Low-dose Oral Immunotherapy Research Articles

Six-year follow-up of low-dose oral immunotherapy for children with wheat-induced anaphylaxis

Six-year follow-up of low-dose oral immunotherapy for children with wheat-induced anaphylaxis

Predictive modeling for cow's milk allergy remission by low-dose oral immunotherapy in young children

BackgroundThe effectiveness of slow low-dose oral immunotherapy (SLOIT) for cow's milk (CM) allergy has been reported. Most OIT studies have discussed the target populations over 4 years old. Furthermore, no predicting modeling is reported for CM allergy remission by CM-SLOIT under 4 years of age. ObjectiveWe sought to develop a predictive model for CM allergy remission by SLOIT after 3 years in young children who started CM-SLOIT under 4 years of age. MethodsWe included young children with cow's milk allergy or cow's milk sensitization (development modeling set with 120 children and validation modeling set with 71 children). We did logistic regression analysis to develop the models. We calculated the area under the receiver operating curves (ROC-AUCs) to evaluate the predictive modeling performance. ResultsThe model (CM-sIgE before SLOIT + age at beginning SLOIT + serum TARC before starting SLOIT + CM-sIgE titer one year after OIT) showed good discrimination with the ROC-AUC of 0.83 (95% CI:0.76–0.91) on internal validation. Applying the model to the validation set gave good discrimination (ROC-AUC = 0.89, 95% CI:0.80–0.97) and a reasonable calibration (intraclass correlation coefficient = 0.88, 95% CI:0.62–0.97). ConclusionWe developed and validated predictive modeling for determining the remission rate of CM allergy at 3 years after SLOIT under 4 years of age in children with CM allergy. This predictive model is highly accurate and can support CM allergy management. (226 words)

Low-dose oral immunotherapy in immunoglobulin E-mediated food allergies.

Nowadays, the management of food allergies has increasingly moved from conventional oral immunotherapy (OIT) to low-dose OIT or low-dose OIT utilizing hypoallergenic foods. This shift is largely because the latter appears to induce oral tolerance with fewer adverse effects than the former. However, the mechanisms underpinning such differences remain unclear. To better understand these mechanisms, we conducted a comparative study scrutinizing the mechanisms of OIT, especially those of low-dose desensitization. We also summarized articles on low-dose OIT and low-dose OIT using hypoallergenic foods. We examined the efficacy, safety, and immunological parameters of low-dose OIT and those of low-dose OIT with hypoallergenic foods with the aim of shedding some light on low-dose OIT and its therapeutic application in inducing oral tolerance for individuals with food allergies.

Effectiveness and safety of low-dose oral immunotherapy protocols in paediatric milk and egg allergy.

Effectiveness and safety of low-dose oral immunotherapy protocols in paediatric milk and egg allergy.

Efficacy and safety of low- and high-dose slow oral egg immunotherapy for hen's egg allergy: Single-center non-inferiority randomized trial.

Low-dose oral immunotherapy (OIT) is a safe treatment for hen's egg allergy; however, comparison of its therapeutic effects with those of high-dose OIT has not been reported. To compare the efficacy of low- and high-dose boiled egg-white (EW) OIT for hen's egg allergy. Patients with hen's egg allergy were randomly assigned to two groups: OIT using hard-boiled EW with a maximum maintenance dose of 2 and 20 g in the low-dose (L-D) and high-dose (H-D) groups, respectively. The intake dose was ingested twice a week, increased by approximately 20% per week until reaching the target maintenance dose (2 or 20 g hard-boiled EW), and maintained thereafter according to the schedule. The threshold was confirmed via oral food challenge (OFC) after 6 months, and the difference in the proportion of subjects passing the exit OFC between groups was evaluated. Fifty-two patients (L-D, n = 23; H-D, n = 29) were enrolled. Thirty-three patients (L-D, n = 17; H-D, n = 16) completed the 6-month OIT and underwent an exit OFC. In total, three (L-D, 3/17; H-D, 3/16) patients in each group tested negative for an exit OFC with a 20-g reactive dose (p = 1.000). EW-specific IgE levels in both groups decreased significantly after OIT (L-D, p < 0.001; H-D, p = 0.002). A threshold-elevating effect was observed in the L-D group, not inferior to that in the H-D group. Low-dose OIT may be appropriate to treat hen's egg allergy for the first 6 months.

Personalized management for unmet needs with food allergy.

