Sustained Unresponsiveness Research Articles

M241 NOT YOUR ORDINARY CASE OF ACHIEVING SUSTAINED UNRESPONSIVENESS IN AN ADULT WHO COMPLETED SHRIMP OIT

Oral immunotherapy is an emerging therapy, but the focus is primarily on children. There are also questions as to when a patient may have achieved sustained unresponsiveness. I present a case of an adult who completed OIT to shrimp and then successfully achieved sustained unresponsiveness and this process was guided by basophil activation testing (BAT) through unusual circumstances.

Oral Immunotherapy for Food-Allergic Children: A Pro-Con Debate.

The prevalence of food allergy has increased in recent years, especially in children. Allergen avoidance, and drugs in case of an allergic reaction, remains the standard of care in food allergy. Nevertheless, increasing attention has been given to the possibility to treat food allergy, through immunotherapy, particularly oral immunotherapy (OIT). Several OIT protocols and clinical trials have been published. Most of them focus on children allergic to milk, egg, or peanut, although recent studies developed protocols for other foods, such as wheat and different nuts. OIT efficacy in randomized controlled trials is usually evaluated as the possibility for patients to achieve desensitization through the consumption of an increasing amount of a food allergen, while the issue of a possible long-term sustained unresponsiveness has not been completely addressed. Here, we evaluated current pediatric OIT knowledge, focusing on the results of clinical trials and current guidelines. Specifically, we wanted to highlight what is known in terms of OIT efficacy and effectiveness, safety, and impact on quality of life. For each aspect, we reported the pros and the cons, inferable from published literature. In conclusion, even though many protocols, reviews and meta-analysis have been published on this topic, pediatric OIT remains a controversial therapy and no definitive generalized conclusion may be drawn so far. It should be an option provided by specialized teams, when both patients and their families are prone to adhere to the proposed protocol. Efficacy, long-term effectiveness, possible role of adjuvant therapies, risk of severe reactions including anaphylaxis or eosinophilic esophagitis, and impact on the quality of life of both children and caregivers are all aspects that should be discussed before starting OIT. Future studies are needed to provide firm clinical and scientific evidence, which should also consider patient reported outcomes.

Combining Anti-IgE Monoclonal Antibodies and Oral Immunotherapy for the Treatment of Food Allergy.

Immunoglobulin E (IgE)-mediated food allergy is a real public health problem worldwide. The prevalence of food allergy is particularly high in children. Patients with food allergy experience high morbidity with a change in quality of life due to the risk of severe anaphylaxis. Current treatment options are poor. Allergen avoidance is widely recommended but exposes patients to accidental ingestion. Oral immunotherapy is also used in patients with food allergies to the most common allergens. Oral immunotherapy consists of a daily administration of small, gradually increasing amounts of allergens to induce desensitisation. This procedure aims at inducing immune tolerance to the ingested food allergens. However, some patients experience adverse reactions and discontinue oral immunotherapy.Given that IgE plays a crucial role in food allergy and anti-IgE are effective in allergic asthma, the use of anti-IgE therapeutic monoclonal antibodies (mAbs) such as omalizumab has been assessed in food allergy patients. The use of omalizumab as a monotherapy in food allergy has not been extensively studied but looks promising. There is more published evidence regarding the effect of omalizumab and oral immunotherapy in food allergy. Given the promising results of oral immunotherapy regarding sustained tolerance in clinical trials and the potential capacity of omalizumab to reduce symptoms in case of accidental exposure, a strategy combining oral immunotherapy with omalizumab pre-treatment has been suggested as a safer option in patients with severe food allergy compared to isolated therapy. Omalizumab seems useful in ensuring safer administration of oral immunotherapy with the oral immunotherapy maintenance dose being reached more rapidly. Quality-of-life improvement is greater with oral immunotherapy + omalizumab compared to oral immunotherapy alone. Moreover, sustained unresponsiveness is achieved more frequently with omalizumab. Considering that precision medicine and personalised therapy are major goals for allergic diseases, predictive biomarkers are crucial in order to identify food allergy patients more likely to benefit from anti-IgE therapies.

Food immunotherapy practice: Nation differences across Europe, the FIND project.

