and sixty-six cases were collected from March 2014 to March 2016. RESULTS: The cases included 240 events of immediate-type food allergies caused by cow's milk (n = 100), hen's egg (n = 42), wheat (n = 40), and peanuts (n = 11). Exercise-related events were reported in 19 cases; however, the diagnosis of food-dependent exercise-induced anaphylaxis with a specific causative food was only made in 4 cases (wheat, n = 2; fish, n = 1; squid, n = 1). The frequent reasons for the causative intake included programmed intake (n = 48), failure to check the food labeling (n = 43), and consuming an inappropriate food (n = 26). AAIs were used at schools or nurseries in 67 cases, with school or nursery staff members administering the AAI in 39 cases (58%). On arriving at the hospital, the symptom grade was improved in 71% of the cases, while grade 4 symptoms remained in 20% of the cases. No lethal cases or sequelae were reported. CONCLUSIONS: AAIs were used effectively, even by school teachers. The need to visit a hospital after the use of an AAI should be emphasized because additional treatment might be required.

[AN EVALUATION OF SPONTANEOUS HISTAMINE RELEASE AND THE LOW RESPONDERS IN A BASOPHIL HISTAMINE RELEASE TEST].

BACKGROUND: We evaluated the clinical significance of the spontaneous histamine release ratio (SHR/T) and low responders in the automated basophil histamine release test (AllerportⓇ HRT). METHODS: This study analyzed the outcomes of 101 oral food challenges (OFC) with egg, milk or wheat (challenge-positive: n=79) in relation to the SHR/T. The traditional HRT low responders (n=27) were separated into two groups:"LOW"responders (n=10), who showed a ≥10% concentration-dependent maximum histamine release in response to the anti-human IgE stimulation, and"NON"responders who did not fulfill the criteria (n=17). RESULTS: Among the 34 patients with ≥20% SHR/T, 32 patients (94%) had a positive OFC with a low threshold dose which provoked severe symptoms. Among the"LOW"responders, four cases showed ≥10% allergen-specific maximum histamine release. On the other hand, concentration-dependent histamine release was not seen in the"NON"responders, suggesting the basophil function was not detected in this subgroup. CONCLUSION: The present study suggested that SHR/T could be an indicator of basophil activation and hypersensitivity in vivo. We also suggested that significant basophil functions might be detected among the "LOW"responders, but not among the"NON"responders.

Development of a prediction model of severe reaction in boiled egg challenges.

BACKGROUND: We have proposed a new scoring system (Anaphylaxis SCoring Aichi: ASCA) for a quantitative evaluation of the anaphylactic reaction that is observed in an oral food challenge (OFC). Furthermore, the TS/Pro (Total Score of ASCA/cumulative protein dose) can be a marker to represent the overall severity of a food allergy. We aimed to develop a prediction model for a severe allergic reaction that is provoked in a boiled egg white challenge. METHODS: We used two separate datasets to develop and validate the prediction model, respectively. The development dataset included 198 OFCs, that tested positive. The validation dataset prospectively included 140 consecutive OFCs, irrespective of the result. A 'severe reaction' was defined as a TS/Pro higher than 31 (the median score of the development dataset). A multivariate logistic regression analysis was performed to identify the factors associated with a severe reaction and develop the prediction model. RESULTS: The following four factors were independently associated with a severe reaction: ovomucoid specific IgE class (OM-sIgE: 0-6), aged 5 years or over, a complete avoidance of egg, and a total IgE < 1000 IU/mL. Based on these factors, we made a simple scoring prediction model. The model showed good discrimination in a receiver operating characteristic analysis; area under the curve (AUC) = 0.84 in development dataset, AUC = 0.85 in validation dataset. The prediction model significantly improved the AUC in both datasets compared to OM-sIgE alone. CONCLUSIONS: This simple scoring prediction model was useful for avoiding risky OFC.

[SIX CASES OF WHEAT-DEPENDENT EXERCISE-INDUCED ANAPHYLAXIS IN CHILDREN].

