Filaggrin loss-of-function mutations are associated with persistence of egg and milk allergy.

BACKGROUND: A genetic defect in the epidermal barrier protein filaggrin (FLG) plays a major role in the etiology of eczema and associated allergic airways diseases. However, it is still controversial to what extend loss-of-function (LOF) mutations in FLG contribute to the development and persistence of food allergies. OBJECTIVES: This study tested association of FLG LOF mutations with allergic reactions to diverse foods and investigated their potential effect on the persistence of early food allergies. METHODS: This study recruited 890 children with challenge-proven food allergy for the German Genetics of Food Allergy Study (GOFA). Longitudinal data were available for 684 children. All children were clinically characterized, including their allergic responses to specific foods, and genotyped for the 4 most common LOF mutations in FLG; R501X, 2282del4, R2447X, and S3247X. Associations between FLG mutations and food allergies were analyzed by logistic regression using the German Multicenter Allergy Study cohort as the control population. RESULTS: FLG mutations were associated with allergies to diverse foods including hen's egg (HE), cow's milk (CM), peanut, hazelnut, fish, soy, cashew, walnut, and sesame with similar risk estimates. Effects remained significant after adjusting for the eczema status. Interestingly, FLG mutations increased the risk of a persistent course of HE and CM allergy. CONCLUSIONS: Using the gold standard for food allergy diagnosis, this study demonstrates that FLG LOF mutations confer a risk of any food allergy independent of eczema. These mutations predispose to the persistence of HE and CM allergy and should be considered in the assessment of tolerance development.

Organ-specific symptom patterns during oral food challenge in children with peanut and tree nut allergy.

BACKGROUND: Peanut and tree nut allergies are common in childhood and often severe in nature. The clinical picture shows a wide variety of symptoms. OBJECTIVE: To analyze the distribution of clinical symptoms and severity during oral food challenges (OFC) in children. METHODS: Analysis of 1.013 prospectively recorded, positive OFCs with peanut (n = 607), hazelnut (n = 266), walnut (n = 97), and cashew (n = 43). Symptoms were categorized as immediate-type skin, gastrointestinal, upper and lower respiratory, cardiovascular symptoms, and eczema exacerbation. Symptom severity and treatment were recorded. RESULTS: Skin symptoms presented in 78%, followed by gastrointestinal (47%), upper (42%), and lower respiratory symptoms (32%). Cardiovascular symptoms presented in 6%. In three-quarter of the reactions, more than one organ was involved. Importantly, severe reactions occurred at every dose level. Peanut- and cashew-allergic patients had a higher relative risk of gastrointestinal symptoms compared with hazelnut- and walnut-allergic patients. Patients without vomiting had a 1.7 times higher risk developing immediate-type skin and/or lower respiratory symptoms. Three-quarter of the patients ever had eczema but worsening presented in only 10.5% of the OFCs. In patients with multiple food allergies, organs involved, eliciting dose and severity differed between allergens. CONCLUSION: Although comparisons between allergen groups with different clinical history, severity, comorbidities and laboratory data are difficult and might contain bias, our data confirm the high allergenic potential of peanut and tree nuts. The rare occurrence of eczema worsening emphasizes that avoidance diets of peanuts and tree nuts to cure eczema seem to be unnecessary and may hamper tolerance maintenance.

Pea (Pisum sativum) allergy in children: Pis s 1 is an immunodominant major pea allergen and presents IgE binding sites with potential diagnostic value.