Patients with food allergies are at risk of experiencing accidental allergic symptoms in real life. Low thresholds may be a risk factor for accidental allergic reactions. Therefore, the evaluation of this threshold is required for the management of food allergies. We have suggested a management approach to identify the threshold dose and the consumable dose, considering patient age and the severity of food allergies. A younger age is a risk factor for accidental allergic reactions, and school-age children are likely to have a lower quality of life (QOL) than younger children. Additionally, patients with a low threshold may have difficulty in acquiring tolerance. We performed a stepwise oral food challenge (OFC) to evaluate the threshold and consumable doses for patients with food allergies. Performing a low-dose OFC for the first step would identify the dose that could be consumed at home safely and avoid the complete elimination of allergic foods. Identifying the threshold dose would be effective in managing the risk of accidental ingestion. For patients who react to low-dose OFC, low-dose oral immunotherapy (OIT) would be expected to prevent the experience of allergic reactions by accidental ingestion and consume medium doses safely. For food allergy patients and their caregivers, identifying the consumable dose would help manage the diet and eliminate their anxiety. Low-dose OFC and low-dose OIT are effective and well tolerated, which would improve their QOL. Considering the severity of food allergy and age, determining a safe threshold with no reactions would meet the unmet needs of patients with food allergy.

Long-term follow-up of fixed low-dose oral immunotherapy for children with wheat-induced anaphylaxis

Wheat allergy is one of the most common food allergies that induce anaphylaxis.1 In Japan, wheat is the third leading cause of allergic symptoms due to accidental exposure.2 Furthermore, patients with a history of wheat-induced anaphylaxis are less likely to acquire tolerance.3 Although oral immunotherapy (OIT) increases the threshold, adverse reactions commonly occur, with a risk of developing severe adverse reactions.1 In previous wheat OIT trials, patients sometimes developed severe adverse reactions and discontinued the OIT protocol.

Precision medicine for cow's milk immunotherapy in clinical practice.

Several novel immunotherapies have recently been reported for the treatment of cow's milk allergy (CMA). However, systematic methods for the selection of immunotherapy in clinical practice have not been investigated. In this review, we have provided suggestions for safe and effective immunotherapy for patients with CMA. Recent studies on cow's milk immunotherapy, using lower target doses, heated or baked cow's milk, combination treatment with adjuvants, or various routes of immunotherapy, included school-aged children with severe allergies, infants, and patients with mild CMA. These patients were administered various maintenance doses for various time periods. In the selection of immunotherapy, it would be useful to consider the patient's age and CMA severity at baseline: threshold dose, history of cow's milk anaphylaxis, and cow's milk-specific IgE levels. Considering the risks and benefits for patients with CMA, appropriate treatment should be selected based on the current evidence. Low-dose oral immunotherapy may be useful in clinical practice for school-aged children with severe CMA. Additional studies are needed to assess the indications for immunotherapy to select appropriate treatments in real-life settings.

Long-term follow-up of fixed low-dose oral immunotherapy for children with severe cow's milk allergy.

The efficacy and safety of cow's milk (CM) low-dose oral immunotherapy (LOIT) at one-year follow-up have been previously reported. We investigated the outcome of fixed long-term LOIT in children with severe CM allergy. Children with positive reactions to oral food challenge (OFC) with 3mL CM were included. The LOIT group (n=33) ingested up to 3mL CM for 1year. After a two-week CM avoidance, 3 and 25mL OFCs were performed. Children with positive reactions continued with 3mL ingestion, with OFCs repeated yearly. Regular home consumption of 25mL CM after passing the OFCs was defined as 25mL short-term unresponsiveness (25mL STU). The historical control group (n=16) with reactions to 3mL OFC eliminated daily CM ingestion. The proportion of 25mL STU in the LOIT group was 27%, 52%, and 61% after 1, 2, and 3years, respectively, and the 3-year percentage was significantly higher than that in the historical control group (13%, P=.002). In the LOIT group, only one child developed severe symptoms. Furthermore, in this group, CM- and casein-specific immunoglobulin E (sIgE) levels decreased significantly and casein-specific IgG and IgG4 levels increased significantly after 3years, whereas the historical control group presented no significant change in these parameters. Baseline sIgE levels were significantly low in children achieving 25mL STU. Continued fixed LOIT yields immunologic improvement and may be effective and safe for severe CM allergy.