Food allergen immunotherapy (FA-AIT) practice is known to vary globally. This project aims to identify and characterize European centres performing FA-AIT. An EAACI task force conducted an online survey to gather relevant information regarding FA-AIT practice and setting-specific resources after reviewing the published literature and congress abstracts throughout Europe. We identified 102 FA-AIT centres in 18 countries; only Spain (n = 39) and France (n = 16) had ≥10 such centres. Overall, most facilities were hospital-based (77.5%), publicly funded (80.4%) and delivered FA-AIT as routine clinical care (80.4%). On average, departments had 3 allergists/paediatric allergists and 2 nurses. Surveyed centres had provided FA-AIT for a median of 9years [1-24] to a median of 105 [5-2415] patients. The estimated total number of treated patients was 24875, of whom 41.3% received AIT for milk, 34.2% egg, 12.8% peanut and 11.7% other foods. Anaphylaxis to AIT doses requiring over 4-6h of observation was reported by 70.6% of centres, ICU admissions by 10.8% and eosinophilic esophagitis by 45.1%. Quality of life and sustained unresponsiveness were evaluated in 20.6% and 54.9% of centres, respectively. The main contraindications for food AIT were severe asthma (57%-63%), eosinophilic esophagitis (56%-48%) and age below 5years (47%-41%). In Europe, FA-AIT is provided mostly in clinical practice. Significant variation is seen in the number of centres per country, facility characteristics and inclusion/exclusion criteria, and in certain aspects of protocols. Potential inequality in access to AIT has been identified as well as the need for education and guidance for treatment standardization.

Sustained Unresponsiveness Induced by Oral Immunotherapy Is Not a Completely Symptom-Free Condition: A Prospective Case Series.

Sustained Unresponsiveness Induced by Oral Immunotherapy Is Not a Completely Symptom-Free Condition: A Prospective Case Series.

Antihistamine premedication improves safety and efficacy of allergen immunotherapy

BackgroundAllergen immunotherapy (AIT)–associated adverse events are a major concern for safety and efficacy of AIT. Presently, there is no consensus to whether antihistamine premedication could improve such conditions. ObjectiveTo identify the superiority of antihistamine pretreatment in AIT. MethodsA comprehensive literature search for randomized controlled trials reporting the effects of antihistamine premedication on safety and efficacy of AIT was performed in MEDLINE, Embase, and Cochrane Library databases. Safety was evaluated according to the number of patients reporting systemic adverse reactions (SARs, the primary outcome) and efficacy according to the number of patients achieving target maintenance dose (TMD) and sustained unresponsiveness to allergen. ResultsA total of 11 randomized controlled trials (including 609 patients) satisfied the inclusion criteria for the meta-analysis. All premedication protocols were temporary. Pooled analysis revealed that compared with control patients, significantly fewer antihistamine-pretreated patients reported total and moderate-to-severe SARs (odds ratio [OR], 0.36; 95% confidence interval [CI], 0.23-0.56; P < .05 and OR, 0.20; 95% CI, 0.06-0.74; P < .05, respectively) and total and moderate-to-severe SAR episodes (OR, 0.42; 95% CI, 0.34-0.53; P < .05 and OR, 0.09; 95% CI, 0.01-0.50; P < .05, respectively). Similarly, antihistamine pretreatment significantly increased the number of patients achieving TMD (OR, 2.94; 95% CI, 1.72-5.03; P < .05), but not sustained unresponsiveness (OR, 1.65; 95% CI, 0.77-3.54; P = 0.2), compared with the control group. Subgroup analysis according to different allergens and dose-escalating approaches also displayed superiority of antihistamine pretreatment than control. ConclusionAntihistamine premedication can markedly improve safety and efficacy of AIT by reducing frequency and severity of SAR and increasing TMD.

Novel application of a discrete time-to-event model for randomized oral immunotherapy clinical trials with repeat food challenges.

