Double-blind Placebo-controlled Food Challenge Research Articles

Exploratory immunogenicity outcomes of peanut oral immunotherapy: Findings from the PALISADE trial.

Immunoglobulin E (IgE) and immunoglobulin G4 (IgG4) to peanut and its components may influence the clinical reactivity to peanut. Allergen-specific immunotherapy is known for modifying both IgE and IgG4. Peanut oral immunotherapy may influence these serological parameters. Exploratory analyses of serological data from participants receiving peanut (Arachis hypogaea) allergen powder-dnfp (PTAH) and placebo in the double-blind, randomized, phase 3 PALISADE trial were conducted to evaluate potential relationships between peanut-specific and peanut component-specific (Ara h 1, Ara h 2, Ara h 3, Ara h 6, Ara h 8, and Ara h 9) IgE and IgG4 levels and clinical outcomes. A total of 269 participants (PTAH, n=202; placebo, n=67) were analyzed. No relationship was observed between specific IgE and IgG4 levels at screening and maximum tolerated peanut protein dose during screening or response status during exit double-blind placebo-controlled food challenge (DBPCFC). In PTAH-treated participants, no relationship was observed between IgE and IgG4 levels at screening and maximum symptom severity during exit DBPCFC. Postscreening ratios (ie, postscreening/screening) in the PTAH group were significant at the end of updosing and exit visit for most components. Postscreening changes in specific IgE levels were more pronounced with PTAH versus placebo for most components. Specific IgE and IgG4 levels at screening are not correlated with screening or exit DBPCFC results, and are not predictive of clinical response to PTAH. Peanut (Arachis hypogaea) allergen powder-dnfp contains the relevant and immunodominant allergens, inducing immunological changes with the treatment. ClinicalTrials.gov identifier: NCT02635776.

Patch test in the diagnosis of food allergy

Food allergens are capable of producing adverse reactions through multiple mechanisms of an allergic or non-allergic nature, and through different routes of exposure; generally by ingestion or contact, as in protein contact dermatitis or contact urticaria, including inhalation. Food allergy reactions, in turn, can be mediated by immediate hypersensitivity mechanisms, delayed hypersensitivity or mixed immediate-delayed mechanisms. The reference diagnostic method in food allergy is the double-blind placebo-controlled food challenge test (DBPCFC), but skin and serological tests are important in the clinical context. The diagnosis of immediate food allergy depends on well-standardized allergological tests, such as the skin prick test (SPT) or specific IgE dosing, which are ideally tested by food challenge testing. However, the diagnosis of delayed mechanism food allergy and mixed allergies, which combine both immune mechanisms, is more complex. Delayed hypersensitivity reactions are evaluated with the epicutaneous patch test, or patch testing, for the diagnosis of contact dermatitis. The atopy patch test is initially used for the investigation of inflammatory reactions, which may be linked to food allergens in patients with atopic dermatitis. It was later applied in other diseases, whose pathogenesis is mainly mediated by a mechanism of delayed hypersensitivity to protein allergens: eosinophilic esophagitis, enterocolitis induced by food proteins, protein contact dermatitis, contact urticaria, among other disorders.

Home-Based Double-Blind, Placebo-Controlled Challenges for Diagnosis of Delayed Gluten/Milk Hypersensitivity in Children

Delayed hypersensitivity to gluten and milk protein is frequently reported but may be difficult to diagnose. We aimed to explore if a method of home-based double-blind placebo-controlled food challenges (H-FC) can identify and reduce unnecessary elimination diets in children. We included 73 of 92 children aged 1 to 17 years referred to a tertiary allergy clinic from 2011 to 2021 due to self-reported, delayed symptoms to gluten or milk. The children were randomized to H-FC, receiving gluten/milk protein or placebo for 5 to 7 days in a double-blind crossover manner, separated by 3 washout weeks. Patients/parents recorded symptoms using standardized forms. Two crossover periods were used from 2011 to 2016 and 3 periods from 2017 to 2021. A positive challenge required significantly more symptoms during the active period versus the placebo period. After the challenge, reintroduction of milk/gluten was assessed by a follow-up interview. The primary outcome was the proportion of children with a positive challenge. The children, with a mean age of 11 years, had followed a strict gluten-free or milk-protein-free diet for a median duration of 24 months (range: 3-180 months). A positive challenge was observed in 18 of 73 children (25%), more often using 2 (35%) compared with 3 challenge periods (12%). At follow-up, 44 of 55 (80%) children with a negative challenge had successfully reintroduced milk/gluten. H-FC may be an effective method in avoiding unnecessary elimination diets in children. Only 25% of the challenges were positive, and 80% of the children with negative challenges succeeded in reintroducing the food. Three challenge periods may be necessary to reduce false-positive outcomes.