BACKGROUND: Food allergy to pea (Pisum sativum) has been rarely studied in children at the clinical and molecular levels. OBJECTIVE: To elucidate the allergenic relevance and diagnostic value of pea 7S globulin Pis s 1, nsLTP, and 2S albumins PA1 and PA2 in children. METHODS: Children with pea-specific IgE ≥ 0.35 kUA /L and clinical evidence of pea allergy or tolerance were included in the study. IgE binding against pea total protein extract, recombinant (r) rPis s 1, rPA1, rPA2, and natural nsLTP was analysed using IgE immunoblot/inhibition. Mediator release potency was investigated in passively sensitized rat basophil leukaemia (RBL) 2H3-cells. IgE binding to synthetic overlapping peptides of Pis s 1 was detected on multipeptide microarrays. RESULTS: 19 pea-sensitized children were included, 14 with doctors' diagnosed allergy and 5 with tolerance to pea (median age 3.5 and 4.5 years, respectively). 11/14 (78%) pea-allergic and 1/5 (20%) tolerant children were sensitized to Pis s 1. Under the reducing conditions of immunoblot analysis, IgE binding to rPA1 was negligible, sensitization to rPA2 and nsLTP undetectable. Compared to pea total protein extract, rPis s 1 displayed on average 58% IgE binding capacity and a 20-fold higher mediator release potency. Selected Pis s 1-related peptides displayed IgE binding in pea-allergic but not in pea-tolerant children. CONCLUSIONS AND CLINICAL RELEVANCE: In this study group, Pis s 1 is a major immunodominant allergen in pea-allergic children. Evidence for sensitization to nsLTP and 2S albumins was low but requires further verification with regard to conformational epitopes. Recombinant Pis s 1 and related peptides which were exclusively recognized by pea-allergic children may improve in vitro diagnosis of pea allergy once verified in prospective studies with larger study groups.

Comparison of Six Different Allergen Extracts for Subcutaneous Specific Immunotherapy in Children: An Open-Labelled, Prospective, Controlled Observational Trial.

BACKGROUND: Numerous products are available for subcutaneous (SCIT) and sublingual allergen-specific immunotherapy, but there are no information about the direct comparability regarding efficacy, safety, and tolerability of the different extracts. AIMS: The aim of this open-labelled, prospective, controlled observational trial was to test the feasibility of a comparison of different products for SCIT in children. METHODS: Pediatrician practices recruited patients with a confirmed diagnosis of a seasonal allergic rhinoconjunctivitis (AR) with or without asthma and an allergic sensitization against grass pollen allergen. Every patient was offered SCIT with one out of six allergen extracts: ALK SQ Depot, ALK Avanz, Allergovit, Depigoid, Purethal, Pollinex Quattro. Scores for symptoms and medications were calculated and the difference between treatment years and baseline were recorded. RESULTS: In total, 284 were recruited and 255 children (89.8%; mean age 10.4, SD 3.54 years; 65% males) participated in this trial. Overall, 49,649 patient days were recorded in the electronic database (mean 183.2 days/patient). There was no significant difference in the AR and asthma symptom score or the medication score between the six different SCIT preparations. Similarly, no differences were observed in terms of safety and tolerability. CONCLUSION: The comparison of different SCIT products using an online tool is feasible. Based on our preliminary data, all extracts indicated efficacy; however, larger groups would be necessary to demonstrate superiority or non-inferiority of one specific SCIT product.

Further investigations of the IgE response to tetanus and diphtheria following covaccination with acellular rather than cellular Bordetella pertussis.

BACKGROUND: It has previously been shown in an uncontrolled study that the IgE response to vaccine antigens is downregulated by co-vaccination with cellular Bordetella pertussis vaccine. METHODS: In the present study, we compared in a controlled trial the humoral immune response to diphtheria toxoid (D) and tetanus toxoid (T) in relation to co-vaccinated cellular or acellular B pertussis vaccine. IgE, IgG4, and IgG to D and T were analyzed at 2, 7, and 12 months of age in sera of children vaccinated with D and T (DT, N = 68), cellular (DTPw, N = 68), 2- or 5-component acellular B pertussis vaccine (DTPa2, N = 64; DTPa5, N = 65). RESULTS: One month after vaccination, D-IgE was detected in 10% sera of DTPw-vaccinated children, whereas vaccination in the absence of whole-cell pertussis resulted in 50%-60% IgE positivity. Six months after vaccination, the IgE antibody levels were found to be more persistent than the IgG antibodies. These diphtheria findings were mirrored by those for tetanus. Only minor differences between vaccine groups were found with regard to D-IgG and T-IgG. No immediate-type allergic reactions were observed. CONCLUSION: Cellular (but not acellular) B pertussis vaccine downregulates IgE to co-vaccinated antigens in infants. We assume that the absence of immediate-type allergic reactions is due to the high levels of IgG antibodies competing with IgE antibodies.