The evaluation of double-blind, placebo-controlled food challenges (DBPCFC) generally focuses on a participant passing a challenge at a predetermined dose, and does not consider the dose of reaction for those who fail or are censored due to study discontinuation. Further, a number of food allergy trials have incorporated multiple DBPCFCs throughout the duration of the study in order to evaluate changes in reaction over time including sustained unresponsiveness from treatment. Outcomes arising from these trials are commonly modeled using Chi-squared or Fisher's exact tests at each time point. We propose applying time-to-event methodology to food allergy trials in order to exploit the inherent granularity of challenge outcomes that additionally accommodates repeated DBPCFCs. Specifically, we consider dose-to-failure for each study challenge and extend the cumulative tolerated dose across challenges to result in a dose-time axis. A discrete time-to-event framework is applied to the dose-time outcome to assess the efficacy of treatment across the entire study period. We illustrate ideas with data from the Peanut Oral Immunotherapy Study: Safety, Efficacy and Discovery (POISED) trial, conducted at Stanford University, which evaluated the efficacy of oral immunotherapy on desensitization and sustained unresponsiveness in peanut allergic children and adults. We demonstrate the advantages of time-to-event approaches for assessing the efficacy of treatment over time and incorporating information for those who failed or were lost to follow up. Further, we introduce a dose-time outcome that is interpretable to clinicians and allows for examination of such outcomes over time.

Oral immunotherapy in food allergies: A practical update for pediatricians

Food oral immunotherapy (OIT) is a promising treatment for persistent and severe food allergies (FAs) in children, but also for accelerating tolerance to cow's milk and cooked egg in young children. In the near future, pediatricians will increasingly encounter severely allergic children undergoing FA-OIT. FA-OIT consists in daily ingestion of increasing doses of the allergen during the up-dosing phase, and ingestion of a constant dose during the maintenance phase. The global aim is to increase the reactive threshold of allergic patients, and finally enable them to ingest a target quantity of allergen without any reaction throughout the treatment (desensitization). Many studies showed the efficacy of FA-OIT in desensitization, and some of them in sustained unresponsiveness. This corresponds to tolerance after FA-OIT discontinuation, especially for cow's milk and hen's egg allergy. However, there is an ongoing debate about the safety of the treatment. Side effects are frequent, notably aversion to the allergen and oral syndromes as well as systemic allergic symptoms. These reactions occur mainly during the up-dosing phase and become less frequent with time, but they are common causes of FA-OIT discontinuation. Patients and their families must be trained to manage these reactions at home. Long-term side effects can also occur, such as eosinophilic esophagitis. Pediatricians play an important role in maintaining patient motivation; they also provide knowledge on possible allergic reactions and the reactogenic cofactors (mainly fever and viral infection, anti-inflammatory intake, physical activity), and refer the patient to the relevant specialists in the case of long-term care. Other routes of administration for food immunotherapy (epicutaneous and sublingual) and different adjuvant treatments (probiotics, anti-IgE molecule) are currently under study. This will allow us to improve the efficacy of immunotherapy and reduce the risk of any side effects, in order to provide a more favorable risk–benefit ratio.

Wheat oral immunotherapy.

The prevalence of food allergy is increasing on a global scale, and therefore increased attention is being paid to specific food allergy epidemiology and management. There has been a large amount of progress made in the last decade on human trials of wheat oral immunotherapy (WOIT). To date, there has been one multicenter, double-blind, randomized controlled trial of WOIT, one randomized, noncontrolled trial of WOIT, and several smaller, nonrandomized clinical trials of WOIT. WOIT trials are generally limited by smaller sample sizes, affecting the demographic skew of evaluated patients. In addition, there is minimal standardization of efficacy and safety outcomes between trial protocols, making head-to-head comparison challenging. However, some common themes emerge. The majority of WOIT regimens result in successful desensitization, and success is more likely with higher maintenance dosing for longer periods of time. Limited studies have looked at sustained unresponsiveness in WOIT. WOIT can induce allergic reactions, including anaphylaxis, but more severe reactions often have an associated augmenting factor, such as exercise. Lower maintenance doses likely are associated with less severe reactions, and food modification and/or adjunct therapeutics may also decrease the risk of reactions. WOIT trials are ongoing and will optimize updosing protocols and maintenance doses to improve efficacy and safety.

Emerging developments in the forefront of peanut oral immunotherapy.