Partial Egg Consumption Modifies the Diagnostic Performance of Allergy Tests to Predict Outcome of Double-Blind Placebo-Controlled Food Challenges to Egg

Many children are consuming some egg when they are diagnosed with egg allergy. We hypothesized that egg consumption could modify the diagnostic performance of allergy tests. To stratify diagnostic performance of tests according to egg consumption status. The BAT2 study (NCT03309488) participants underwent oral food challenge (OFC), food-frequency questionnaires, skin prick test (SPT), specific immunoglobulin E (sIgE) and specific immunoglobulin G4 (sIgG4) and basophil activation test (BAT). At study entry, 45% of participants reported partial egg consumption ("consumers") and 55% were avoiding egg strictly ("avoiders"). Avoiders had larger SPT (P < .001), higher BAT to egg (P < .001), sIgE to egg white (EW; P= .001) and to ovalbumin (OVA; P= .001), but not to ovomucoid (P= .231). Consumers had higher levels of sIgG4 to all egg allergens (P < .001) than avoiders. In consumers, the test with the best diagnostic performance was BAT (area under the curve [AUC]= .912) followed by SPT to raw egg (AUC= 0.805), EW-sIgE (AUC= 0.738), and OVA-sIgE (AUC= 0.732). In avoiders, the best tests were BAT (AUC= 0.834) and EW-sIgE (AUC= 0.833) followed by OVA-sIgE (AUC= 0.793) and SPT to EW (AUC=0.789). Using 100% sensitivity and 100% specificity cut-offs, the proportion of patients requiring OFC were 33% for BAT, 53% for SPT to raw egg, 61% for OVA-sIgE, and 73% for EW-sIgE for consumers; and 73% for BAT, 79% for EW-sIgE, and 93% for SPT to EW for avoiders. The diagnostic performance of tests is influenced by the immunomodulatory effect of egg consumption. BAT is the most reliable test and reduced the need for OFC, particularly in partial egg consumers.

Interaction Between Baseline Participant Factors and Treatment Effects Following Peanut Oral Immunotherapy

The Probiotic Peanut Oral Immunotherapy-003 multicenter randomized trial found that both probiotic peanut oral immunotherapy (PPOIT) and peanut OIT alone (OIT) were effective compared with placebo in inducing clinical remission after 18 months of treatment, and improving health-related quality of life (HRQL) at 12 months after treatment. Understanding treatment effect modifiers can optimize outcomes through precision care. This post hoc study examined baseline clinical and demographic participant factors that modified treatment effects. The study sample included 201 children (aged 1-10 years) with challenge-confirmed peanut allergy. Exposure variables were baseline clinical and demographic factors. Outcomes were remission (double-blind, placebo-controlled food challenge, cumulative 4,950-mg peanut protein at 8 weeks after treatment) and HRQL (change in Food Allergy Quality of Life Questionnaire-Parent Form score). Interactions between baseline factors and treatment effects on remission and HRQL were explored with regression models. A higher degree of peanut sensitivity (large peanut skin prick test, high peanut specific IgE, and low reaction-eliciting dose at study entry challenge) and other concurrent allergic conditions (multiple food allergies, asthma, or wheeze) were associated with the decreased likelihood of attaining remission after both PPOIT and OIT treatment. History of anaphylaxis was associated with the reduced likelihood of remission after PPOIT compared with OIT. For the HRQL outcome, there was evidence that sex, history of anaphylaxis, and age modified treatment effects. Baseline participant factors modify PPOIT and OIT effects on remission and HRQL. Considering modifiers of treatment effect during participant selection may optimize treatment success and clinical trial design toward specific outcomes, such as the achievement of remission.

Systematic review and meta-analyses on the accuracy of diagnostic tests for IgE-mediated food allergy.

