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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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Skin tape proteomics identifies pathways associated with transepidermal water loss and allergen polysensitization in atopic dermatitis.
Goleva, E, Calatroni, A, LeBeau, P, Berdyshev, E, Taylor, P, Kreimer, S, Cole, RN, Leung, DYM
The Journal of allergy and clinical immunology. 2020;(6):1367-1378
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Abstract
BACKGROUND Atopic dermatitis (AD) and food allergy (FA) are associated with skin barrier dysfunction. OBJECTIVE Skin biomarkers are needed for skin barrier interventions studies. METHODS In this study, skin tape strip (STS) samples were collected from nonlesional skin of 62 children in AD FA+, AD FA-, and nonatopic groups for mass spectrometry proteomic analysis. transepidermal water loss and allergic sensitization were assessed. STS proteomic analysis results were validated in an independent cohort of 41 adults with AD with and without FA versus nonatopic controls. RESULTS A group of 45 proteins was identified as a principal component 1 (PC1) with the highest expression in AD FA+ STSs. This novel set of STS proteins was highly correlative to skin transepidermal water loss and allergic sensitization. PC1 proteins included keratin intermediate filaments; proteins associated with inflammatory responses (S100 proteins, alarmins, protease inhibitors); and glycolysis and antioxidant defense enzymes. Analysis of PC1 proteins expression in an independent adult AD cohort validated differential expression of STS PC1 proteins in the skin of adult patients with AD with the history of clinical reactions to peanut. CONCLUSIONS STS analysis of nonlesional skin of AD children identified a cluster of proteins with the highest expression in AD FA+ children. The differential expression of STS PC1 proteins was confirmed in a replicate cohort of adult AD patients with FA to peanut, suggesting a unique STS proteomic endotype for AD FA+ that persists into adulthood. Collectively, PC1 proteins are associated with abnormalities in skin barrier integrity and may increase the risk of epicutaneous sensitization to food allergens.
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β-1,3-glucanase rOle e 9 and MnSOD rAsp f 6 IgE reactivity are the signature of atopic dermatitis in the Mediterranean area.
Scala, E, Abeni, D, Guerra, EC, Pirrotta, L, Locanto, M, Meneguzzi, G, Giani, M, Russo, G, Asero, R
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 2020;(4):487-498
Abstract
BACKGROUND Atopic dermatitis (AD) represents a chronic skin disorder seriously affecting patients' QoL and is often associated with immunological imbalance, disorders of the skin barrier function and environmental factors. OBJECTIVE We extensively studied the proteomic IgE sensitization profile in a large AD Mediterranean cohort. METHODS A total of 588 individuals with moderate-severe (70.6%) or mild and/or history of (29.4%) AD were evaluated in comparison to 1285 unselected atopic controls (AC) with a history of adverse reactions to foods, allergic rhinitis and/or bronchial asthma by means of ImmunoCAP ISAC112 ® and Allergy Explorer-ALEX® microarray analysis. RESULTS The olive tree pollen β-1,3-glucanase rOle e 9 and the manganese superoxide dismutase from Aspergillus rAsp f 6 were the molecules most significantly associated with AD occurrence and allowed to discriminate among the moderate and severe forms of disease. An IgE hyper-reactivity to cypress, grasses, olive tree, house dust mites (including rDer p 11), and to all cross-reactive components except profilin and polcalcin was observed. About 60% of adults with severe AD were sensitized to nsLTPs. Cross-reactive carbohydrate determinants (CCDs) IgE was found in about one-third of AD participants. Hen eggs nGal d 1 IgE sensitization was more prevalent in the paediatric population, whilst rAsp f 6 and rOle e 9 reactivity was found particularly in older patients. Despite the status of widespread IgE sensitization to both environmental and food allergens, a reduced frequency of patient-reported severe reactions to food or of asthma was observed in AD patients compared to AC, particularly in case of concomitant Ole e 9 reactivity. CONCLUSION AND CLINICAL RELEVANCE Testing IgE reactivity to a large panel of molecular components unveils important associations between IgE reactivity profiles and AD clinical presentation, highlights the allergens useful for a precise AD signature and allows the detection of interesting sensitisations patterns.
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Association of Japanese cedar pollinosis and sensitization with HLA-DPB1 in the Japanese adolescent.
