Low-dose oral immunotherapy for severe persistent cow’s milk allergy in school-aged children and adolescents

Future therapies for food allergies

IntroductionThe standard care of severe food allergy in both adults and children means avoidance of allergens. In recent years promising results of oral immunotherapy (OIT) have been reported in children. In adults, information on OIT in severe food allergy is very limited.ObjectiveWe aimed to study if OIT is possible in adults.MethodsWe report OIT results in 10 adult patients with milk OIT, nine adult patients with peanut OIT, and four adult patients with egg OIT. The allergy was confirmed with allergen specific IgE tests and oral food challenges (open in milk allergy and double‐blind in peanut and egg allergy). The OIT was performed as open.ResultsThe median dose of protein that led to discontinuation of allergen challenge because of symptoms was 7.5 mg in milk allergy, 25 mg in peanut allergy, and 15 mg in egg allergy. The median period of OIT was 515 days. Currently on OIT are 6/10 milk allergic patients, 4/9 peanut allergic patients and 3/4 egg allergic patients. The median dose of milk protein increased by 60‐fold during OIT compared to the allergen challenge dose. In peanut OIT the median dose increased by eightfold and in egg allergy the dose increased with OIT by 35‐fold. Local itching was the most common side effect of OIT (73.9% of the patients), four patients reported having used epinephrine autoinjector and three patients having needed emergency room treatment.Conclusions and Clinical RelevanceOIT can be given in adult patients with severe milk, peanut, or egg allergy only in selected cases. OIT leads into desensitization but it is not clear whether persistent tolerance can be achieved. Mild adverse events during OIT are common.

Oral immunotherapy (OIT) is a promising but still experimental method to treat children with cow's milk (CM) allergy (CMA). We evaluated changes in allergic, immunological and inflammatory parameters, which happened during the six-month OIT for CMA. We treated 28 school-aged children with CMA using OIT with a double-blind placebo-controlled design. After the controlled study finished, the placebo group was treated with the same but open-label OIT protocol. Sixteen immune variables were tested before and after the six-month OIT. Before OIT, the median serum CM-specific immunoglobulin (Ig) E was 18.0kIU/L in the intervention group and 9.4kIU/L in the placebo group (p=0.46). At six months, interleukin (IL)-6 and IL-10 were significantly higher in the intervention group. When the changes during the blinded and open OIT were analysed together for both groups, blood eosinophils and serum total IgE decreased and milk-specific IgG and IgG4, serum IL-4 and IL-6, and serum leptin and resistin increased significantly. Preliminary evidence was found that markers of allergy such as blood eosinophils and serum IgE decreased and milk-specific IgG and IgG4 increased during OIT. Adipokines, leptin and resistin, which functionally are cytokines linked to Th1-type response, increased during OIT.

BackgroundSome studies addressed the issue of omalizumab (OML) effectiveness in children starting their first oral immunotherapy (OIT) attempt but no study investigated the possible role of OML in the setting of patients with persisting milk allergy after a failed OIT attempt.MethodsSingle‐center, prospective, observational study in a selected group of patients with a persisting and severe cow milk (CM) allergy associated with moderate allergic asthma, in which a previous OIT attempt had already failed. We performed an open oral food challenge (OFC) to identify patients who tolerated less than 173 mg of cow's milk protein. At the end of the recruitment, we have found four patients with a mean age of 16.25 years (8–24) who had suspended a previous OIT attempt and still reacted to an amount of CM equal or below 173 mg. Enrolled patients, after an 8‐week course of OML along with a CM avoiding diet, underwent again an open OFC with CM to re‐evaluate their threshold. Eventually, a new OIT course was started using the same OIT protocol of the previous attempt, maintaining cotreatment with OML for the first 12 months. For each patient, we documented: the threshold of CM at OFC, level of specific immunoglobulin E (IgE) and IgG4 for milk, and quality of life (QoL).ResultsDuring OIT the four patients experienced no reactions or extremely mild ones (oral itching, transient mild abdominal pain). All increased their threshold of CM in OML if compared with the baseline and maintained it long after that biologic therapy had discontinued. Specific milk proteins IgG4 levels significantly increased in all.ConclusionIn this series, OML was effective in patients with severe CM allergy who had previously failed OIT, allowing milk intake without adverse reactions and improving the QoL.