The European Academy of Allergy and Clinical Immunology (EAACI) is updating the Guidelines on Food Allergy Diagnosis. We aimed to undertake a systematic review of the literature with meta-analyses to assess the accuracy of diagnostic tests for IgE-mediated food allergy. We searched three databases (Cochrane CENTRAL (Trials), MEDLINE (OVID) and Embase (OVID)) for diagnostic test accuracy studies published between 1 October 2012 and 30 June 2021 according to a previously published protocol (CRD42021259186). We independently screened abstracts, extracted data from full texts and assessed risk of bias with QUADRAS 2 tool in duplicate. Meta-analyses were undertaken for food-test combinations for which three or more studies were available. A total of 149 studies comprising 24,489 patients met the inclusion criteria and they were generally heterogeneous. 60.4% of studies were in children ≤12 years of age, 54.3% were undertaken in Europe, ≥95% were conducted in a specialized paediatric or allergy clinical setting and all included oral food challenge in at least a percentage of enrolled patients, in 21.5% double-blind placebo-controlled food challenges. Skin prick test (SPT) with fresh cow's milk and raw egg had high sensitivity (90% and 94%) for milk and cooked egg allergies. Specific IgE (sIgE) to individual components had high specificity: Ara h 2-sIgE had 92%, Cor a 14-sIgE 95%, Ana o 3-sIgE 94%, casein-sIgE 93%, ovomucoid-sIgE 92/91% for the diagnosis of peanut, hazelnut, cashew, cow's milk and raw/cooked egg allergies, respectively. The basophil activation test (BAT) was highly specific for the diagnosis of peanut (90%) and sesame (93%) allergies. In conclusion, SPT and specific IgE to extracts had high sensitivity whereas specific IgE to components and BAT had high specificity to support the diagnosis of individual food allergies.

Safety and immunopharmacology of ASP0892 in adults or adolescents with peanut allergy: two randomized trials.

New treatment options with improved safety and novel mechanisms of actions are needed for patients with peanut allergy. To evaluate the safety, tolerability, and immunogenicity of ASP0892, a peanut DNA vaccine, after intradermal (id) or intramuscular (im) administration in adult or adolescent patients with peanut allergy in two phase 1 studies. ASP0892 or placebo was administered every 2 weeks for a total of 4 doses. The doses were 1 mg or 4 mg id or 4 mg im for adults, and 1 mg or 4 mg id for adolescents. Immunologic parameters were assessed longitudinally. Thirty-one adults (mean age 24.3 years, 17 males) received ASP0892 (9, 8, 8 patients for 1 mg id, 4 mg id or 4 mg im, respectively) or placebo (2 patients/group). Twenty adolescents (mean age 14.2 years, 11 males) received ASP0892 (8 patients/group) or placebo (2 patients/group). In both studies, the most common treatment-emergent adverse event (TEAE) was injection site pruritus. No deaths or treatment withdrawal were related to TEAEs. No serious TEAEs related to treatment were observed in adult or adolescent patients. ASP0892 treatment led to modest increases in allergen-specific IgG and/or IgG4 in adults (1 mg id, 4 mg im) and adolescents (1 mg id, 4 mg id). No improvements in clinical outcomes, including double-blind placebo-controlled food challenge, were found after ASP0892 treatment. In two phase 1 studies, ASP0892 was well tolerated with modest but not clinically relevant changes in immune responses. NCT02851277, NCT03755713.

Gut microbiota and fecal metabolites in sustained unresponsiveness by oral immunotherapy in school-age children with cow's milk allergy

BackgroundOral immunotherapy (OIT) can ameliorate cow's milk allergy (CMA); however, the achievement of sustained unresponsiveness (SU) is challenging. Regarding the pathogenesis of CMA, recent studies have shown the importance of gut microbiota (Mb) and fecal water-soluble metabolites (WSMs), which prompted us to determine the change in clinical and gut environmental factors important for acquiring SU after OIT for CMA. MethodsWe conducted an ancillary cohort study of a multicenter randomized, parallel-group, delayed-start design study on 32 school-age children with IgE-mediated CMA who underwent OIT for 13 months. We defined SU as the ability to consume cow's milk exceeding the target dose in a double-blind placebo-controlled food challenge after OIT followed by a 2-week-avoidance. We longitudinally collected 175 fecal specimens and clustered the microbiome and metabolome data into 29 Mb- and 12 WSM-modules. ResultsDuring OIT, immunological factors improved in all participants. However, of the 32 participants, 4 withdrew because of adverse events, and only 7 were judged SU. Gut environmental factors shifted during OIT, but only in the beginning, and returned to the baseline at the end. Of these factors, milk- and casein-specific IgE and the Bifidobacterium-dominant module were associated with SU (milk- and casein-specific IgE; OR for 10 kUA/L increments, 0.67 and 0.66; 95%CI, 0.41–0.93 and 0.42–0.90; Bifidobacterium-dominant module; OR for 0.01 increments, 1.40; 95%CI, 1.10–2.03), and these associations were observed until the end of OIT. ConclusionsIn this study, we identified the clinical and gut environmental factors associated with SU acquisition in CM-OIT.