Morii, W, Sakai, A, Ninomiya, T, Kidoguchi, M, Sumazaki, R, Fujieda, S, Noguchi, E
Allergology international : official journal of the Japanese Society of Allergology. 2018;(1):61-66
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Abstract
BACKGROUND Allergic rhinitis (AR) is a heterogeneous disorder that significantly affects daily activity, work productivity, sleep, learning, and quality of life in all generations. Japanese cedar (JC) pollen is the most common allergen responsible for the development of AR in Japan. AR caused by JC pollen is considered to be a multifactorial inheritance disease that is caused by both environmental and genetic factors. The aim of this study was to investigate whether Human Leukocyte Antigen-DPB1 (HLA-DPB1) is associated with JC sensitization/pollinosis. METHODS Subjects in the present study were 544 students at the University of Tsukuba from 2013 to 2015. PCR-SSOP was performed to determine each individual's HLA-DPB1 alleles. Logistic regression analysis was performed to examine relationships between JC-related phenotypes and alleles/amino acid polymorphisms of HLA-DPB1. RESULTS HLA-DPB1*02 allele were significantly associated with both JC sensitization/pollinosis (q < 0.05). Furthermore, HLA-DPB1*02:01 and HLA-DPB1*02:02 had a protective tendency for JC sensitization/pollinosis, and HLA-DPB1*05:01 had a susceptible tendency for sensitization (P < 0.05). In amino acid polymorphism analyses, Glutamic acid in position 69, Glycine-Glycine-Proline-Methionine in positions 84-87, Threonine in position 170 and Methionine in position 205 were also observed to have a protective tendency for JC sensitization (P < 0.05). Amino acid positions 69 and 84-87 were located in binding pocket 5 and 1 of HLA-DPβ1, respectively. CONCLUSIONS Amino acid changes in the allergen-binding pocket of HLA-DPβ1 are likely to influence pollinosis/sensitization to the allergenic peptide of JC pollen and determine the pollinosis risk for each individual exposed to JC pollen.
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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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Abstract
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.
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Vitamin D supplementation during pregnancy and infancy reduces aeroallergen sensitization: a randomized controlled trial.
Grant, CC, Crane, J, Mitchell, EA, Sinclair, J, Stewart, A, Milne, T, Knight, J, Gilchrist, C, Camargo, CA
Allergy. 2016;(9):1325-34
Abstract
BACKGROUND Vitamin D has immune-modulating effects. We determined whether vitamin D supplementation during pregnancy and infancy prevents aeroallergen sensitization and primary care respiratory illness presentations. METHODS A randomized, double-blind, placebo-controlled parallel-group trial. We assigned pregnant women, from 27-week gestation to birth, and then their infants, from birth to 6 months, to placebo or one of two dosages of daily oral vitamin D. Woman/infant pairs were randomized to: placebo/placebo, 1000 IU/400 IU or 2000 IU/800 IU. When the children were 18 months old, we measured serum-specific IgE antibodies and identified acute primary care visits described by the doctor to be due to a cold, otitis media, an upper respiratory infection, croup, asthma, bronchitis, bronchiolitis, a wheezy lower respiratory infection or fever and cough. RESULTS Specific IgE was measured on 185 of 260 (71%) enrolled children. The proportion of children sensitized differed by study group for four mite antigens: Dermatophagoides farinae (Der-f1, Der-f2) and Dermatophagoides pteronyssinus (Der-p1, Der-p2). With results presented for placebo, lower dose, and higher dose vitamin D, respectively (all P < 0.05): Der-f1 (18%, 10%, 2%), Der-f2 (14%, 3%, 2%), Der-p1 (19%, 14%, 3%) and Der-p2 (12%, 2%, 3%). There were study group differences in the proportion of children with primary care visits described by the doctor as being for asthma (11%, 0%, 4%, P = 0.002), but not for the other respiratory diagnoses. CONCLUSIONS Vitamin D supplementation during pregnancy and infancy reduces the proportion of children sensitized to mites at age 18 months. Preliminary data indicate a possible effect on primary care visits where asthma is diagnosed.
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A comparative analysis of metal allergens associated with dental alloy prostheses and the expression of HLA-DR in gingival tissue.
Zhang, X, Wei, LC, Wu, B, Yu, LY, Wang, XP, Liu, Y
Molecular medicine reports. 2016;(1):91-8
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Abstract
The present study aimed to provide guidance for the selection of prosthodontic materials and the management of patients with a suspected metal allergy. This included a comparison of the sensitivity of patients to alloys used in prescribed metal‑containing prostheses, and correlation analysis between metal allergy and accompanying clinical symptoms of sensitized patients using a patch test. The results from the patch test and metal component analyses were processed to reach a final diagnosis. In the present study, four dental alloys were assessed. Subsequent to polishing the surface of a metal restoration, the components were analyzed using an X‑ray fluorescence microscopy and spectrometry. Immunohistochemical analysis, reverse transcription‑polymerase chain reaction and western blotting were used to detect the expression levels of human leukocyte antigen (HLA)‑DR in gingival tissues affected by alloy restoration, and in normal gingival tissue samples. Positive allergens identified in the patch test were consistent with the components of the metal prostheses. The prevalence of nickel (Ni) allergy was highest (22.8%), and women were significantly more allergic to palladium and Ni than men (P<0.05). The protein and gene expression levels of HLA‑DR in the Ni‑chromium (Cr) prosthesis group were significantly higher, compared with those in the other groups (P<0.01); followed by cobalt‑Cr alloy, gold alloy and titanium alloy. In conclusion, dentists require an understanding of the corrosion and allergy rates of prescribed alloys, in order to reduce the risk of allergic reactions. Patch testing for hypersensitive patients is recommended and caution is required when planning to use different alloys in the mouth.