Oral immunotherapy (OIT) is an established and successful treatment regimen for food allergy.1 However, the occurrence of adverse events (AEs), such as anaphylaxis, due to overdose of allergenic foods is a major issue during OIT.1 In a prevention trial for hen egg allergy, we confirmed that a 'tiny' dose of hen egg can induce immunotolerance in young children.2 We designed several OIT protocols for children with food allergy based on shared decision-making. We classified the children into four OIT groups according to the four dosing strategies: super ultra-low dose (group A, starting at 1/10,000 of the initial threshold dose), ultra-low dose (group B, starting at 1/100 of the initial threshold dose), low dose (group C, starting at 1/10 of the initial threshold dose) and conventional slow dose (group D, starting just below or full of the initial threshold dose). For groups A, B and C, the maintenance dose was 1/10 of the initial threshold dose; for group D, the maintenance dose was more than the initial threshold dose. Children who continued avoidance without OIT were the avoidance group (group E). Additional information about study methods and findings are available in the following the repository (https://doi.org/10.5281/zenodo.8377790). We included 217 children. The median age was 6 years, and 69.6% children had atopic dermatitis. Figure 1 shows the outcomes of OIT. The proportions of children who increased the cumulative tolerated dose were 69.7%, 88.2%, 70.6% and 56.8% in groups A, B, C and D, respectively, which was higher than the proportion in group E (26.3%; p < .05). The rate was higher in group B (88.2%) than in group D (56.8%; p < .001). The incidence rates of AEs related to OIT in groups A, B, C and D were 24.2%, 13.7%, 29.4% and 70.5%, respectively (p < .01 or p < .001). There was a significant difference in food-specific IgE level between group B (93.8%) and group E (61.1%; p < .05). In groups A, B and C (low-dose OITs), almost all AEs had minimal symptoms, such as itchy mouth/throat (27.6%, 13.7% and 23.8%), and anaphylaxis was absent. However, children in conventional OIT group D experienced many allergic symptoms (70.5%), including anaphylaxis. Our study highlights that ultra-low dose OIT was effective and safe methods that could induce immunotolerance and increase the tolerated dose in the OFC without serious AEs compared with conventional OIT. The strength of our study was that we used various OIT strategies as active comparators. Our efficacy results were similar to those for conventional egg OIT reported in the Cochrane review.1 Tiny doses of allergens may be sufficient to induce immunotolerance in childhood egg and milk allergy. Regarding OIT safety, a Cochrane review demonstrated 75% AE rate in egg OIT,1 but in our study, only 13.7% receiving ultra-low dose OIT had AEs. Children with severe food allergy can be treated with ultra-low dose OIT because the starting dose is significantly lower than the threshold. Most physicians believe that large quantities of allergenic foods are required for immune tolerance. The understanding of immune tolerance in OIT, at least in milk and egg OIT in children, needs to be revised. According to our OFC data, even children highly IgE-sensitized to cow milk had very low-dose thresholds, termed the eliciting dose or ED.3 For example, the threshold of ED10 for cow milk with IgE 100 UA/mL was 0.07 mL of milk. Absolute avoidance of hen egg did not provide better future tolerance for hen egg allergy.4 Our physicians encourage children and their families to conduct OFC despite ultra-low doses. Food-allergic children could induce immunotolerance despite ultra-low doses (not up-dosing over eliciting dose). Regarding AEs, anaphylaxis during OFC could lead to acute stress symptoms because of the negative experience of a traumatic event.5 The purpose of OFC is not only to evaluate the eliciting dose but also to secure a safe dose without any symptoms and without the capacity to induce allergic reactions. The final goal for children and families is that the children can enjoy eating, feel safely happy and increase the threshold with ultra-low-dose allergenic food without stress. Importantly, in addition to OIT, children must have complete eczema treatment because eczema management influences food allergy tolerance.6, 7 Our study has several limitations. First, this study had a retrospective, design, included a small and heterogeneous population, and lacked standardization of treatment groups, which are the features of a clinical trial. Therefore, this study's quality was lower than that of a prospective randomized controlled trial. Second, the OIT method used for each patient was determined after consulting physicians, and we cannot currently recommend a uniform OIT approach for all children with food allergy.8 Nevertheless, our study was conducted in the real-world clinical setting. Future clinical studies are warranted to elucidate the role of allergen quantity in the immune mechanism underlying the anti-allergic response observed in humans to standardize the OIT method. We will evaluate the results of a randomized controlled trial (STITCH study, UMIN000043354) to further investigate patient-oriented allergies in the near future.9 Third, the pre-OIT characteristics were imbalanced, and the baseline threshold of reactivity was higher for the 'conventional' arm. However, we performed propensity score weighting analysis to adjust for this imbalance. In summary, ultra-low dose OIT was found to be more effective and safer than conventional OITs among children who were allergic to hen egg and cow milk. This study was funded by the National Center for Child Health and Development. YM, KY and YO contributed to the study design. YM and LY analysed the data and prepared the study results. All co-authors contributed to the interpretation of the findings. YM and KY led the drafting of the manuscript. All co-authors contributed to revising the manuscript and approved the final version. We would like to thank the children and their families for participating in our study. This study was funded and supported by the grant of National Center for Child Health and Development, Japan. The findings and conclusions of this article are solely the responsibility of the authors. None. This study was approved by the Ethics Review Committee of the National Center for Child Health and Development (number: 2027). We published the research plan and guaranteed an opt-out opportunity on the National Center for Child Health and Development homepage for using medical chart data. We checked a statement confirming receipt written informed consent from patients. Currently, individual participant data sharing is unavailable because the IRB permission is not yet obtained under the Ethical Guidelines for Medical and Biological Research Involving Human Subjects and Personal Information Protection Commission, Japan. The individual participant data sharing will be available after the IRB permission is granted. Any data queries can be emailed to the Primary Investigator Kiwako Yamamoto-Hanada at [email protected].