Oral Immunotherapy for Peanut Allergy in Children 1 to Less Than 4 Years of Age

BackgroundPeanut allergy is a common childhood allergy, and the only approved treatment for children 4 to 17 years of age is peanut allergen powder-dnfp (PTAH) oral immunotherapy.MethodsFor this phase 3, randomized, double-blind, placebo-controlled trial, we enrolled peanut-allergic children 1 to <4 years of age who experienced dose-limiting symptoms from ≤300 mg peanut protein during a screening double-blind, placebo-controlled food challenge (DBPCFC). Participants received PTAH or placebo, randomized in a 2:1 ratio, for approximately 12 months. At the trial conclusion, all participants underwent an exit BDPCFC. The primary end point was desensitization (i.e., tolerating a ≥600-mg single dose of peanut protein with only mild allergy symptoms).ResultsIn the PTAH-treated group (n=98), 73.5% of participants tolerated a single dose of ≥600 mg peanut protein at exit DBPCFC compared with 6.3% in the placebo group (n=48). Most participants experienced an adverse event (98.0% of PTAH-treated and 97.9% of placebo-treated participants), which was mild or moderate in grade for 93.2% of participants (92.9% in PTAH-treated and 93.8% in placebo-treated participants). Treatment-related adverse events, which were mild to moderate, were experienced by 75.5% of PTAH-treated and 58.3% of placebo-treated participants. Three treatment-related systemic allergic reactions, none of which were severe or serious in grade, were noted in two PTAH-treated participants (2%).ConclusionsIn peanut-allergic children 1 to <4 years of age treated with PTAH for approximately 12 months, the majority tolerated all peanut protein dose levels assessed. PTAH-treated patients had more treatment-related adverse events, which were mild to moderate severity. (Funded by Aimmune Therapeutics; ClinicalTrials.gov number, NCT03736447.)

Desensitization and remission after peanut sublingual immunotherapy in 1- to 4-year-old peanut-allergic children: A randomized, placebo-controlled trial

Prior studies of peanut sublingual immunotherapy (SLIT) have suggested a potential advantage with younger age at treatment initiation. We studied the safety and efficacy of SLIT for peanut allergy in 1- to 4-year-old children. Peanut-allergic 1- to 4-year-old children were randomized to receive 4 mg peanut SLIT versus placebo. Desensitization was assessed by double-blind, placebo-controlled food challenge (DBPCFC) after 36monthsoftreatment. Participants desensitized to at least443mg peanut protein discontinued therapy for 3 months and then underwent DBPCFC to assess for remission. Biomarkers were measured at baseline and longitudinally during treatment. Fifty participants (25 peanut SLIT, 25 placebo) with a median age of 2.4 years were enrolled across 2 sites. The primary end point of desensitization was met with actively treated versus placebo participants having a significantly greater median cumulative tolerated dose (4443 mg vs 143 mg), higher likelihood of passing the month 36 DBPCFC (60% vs 0), and higher likelihood of demonstrating remission (48% vs 0). The highest rate of desensitization and remission was seen in1- to 2-year-olds, followed by 2- to 3-year-olds and 3- to 4-year-olds. Longitudinal changes in peanut skin prick testing, peanut-specific IgG4, and peanut-specific IgG4/IgE ratio were seen in peanut SLIT but not placebo participants. Oropharyngeal itching was more commonly reported by peanut SLIT than placebo participants. Skin, gastrointestinal, upper respiratory, lower respiratory, and multisystem adverse events were similar between treatment groups. Peanut SLIT safely induces desensitization and remission in 1- to 4-year-old children, with improved outcomes seen with younger age at initiation.

Basophil activation test as predictor of severity and threshold of allergic reactions to egg.

