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Probiotic peanut oral immunotherapy versus oral immunotherapy and placebo in children with peanut allergy in Australia (PPOIT-003): a multicentre, randomised, phase 2b trial.
Loke, P, Orsini, F, Lozinsky, AC, Gold, M, O'Sullivan, MD, Quinn, P, Lloyd, M, Ashley, SE, Pitkin, S, Axelrad, C, et al
The Lancet. Child & adolescent health. 2022;(3):171-184
Abstract
BACKGROUND Oral immunotherapy is effective at inducing desensitisation to allergens and induces sustained unresponsiveness (ie, clinical remission) in a subset of patients, but causes frequent reactions. We aimed to investigate whether addition of a probiotic adjuvant improved the efficacy or safety of peanut oral immunotherapy. METHODS PPOIT-003, a multicentre, randomised, phase 2b trial, was conducted in three tertiary hospitals in Australia (Adelaide [SA], Melbourne [VIC], and Perth [WA]) in children aged 1-10 years, weighing more than 7 kg, with peanut allergy confirmed by a double-blind placebo-controlled food challenge (cumulative 4950 mg dose of peanut protein) and positive peanut skin prick test (≥3 mm) or peanut-specific IgE (≥0·35 kU/L). Children were randomly assigned (2:2:1) to receive probiotic and peanut oral immunotherapy (PPOIT), placebo probiotic and peanut oral immunotherapy (OIT), or placebo probiotic and placebo OIT (placebo) for 18 months, and were followed up until 12 months after completion of treatment. Oral immunotherapy consisted of increasing doses of peanut protein (commercially available food-grade 12% defatted peanut flour [50% peanut protein]) until a 2000 mg daily maintenance dose was reached. The probiotic adjuvant was a daily dose of 2 × 1010 colony-forming units of the probiotic Lactobacillus rhamnosus ATCC 53103. Placebo immunotherapy comprised maltodextrin, brown food colouring, and peanut essence, and placebo probiotic was maltodextrin. Dual primary outcomes were 8-week sustained unresponsiveness, defined as no reaction to a cumulative dose of 4950 mg peanut protein at treatment completion and 8 weeks after treatment completion, in the PPOIT versus placebo groups and the PPOIT versus OIT groups, analysed by intention to treat. Safety endpoints were adverse events during the treatment phase, and peanut ingestion and reactions in the 12-month post-treatment period. This study is registered with the Australian New Zealand Clinical Trials Registry, 12616000322437. FINDINGS Between July 4, 2016, and Sept 21, 2020, 201 participants were enrolled and included in the intention-to-treat analysis. 36 (46%) of 79 children in the PPOIT group and 42 (51%) of 83 children in the OIT group achieved sustained unresponsiveness compared with two (5%) of 39 children in the placebo group (risk difference 40·44% [95% CI 27·46 to 53·42] for PPOIT vs placebo, p<0·0001), with no difference between PPOIT and OIT (-5·03% [-20·40 to 10·34], p=0·52). Treatment-related adverse events were reported in 72 (91%) of 79 children in the PPOIT group, 73 (88%) of 83 children in the OIT group, and 28 (72%) of 39 children in the placebo group. Exposure-adjusted incidence of adverse events was 10·58 in the PPOIT group, 11·36 in the OIT, and 2·09 in the placebo group (ratio 0·92 [95% CI 0·85 to 0·99] for PPOIT vs OIT, p=0·042; 4·98 [4·11-6·03] for PPOIT vs placebo, p<0·0001; 5·42 [4·48-6·56] for OIT vs placebo, p<0·0001), with differences seen primarily in gastrointestinal symptoms and in children aged 1-5 years. During the 12-month post-treatment period, 60 (85%) of 71 participants in the PPOIT group, 60 (86%) of 70 participants in the OIT group, and six (18%) of 34 participants in the placebo group were eating peanut; rescue epinephrine use was infrequent (two [3%] of 71 in the PPOIT group, four [6%] of 70 in the OIT group, and none in the placebo group). INTERPRETATION Both PPOIT and OIT were effective at inducing sustained unresponsiveness. Addition of a probiotic did not improve efficacy of OIT, but might offer a safety benefit compared with OIT alone, particularly in preschool children. FUNDING National Health and Medical Research Council Australia and Prota Therapeutics.
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The Effect of Broccoli Sprout Extract on Seasonal Grass Pollen-Induced Allergic Rhinitis.