BACKGROUND: Cow's milk allergy is the most common food allergy in young children. In areas outside the United States, milk from other mammals has been studied as a possible and desirable alternative for children with cow's milk allergy. OBJECTIVES: We chose to further investigate water buffalo's milk as an alternative for cow's milk allergic children in the United States. METHODS: Children with cow's milk allergy were skin prick tested with water buffalo's milk. Additionally, subjects were followed clinically for 1 year after the test to determine how many of the subjects had persistent cow's milk allergy. RESULTS: In total, 30 children, age 8 months to 8 years, were skin prick tested to water buffalo's milk with 73% (22/30) having a positive test. All children with a negative water buffalo's milk skin test also had a negative cow's milk skin test. In follow-up, most (7 of 8) of the children with a negative skin prick test (SPT) to water buffalo's milk were found to have outgrown their cow's milk allergy. In comparison, all of the subjects with a positive skin test to water buffalo's milk had persistent cow's milk allergy. After adjusting for this, we determined that 96% (22/23) of the children with persistent cow's milk allergy were positive on skin testing to water buffalo's milk. CONCLUSIONS: In this population, the vast majority of children with persistent cow's milk allergy were positive on skin prick testing to water buffalo's milk. These results indicate that water buffalo's milk is unlikely to be a successful alternative for children with cow's milk allergy.