Wheat-dependent exercise-induced anaphylaxis (WDEIA) is often reported in adults for whom the specific IgE to ω-5 gliadin can be a useful diagnostic test. However, few cases of WDEIA in children have been reported. We herein report six cases (aged 7-16 years) of children with WDEIA, who had no clinical history of immediate-type wheat allergy but who were diagnosed by a wheat ingestion + exercise provocation test. The specific IgE to wheat ranged <0.35-3.49 (median 1.64) UA/ml. Skin prick tests using wheat extract were performed on 3 patients who showed either a negative or low specific IgE titer to wheat, and all of them resulted in negative findings. The specific IgE to ω-5 gliadin was below the detection limit in all cases. Aspirin-supplemented provocation tests were performed to 4 cases who had negative results in the wheat + exercise test. All of these resulted in a positive reaction, and two of them provoked the occurrence of anaphylactic shock, which was relieved by the intramuscular injection of adrenaline. WDEIA in children cannot be ruled out by serological tests alone. On the other hand, severe symptoms might be provoked by the provocation test. Therefore, a safe procedure is warranted for the diagnosis of WDEIA in children.

The relationship between the season of birth and early-onset food allergies in children.

BACKGROUND: This study examined the relationship between the season of birth (SoB) and other factors with the development of FA. METHODS: A multicenter, cross-sectional pilot study recruited 1197 patients with FA. The main study recruited 440 incident cases (FA group) definitively diagnosed as FA at 0-1 year of age. In both studies, the frequency of autumn-winter births (AWBs) in FA patients was compared to the regional control population. In the main study, we analyzed the differences in the SoB and other factors between patients in the FA group and those in the non-FA group (n = 332) in allergy clinics. RESULTS: The pilot study showed that the frequency of AWB (57.6%) in the FA patients was significantly higher than that of the regional control population (50.4%, OR, 1.34; p < 0.001). The main study also showed the dominance of AWB (62.7%) in the FA group in comparison with that in the regional control population (50.2%, OR, 1.70; p < 0.001). Preterm birth (OR, 0.43; p = 0.027) and the presence of two or more elder siblings (OR, 0.27; p = 0.012) were significantly associated with a lower frequency of FA than those of non-FA. AWB (RR, 1.21; p = 0.020) and preterm birth (RR, 0.55; p = 0.017) were significantly associated with a number of trigger foods. The SoB effect was observed in FA patients irrespective of the presence of infantile eczema. CONCLUSIONS: AWB was predominant in the patients with newly diagnosed food allergies.

Sun exposure inversely related to food sensitization during infancy.

BACKGROUND: Autumn and winter birth (AWB) has been reported to be a risk factor for the development of food allergies. However, the association between seasonal factors and allergic sensitization during early infancy remains unclear. METHODS: We collected data from 732 patients regarding the total and specific immunoglobulin E (tIgE, sIgE) levels in infants younger than 6 months old from November 2001 to October 2012 from the institutional clinical database system. We then analyzed the relationship between the birth month and the value of each parameter. Furthermore, we identified any correlations between the number of sensitized patients and the monthly climatological parameters. RESULTS: The number of tIgE samples obtained from AWB patients (n = 482) was 2.1 times higher than that from patients born in the spring and summer (SSB, n = 225). The number of sIgE samples to egg white, cow's milk, and wheat, the sensitized ratio and the median sIgE titer were also all higher in AWB. The number of sensitized AWB patients to these allergens was 2.75, 3.05, and 3.97 times higher, respectively. A periodic change in the number of sensitized patients was observed annually (highest in October-November and lowest in May). Among the climatological parameters examined, the average solar radiation during the 3-month period after birth showed the strongest negative correlation with the number of sensitized patients (egg white: r = -0.976, cow's milk: r = -0.969, wheat: r = -0.975). CONCLUSIONS: The amount of solar radiation immediately after birth had a strong negative correlation with allergen sensitization before 6 months of age.

A workshop with practical training for anaphylaxis management improves the self-efficacy of school personnel.

BACKGROUND: School personnel are required to guarantee a secure school environment for children suffering from severe food allergies. We organized a workshop for school personnel to learn the appropriate management of anaphylaxis that included practical training with an adrenaline auto-injector (AAI). The objective of this study was to evaluate the workshop in terms of the improvement of self-efficacy (SE) of participants to deal with anaphylaxis. METHODS: All 93 school nurses, 73 schoolteachers and 110 childcare workers participating in the study completed a questionnaire before and after the workshop. The SE of the participants was evaluated using an original 15-item questionnaire. RESULTS: Before the workshop, the SE of school nurses was the highest among the profession groups, and being involved with children prescribed an AAI was a common factor associated with a high SE. After the workshop, the SE increased in all groups, but most apparently in school nurses and those involved with children prescribed an AAI. The presence of an emergency plan was positively associated with the SE of schoolteachers only after the workshop, even though no such association existed beforehand. CONCLUSIONS: Practical instruction of school nurses and school personnel involved with children prescribed an AAI resulted in dramatic improvement of the SE. These people are expected to play a central role in the development of an anaphylaxis management plan in their schools.