Identifying patients at risk of severe allergic reactions and/or low threshold of reactivity is very important, particularly for staple foods like egg. One hundred and fifty children underwent double-blind placebo-controlled food challenge (DBPCFC) to baked egg (BE), skin prick testing and blood collection for serology and basophil activation test (BAT). Patients who passed BE DBPCFC underwent loosely cooked egg (LCE) DBPCFC. Severity of allergic reactions was classified following Practall guidelines and threshold dose was determined during DBPCFC. Sixty out of 150 (40%) children reacted to BE and 16 out of 77 (21%) to LCE on DBPCFC. Considering DBPCFC to BE, 23 children (38%) had severe reactions and 33 (55%) reacted to 0.13 g or less of egg protein (low threshold group). Two children (2 out of 16 = 12%) had severe reactions to LCE. Demographic, clinical and most immunological features were not significantly different between severe/non-severe BE reactors or low/high threshold groups. Severe BE reactors had higher ovomucoid-sIgE (p = .009) and higher BAT to BE (p = .001). Patients with lower threshold to BE had higher IgE-specific activity (p = .027) and BAT to egg (p = .007) but lower severity score (p = .008). Optimal cut-offs for ovomucoid-sIgE had 100% sensitivity, 35% specificity and 60% accuracy and for BAT 76% sensitivity, 74% specificity and 75% accuracy to identify BE severe reactors. Optimal cut-offs for specific activity had 70% sensitivity, 68% specificity and 69% accuracy and for BAT 70% sensitivity, 72% specificity and 71% accuracy to identify low threshold patients. BAT was the best biomarker to predict severity and threshold of allergic reactions to BE and can be useful when making decisions about management of egg allergy.

Challenge-verified thresholds for allergens mandatory for labeling: How little is too much for the most sensitive patient?

It is mandatory to label food products with the 14 main allergens in the EU. Reasonable allergen labeling requires knowledge of population-based thresholds derived from food challenges. The aim of this study was to evaluate the threshold-distribution in clinically verified food allergic patients for allergens mandatory for labeling. All positive open oral food challenges and double-blind placebo-controlled food challenges (DBPCFC) performed at the Allergy Center, Odense University Hospital, Denmark (2000-2022) were included. For each included challenge, the cumulative threshold (LOAEL) was obtained and NOAEL estimated. Data were modelled as an interval censored log-normal distribution. Overall, 38 of all 2612 challenges (1.5%) in 1229 patients (717 male, 986 children) reacted to <5 mg protein. The majority of the most sensitive patients reacted with a Sampson severity score of 2-3. Using interval censored log-normal models only five groups (hens´ egg, fish, peanut, milk, tree-nuts) elicited reactions after ingestion of 0.5 mg protein and in low frequencies of the population. Hen's egg was the most potent allergen, with reactivity to <0.5 mg protein in 0.24% [0.13-0.44%] of egg allergic patients while the estimated fraction of allergic patients reacting to a eliciting dose on 0.5 mg protein for most other allergens were below 0.04%. Our data demonstrates that the majority of food allergic patients as expected tolerating traces of allergenic foods without developing severe allergic symptoms and signs. Hen's egg appears to be the food most likely to elicit reactions in the most sensitive individuals at very low doses.

Immune response evolution in peanut epicutaneous immunotherapy for peanut-allergic children.

Epicutaneous immunotherapy with investigational Viaskin™ Peanut 250 μg (DBV712) has demonstrated statistically superior desensitization versus placebo in peanut-allergic children in clinical trials. It is unclear whether serologic biomarkers predict response. Serum-specific IgG4 and IgE (whole peanut and components) from subjects enrolled in the phase 3 Efficacy and Safety of Viaskin Peanut in Children With IgE-Mediated Peanut Allergy study were examined by exploratory univariate and multivariate analyses to determine trajectories and predictors of treatment response, based upon peanut protein eliciting dose (ED) at Month (M) 12 double-blind placebo-controlled food challenge. Among Viaskin Peanut-treated subjects, peanut sIgG4 significantly increased from baseline through M12 and peanut sIgE peaked at M3 and fell below baseline by M12, with sIgG4 and sIgE peanut components mirroring these trajectories. Placebo subjects had no significant changes. By univariate analysis, M12 peanut sIgG4/sIgE was higher in treatment responders (p< 0.001) and had highest area under the curve (AUC) for predicting ED ≥300 mg and ≥1000 mg (AUC 69.5% and 69.9%, respectively). M12 peanut sIgG4/sIgE >20.1 predicted M12 ED ≥300 mg (80% positive predictive value). The best performing component was Ara h 1 sIgE <15.7 kUA /L (AUC 66.5%). A multivariate model combining Ara h 1 and peanut sIgG4/sIgE had an AUC of 68.2% (ED ≥300 mg) and 67.8% (ED ≥1000 mg). Peanut sIgG4 rise most clearly differentiated Viaskin Peanut versus placebo subjects. sIgG4/sIgE ratios >20.1 and the combination of Ara h 1 and peanut sIgG4/sIgE had moderate ability to predict treatment response and could potentially be useful for clinical monitoring. Additional data are needed to confirm these relationships.