Background. Oral immunotherapy (OIT) is a promising strategy for severe and persistent cow's milk (CM) allergy. However, clinical experience concerning long-term follow-up is scarce. The objective is to assess long-term efficacy and safety of maintenance phase of OIT in real-life. Methods. Prospective study of children with severe IgE-mediated CM allergy that underwent CM-OIT, and were followed-up by the authors, up to 15 years. Complete desensitisation was defined when maintenance dose of 200 mL daily was achieved. Characterization (clinical and laboratory) was performed before and after OIT during follow-up. Results. Thirty-three patients enrolled: 58% male, 70% asthmatics and 67% with previous history of CM-anaphylaxis. Mean age at onset of CM-OIT was 7±2.8 years. Complete desensitisation was ensured in 94% (free diet with dairy 200mL of CM or equivalent). During maintenance phase 79% developed allergic reactions, with anaphylaxis in 33%, including exercise-induced anaphylaxis in 15% and with cheese intake in 15%. We stress that eosinophilic esophagitis appeared in 12%. Specific IgE levels and skin prick tests (SPT) to CM and casein have significantly decreased, and in most patients (61%) SPT became negative. When available, specific IgG4 levels have significantly increased. Conclusions. This real-life study supports long-term efficacy and safety of CM-OIT. CM-OIT had a high success rate, allowing diet without restrictions with persistence of the effect up to 15 years. However, one-third of patients experienced anaphylaxis during maintenance phase. CM-OIT should always be performed by allergy experts and only motivated families should be enrolled, since long-term follow-up is required, and daily intake of CM is needed to ensure desensitization.

The safety and efficacy of long-term milk oral immunotherapy (OIT) in Finnish children with persistent cow's milk allergy (CMA) were evaluated in an open-label, non-randomized study. During the 11-year study, 296 children aged 5years or older with immunoglobulin E (IgE)-mediated CMA started milk OIT. Follow-up data were collected at three time points: the post-buildup phase, 1year thereafter, and at the cross-sectional long-term follow-up between January 2016 and December 2017. Patients were divided according to baseline milk-specific IgE (sIgE) level and by the amount of milk consumption at the long-term follow-up. The high-dose group consumed ≥2dL of milk daily, while the failure group consumed <2dL of milk or were on a milk-avoidance diet. Out of the initial study group, 244/296 (83%) patients participated in the long-term follow-up. Among these patients, 136/244 (56%) consumed ≥2dL of milk daily. The median follow-up time was 6.5years. Of the recorded markers and clinical factors, the baseline milk sIgE level was most associated with maintaining milk OIT (P<0.001). Respiratory symptoms in the post-buildup phase increased the risk of treatment failure (OR 3.5, 95% CI: 1.5-8.1, P=0.003) and anaphylaxis (OR 14.3, 95% CI: 1.8-114, P=0.01). More than half of the patients were able to maintain the targeted milk dose in their daily diet. Baseline milk sIgE level and reactivity during the early treatment stage strongly predicted the long-term outcome and safety of milk OIT.

To study the efficacy of oral immunotherapy (OIT) in schoolchildren with cow's milk (CM) allergy (CMA). Twenty-eight children aged 6-14 years with CMA documented by oral challenge were enrolled into a randomized, double-blind, placebo-controlled OIT study. In the active treatment, CM protein amount was increased during 23 weeks from 0.06 mg to a maximum of 6400 mg (200 mL of milk). Twenty-four (86%) patients completed the protocol: 16/18 in active and 8/10 in placebo groups. All children in the active and 2/3 in the placebo group suffered from symptoms considered by the parents as induced by milk. The children were contacted by phone 12 months later, and 13 (81%) used daily CM or milk products corresponding 6400 mg of CM protein. After double-blind OIT, all 10 children in the placebo group completed successfully an open-label OIT by an identical protocol, and all used daily CM or milk products 6 months later. Three to 3.5 years later, one child more had discontinued daily milk use. Thus, the long-term success rate was 22/28 (79%). This placebo-controlled, double-blind study confirmed that OIT was effective in desensitizing schoolchildren with CMA. With occasional exceptions, the reached desensitization sustained for more than 3 years.

