Conflicting verdicts on peanut oral immunotherapy from the Institute for Clinical and Economic Review and US Food and Drug Administration Advisory Committee: Where do we go from here?
Thomas EiweggerAikaterini AnagnostouStefania ArasiPhilippe BéginMoshe Ben‐ShoshanKirsten BeyerKatharina BlümchenHelen A. BroughJean‐Christoph CaubetEdmond S. ChanMeng ChenR. Sharon ChinthrajahCarla M. DavisAnne Des RochesGeorge Du ToitArnon ElizurStephen J. GalliGeir HålandKarin Hoffmann‐SommergruberHarold KimDonald Y.M. LeungAndrew LongAntonella MuraroUlugbek NurmatovGiovanni Battista PajnoVanitha SampathJamie SaxenaSayantani SindherJulia UptonMargitta WormKari C. Nadeau
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Keywords:
Peanut Allergy
Oral immunotherapy
Advisory committee
Oral food challenge
The development of oral tolerance or food allergy is an active process, related to dynamic interactions between host immune cells, microbiome, dietary factors, and food allergens. Oral tolerance is the default immune response in the gut. A food allergy occurs when this process fails and a pathologic Th2 response is activated. Oral food immunotherapy (OIT) aims to restore immune tolerance in food-allergic individuals. The stimulation of Tregs production seems to represent a crucial step in inducing long-term tolerance, but other mechanisms (e.g., the suppression of mast cell and basophil reactivity, changes in allergen-specific cells with regulatory markers) are involved. Several studies reported the efficacy of OIT in terms of "sustained unresponsiveness" (SU), an operational definition of immune tolerance. In successfully treated subjects, the ability to pass an oral food challenge 2 to 8 weeks after stopping the food allergen exposure seems to be conditioned by the treatment starting age, frequency, amount or type of food consumed, and by the duration of the maintenance phase. Based on the available data, the percentage of milk- and egg-allergic subjects achieving sustained unresponsiveness after an OIT ranges from 21% to 58,3%. A comprehensive understanding of mechanisms underlying the induction of oral tolerance with OIT, or natural tolerance to food allergens in healthy individuals, could potentially lead to advances in development of better treatment options for food allergic patients.
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BackgroundAdditional information is needed to inform optimal patient selection, expected outcomes, and treatment end points for clinical peanut oral immunotherapy (OIT).ObjectiveTo provide insight into the optimal patient selection, expected outcomes, and treatment end points for clinical peanut oral immunotherapy by analyzing a real-world peanut OIT cohort.MethodsRecords were reviewed for 174 children undergoing peanut OIT at a pediatric allergy clinic. Patient age, peanut skin prick test results, and peanut-specific immunoglobulin E (sIgE) results, with inclusion of additional foods in OIT, were analyzed for correlations with OIT outcomes.ResultsTo date, 144 patients have achieved maintenance dosing, 50 of whom transitioned to ad lib twice-weekly peanut ingestion. A total of 30 discontinued OIT. In addition, 47 patients who underwent multifood OIT had no significant difference in reactions (FDR-adjusted P = .48) or time-to-reach maintenance (FDR-adjusted P = .48) compared with those on peanut OIT alone. Age at initiation inversely correlated with achievement of maintenance: 92% of patients 0.5 to less than 5 years, 81% of those 5 to less than 11 years, and 70% of those 11 to less than 18 years reached and continued maintenance (P = .01). Baseline peanut-sIgE level positively correlated with number of reactions during updosing (P < .001) and maintenance (P = .005), though it was not significantly different in patients achieving successful maintenance vs those who discontinued OIT (P = .09). Furthermore, 66% of patients experienced greater than or equal to 1 adverse reaction during OIT. Of those on ad lib peanut ingestion, 2 reported mild reactions after lapses in peanut consumption.ConclusionClinical peanut OIT has similar outcomes to research protocols. OIT can be successful in older children and those with high peanut-sIgE levels, though these factors affect outcomes. Clinical and laboratory criteria can guide successful transition to intermittent ad lib peanut consumption.
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Abstract Prevalence rates of food allergy have increased rapidly in recent decades. Of concern, rates of increase are greatest among children under 5 yrs of age and for those food allergies that persist into adulthood such as peanut or tree nut allergy and shellfish allergy. Given these trends, the overall prevalence of food allergy will compound over time as the number of children affected by food allergy soars and a greater proportion of food‐allergic children are left with persistent disease into adulthood. It is therefore vital to identify novel curative treatment approaches for food allergy. Acquisition of oral tolerance to the diverse array of ingested food antigens and intestinal microbiota is an active immunologic process that is successfully established in the majority of individuals. In subjects who develop food allergy, there is a failure or loss of oral tolerance acquisition to a limited number of food allergens. Oral immunotherapy ( OIT ) offers a promising approach to induce specific oral tolerance to selected food allergens and represents a potential strategy for long‐term curative treatment of food allergy. This review will summarize the current understanding of oral tolerance and clinical trials of OIT for the treatment of food allergy.