Yusin, J, Wang, V, Henning, SM, Yang, J, Tseng, CH, Thames, G, Arnold, I, Heber, D, Lee, RP, Sanavio, L, et al
Nutrients. 2021;(4)
Abstract
Patients exposed to pollutants are more likely to suffer from allergic rhinitis and may benefit from antioxidant treatment. Our study determined if patients diagnosed with grass-induced allergic rhinitis could benefit from broccoli sprout extract (BSE) supplementation. In total, 47 patients were confirmed with grass-induced allergic rhinitis and randomized to one of four groups: group 1 (nasal steroid spray + BSE), group 2 (nasal steroid spray + placebo tablet), group 3 (saline nasal spray + BSE) and group 4 (saline nasal spray + placebo tablet). Peak Nasal Inspiratory Flow (PNIF), Total Nasal Symptoms Scores (TNSS) and nasal mucus cytokine levels were analyzed in samples collected before and after the 3-week intervention. Comparing before and after the intervention, PNIF improved significantly when comparing Groups 1 and 2, vs. placebo, at various time points (p ≤ 0.05 at 5, 15, 60 and 240 min) following nasal challenge, while TNSS was only statistically significant at 5 (p = 0.03), 15 (p = 0.057) and 30 (p = 0.05) minutes. There were no statistically significant differences in various cytokine markers before and after the intervention. Combining nasal corticosteroid with BSE led to the most significant improvement in objective measures.
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Birch Pollen Related Pear Allergy: A Single-Blind Oral Challenge TRIAL with 2 Pear Cultivars.
de Jong, NW, Terlouw, S, van Boven, FE, van Maaren, MS, Schreurs, MWJ, van den Berg-Somhorst, DBPM, Esser, D, Bastiaan-Net, S
Nutrients. 2021;(4)
Abstract
Approximately 70% of birch pollen allergic patients in Europe experience hypersensitivity reactions to Immunoglobulin E (IgE) cross-reactive food sources. This so-called pollen-food syndrome (PFS) is defined by allergic symptoms elicited promptly by the ingestion of fruits, nuts, or vegetables in these patients. So far, in the literature, less attention has been given to Bet v 1 cross-reactive symptoms caused by pear (Pyrus communis). In the Netherlands, pears are widely consumed. The primary objective of this study was to measure the type and severity of allergic symptoms during pear challenges in birch pollen allergic patients, with a positive history of pear allergy, using two different pear varieties. Fifteen patients were included, skin prick test (SPT), prick-to-prick test (PTP), specific Immunoglobulin E (sIgE), and single-blind oral challenges were performed with two pear (Pyrus communis) varieties: the 'Cepuna' (brand name Migo®) and the 'Conference' pears. All patients were sensitized to one or both pear varieties. A total of 12 out of 15 participants developed symptoms during the 'Cepuna' food challenge and 14/15 reacted during the 'Conference' challenge. Challenges with the 'Cepuna' pears resulted in less objective symptoms (n = 2) in comparison with challenges with 'Conference' pears (n = 7). Although we did not find significance between both varieties in our study, we found a high likelihood of fewer and less severe symptoms during the 'Cepuna' challenges. Consequently selected pear sensitized patients can try to consume small doses of the 'Cepuna' pear outside the birch pollen season.
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Effects of Lactobacillus pentosus in Children with Allergen-Sensitized Atopic Dermatitis.
Ahn, SH, Yoon, W, Lee, SY, Shin, HS, Lim, MY, Nam, YD, Yoo, Y
Journal of Korean medical science. 2020;(18):e128
Abstract
BACKGROUND Recent studies have shown that oral administration of probiotics may improve the immune imbalance caused by dysbiosis of the gut microbiome in atopic dermatitis (AD). This study aimed to investigate the clinical and immunological effects of Lactobacillus pentosus in children with mild to moderate AD. METHODS Children aged 2-13 years with AD were randomized to receive either 1.0 × 1010 colony-forming units of L. pentosus or placebo, daily, for 12 weeks. The clinical severity of AD and transepidermal water loss were evaluated. Blood eosinophil counts, serum total immunoglobulin E (IgE), and cytokine levels were measured. The diversity and composition of the gut microbiota were also analyzed. RESULTS Eighty-two children were recruited, and 41 were assigned to the probiotics intervention group. The mean scoring of atopic dermatitis (SCORAD) indices at baseline were 30.4 and 34.3 for the probiotics and placebo groups, respectively. At week 12, the mean indices were 23.6 and 23.1 for the probiotics and placebo groups, respectively. Clinical severity decreased significantly over time in both groups, with no significant difference between the two groups. In both groups, there were no significant differences in cytokine levels, microbial diversity, or the relative abundance of the gut microbiota at week 12 compared with the corresponding baseline values. The mean subjective scores of SCORAD indices after intervention for the probiotics group were significantly lower than those for the placebo group in IgE sensitized AD (P = 0.019). CONCLUSION Our results show improved symptoms in the probiotics and placebo groups, and we could not find additional effects of L. pentosus in AD. However, the mean subjective scores of SCORAD indices for the probiotics group are significantly improved compared with those for the placebo group in allergen-sensitized AD.