Skripak J, Nash S, Rowley H, et al. J Allergy Clin Immunol. 2008;122(6):1154–1160PURPOSE OF THE STUDY. To determine the safety and efficacy of milk oral immunotherapy (OIT) in desensitizing children with cow's milk allergy.STUDY POPULATION. Twenty children, 6 and 21 years of age, with an immunoglobulin E (IgE)-mediated cow's milk allergy.METHODS. This study was a randomized, placebo-controlled trial with subjects randomly assigned to milk or placebo OIT. OIT was administered in 3 phases: (1) initial build-up day; (2) daily home dosing with 8 weekly, in-office, dose increases; and (3) continued home daily maintenance dosing (500 mg) for 13 weeks. Before and after OIT, subjects had double-blind, placebo-controlled, food challenges, end point-titration skin-prick tests, and milk-specific serological studies performed. Symptom diaries and adverse reactions were recorded.RESULTS. Subjects were randomly assigned to milk (N = 12) or placebo (N = 7) OIT. Food challenges after OIT showed a significant difference in the cumulative dose that induced a reaction between the 2 groups. The active treatment group had a median milk threshold of 40 mg before OIT and 5140 mg after OIT, whereas the placebo group showed no change from their median pre-OIT level of 40 mg (P = .002). There were no significant differences between groups in the change from baseline to end of OIT for end point-titration skin-prick test results and levels of milk-specific IgE; however, milk-specific IgG4 showed a significant increase in the active group (P = .002). Six of 7 subjects on placebo underwent open-label active treatment after the study, and all demonstrated a significant change in the milk dose threshold after OIT (median dose: 8140 mg). Adverse events (typically mild-to-moderate severity) were seen in 35% of subjects who received active treatment and in 1% of those who received placebo treatments, with 90% of adverse reactions being transient and requiring no treatment. Four epinephrine doses were used in 4 different subjects who received active treatment.CONCLUSIONS. Milk OIT is effective in the treatment of cow's milk allergy, with anticipated and acceptable adverse effects noted.REVIEWERS COMMENTS. Oral and sublingual administration of allergen-specific immunotherapy has become increasingly important in the field of food allergies. These therapies have the potential not only to protect patients from serious reactions (clinical desensitization) but also possibly to allow for development of tolerance to the food allergen. This study demonstrated an increased threshold for reactions to milk in children treated with OIT, indicating clinical desensitization to the allergen. Of the reactions noted, most were not serious and did not require any treatment, which illustrates the relative safety of OIT. However, dosing protocols and length of therapy need to be further investigated (including long-term tolerance assessments), to provide improved efficacy with the lowest adverse effects.

The effect of infant cow's milk protein consumption on subsequent IgE-mediated cow's milk allergic outcomes in a high-risk pediatric population.

Food allergy: Are we getting closer to a cure?

Goat's milk (GM) allergy associated with tolerance to cow's milk (CM) has been reported in patients without history of CM allergy and in CM-allergic children successfully treated with oral immunotherapy. The IgE antibodies from GM-allergic/CM-tolerant patients recognize caprine β-casein (βcap) without cross-reacting with bovine β-casein (βbov) despite a sequence identity of 91%. In this study, we investigated the non-cross-reactive IgE-binding epitopes of βcap. Recombinant βcap was genetically modified by substituting caprine domains with the bovine counterparts and by performing site-directed mutagenesis. We then evaluated the recognition of modified βcap by IgE antibodies from 11 GM-allergic/CM-tolerant patients and 11 CM-allergic patients or by monoclonal antibodies (mAb) raised against caprine caseins. The allergenic potency of modified βcap was finally assessed by degranulation tests of humanized rat basophil leukaemia (RBL)-SX38 cells. Non-cross-reactive epitopes of βcap were found in domains 44-88 and 130-178. The substitutions A55T/T63P/L75P and P148H/S152P induced the greatest decrease in IgE reactivity of GM-allergic/CM-tolerant patients towards βcap. The pivotal role of threonine 63 was particularly revealed as its substitution also impaired the recognition of βcap by specific mAb, which could discriminate between βcap and βbov. The modified βcap containing the five substitutions was then unable to trigger the degranulation of RBL-SX38 cells passively sensitized with IgE antibodies from GM-allergic/CM-tolerant patients. Although IgE-binding epitopes are spread all over βcap, a non-cross-linking version of βcap was generated with only five amino acid substitutions and could thus provide new insight for the design of hypoallergenic variants.