Despite the COVID-19 pandemic, progress continued in the field of peanut oral immunotherapy over the past 12 to 18 months. Of importance, the first oral immunotherapy product for the treatment of peanut allergy was approved by the US Food and Drug Administration in January 2020. Suggested modifications to the practice of oral immunotherapy, some of which may have lasting impacts, were circulated as a result of the pandemic. New advances in pathophysiology, sustained unresponsiveness, quality of life, safety, and cost effectiveness were also published. During 2020, COVID-19 influenced the daily practice of allergy and immunology, with peanut oral immunotherapy being no exception. However, clinicians now have a FDA-approved treatment option for peanut allergy in children, a welcome development for a difficult disease. Future research is needed to clarify several knowledge deficits surrounding the best use of peanut OIT.

Transcriptomic and Gene Set Enrichment Analysis of Peanut stimulated CD4+ T cells during Peanut Oral Immunotherapy

Early studies suggest that oral immunotherapy (OIT) decreases Th2 cytokine production, a possible mechanism for desensitization. However, data remains limited on the differences between individuals who develop transient desensitization (TD) versus sustained unresponsiveness (SU), a longer-lasting protection after OIT.

Mechanisms of oral immunotherapy.

Food allergy presents a significant global health concern with up to 10% of the population affected in developed nations and a steadily increasing prevalence. In many cases, particularly with peanut, tree nut and shellfish, food allergy is a lifelong and potentially life-threatening diagnosis. While no 'cure' for IgE-mediated food allergy exists, oral immunotherapy (OIT) is a promising treatment modality with the peanut OIT drug Palforzia (Aimmune Therapeutics) the only treatment for food allergy that is currently approved by the United States Food and Drug Administration. OIT primarily induces a state of desensitization with only a minority of subjects achieving sustained unresponsiveness, a state of limited clinical remission that appears to be immunologically distinct from natural tolerance. Early humoural changes during OIT include an initial increase in allergen-specific IgE, which eventually decreases to below baseline levels as OIT progresses, and a gradual increase in allergen-specific IgA and IgG4 that continues throughout the course of OIT. Basophil hyporesponsiveness and decreased skin prick test wheal size are observed within the first year of OIT, and persistence after completion of therapy has been associated with sustained unresponsiveness. In the T-cell compartment, there is an initial expansion followed by a decline in the number and activity of T helper 2 (TH 2) cells, the latter of which may be dependent on an expansion of IL-10-producing cells, including regulatory T-cells. Our understanding of the immunomodulatory effects of OIT continues to evolve, with new technologies such as single-cell transcriptional profiling and antibody epitope analysis allowing for more detailed study of T-cell and B-cell responses to OIT. In this review, we present evidence to illustrate what is currently known about the immunologic changes induced by OIT, explore potential mechanisms and emphasize knowledge gaps where future research is needed.

Home-Based Up-Dosing in Build-Up Phase of Oral Immunotherapy of Egg Allergy Is Safe and Feasible in Real-World Practice.

Oral immunotherapy (OIT) has emerged to build sustained unresponsiveness or tolerance in patients with egg allergy. However, it is important to increase compliance and ensure safety because OIT requires an extended period of time and has a risk of side effects like anaphylaxis. We aimed to show the feasibility and safety of OIT during the build-up phase using a home-based, up-dosing method in children with egg allergy. Sixteen patients aged 4 to 12 years with egg allergy were enrolled. Patients increased the dose of boiled egg white (EW) by 5% per day at home and 25% per month at the hospital, with a target dose of 40 g of boiled EW (4.0 g of EW proteins). A historical control group (n = 16) was matched for age, sex, and clinical characteristics for comparisons with the OIT group. Oral food challenge (OFC) tests were performed after completing the build-up phase. In the OIT group, 93.8% (15/16) of patients achieved desensitization, with only 1 patient discontinuing OIT before the maintenance phase due to repeated allergic reactions. Mild allergic reactions and anaphylaxis occurred in 12 (75.0%) and 2 patients (12.5%), respectively. However, there were no significant adverse reactions such as serious anxiety or life-threatening events that required discontinuation of treatment. On the contrary, only 1 patient (6.3%) in the control group passed an OFC of 40 g of boiled EW during the same period (P < 0.001). Our results suggest that home-based up-dosing protocols using boiled eggs may be safe and feasible for the build-up phase of OIT in children with egg allergy.