Acute eosinophilic pneumonia occurring in a dedicator of cytokinesis 8 (DOCK8) deficient patient.

Dedicator of cytokinesis 8 (DOCK8) deficiency is an autosomal recessive type of combined immunodeficiency with elevated IgE. In this report, we describe a Japanese girl of non-consanguineous family suffering from acute eosinophilic pneumonia (AEP) as a presenting feature of DOCK8 deficiency. Although AEP was self-limiting, consecutively experienced recurrent respiratory infections, severe atopic dermatitis, and vulnerability to viral infections, prompted us to evaluate the possibility of DOCK8 deficiency. Immunological assessments demonstrated decreased IgM, increased IgE, T lymphocytepenia, especially in CD4 T cells, decreased PHA blastogenesis, and decreased CD27(+) CD19(+) memory B cells. Western blotting revealed the absence of DOCK8 protein. Investigation of genomic DNA by multiplex ligation-dependent probe amplification (MLPA) revealed a heterozygous large deletion of 77 kb spanning from intron 5 to exon 22. DOCK8 cDNA sequencing revealed a nonsense mutation at position 740 (E740X). As far as we know, this is the first Japanese case of DOCK8 deficiency.

[Establishment of "Anaphylaxis Scoring Aichi (ASCA)," a new symptom scoring system to be used in an oral food challenge (OFC)].

BACKGROUND: An original symptom score sheet named "Anaphylaxis Scoring Aichi (ASCA)" was created to quantitatively determine the severity of allergic symptoms provoked in an oral food challenge. METHODS: ASCA lists and sorts subjective and objective symptoms into five organs (respiratory, skin-mucosal, gastrointestinal, psycho-neurological and cardiovascular). The organ scores were given (0 to 60 points) in accordance with the severity of each symptom. The total score was defined as the sum of the highest 5 organ scores (maximum 240 points) observed throughout the course of an OFC. This study evaluated the ASCA score in 253 cases of a positive food challenge (age 1-16 years, mean 5.3±3.2 years) conducted from April to August 2011 in our institute. The results were compared to the modified anaphylaxis grading presented in the Japanese Pediatric Guideline for Oral Food Challenge Test in Food Allergy 2009. At the same time, we evaluated the indications of symptomatic treatment using ASCA score. RESULTS: The total score closely correlated with the anaphylaxis grading, but there was a wide range of overlap between grade 2 and grade 3. All cases with a total score≥60 points were equivalent to grade 4 or 5, and that were consisted of three or more organ symptoms. These severe cases contained respiratory or skin/mucosal symptoms, and despite the early induction of initial therapy, the symptoms became worse. CONCLUSION: ASCA is therefore considered to be a useful tool for use in an oral food challenge test.

[Clinical evaluation of ω-5 gliadin-specific IgE test].

OBJECTIVE: To reveal the clinical utility of an IgE test specific to ω-5 gliadin in the diagnosis of immediate-type wheat allergy. METHODS: We detected ω-5 gliadin-specific IgE in sera from all patients examined for wheat-specific IgE in our allergy clinic between January and October, 2008. The diagnostic value of the test was analyzed against the true diagnosis of wheat allergy based on oral wheat challenge or convincing clinical history. Subjects comprised 233 patients (median age, 3.6 years), 59 patients were diagnosed with wheat allergy, and 174 were judged to have no wheat allergy. RESULTS: The prevalence of being diagnosed as wheat allergy was 68% in the patients with CAP score 2 to ω-5 gliadin IgE (n=31), and 87% in those with CAP score 3 (n=15). All of the 3 patients with CAP score 4 or more were wheat allergic. However, 24% of patients with wheat allergy showed negative results (<0.35 UA/ml). According to the data, we proposed the probability curve of ω-5 gliadin-specific IgE. CONCLUSIONS: IgE testing specific to ω-5 gliadin can offer a useful clinical marker for the diagnosis of immediate-type wheat allergy. But the data should always be evaluated with wheat-specific IgE titers, because of the low clinical sensitivity to detect the patients with wheat allergy.