Introduction and gradual incremental escalation of a low dose of baked milk may accelerate the resolution of severe cow's milk (CM) allergy for some children. The purpose of our study was to evaluate the efficacy and safety of baked milk oral immunotherapy (OIT) in children with CM allergy after a low-dose baked milk oral food challenge (OFC). In a retrospective analysis of OFC performed between 2013 and 2018 at the Children's Hospital of Toulouse (France), we identified 64 children with CM allergy and high milk and casein-specific IgE levels, who underwent a total of 171 milk OFC. Mean age at 1st OFC was 4.8years. Mean CM-specific IgE was 47.9 kUA/L, and mean casein-specific IgE was 42.3 kUA/L. Most children were treated with baked milk OIT. Our study shows that 67.2% of the children did not react to 1st low-dose baked milk OFC (168.6mg of CM protein). Eighteen percent of children stopped the OIT at home. Finally, desensitization to fresh milk was achieved in 27 children (42.2% of children allergic to CM). Children with lower CM-specific IgE levels have a significantly higher probability of becoming desensitized to unbaked CM. Most children with CM allergy and high milk and casein-specific IgE levels tolerate the introduction of baked milk. However, the occurrence of anaphylactic reactions during OIT remains possible.

The progressive increase in incidence in cow’s milk proteins allergy (CMPA) in the past decades required primary prevention strategies for children at high-risk. Evidence of the role of gut microbiota in promoting the maturation of the immune system during early life encouraged supplementing the diet with probiotics in order to facilitate tolerance and delay or prevent sensitization. The efficacy of this strategy has not been consistently proven [1]. Breastfeeding is the most common therapeutic approach to CMPA in infants, although recent data showed that human milk has no effect on the development of allergy [2]. Use of special formulas is recommended in infants who are allergic or at high risk for CMPA. Extensively hydrolysed formulas (eHF) are the first therapeutic option. Amino acid-based formulas (AAFs) are recommended in infants who fail to respond to eHF, or have poor growth and IgE-mediated gastrointestinal disorders, or severe atopic eczema [3]. Hydrolysed formulas that do not originate from CMP are tolerated in 90% of children with CMPA. Use of soy milk is contraindicated in the first six months of life because of allergenic proteins and the presence of phytates and phytoestrogens [4]. The primary therapy for CMPA remains a strict avoidance of CMP, which promotes natural acquisition of tolerance in 80% of cases within the first 3 years of life. When the reintroduction of food causes severe clinical manifestations, diet restriction cannot be considered a solution, but instead exposes the infant to the constant danger of accidental exposure. Oral Immunotherapy (OIT) in food allergy requires the oral administration of increasing amounts of food up to a target dose, with the aim of reaching tolerance acquisition, which is considered complete when it is fully dose-independent[5]. OIT guidelines are not yet available. In severe, IgE-mediated clinical reactions to CMP, the combined therapy with Omalizumab, before and during “rush” OIT, reduced the number of severe adverse reactions and the duration of therapy while enhancing the possibilities of tolerance acquisition [6]. The use of Interferon-gamma (IFN-g) administered subcutaneously, as adjuvant in oral immunotheraphy (OIT + IFN- g), is a recent treatment. Unlike Omalizumab, the efficacy of IFN-g has been demonstrated in non-IgE-mediated food allergy. IFN-g seems to play a key role in the induction of tolerance but not in its maintenance. In studies on IgE-mediated CMPA, duration of treatment in patients with combined therapy (OIT + IFN-g) is 2-3 months compared to 6-12 months for patients treated exclusively with OIT [7].