Physician's appraisal vs documented signs and symptoms in the interpretation of food challenge tests: The EuroPrevall birth cohort.

BACKGROUND: Blinded food challenges are considered the current gold standard for the diagnosis of food allergies. We used data from a pan-European multicenter project to assess differences between study centers, aiming to identify the impact of subjective aspects for the interpretation of oral food challenges. METHODS: Nine study centers of the EuroPrevall birth cohort study about food allergy recruited 12 049 newborns and followed them for up to 30 months in regular intervals. Intensive training was conducted and every center visited to ensure similar handling of the protocols. Suspected food allergy was clinically evaluated by double-blind, placebo-controlled food challenges using a nine dose escalation protocol. The primary challenge outcomes based on physician's appraisal were compared to documented signs and symptoms. RESULTS: Of 839 challenges conducted, study centers confirmed food allergy in 15.6% to 53.6% of locally conducted challenges. Centers reported 0 to 16 positive placebo challenges. Worsening of eczema was the most common sign when challenged with placebo. Agreement between documented objective signs and the challenge outcome assigned by the physician was heterogeneous, with Cohen's kappa spanning from 0.42 to 0.84. CONCLUSIONS: These differences suggest that the comparison of food challenge outcomes between centers is difficult despite common protocols and training. We recommend detailed symptom assessment and documentation as well as objective sign-based challenge outcome algorithms to assure accuracy and comparability of blinded food challenges. Training and supervision of staff conducting food challenges is a mandatory component of reliable outcome data.

Maternal filaggrin mutations increase the risk of atopic dermatitis in children: an effect independent of mutation inheritance.

Epidemiological studies suggest that allergy risk is preferentially transmitted through mothers. This can be due to genomic imprinting, where the phenotype effect of an allele depends on its parental origin, or due to maternal effects reflecting the maternal genome's influence on the child during prenatal development. Loss-of-function mutations in the filaggrin gene (FLG) cause skin barrier deficiency and strongly predispose to atopic dermatitis (AD). We investigated the 4 most prevalent European FLG mutations (c.2282del4, p.R501X, p.R2447X, and p.S3247X) in two samples including 759 and 450 AD families. We used the multinomial and maximum-likelihood approach implemented in the PREMIM/EMIM tool to model parent-of-origin effects. Beyond the known role of FLG inheritance in AD (R1meta-analysis = 2.4, P = 1.0 x 10-36), we observed a strong maternal FLG genotype effect that was consistent in both independent family sets and for all 4 mutations analysed. Overall, children of FLG-carrier mothers had a 1.5-fold increased AD risk (S1 = 1.50, Pmeta-analysis = 8.4 x 10-8). Our data point to two independent and additive effects of FLG mutations: i) carrying a mutation and ii) having a mutation carrier mother. The maternal genotype effect was independent of mutation inheritance and can be seen as a non-genetic transmission of a genetic effect. The FLG maternal effect was observed only when mothers had allergic sensitization (elevated allergen-specific IgE antibody plasma levels), suggesting that FLG mutation-induced systemic immune responses in the mother may influence AD risk in the child. Notably, the maternal effect reported here was stronger than most common genetic risk factors for AD recently identified through genome-wide association studies (GWAS). Our study highlights the power of family-based studies in the identification of new etiological mechanisms and reveals, for the first time, a direct influence of the maternal genotype on the offspring's susceptibility to a common human disease.

Randomized placebo-controlled trial of hen's egg consumption for primary prevention in infants.