Oral Immunotherapy and Basophil and Mast Cell Reactivity in Food Allergy.

Basophil activation tests (BATs) can closely monitor, in vitro, a patient’s propensity to develop type I hypersensitivity reactions. Because of their high specificity and sensitivity, BATs have become promising diagnostic tools, especially in cases with equivocal clinical histories, skin prick test results, and/or levels of specific IgE to allergen extracts. BATs also are useful as tools for monitoring the effects of treatment, since oral immunotherapy (OIT) studies report a diminution in patients’ basophil responsiveness over the course of OIT. This review will discuss the BAT findings obtained before, during, and after OIT for food allergy. We will mainly focus on the association of basophil responsiveness, and alterations in basophil surface markers, with clinical outcomes and other clinical features, such as blood levels of specific IgG and IgE antibodies. The detailed analysis of these correlations will ultimately facilitate the use of BATs, along with other blood biomarkers, to differentiate short-term desensitization versus sustained unresponsiveness and to improve treatment protocols. Given the critical anatomic location of mast cells adjacent to the many IgE+ plasma cells found in the gastrointestinal tissues of allergic individuals, we will also discuss the role of gastrointestinal mast cells in manifestations of food allergies.

A 5-Year Summary of Real-Life Dietary Egg Consumption After Completion of a 4-Year Egg Powder Oral Immunotherapy (eOIT) Protocol

EH Kim, SM Jones, AW Burks. J Allergy Clin Immunol . 2020;145(4):1292–1295.e1 To assess long-term outcomes of children treated with egg oral immunotherapy (eOIT). Subjects who participated in the original clinical trial ( N = 55), with a median age of 12.7 years at the initiation of the follow-up period. After completing up to 4 years of eOIT, those subjects who achieved sustained unresponsiveness (SU) were instructed to introduce dietary egg ad libitum. Subjects who had not achieved …

Study protocol of a multicentre, randomised, controlled trial evaluating the effectiveness of probiotic and peanut oral immunotherapy (PPOIT) in inducing desensitisation or tolerance in children with peanut allergy compared with oral immunotherapy (OIT) alone and with placebo (the PPOIT-003 study)

IntroductionPeanut allergy is the the most common cause of life-threatening food-induced anaphylaxis. There is currently no effective long-term treatment. There is a pressing need for definitive treatments that improve the...

Food allergy oral immunotherapy.

Food allergy oral immunotherapy (OIT) has demonstrated efficacy in promoting clinically relevant immunomodulation that leads to desensitization (reduced reactivity while on OIT) in the majority of treated individuals; however, sustained unresponsiveness after OIT cessation for a specified interval has only been observed in a subset. The potential therapeutic benefits of OIT must be balanced with the risk for adverse events. These adverse events may range from self-limited or easily treated oropharyngeal, respiratory, or gastrointestinal symptoms to persistent abdominal symptoms that lead to cessation of therapy and to anaphylaxis. To date, the majority of studies have evaluated single-allergen OIT approaches; however, multi-allergen OIT has demonstrated favorable safety and efficacy outcomes, and is the subject of ongoing investigation. Recent U.S. Food and Drug Administration approval of the first licensed OIT product for peanut allergy challenges the long-standing paradigm of dietary food avoidance as the sole option for individuals with food allergy. Yet, the limitations of this "first-generation" treatment support the need for continued research and development of next-generation therapies to improve efficacy, minimize risk, and allow for broad applicability to both individuals with single-food allergy and those with multifood allergies. Optimizing future therapies will require developing novel approaches that maximize both efficacy and safety and/or tolerability outcomes, potentially through the combination with biologic therapies or adjuvants. Shared decision-making among patients, physicians, and parents and/or caregivers is critical to select optimal candidates for treatment with OIT by balancing the potential therapeutic benefit and possible risk reduction with a realistic consideration of OIT treatment burden and the risk of treatment-related adverse events.