Successful sublingual immunotherapy for severe egg allergy in children: a case report

BackgroundEgg allergy is one of the most common food allergies in children. To date, oral immunotherapy (OIT) has been considered as a promising treatment option for egg allergy. However, safety issues remain concerning severe adverse events requiring epinephrine injection. Hence, establishing a safer method to treat egg allergy would be beneficial. We report here two children with egg allergy who were safely treated with sublingual immunotherapy (SLIT) before transitioning to OIT.Case presentationPatient 1 was a 7-year-old girl and Patient 2 was a 5-year-old girl. Although OIT for egg had been attempted in both patients, severe anaphylactic symptoms were induced by ingesting only 0.1 g of heated whole egg. Therefore, SLIT was conducted with aqueous suspensions consisting of water and heated whole egg powder. Suspensions were administered sublingually, kept in the mouth for 2 min, and spat out immediately thereafter. SLIT was continued for 7 months for Patient 1 and 8 months for Patient 2 due to the exploratory character of the study. Afterwards, the patients successfully transferred to low-dose OIT with 1 g of heated whole egg (≒170 mg of egg protein) daily, and are continuing the therapy as of June 2020. As for adverse reactions, Patient 1 expressed oral cavity itchiness once at the beginning of SLIT. Patient 2 had no adverse reaction. The levels of antigen-specific IgE decreased in both patients after SLIT, and further decreased after switching to OIT.ConclusionsFew clinical studies have evaluated the efficacy and safety of SLIT for egg allergy. Although the treatment was conducted in only two patients, our results have shown that SLIT is a promising treatment procedure for egg allergy. Further clinical trials will be needed to additionally assess the efficacy and safety of SLIT in children with food allergy.

A randomized trial of oral immunotherapy for pediatric cow's milk-induced anaphylaxis: Heated vs unheated milk.

BackgroundSevere reactions may develop during cow's milk (CM) oral immunotherapy (OIT). We investigated the safety and efficacy of low‐dose OIT with heated milk (HM) or unheated milk (UM) in children with anaphylaxis.MethodsChildren with symptom onset after ingestion of 3‐mL HM on a double‐blind, placebo‐controlled food challenge were randomly assigned to the HM (n = 17) or UM (n = 16) group. HM group ingested milk powder heated at 125°C for 30 seconds, whereas the UM group used UM. Patients were hospitalized for 5 days; the HM or UM was gradually increased to 3 mL/day; 3‐mL/day ingestion was continued at home. One year later, the patients underwent 2‐day consecutive 3‐ and 25‐mL HM‐oral food challenges (OFCs) after 2‐week avoidance.ResultsAt baseline, milk‐ and casein‐specific immunoglobulin E (IgE) levels were 56.0 and 51.4 kUA/L in the HM group, and 55.2 and 65.6 kUA/L in the UM group, respectively. One year later, 35% and 18% in the HM group and 50% and 31% in UM group passed the 3 and 25 mL OFCs, respectively. Rates of moderate or severe symptoms and respiratory symptoms per home dose were significantly lower in the HM than in the UM group (0.7% and 1.2% vs 1.4% and 2.6%, respectively, P < .001). β‐lactoglobulin‐specific IgG4 levels significantly increased from baseline only in the UM group, whereas casein‐specific IgG4 levels significantly increased from baseline in both groups.ConclusionsHM‐OIT induced immunological changes more safely than the UM‐OIT. The possibility of lower treatment efficacy with HM‐OIT needs to be evaluated in larger studies.

Specific IgG4/IgE response after rapid desensitization to low-dose oral immunotherapy with adjunct omalizumab in multi-food allergic patients

Specific IgG4/IgE response after rapid desensitization to low-dose oral immunotherapy with adjunct omalizumab in multi-food allergic patients

Novel insights regarding anaphylaxis in children - With a focus on prevalence, diagnosis, and treatment.

Anaphylaxis is a serious allergic reaction that occurs rapidly and causes a life-threatening response involving the whole body. This reaction often leads to difficulty in breathing and can result in death. The estimated prevalence of anaphylaxis is 0.05%-2%, which is reported to be increasing in children. Although drugs and venom are the most common causes of anaphylaxis in adults, food is the most common cause of anaphylaxis in children. An interesting association between food-dependent exercise-induced anaphylaxis (FDEIA) and oral immunotherapy (OIT) has recently been reported. A provocation test to determine the diagnostic and augmenting factors of FDEIA has been reported in recent years. Remarkably, several articles showed allergic symptoms without exercise in children with FDEIA and in those with FDEIA development after OIT. Regarding OIT, full-dose OIT poses a risk of adverse reactions, including anaphylaxis. Recent trials have shown the efficacy and safety of low-dose OIT in patients with food-induced anaphylaxis. In this review, we summarized the novel insights regarding anaphylaxis in the pediatric population.