BACKGROUND: Hen's egg is the most common cause of food allergy in early childhood. OBJECTIVE: We investigated the efficacy and safety of early hen's egg introduction at age 4 to 6 months to prevent hen's egg allergy in the general population. METHODS: This randomized, placebo-controlled trial included 4- to 6-month-old infants who were not sensitized against hen's egg, as determined based on specific serum antibodies (IgE). These infants were randomized to receive either verum (egg white powder) or placebo (rice powder) added to the first weaning food 3 times a week under a concurrent egg-free diet from age 4 to 6 until 12 months. The primary outcome was sensitization to hen's egg (increased specific serum IgE levels) by age 12 months. Hen's egg allergy (secondary outcome) was confirmed by double-blind, placebo-controlled food challenges. RESULTS: Among 406 screened infants, 23 (5.7%) had hen's egg-specific IgE before randomization. Seventeen of 23 underwent subsequent double-blind, placebo-controlled food challenges, and 16 were confirmed as allergic, including 11 with anaphylactic reactions. Of the 383 nonsensitized infants (56.7% male), 184 were randomized to verum and 199 to placebo. At 12 months of age, 5.6% of the children in the verum group were hen's egg sensitized versus 2.6% in the placebo group (primary outcome; relative risk, 2.20; 95% CI, 0.68-7.14; P = .24), and 2.1% were confirmed to have hen's egg allergy versus 0.6% in the placebo group (relative risk, 3.30; 95% CI, 0.35-31.32; P = .35). CONCLUSION: We found no evidence that consumption of hen's egg starting at 4 to 6 months of age prevents hen's egg sensitization or allergy. In contrast, it might result in frequent allergic reactions in the community considering that many 4- to 6-month-old infants were already allergic to hen's egg.

The component-specific to total IgE ratios do not improve peanut and hazelnut allergy diagnoses.

BACKGROUND: Specific IgE measurement predicts the outcome of oral food challenges with considerable uncertainty when evaluating food allergy. OBJECTIVE: Our aim was to assess whether accounting for the ratio of component- or allergen-specific to total IgE can improve this prediction. METHODS: This multicenter study collected blood samples from children with suspected peanut or hazelnut allergy referred to allergy specialist clinics for food challenges. Specific IgE to peanuts, hazelnuts, and their components (Ara h 1, Ara h 2, Ara h 3, Ara h 8, Cor a 1, Cor a 8, Cor a 9, and Cor a 14) and total IgE levels were determined by using the ImmunoCAP-FEIA. Specific to total IgE ratios were compared with raw IgE levels in terms of discrimination and prediction. RESULTS: Eighty-eight (43%) of 207 children with suspected peanut allergy and 44 (31%) of 142 children with suspected hazelnut allergy had symptoms during food challenge. Discrimination was similar for raw and ratio measures: areas under the curve of 0.93 for Ara h 2-specific IgE versus 0.92 for the Ara h 2-specific/total IgE ratio and 0.89 for Cor a 14-specific IgE versus 0.87 for the Cor a 14-specific/total IgE ratio. The probability for a positive peanut challenge with 0.35 kU/L Ara h 2-specific IgE was 16% when the total IgE level was greater than 500 kU/L compared with 51%/48% for low/medium total IgE levels (<100/100-500 kU/L). A positive hazelnut challenge with 0.35 kU/L Cor a 14-specific IgE was estimated in 7% when total IgE levels were high compared with 34%/32% with low/medium total IgE levels. CONCLUSIONS: Raw Ara h 2- and Cor a 14-specific IgE levels were the best single predictors for pediatric peanut and hazelnut allergies, suggesting the omission of challenges at very high levels. Calculating ratio measures did not improve prediction in this population. However, estimation of individual probabilities for challenge outcomes could be supported by total IgE levels because high levels might indicate lower probabilities at a given component-specific IgE level.

Wheat protein recognition pattern in tolerant and allergic children.

BACKGROUND: Wheat is one of the most common food allergens in early childhood. In contrast to other food allergies, wheat-specific IgE correlates badly with clinical symptoms and relevant components have been identified mostly for wheat-depended exercise-induced anaphylaxis. Moreover, a high percentage of patients present with immediate type symptoms but wheat-specific IgE cannot be detected with commercial available systems. OBJECTIVE: We addressed the question whether the IgE recognition pattern between wheat allergic (WA) and clinically tolerant (WT) children differs in order to identify individual proteins useful for component-resolved diagnostics. METHODS: Sera of 106 children with suspected wheat allergy, of whom 44 children had clinical relevant wheat allergy and 62 were tolerant upon oral food challenge, were analyzed for wheat-specific IgE using the ImmunoCap system as well as immunoblots against water and salt soluble, and water-insoluble protein fractions. 40 randomly selected sera were analyzed for specific IgE to ω5-gliadin. RESULTS: Sixty-three percent of the WT and 86% of the WA children were sensitized to wheat with >0.35 kUA /l in ImmunoCAP analysis. We could confirm the role of α-, ß-, γ-, and ω-gliadins, and LMW glutenin subunits as major allergens and found also IgE binding to a broad spectrum of water- and salt-soluble protein bands. It is of great importance that wheat allergic and tolerant patients showed IgE binding to the same protein bands. WT and WA did not significantly differ in levels of ω5-gliadin-specific IgE. CONCLUSIONS & CLINICAL RELEVANCE: Children with challenge proven clinical relevant food allergy and tolerant ones had a similar spectrum of IgE binding to the same protein bands. These findings imply that component-resolved diagnostics might not be helpful in the diagnostic work-up of wheat allergy.