Post hoc analysis examining symptom severity reduction and symptom absence during food challenges in individuals who underwent oral immunotherapy for peanut allergy: results from three trials

PurposePeanut allergy and its current management, involving peanut avoidance and use of rescue medication during instances of accidental exposure, are burdensome to patients and their caregivers and can be a source of stress, uncertainty, and restriction. Physicians may also be frustrated with a lack of effective and safe treatments other than avoidance in the current management of peanut allergy. Efficacy, determined using double-blind, placebo-controlled food challenges (DBPCFCs), of oral immunotherapy with peanut (Arachis hypogaea) allergen powder-dnfp (PTAH; Palforzia®) was demonstrated versus placebo in children and adolescents aged 4 to 17 years in multiple phase 3 trials; continued benefit of PTAH was shown in a follow-on trial. The DBPCFC is a reproducible, rigorous, and clinically meaningful assessment accepted by regulatory authorities to evaluate the level of tolerance as an endpoint for accidental exposures to peanut in real life. It also provides useful clinical and patient-relevant information, including the amount of peanut protein an individual with peanut allergy can consume without experiencing dose-limiting symptoms, severity of symptoms, and organs affected upon ingestion of peanut protein. We explored symptoms of peanut exposure during DBPCFCs from phase 3 and follow-on trials of PTAH to further characterize treatment efficacy from a perspective relevant to patients, caregivers, and clinicians.MethodsSymptom data recorded during screening and/or exit DBPCFCs from participants aged 4 to 17 years receiving PTAH or placebo were examined post hoc across three PTAH trials (PALISADE [ARC003], ARC004 [PALISADE follow-on], and ARTEMIS [ARC010]). The maximum peanut protein administered as a single dose during DBPCFCs was 1000 mg (PALISADE and ARTEMIS) and 2000 mg (ARC004). Symptoms were classified by system organ class (SOC) and maximum severity. Endpoints were changes in symptom severity and freedom from symptoms (ie, asymptomatic) during DBPCFC. Relative risk (RR) was calculated for symptom severity by SOC and freedom from symptoms between groups; descriptive statistics were used to summarize all other data.ResultsThe risk of any respiratory (RR 0.42 [0.30–0.60], P < 0.0001), gastrointestinal (RR 0.34 [0.26–0.44], P < 0.0001), cardiovascular/neurological (RR 0.17 [0.08–0.39], P < 0.001), or dermatological (RR 0.33 [0.22–0.50], P < 0.0001) symptoms was significantly lower in participants treated with PTAH versus placebo upon exposure to peanut at the end of the PALISADE trial (ie, exit DBPCFC). Compared with placebo-treated participants (23.4%), the majority (76.3%) of PTAH-treated participants had no symptoms at the exit DBPCFC when tested at the peanut protein dose not tolerated (ie, reactive dose) during the screening DBPCFC. Significantly higher proportions of PTAH-treated participants were asymptomatic at doses ≤ 100 mg in the exit DBPCFC compared with placebo-treated participants (PALISADE: 69.35% vs 12.10%, RR 5.73 [95% confidence interval (CI) 3.55–9.26]; P < 0.0001; ARTEMIS: 67.42% vs 13.95%, RR 4.83 [95% CI 2.28–10.25]; P < 0.0001); findings were similar at peanut protein doses ≤ 1000 mg (PALISADE: RR 15.56 [95% CI 5.05–47.94]; P < 0.0001; ARTEMIS: RR 34.74 [95% CI 2.19–551.03]; P < 0.0001). In ARC004, as the period of PTAH maintenance became longer, greater proportions of participants were asymptomatic at doses of peanut protein ≤ 1000 mg in the exit DBPCFC (from 37.63% after ~ 6 months of maintenance treatment [exit DBPCFC of PALISADE] to 45.54% after ~ 13 months and 58.06% after ~ 20 months of overall PTAH maintenance treatment).ConclusionsPTAH significantly reduced symptom severity due to exposure to peanut, which is clinically relevant. When exposed to peanut, participants with peanut allergy treated with PTAH rarely had moderate or severe respiratory or cardiovascular/neurological symptoms. Oral immunotherapy with PTAH appears to reduce frequency and severity of allergic reactions in individuals with peanut allergy after accidental exposure to peanut and may enable them and their families to have an improved quality of life.Trial registration ClinicalTrials.gov, NCT02635776, registered 17 December 2015, https://clinicaltrials.gov/ct2/show/NCT02635776?term=AR101&draw=2&rank=7; ClinicalTrials.gov, NCT02993107, registered 08 December 2016, https://clinicaltrials.gov/ct2/show/NCT02993107?term=AR101&draw=2&rank=6; ClinicalTrials.gov, NCT03201003, registered 22 June 2017, https://clinicaltrials.gov/ct2/show/NCT03201003? term = AR101&draw = 2&rank = 9