Single-Center Noninferiority Randomized Trial on the Efficacy and Safety of Low- and High-Dose Rush Oral Milk Immunotherapy for Severe Milk Allergy

Introduction: Oral immunotherapy (OIT) has been reported to be effective but associated with a risk of severe symptoms. Thus, an OIT method with decreased risk is required. Objectives: We aimed to evaluate the efficacy and safety of low- and high-dose OIT regimens in children with severe milk allergy. Methods: Overall, 33 participants (median age, 9 years; median final dose of the milk oral food challenge [OFC], 2 mL) were included. The participants were randomly assigned to groups that received either a low (20 mL; n = 19) or high (100 mL; n = 14) maintenance target dose of OIT. The dose was gradually increased to the target dose in the rush escalation phase and was then maintained daily at home. The primary endpoint was the final OFC dose at 6 months of OIT. Adverse events during OIT were evaluated. Results: The final OFC dose after OIT was significantly higher than that before OIT in both groups (low-dose, p = 0.000; high-dose, p = 0.006), but there was no significant difference in the final OFC dose between the 2 groups (p = 0.767). In the maintenance phase, the high-dose group had significantly more severe symptoms than did the low-dose group (0.5%, 11/2,355 total intake events vs. 0.1%, 4/3,230 total intake events; p = 0.018). Conclusions: An equally increased dose effect was observed for maintenance OIT doses of 20 and 100 mL in children with severe milk allergy. The risk of severe symptoms in the maintenance phase was lower in the low-dose group. A low-dose OIT regimen is recommended for severe milk allergy.

Slow low-dose oral immunotherapy: Threshold and immunological change

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

Effectiveness and Safety of Double-Blind, Placebo-Controlled, Low-Dose Oral Immunotherapy with Low Allergen Egg-Containing Cookies for Severe Hen’s Egg Allergy: A Single-Center Analysis

Introduction: The usefulness of low-dose oral immunotherapy (OIT) for the treatment of egg allergy has been unclear. Objective: To evaluate the efficacy and safety of OIT with low allergen cookies (LACs) containing a low dose of hen’s egg. Method: Thirty-three patients with severe hen’s egg allergy were randomly administered either OIT with LACs (n = 21) or placebo (n = 12). Two patients in the LACs group withdrew before completing OIT. The primary endpoint was the number of good responders (G-R), patients with negative results in the oral food challenge (OFC) with a final dose of 2 g hard-boiled egg whites after 4 months of OIT, in each group. Total OFC Aichi score for anaphylaxis/cumulative protein dose (TS/Pro) as the marker of severity of food allergy was also compared. Adverse events during OIT were evaluated using patients’ diaries. Results: The proportion of G-R in the LACs group was higher than in the placebo group (7/19 [37%] vs. 1/12 [8%], χ² test; p = 0.077). The TS/Pro after OIT in the LACs group was lower than in the placebo group (median score, 44.2 vs. 104.1, p = 0.059; Mann-Whitney U test). The threshold and TS/Pro before and after OIT significantly improved in the LACs group (p = 0.015, p = 0.027, respectively; Wilcoxon signed-rank test). There were 99 recorded incidences of symptoms of 1,938 intake events in the LACs group during OIT. Of these, 90 were mild; no severe symptoms occurred. Conclusions: OIT with LACs potentially increases the OFC threshold and decreases allergy severity and is a relatively safe treatment modality.

Low Dose Oral Immunotherapy In Children With Egg and Milk Allergies: A Retrospective Case Series Study

Low Dose Oral Immunotherapy In Children With Egg and Milk Allergies: A Retrospective Case Series Study

Efficacy, Safety, and Quality of Life in a Multicenter, Randomized, Placebo-Controlled Trial of Low-Dose Peanut Oral Immunotherapy in Children with Peanut Allergy