Association of food allergy and atopic dermatitis exacerbations.

BACKGROUND: Atopic dermatitis (AD) and food allergy frequently coexist in children. OBJECTIVE: To examine the association between food allergy and AD. METHODS: Between 2001 and 2011, children referred to our tertiary care center underwent double-blind, placebo-controlled food challenges (DBPCFCs) for one or more suspected food allergies as part of regular care. Immediate reactions were observed and recorded by allergy nursing staff, whereas late reactions were ascertained by semistructured telephone interview 48 hours after challenge. To test to which degree specific IgE results were predictive in the outcome of DBPCFCs in children with and without (previous and current) AD, logistic regression analysis was performed. RESULTS: A total of 1186 DBPCFCs were studied. Sensitization to foods occurred significantly more often in children with previous AD. The association between specific IgE results and the outcome of DBPCFCs was significant for children with and without (previous and current) AD but stronger for children without current AD. The positivity rate of DBPCFCs in children with mild, moderate, and severe AD was 53.3%, 51.7%, and 100%, respectively. Children with AD and a history of worsening AD as their only symptom reacted as often to placebo as to challenge food. CONCLUSION: Children with current AD are more frequently asymptomatically sensitized to the foods in question than those without AD. In addition, children suspected of food allergy should be considered for testing, regardless of the severity of their AD. Our results suggest that children with exacerbation of AD in the absence of other allergic symptoms are unlikely to be food allergic.

[Food allergy in childhood]. / Nahrungsmittelallergien im Kindesalter.

IgE-mediated immediate type reactions are the most common form of food allergy in childhood. Primary (often in early childhood) and secondary (often pollen-associated) allergies can be distinguished by their level of severity. Hen's egg, cow's milk and peanut are the most common elicitors of primary food allergy. Tolerance development in hen's egg and cow's milk allergy happens frequently whereas peanut allergy tends toward a lifelong disease. For the diagnostic patient history, detection of sensitization and (in many cases) oral food challenges are necessary. Especially in peanut and hazelnut allergy component-resolves diagnostic (measurement of specific IgE to individual allergens, e. g. Ara h 2) seem to be helpful. In regard to therapy elimination diet is still the only approved approach. Patient education through dieticians is extremely helpful in this regard. Patients at risk for anaphylactic reactions need to carry emergency medications including an adrenaline auto-injector. Instruction on the usage of the adrenaline auto-injector should take place and a written management plan handed to the patient. Moreover, patients or caregivers should be encouraged to attending a structured educational intervention on knowledge and emergency management. In parallel, causal therapeutic options such as oral, sublingual or epicutaneous immunotherapies are currently under development. In regard to prevention of food allergy current guidelines no longer advise to avoid highly allergenic foods. Current intervention studies are investigating wether early introduction of highly allergic foods is effective and safe to prevent food allergy. It was recently shown that peanut introduction between 4 and 11  months of age in infants with severe atopic dermatitis and/or hen's egg allergy (if they are not already peanut allergic) prevents peanut allergy in a country with high prevalence.

A Novel Multipeptide Microarray for the Specific and Sensitive Mapping of Linear IgE-Binding Epitopes of Food Allergens.