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Does providing written dietary advice improve the ingestion of non-allergic nuts in children with existing nut allergies? - A randomized controlled trial.
Norman, M, South, C, Quinn, P, Chan, D, Palmer, S, Netting, M, Gold, M
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 2016;(5):741-8
Abstract
BACKGROUND Allergy to one or more nuts is common in children and often complete nut avoidance is advised. More recently, introduction of non-allergic nuts into the diet is advised by some allergists. OBJECTIVE This study aims to determine whether the provision of additional written dietary advice increases the ingestion of non-allergic nuts by children with nut allergy. Secondary aims include determining which factors facilitate or prevent successful inclusion of non-allergic nuts in the diet, and how inclusion influences quality of life, sensitization and the rate of nut reactions. METHODS This is a randomized, double-blinded, controlled trial of children with nut allergy who were asked to ingest one or more non-allergic nuts. Participants were 75 children aged 2-16 years (Intervention=36, Control=39), recruited in Adelaide, Australia. Randomized participants were supplied with the intervention (recipe booklet and monthly reminder text messages) or provided standard verbal dietary advice. After 6 months participants were assessed by a blinded investigator with regard to nut ingestion, quality of life, sensitization and nut reactions. RESULTS The intervention did not increase the ingestion of non-allergic nuts. A negative hospital challenge was a predictor of successful introduction. Parental report of child concern about a reaction was the greatest barrier. Ingestion of non-allergic nuts did not improve quality of life or change nut sensitization. Few nut reactions occurred during the study. CONCLUSIONS AND CLINICAL RELEVANCE Ingestion of non-allergic nuts by children with nut allergy was not improved by additional dietary intervention. Selective introduction of non-allergic nuts is difficult to achieve when the child is anxious about introduction and challenges cannot be done in a medically supervised setting. CAPSULE SUMMARY This dietary intervention did not improve non-allergic nut ingestion by nut allergic children. Hospital challenge increased introduction rates, whilst parentally reported child concern about a reaction reduced success. Non-allergic nut ingestion did not change quality of life or sensitization.
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The clinical effect of vitamin D supplementation combined with grass-specific sublingual immunotherapy in children with allergic rhinitis.
Jerzynska, J, Stelmach, W, Rychlik, B, Lechańska, J, Podlecka, D, Stelmach, I
Allergy and asthma proceedings. 2016;(2):105-14
Abstract
BACKGROUND An important issue in sublingual immunotherapy (SLIT) is how to improve efficacy. OBJECTIVE To compare the clinical efficacy of SLIT with vitamin D supplementation with placebo in children with allergic rhinitis. Secondary end points included lung function, exhaled nitric oxide concentration, methacholine bronchial provocation test, and serum level of calcifediol (25[OH]D). METHODS Fifty children, ages 5-12 years, sensitive to grass pollen, with allergic rhinitis (eight patients had concomitant asthma) participated in a 5-month prospective, randomized, double-blind, placebo-controlled trial. Children received a 5-grass pollen sublingual 300 IR tablet with either vitamin D 1000 IU daily supplementation or placebo. RESULTS When compared with the placebo group, SLIT plus vitamin D group therapy was more effective in the reduction of nasal symptoms (p = 0.04), asthma symptoms (p = 0.001), and the combined symptom-medication score (p = 0.001); there was no significant difference between the groups in medication and ocular scores. We observed a significant improvement of forced expiratory volume in 1 second (vitamin D group, p = 0.014; placebo group, p = 0.015) and the proportion of a person's vital capacity expired in the first second of forced expiration levels (vitamin D group, p = 0.004; placebo group, p < 0.001), within both groups, between visits. Fractional exhaled nitric oxide and provocative dose producing a 20% fall in forced expiratory volume in 1 second results did not statistically significantly differentiate the study participants in terms of receiving SLIT along with vitamin D or placebo. We showed a significant increase in calcifediol in the SLIT plus vitamin D group as well as in SLIT plus placebo group. CONCLUSIONS Vitamin D supplementation combined with grass-specific SLIT was more effective in the reduction of nasal and asthma symptoms. Vitamin D supplementation combined with SLIT provides an effective and well-tolerated new immunotherapy modality for treating children with allergic rhinitis. A 5-grass pollen sublingual 300 IR tablet was effective in both studied groups and also in children with comorbid mild asthma.
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Oral tolerance induction with wheat: a valid therapeutic option in allergic patients.
Vila, L, García, V
Journal of investigational allergology & clinical immunology. 2015;(1):77-8