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Effect of Lactobacillus plantarum YIT 0132 on Japanese cedar pollinosis and regulatory T cells in adults.
Suzuki, S, Kubota, N, Kakiyama, S, Miyazaki, K, Sato, K, Harima-Mizusawa, N
Allergy. 2020;(2):453-456
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Allergic sensitisation in infants younger than one year of age.
Skjerven, HO, Hunderi, JOG, Carlsen, KH, Rolfsjord, LB, Nordhagen, L, Berents, TL, Bains, KES, Buchmann, M, Carlsen, KCL
Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. 2020;(2):203-206
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Egg oral immunotherapy in children (SEICAP I): Daily or weekly desensitization pattern.
Martín-Muñoz, MF, Belver, MT, Alonso Lebrero, E, Zapatero Remón, L, Fuentes Aparicio, V, Piquer Gibert, M, Plaza, AM, Muñoz Román, C, Martorell-Calatayud, C, Martorell-Aragonés, A, et al
Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. 2019;(1):81-92
Abstract
BACKGROUND Studies are required before incorporating egg oral immunotherapy (OIT) into clinical practice. The Spanish Society of Pediatric Allergy, Asthma and Clinical Immunology (SEICAP) conducted a multicenter, randomized controlled study assessing the effectiveness and safety of the OIT using pasteurized egg white (PEW) in egg-allergic children. METHODS One hundred and one egg-allergic children (6-9 years) were randomized for 1 year: 25 to an egg-free-diet (CG) and 76 to OIT (target dose 3.3 g PEW proteins), PI (30% weekly plus 5% daily increments) or PII (only 30% weekly increments) buildup patterns. Egg skin prick test, sIgE and sIgG4 serum levels, PEW double-blind placebo-controlled food challenge (DBPCFC), and dosing adverse reactions (DARs) were evaluated in all patients from inclusion (T0) until completing 1 year of follow-up (T12). At T12, egg-allergic control patients could start OIT. The effectiveness and safety of OIT and the effect of the buildup pattern were analyzed. RESULTS At T12, 4/25 (16.0%) CG patients passed the PEW DBPCFC vs 64/76 (84.2%) OIT that reached total desensitization (P = 0.000); 12 egg-allergic control patients started OIT. Finally, 72/88 (81.81%) patients reached total desensitization, 96.15% PI vs 75.80% on PII (P = 0.01). Induction period (121.12 ± 91.43, median 98.00 days) was longer in patients on PII buildup pattern, and those with allergic asthma, minor threshold dose, or higher egg sIgE (P < 0.05). Most patients (89.06%) developed DARs: 74.53% were mild; 21.90% moderate; and 3.5% requiring adrenaline-treatment. Moderate reactions and those requiring adrenaline were more frequent in patients with allergic asthma, PII pattern, or higher egg sIgE serum antibody levels (P < 0.05). CONCLUSIONS PEW OIT is an effective treatment for children with persistent egg allergy. A 30% weekly plus 5% daily increment pattern could be more effective and safer than one with only 30% weekly increments.
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Predicting development of sustained unresponsiveness to milk oral immunotherapy using epitope-specific antibody binding profiles.