BACKGROUND: The identification of B-cell epitopes of food allergens can possibly lead to novel diagnostic tools and therapeutic reagents for food allergy. We sought to develop a flexible, low-tech, cost-effective and reproducible multipeptide microarray for the research environment to enable large-scale screening of IgE epitopes of food allergens. METHODS: Overlapping peptides (15-mer, 4 amino acid offset) covering the primary sequence of either peanut allergen Ara h 1 or all 3 subunits of the soybean allergen Gly m 5 were simultaneously synthesized in-house on a porous cellulose matrix. Identical peptide microarrays created with up to 384 duplicate peptide-cellulose microspots each were investigated for specificity and sensitivity in IgE immunodetection and in direct experimental comparison to the formerly established SPOT™ membrane technique. RESULTS: The in-house microarray identified with 98% reproducibility the same IgE-binding peptides as the SPOT™ membrane technique. Additional IgE-binding peptides were identified using the microarray. While the sensitivity was increased between 2- and 20-fold, the amount of human serum required was reduced by at least two thirds over the SPOT™ membrane technique using the microarray. After subtraction of the potential background, we did not observe non-specific binding to the presented peptides on microarray. CONCLUSIONS: The novel peptide microarray allows simple and cost-effective screening for potential epitopes of large allergenic legume seed storage proteins, and it could be adapted for other food allergens as well, to study allergenic epitopes at the individual subject level in large paediatric and adult study groups of food allergic subjects.

Chemokine levels in serum of children with atopic dermatitis with regard to severity and sensitization status.

BACKGROUND: Many infants with atopic dermatitis (AD) are sensitized against food or airborne allergens. The severity of AD, using the SCORAD, seems to correlate with elevated serum levels of TARC/CCL17. Other chemokines, such as CCL20 or CCL25, have been described in the context of allergic inflammation. The aim of this study was to analyze whether chemokine serum levels differ within a cohort of infants suffering from varying severities of AD with or without allergic sensitization. METHODS: Chemokine serum levels (CCL8, CCL17, CCL20, CCL25) as well as food and airborne allergen-specific IgE were analyzed in infants with AD. RESULTS: About 60.9% (78/128) infants with AD (median age 8.8 months, 49 (38%) girls and 79 (62%) boys) showed a positive screening test to common food allergens and 26.6% to common airborne allergens. There was a strong correlation between serum levels of CCL17 and SCORAD in food-sensitized infants (r(s) = 0.646, p = <1e-04) and airborne-sensitized infants (r(s) = 0.587, p = 0.00065) in contrast to non-sensitized ones. Moreover, food-sensitized infants showed significantly higher levels of CCL25 compared to non-food-sensitized ones (p = 0.007). CONCLUSION: The strong correlation between TARC/CCL17 and SCORAD in infants with specific sensitizations may be accounted for by the impaired skin barrier. As TARC/CCL17 has been found mainly in the (inflamed) skin but not in the gut, the detection of significantly higher levels of CCL25, ligand of CCR9, localized primarily in the gastrointestinal tract, suggests its impact on food allergen-induced inflammation processes in food-sensitized infants.

Modified oral food challenge used with sensitization biomarkers provides more real-life clinical thresholds for peanut allergy.

BACKGROUND: Threshold levels for peanut allergy determined by using oral challenges are important for the food industry with regard to allergen labeling. Moreover, the utility of biological markers in predicting threshold levels is uncertain. OBJECTIVE: We sought to use a modified oral food challenge regimen that might determine threshold levels for peanut allergy mimicking a more real-life exposure and to correlate the eliciting dose (ED) and severity of clinical reaction in children with peanut allergy with B-cell, T-cell, and effector cell markers. METHODS: A modified food challenge procedure with doses scheduled 2 hours apart was used in 63 children with peanut allergy. All children received a maximum of 8 semi-log increasing titration steps of roasted peanuts ranging from 3 to 4500 mg of peanut protein until objective allergic reactions occurred. Severity of symptoms was graded from I to V. Biological markers were measured before challenge. RESULTS: Forty-five of 63 patients showed objective symptoms after greater than 30 minutes, with a median latency of clinical reaction of 55 minutes. By using a log-normal dose-distribution model, the ED5 was calculated to be 1.95 mg of peanut protein. The ED was significantly and inversely correlated with peanut- and Ara h 2-specific IgE levels, skin prick test responses, basophil activation, and TH2 cytokine production by PBMCs. Symptom severity did not correlate with any of the markers or the ED. CONCLUSION: This modified food challenge procedure might better reflect threshold levels for peanut allergy than the standard procedure because most of the patients reacted at a time interval of greater than 30 minutes. By using this model, threshold levels, but not severity, could be correlated with biological markers.