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Specific immunotherapy (SIT) is one of the important lines for the treatment of food allergy. Efficacy tests for clinical response to SIT are limited and subjective. In this study, we aimed to evaluate the validity of food specific Ig E levels as a biomarker of clinical improvement in children with food allergy treated with oral immunotherapy (OIT). We analysed 184 children with food allergy, 143 had undergone 2 years of food OIT and 41 were on allergen restricted diet and considered as control. All patients were subjected to Double-Blind Placebo-Controlled Food Challenge test (DBPCFC), allergic symptom score calculation, and serum food specific Ig E level before and after oral immunotherapy for treated patients and after 2 year of allergen restricted diet for the control group. Receiver Ooperating Ccharacteristic Ccurves (ROCs) analysis was done to determine the cut off, areas under the curve, sensitivity, and specificity were calculated for the specific Ig E test. According to the result of DBPCFC and result of food specific Ig E test, milk Milk allergy was the most frequently food allergy as it was encountered in 76 children out of 184 children (41.3%) , followed by egg and fish allergy in 64(34.7%), and 44 (23.7%) cases, respectively. Oral desensitization was successful in 91 %, 82%, and 67% of patients with milk, Egg, and fish allergy, respectively. The OIT group showed a statistically significant greater reduction in symptom scores compared to the control group (P < 0.001). Also, there was a significant decrease in food specific Ig E level in responders for all types of food allergy tested (P ˂0.001), and . In responders group, there was significant correlation between the specific IgE level and symptom scores (r = 0.5, P = 0.03). Food specific Ig E levels cut off levels were < 0.8, < 2.05, and < 23 IU/ml allowed detection of effective OIT for milk, egg, and fish allergy, respectively. It is concluded that serum specific Ig E is correlated correlates with the clinical response to OIT and offers an advantage over double blind challenge test which is a risky and time consuming process.
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An understanding of how patient characteristics such as age, baseline peanut-specific IgE, and atopic comorbidities may influence potential safety outcomes during peanut oral immunotherapy (P-OIT) could aid in shared decision making between clinicians and patient families.This study explored the relationship between baseline patient characteristics and reactions during P-OIT using a large sample size to better understand potential risk factors influencing P-OIT safety.Data were obtained from the Food Allergy Immunotherapy (FAIT) registry, which collects real-world OIT data from community and academic allergy clinics across Canada. Multivariable logistic regression modeling was performed to examine the relationship between baseline patient characteristics and reactions during P-OIT. Multiple imputation was applied to reduce potential bias caused by missingness and to maximize the use of available information to preserve statistical power.Between April 2017 and June 2021, a total of 653 eligible patients initiated P-OIT. Multivariable regression analysis showed pre-OIT grade 2+ initial reaction (odds ratio [OR] = 1.33, 95% confidence interval [CI] 1.10, 1.61), allergic rhinitis (OR = 1.60, 95% CI 1.08, 2.38), older age (OR = 1.01, 95% CI 1.00, 1.02), and higher baseline peanut-specific IgE (OR = 1.02, 95% CI 1.02, 1.03) were associated with grade 2+ reaction during P-OIT after adjusting for potential risk factors.Our study identified several clinically important risk factors for grade 2+ reactions during P-OIT: pre-OIT grade 2+ initial reaction, allergic rhinitis, older age, and higher baseline peanut-specific IgE. These results highlight the need for individualized risk stratification for OIT.
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Abstract Background Peanut allergy is classically managed by food avoidance. Immunotherapy programs are available at some academic centers for selected patients reacting to small amounts of peanut during food challenge. We aimed to determine and compare reaction thresholds and prevalence of anaphylaxis during peanut oral challenges at multiple specialist allergy centers. Methods A retrospective, international survey of anonymized case records from seven specialist pediatric allergy centers from the UK and Ireland, as well as the Australian HealthNuts study. Demographic information, allergy test results, reaction severity and threshold during open oral peanut challenges were collated and analyzed. Results Of the 1634 children aged 1‐18 years old included, 525 (32%) failed their peanut challenge. Twenty‐eight percent reacted to 25 mg, while 38% only reacted after consuming 1 g or more of whole peanut. Anaphylaxis (55 [11%]) was 3 times more common in teenagers than younger children and the likelihood increased at all ages as children consuming more peanut at the challenge. Children who developed anaphylaxis to 25‐200 mg of whole peanut were significantly older. Previous history of reaction did not predict reaction threshold or severity. Conclusions More than a third of the children in this large international cohort tolerated the equivalent of one peanut in an oral challenge. Anaphylaxis, particularly to small amounts of peanut, was more common in older children. Tailored immunotherapy programs might be considered not only for children with low, but also higher reaction thresholds. Whether these programs could prevent heightened sensitivity and anaphylaxis to peanut with age also deserves further study.
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