Suárez-Fariñas, M, Suprun, M, Chang, HL, Gimenez, G, Grishina, G, Getts, R, Nadeau, K, Wood, RA, Sampson, HA
The Journal of allergy and clinical immunology. 2019;(3):1038-1046
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Abstract
BACKGROUND In a recent trial of milk oral immunotherapy (MOIT) with or without omalizumab in 55 patients with milk allergy treated for 28 months, 44 of 55 subjects passed a 10-g desensitization milk protein challenge; 23 of 55 subjects passed the 10-g sustained unresponsiveness (SU) challenge 8 weeks after discontinuing MOIT. OBJECTIVE We sought to determine whether IgE and IgG4 antibody binding to allergenic milk protein epitopes changes with MOIT and whether this could predict the development of SU. METHODS By using a novel high-throughput Luminex-based assay to quantitate IgE and IgG4 antibody binding to 66 sequential epitopes on 5 milk proteins, serum samples from 47 subjects were evaluated before and after MOIT. Machine learning strategies were used to predict whether a subject would have SU after 8 weeks of MOIT discontinuation. RESULTS MOIT profoundly altered IgE and IgG4 binding to epitopes, regardless of treatment outcome. At the initiation of MOIT, subjects achieving SU exhibited significantly less antibody binding to 40 allergenic epitopes than subjects who were desensitized only (false discovery rate ≤ 0.05 and fold change > 1.5). Based on baseline epitope-specific antibody binding, we developed predictive models of SU. Using simulations, we show that, on average, IgE-binding epitopes alone perform significantly better than models using standard serum component proteins (average area under the curve, >97% vs 80%). The optimum model using 6 IgE-binding epitopes achieved a 95% area under the curve and 87% accuracy. CONCLUSION Despite the relatively small sample size, we have shown that by measuring the epitope repertoire, we can build reliable models to predict the probability of SU after MOIT. Baseline epitope profiles appear more predictive of MOIT response than those based on serum component proteins.
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Association of STAT6 gene variants with food allergy diagnosed by double-blind placebo-controlled food challenges.
van Ginkel, CD, Pettersson, ME, Dubois, AEJ, Koppelman, GH
Allergy. 2018;(6):1337-1341
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This study describes the role of two STAT6 gene variants in food allergy using data of patients and their parents who underwent double-blind placebo-controlled food challenges (DBPCFCs). After quality control, 369 trios were analysed including 262 children (71.0%) with food allergy. Associations were tested by the Family based association test. The A alleles of both SNPs were associated with food allergy (P = .036 and P = .013 for rs324015 and rs1059513, respectively). Furthermore, these A alleles were associated with peanut allergy, higher sIgE levels to both peanut and cow's milk, more severe symptoms and higher eliciting doses during peanut and cow's milk DBPCFCs (all P < .05). In silico analysis indicates that the identified risk variants increase STAT6 expression which stimulates the differentiation of CD4 + T cells to the Th2 subset. In conclusion, STAT6 variants may be involved in the pathophysiology of food allergy and their role seems to be independent of the allergenic food.
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Epicutaneous immunotherapy for the treatment of peanut allergy in children and young adults.
Jones, SM, Sicherer, SH, Burks, AW, Leung, DY, Lindblad, RW, Dawson, P, Henning, AK, Berin, MC, Chiang, D, Vickery, BP, et al
The Journal of allergy and clinical immunology. 2017;(4):1242-1252.e9
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BACKGROUND Peanut allergy is common, life-threatening, and without therapeutic options. We evaluated peanut epicutaneous immunotherapy (EPIT) by using Viaskin Peanut for peanut allergy treatment. OBJECTIVE We sought to evaluate the clinical, safety, and immunologic effects of EPIT for the treatment of peanut allergy. METHODS In this multicenter, double-blind, randomized, placebo-controlled study, 74 participants with peanut allergy (ages 4-25 years) were treated with placebo (n = 25), Viaskin Peanut 100 μg (VP100; n = 24) or Viaskin Peanut 250 μg (VP250; n = 25; DBV Technologies, Montrouge, France). The primary outcome was treatment success after 52 weeks, which was defined as passing a 5044-mg protein oral food challenge or achieving a 10-fold or greater increase in successfully consumed dose from baseline to week 52. Adverse reactions and mechanistic changes were assessed. RESULTS At week 52, treatment success was achieved in 3 (12%) placebo-treated participants, 11 (46%) VP100 participants, and 12 (48%) VP250 participants (P = .005 and P = .003, respectively, compared with placebo; VP100 vs VP250, P = .48). Median change in successfully consumed doses were 0, 43, and 130 mg of protein in the placebo, VP100, and VP250 groups, respectively (placebo vs VP100, P = .014; placebo vs VP250, P = .003). Treatment success was higher among younger children (P = .03; age, 4-11 vs >11 years). Overall, 14.4% of placebo doses and 79.8% of VP100 and VP250 doses resulted in reactions, predominantly local patch-site and mild reactions (P = .003). Increases in peanut-specific IgG4 levels and IgG4/IgE ratios were observed in peanut EPIT-treated participants, along with trends toward reduced basophil activation and peanut-specific TH2 cytokines. CONCLUSIONS Peanut EPIT administration was safe and associated with a modest treatment response after 52 weeks, with the highest responses among younger children. This, when coupled with a high adherence and retention rate and significant changes in immune pathways, supports further investigation of this novel therapy.