Acupuncture in patients with seasonal allergic rhinitis: a randomized trial.

UNLABELLED: Chinese translation BACKGROUND: Acupuncture is frequently used to treat seasonal allergic rhinitis (SAR) despite limited scientific evidence. OBJECTIVE: To evaluate the effects of acupuncture in patients with SAR. DESIGN: Randomized, controlled multicenter trial. (ClinicalTrials.gov: NCT00610584) SETTING: 46 specialized physicians in 6 hospital clinics and 32 private outpatient clinics. PATIENTS: 422 persons with SAR and IgE sensitization to birch and grass pollen. INTERVENTION: Acupuncture plus rescue medication (RM) (cetirizine) (n = 212), sham acupuncture plus RM (n = 102), or RM alone (n = 108). Twelve treatments were provided over 8 weeks in the first year. MEASUREMENTS: Changes in the Rhinitis Quality of Life Questionnaire (RQLQ) overall score and the RM score (RMS) from baseline to weeks 7 and 8 and week 16 in the first year and week 8 in the second year after randomization, with predefined noninferiority margins of -0.5 point (RQLQ) and -1.5 points (RMS). RESULTS: Compared with sham acupuncture and with RM, acupuncture was associated with improvement in RQLQ score (sham vs. acupuncture mean difference, 0.5 point [97.5% CI, 0.2 to 0.8 point; P < 0.001]; RM vs. acupuncture mean difference, 0.7 point [97.5% CI, 0.4 to 1.0 point; P < 0.001]) and RMS (sham vs. acupuncture mean difference, 1.1 points [97.5% CI, 0.4 to 1.9 points; P < 0.001]; RM vs. acupuncture mean difference, 1.5 points [97.5% CI, 0.8 to 2.2 points; P < 0.001]). There were no differences after 16 weeks in the first year. After the 8-week follow-up phase in the second year, small improvements favoring real acupuncture over the sham procedure were noted (RQLQ mean difference, 0.3 point [95% CI, 0.03 to 0.6 point; P = 0.032]; RMS mean difference, 1.0 point [95% CI, 0.2 to 1.9 points; P = 0.018]). LIMITATION: The study was not powered to detect rare adverse events, and the RQLQ and RMS values were low at baseline. CONCLUSION: Acupuncture led to statistically significant improvements in disease-specific quality of life and antihistamine use measures after 8 weeks of treatment compared with sham acupuncture and with RM alone, but the improvements may not be clinically significant.

A randomised multicentre trial of acupuncture in patients with seasonal allergic rhinitis--trial intervention including physician and treatment characteristics.

BACKGROUND: In a large randomised trial in patients with seasonal allergic rhinitis (SAR), acupuncture was superior compared to sham acupuncture and rescue medication. The aim of this paper is to describe the characteristics of the trial's participating physicians and to describe the trial intervention in accordance with the STRICTA (Standards for Reporting Interventions in Controlled Trials of Acupuncture) guidelines, to make details of the trial intervention more transparent to researchers and physicians. METHODS: ACUSAR (ACUpuncture in Seasonal Allergic Rhinitis) was a three-armed, randomised, controlled multicentre trial. 422 SAR patients were randomised to semi-standardised acupuncture plus rescue medication (RM, cetirizine), sham acupuncture plus RM or RM alone. We sent a questionnaire to trial physicians in order to evaluate their characteristics regarding their education about and experience in providing acupuncture. During the trial, acupuncturists were asked to diagnose all of their patients according to Chinese Medicine (CM) as a basis for the semi-standardised, individualized intervention in the acupuncture group. Every acupuncture point used in this trial had to be documented after each session RESULTS: Acupuncture was administered in outpatient clinics by 46 (mean age 47 ± 10 years; 24 female/ 22 male) conventionally-trained medical doctors (67% with postgraduate specialization such as internal or family medicine) with additional extensive acupuncture training (median 500 hours (1st quartile 350, 3rd quartile 1000 hours with 73% presenting a B-diploma in acupuncture training (350 hours)) and experience (mean 14 years in practice). The most reported traditional CM diagnosis was 'wind-cold invading the lung' (37%) and 'wind-heat invading the lung' (37%), followed by 'lung and spleen qi deficiency' (9%). The total number of needles used was higher in the acupuncture group compared to the sham acupuncture group (15.7 ± 2.5 vs. 10.0 ± 1.6). CONCLUSIONS: The trial interventions were provided by well educated and experienced acupuncturists. The different number of needles in both intervention groups could be possibly a reason for the better clinical effect in SAR patients. For future trials it might be more appropriate to ensure that acupuncture and sham acupuncture groups should each be treated by a similar number of needles. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00610584.