Only 2 small placebo-controlled trials on peanut oral immunotherapy (OIT) have been published. We examined the efficacy, safety, immunologic parameters, quality of life (QOL), and burden of treatment (BOT) of low-dose peanut OIT in a multicenter, double-blind, randomized placebo-controlled trial. A total of 62 children aged 3 to 17 years with IgE-mediated, challenge-proven peanut allergy were randomized (1:1) to receive peanut OIT with a maintenance dose of 125 to 250 mg peanut protein or placebo. The primary outcome was the proportion of children tolerating 300 mg or more peanut protein at oral food challenge (OFC) after 16 months of OIT. We measured the occurrence of adverse events (AEs), immunologic changes, and QOL before and after OIT and BOT during OIT. Twenty-three of 31 (74.2%) children of the active group tolerated at least 300 mg peanut protein at final OFC compared with 5 of 31 (16.1%) in the placebo group (P < .001). Thirteen of 31 (41.9%) children of the active versus 1 of 31 (3.2%) of the placebo group tolerated the highest dose of 4.5 g peanut protein at final OFC (P < .001). There was no significant difference between the groups in the occurrence of AE-related dropouts or in the number, severity, and treatment of objective AEs. In the peanut-OIT group, we noted a significant reduction in peanut-specific IL-4, IL-5, IL-10, and IL-2 production by PBMCs compared with the placebo group, as well as a significant increase in peanut-specific IgG4 levels and a significant improvement in QOL; 86% of children evaluated the BOT positively. Low-dose OIT is a promising, effective, and safe treatment option for peanut-allergic children, leading to improvement in QOL, a low BOT, and immunologic changes showing tolerance development.

High- and low-dose oral immunotherapy similarly suppress pro-allergic cytokines and basophil activation in young children.

Mechanisms underlying oral immunotherapy (OIT) are unclear and the effects on immune cells at varying maintenance doses are unknown. We aimed to determine the immunologic changes caused by peanut OIT in preschool aged children and determine the effect on these immune responses in groups ingesting low or high-dose peanut OIT (300mg or 3000mg, respectively) as maintenance therapy. Blood was drawn at several time-points throughout the OIT protocol and PBMCs isolated and cultured with peanut antigens. Secreted cytokines were quantified via multiplex assay, whereas Treg and peanut-responsive CD4 T cells were studied with flow cytometry. Basophil activation assays were also conducted. Th2-, Th1-, Th9- and Tr1-type cytokines decreased over the course of OIT in groups on high- and low-dose OIT. There were no significant differences detected in cytokine changes between the high- and low-dose groups. The initial increase in both the number of peanut-responsive CD4 T cells and the number of Tregs was transient and no significant differences were found between groups. Basophil activation following peanut stimulation was decreased over the course of OIT and associated with increased peanut-IgG4/IgE ratios. No differences were found between high- and low-dose groups in basophil activation at the time of desensitization or sustained unresponsiveness oral food challenges. Peanut OIT leads to decreases in pro-allergic cytokines, including IL-5, IL-13, and IL-9 and decreased basophil activation. No differences in T cell or basophil responses were found between subjects on low or high-dose maintenance OIT, which has implications for clinical dosing strategies.

Dietary Supplementation with Nondigestible Oligosaccharides Reduces Allergic Symptoms and Supports Low Dose Oral Immunotherapy in a Peanut Allergy Mouse Model.

ScopeA major downside of oral immunotherapy (OIT) for food allergy is the risk of severe side effects. Non‐digestible short‐ and long‐chain fructo‐oligosaccharides (scFOS/lcFOS) reduce allergy development in murine models. Therefore, it is hypothesized that scFOS/lcFOS can also support the efficacy of OIT in a peanut allergy model.Methods and ResultsAfter sensitization to peanut extract (PE) using cholera toxin, C3H/HeOuJ mice are fed a 1% scFOS/lcFOS or control diet and receive OIT (1.5 or 15 mg PE). Hereafter, mice are exposed to PE via different routes to determine the safety and efficacy of treatment in clinical outcomes, PE‐specific antibody production, and numbers of various immune cells. scFOS/lcFOS increases short‐chain fatty acid levels in the caecum and reduce the acute allergic skin response and drop in body temperature after PE exposure. Interestingly, 15 mg and 1.5 mg OIT with scFOS/lcFOS induce protection against anaphylaxis, whereas 1.5 mg OIT alone does not. OIT, with or without scFOS/lcFOS, induces PE‐specific immunoglobulin (Ig) IgG and IgA levels and increases CD103+ dendritic cells in the mesenteric lymph nodes.ConclusionsscFOS/lcFOS and scFOS/lcFOS combined with low dose OIT are able to protect against a peanut‐allergic anaphylactic response.