Tolerance Induction in Cow's Milk Allergic Children by Heated Cow's Milk Protein: The iAGE Follow-Up Study.

Accelerating the induction of tolerance to cow's milk (CM) reduces the burden of cow's milk allergy (CMA). In this randomised controlled intervention study, we aimed to investigate the tolerance induction of a novel heated cow milk protein, the iAGE product, in 18 children with CMA (diagnosed by a paedriatric allergist). Children who tolerated the iAGE product were included. The treatment group (TG: n = 11; mean age 12.8 months, SD = 4.7) consumed the iAGE product daily with their own diet, and the control group (CG: n = 7; mean age 17.6 months, SD = 3.2) used an eHF without any milk consumption. In each group, 2 children had multiple food allergies. The follow-up procedures consisted of a double-blind placebo-controlled food challenge (DBPCFC) with CM t = 0, t = 1 (8 months), t = 2 (16 months), and t = 3 (24 months). At t = 1, eight (73%) of 11 children in the TG had a negative DBPCFC, versus four out of seven (57%) in the CG (BayesFactor = 0.61). At t = 3, nine of the 11 (82%) children in the TG and five of seven (71%) in the CG were tolerant (BayesFactor = 0.51). SIgE for CM reduced from a mean of 3.41 kU/L (SD = 5.63) in the TG to 1.24 kU/L (SD = 2.08) at the end of intervention, respectively a mean of 2.58 (SD = 3.32) in the CG to 0.63 kU/L (SD = 1.06). Product-related AEs were not reported. CM was successfully introduced in all children with negative DBPCFC. We found a standardised, well-defined heated CM protein powder that is safe for daily OIT treatment in a selected group of children with CMA. However, the benefits of inducing tolerance were not observed.

Open-label study of the efficacy, safety, and durability of peanut sublingual immunotherapy in peanut-allergic children

Studies on the efficacy of peanut sublingual immunotherapy (SLIT) are limited. The durability of desensitization after SLIT has not been well described. We sought to evaluate the efficacy and safety of 4-mg peanut SLIT and persistence of desensitization after SLIT discontinuation. Challenge-proven peanut-allergic 1- to 11-year-old children were treated with open-label 4-mg peanut SLIT for 48 months. Desensitization after peanut SLIT was assessed by a 5000-mg double-blind, placebo-controlled food challenge (DBPCFC). Anovel randomly assigned avoidance period of 1 to 17 weeks was followed by the DBPCFC. Skin prick test results immunoglobulin levels, basophil activation test results, TH1, TH2, and IL-10 cytokines were measured longitudinally. Safety was assessed through patient-reported home diaries. Fifty-four participants were enrolled and 47 (87%) completed peanut SLIT and the 48-month DBPCFC per protocol. The mean successfully consumed dose (SCD) during the DBPCFC increased from 48 to 2723 mg of peanut protein after SLIT (P< .0001), with 70% achieving clinically significant desensitization (SCD> 800 mg) and 36% achieving full desensitization (SCD= 5000 mg). Modeled median time to loss of clinically significant desensitization was 22 weeks. Peanut skin prick test; peanut-specific IgE, IgG4, and IgG4/IgE ratio; and peanut-stimulated basophil activation test, IL-4, IL-5, IL-13, IFN-γ, and IL-10 changed significantly compared with baseline, with changes seen as early as 6 months. Median rate of reaction per dose was 0.5%, with transient oropharyngeal itching being the most common, and there were no dosing symptoms requiring epinephrine. In this open-label, prospective study, peanut SLIT was safe and induced clinically significant desensitization in most of the children, lasting more than 17 weeks after discontinuation of therapy.

Characteristics of cow's milk allergy and sensitization in Chinese patients.

Characteristics of cow's milk allergy and sensitization in Chinese patients.

Frequency of food allergy in Europe: An updated systematic review and meta-analysis.