Narcolepsy-Like Sleepiness: A Symptom of Immediate-Type Reactions in Food-Allergic Children.

BACKGROUND: It has been reported that sometimes children fall asleep and can barely be woken up during allergic reactions on food ingestion. Nevertheless, to date, there is scarce data on narcolepsy-like sleepiness as a symptom of allergic reactions. OBJECTIVE: To investigate the frequency of narcolepsy-like sleepiness during oral food challenges and characterize this symptom regarding comorbidities, eliciting allergens, and severity of reactions. METHODS: Children with immediate-type allergic reactions during oral food challenges (89% were double-blind, placebo-controlled) have been analyzed in this study. Narcolepsy-like sleepiness was defined as a somnolent condition during which patients could barely be woken up again, occurring within 2 hours of food intake and which was not due to drug side effects. Logistic generalized estimating equations were used to explore the effect of age, severity of reactions, and eliciting allergens on the occurrence of narcolepsy-like sleepiness. RESULTS: In 106 (12.5%) of all 848 food-allergic children, narcolepsy-like sleepiness was observed during oral food challenges. Children with eczema had a higher risk of developing narcolepsy-like sleepiness (P = .006). Narcolepsy-like sleepiness occurred most often due to an allergic reaction to hazelnut (P = .009) or other tree nuts (P = .003). Moderate to severe reactions occurred more often than mild reactions (P = .026; odds ratio, 1.521; 95% CI, 1.051-2.202) in children with narcolepsy-like sleepiness. CONCLUSIONS: We were able to show for the first time that narcolepsy-like sleepiness is a frequently occurring clinical manifestation of immediate-type allergic reactions on food ingestion in childhood. Further research is needed to unravel the underlying mechanisms to gain a deeper insight into this underestimated symptom.

Walnut allergy in peanut-allergic patients: significance of sequential epitopes of walnut homologous to linear epitopes of Ara h 1, 2 and 3 in relation to clinical reactivity.

BACKGROUND: Peanut allergy is a frequent and potentially life-threatening food allergy. Despite the large taxonomic distance between the plants, peanut-allergic patients often react to tree nuts such as walnuts. While the allergens of peanut and walnut have a high degree of homology in their amino-acid sequences, it is unknown whether this similarity is responsible for the observed co-reactivity. Therefore, we analyzed the binding of specific IgE antibodies to sequential epitopes of peanut and walnut in peanut-allergic patients with and without walnut allergy. METHODS: The IgE binding to previously described sequential epitopes of peanut and the homologous regions of walnut was assessed in 32 peanut-allergic patients using a peptide microarray technology. Twelve patients had a clinically relevant walnut allergy and 20 were tolerant to walnut. Inhibition assays with peanut peptides and corresponding walnut sequences were performed to show specific binding to sequential epitopes. RESULTS: No differences in the recognition of sequential epitopes could be found between peanut-allergic patients with or without walnut allergy. Only a few patients showed IgE binding to walnut sequences that corresponded to sequential epitopes of peanut. In the inhibition assays, no relevant cross-reacting IgE antibodies could be detected for the peptides analyzed. CONCLUSION: Our results indicate that although they share a rather high degree of homology with the corresponding regions of walnut allergens, the sequence stretches previously identified as sequential IgE binding epitopes of Ara h 1, Ara h 2 and Ara h 3 have no IgE binding equivalents in walnut allergens.