Sustained unresponsiveness to peanut after long-term peanut epicutaneous immunotherapy

Sustained unresponsiveness to peanut after long-term peanut epicutaneous immunotherapy

Notch signaling contributes to the establishment of sustained unresponsiveness to food allergens by oral immunotherapy

Oral immunotherapy (OIT) aims to establish desensitization and sustained unresponsiveness (SU) in patients with food allergy by ingestion of gradually increasing doses of specific food allergens. However, little is known about the mechanisms by which OIT induces SU to specific allergens. We investigated the role of Notch signaling, which controls cell fate decisions in many types of immune cells in the induction of SU by OIT treatment. Two types of mouse models, ovalbumin-induced food allergy and OIT, were generated. To elucidate the role of Notch signaling in OIT-induced SU, mice were intraperitoneally injected with the Notch signaling inhibitor N-[(3,5-difluorophenyl)acetyl]-l-alanyl-2-phenylglycine-1,1-dimethylethyl ester during the OIT treatment period. Ovalbumin-sensitized mice were desensitized and also had SU induced by OIT treatment, whereas repeated challenges with ovalbumin caused the development of severe allergic reactions in ovalbumin-sensitized mice. Administration of N-[(3,5-difluorophenyl)acetyl]-l-alanyl-2-phenylglycine-1,1-dimethylethyl ester to mice during the OIT treatment period inhibited the establishment of SU to ovalbumin but did not affect the induction of desensitization. OIT induced a systemic expansion of IL-10-producing CD4+ T cells, including TH2 cells, and myeloid-derived suppressor cells (MDSCs), particularly the monocytic MDSC subpopulation. Inhibition of Notch signaling prevented the OIT-induced expansion of those cells. Invitro cultures of bone marrow cells showed that Notch signaling directly promoted the generation of monocytic MDSCs. In addition, the contribution of MDSCs to OIT-induced SU was confirmed by MDSC depletion with the anti-Gr1 antibody. Notch signaling contributes to the establishment of SU induced by OIT through systemic expansion of immunosuppressive cells, such as IL-10-producing CD4+ T cells and MDSCs.

Long-term, open-label extension study of the efficacy and safety of epicutaneous immunotherapy for peanut allergy in children: PEOPLE 3-year results

The PEPITES (Peanut EPIT Efficacy and Safety) trial, a 12-month randomized controlled study of children with peanut allergy and 4 to 11 years old, previously reported the safety and efficacy of epicutaneous immunotherapy (EPIT) for peanut allergy (250 μg, daily epicutaneous peanut protein; DBV712 250 μg). We sought to assess interim safety and efficacy of an additional 2 years of EPIT from the ongoing (5-year treatment) PEOPLE (PEPITES Open-Label Extension) study. Subjects who completed PEPITES were offered enrollment in PEOPLE. Following an additional 2 years of daily DBV712 250 μg, subjects who had received DBV712 250 μg in PEPITES underwent month-36 double-blind, placebo-controlled food challenge with an optional month-38 sustained unresponsiveness assessment. Of 213 eligible subjects who had received DBV712 250 μg in PEPITES, 198 (93%) entered PEOPLE, of whom 141 (71%) had assessable double-blind, placebo-controlled food challenge at month 36. At month 36, 51.8% of subjects (73 of 141) reached an eliciting dose of ≥1000 mg, compared with 40.4% (57 of 141) at month 12; 75.9% (107 of 141) demonstrated increased eliciting dose compared with baseline; and 13.5% (19 of 141) tolerated the full double-blind, placebo-controlled food challenge of 5444 mg. Median cumulative reactive dose increased from 144 to 944 mg. Eighteen subjects underwent an optional sustained unresponsiveness assessment; 14 of those (77.8%) maintained an eliciting dose of ≥1000 mg at month 38. Local patch-site skin reactions were common but decreased over time. There was no treatment-related epinephrine use in years 2 or 3. Compliance was high (96.9%), and withdrawals due to treatment-related adverse events were low (1%). These results demonstrate that daily EPIT treatment for peanut allergy beyond 1 year leads to continued response from a well-tolerated, simple-to-use regimen.