Food allergy (FA) is increasingly reported in Europe, however, the latest prevalence estimates were based on studies published a decade ago. The present work provides the most updated estimates of the prevalence and trends of FA in Europe. Databases were searched for studies published between 2012 and 2021, added to studies published up to 2012. In total, 110 studies were included in this update. Most studies were graded as moderate risk of bias. Pooled lifetime and point prevalence of self-reported FA were 19.9% (95% CI 16.6-23.3) and 13.1% (95% CI 11.3-14.8), respectively. The point prevalence of sensitization based on specific IgE (slgE) was 16.6% (95% CI 12.3-20.8), skin prick test (SPT) 5.7% (95% CI 3.9-7.4), and positive food challenge 0.8% (95% CI 0.5-0.9). While lifetime prevalence of self-reported FA and food challenge positivity only slightly changed, the point prevalence of self-reported FA, sIgE and SPT positivity increased from previous estimates. This may reflect a real increase, increased awareness, increased number of foods assessed, or increased number of studies from countries with less data in the first review. Future studies require rigorous designs and implementation of standardized methodology in diagnosing FA, including use of double-blinded placebo-controlled food challenge to minimize potential biases.

Reduction in Reaction Severity Following 12 Months of Epicutaneous Immunotherapy with Peanut Patch in Toddlers

<h3>Introduction</h3> In a recent Phase 3 clinical trial (EPITOPE), treatment with a peanut patch containing 250 µg peanut protein for 12 months was statistically superior to placebo in desensitizing peanut-allergic children aged 1-3 years, with 67% vs 33.5% being treatment responders (difference: 33.4%; 95% CI: 22.4, 33.5 [p<0.001]). The ability of the peanut patch to reduce reaction severity, a major goal of allergen immunotherapy, was also characterized in a pre-specified analysis. <h3>Methods</h3> Double-blind, placebo-controlled food challenges (DBPCFC) were performed at baseline and Month 12 to determine eliciting dose (ED). Standardized DBPCFCs were stopped only after sufficient signs/symptoms, in accordance with PRACTALL guidelines. Symptoms in each body system were graded by prespecified criteria (scored 0-3). Maximum severity of symptoms at baseline and Month 12 between active and placebo groups was compared. <h3>Results</h3> At baseline, there was a similar proportion of mild/moderate/severe signs/symptoms between active and placebo (p=0.911). At baseline, an equal percentage of subjects in the active and placebo groups (24.6% in each group) had a maximum symptom severity score of 3 ("severe"). At Month 12, there was a significant difference between groups in maximum symptom severity (p<0.001), with 12.5% of active subjects having a symptom severity score of 3 ("severe") compared with 28.6% in placebo. At Month 12, 36.5% of active subjects had no or mild symptoms compared with 20.4% of placebo. <h3>Conclusion</h3> This analysis suggests that, in addition to achieving desensitization in 1-3-year-old peanut-allergic children, EPIT with a patch containing 250 µg peanut protein may also reduce the severity of allergic reactions.

A Methodology of Epidemiologic Study in the General Population Focusing on Food Allergy - China, 2020.

IntroductionAdverse reactions to food (ARF) are a major worldwide public health and food safety problem. Among the various causes of ARF, food allergies (FA) are particularly serious as the immune response that is triggered can be fatal even at very low doses. However, the prevalence of ARF and FA in the general population in China is presently unclear. This study aims to determine the epidemiological characteristics and risk factors for ARF and FA, which can be a basis for estimating thresholds for major food allergens.MethodsThis is a multicenter, cross-sectional, epidemiologic survey with a case-control study nested among a selected population in China. Random individuals were recruited using stratified cluster random sampling; ARF and FA were comprehensively assessed using modified EuroPrevall FA Project questionnaires as well as structured interviews, sensitization testing, and double-blind placebo-controlled food challenges (DBPCFC).ResultsThis method of epidemiologic study on ARF and FA was a pilot application in Jiangxi Province from January 2020; among the total 21,273 children and adults that completed the questionnaire, 5.8% reported ARF and 4.3% reported FA. ARF were determined to be associated with age, gender, and region. Animal-derived foods were the dominant offending foods, especially shrimp, and skin symptoms were the most commonly reported ARF. Discussion This is the first multi-center, large-scale, epidemiologic study on ARF and FA using standardized methods, including DBPCFC, in the Chinese general population. This study presents an important approach to assessing ARF and FA, provides significant insights about the prevalence of ARF and FA, and facilitates support for updating the list of allergenic food labels: which will be essential for improving ARF prevention and management in China.