Sustained Unresponsiveness Research Articles

Induction of sustained unresponsiveness after egg oral immunotherapy compared to baked egg therapy in children with egg allergy

While desensitization and sustained unresponsiveness (SU) have been shown with egg oral immunotherapy (OIT), the benefits of baked egg (BE) therapy for egg allergy have not been well studied. This study sought to evaluate the safety and efficacy of BE ingestion compared with egg OIT in participants allergic to unbaked egg but tolerant to BE. Children who are BE-tolerant but unbaked egg reactive ages 3 to 16 years were randomized to 2 years of treatment with either BE or egg OIT. Double-blind, placebo-controlled food challenges were conducted after 1 and 2 years of treatment to assess for desensitization, and after 2 years of treatment followed by 8 to 10 weeks off of treatment to assess for SU. Mechanistic studies were conducted to assess for immune modulation. Acohort of participants who are BE-reactive underwent egg OIT and identical double-blind, placebo-controlled food challenges as a comparator group. Fifty participants (median age 7.3 years) were randomized and initiated treatment. SU was achieved in 3 of 27 participants assigned to BE (11.1%) versus 10 of 23 participants assigned to egg OIT (43.5%) (P= .009). In the BE-reactive comparator group, 7 of 39 participants (17.9%) achieved SU. More participants who are BE-tolerant withdrew from BE versus from egg OIT (29.6% vs 13%). Dosing symptom frequency in participants who are BE-tolerant was similar with BE and egg OIT, but more frequent in participants who are BE-reactive. Egg white-specific IgE, skin testing, and basophil activation decreased similarly after BE and egg OIT. Among children allergic to unbaked egg but tolerant to BE, those treated with egg OIT were significantly more likely to achieve SU than were children ingesting BE.

Peanut Oral Immunotherapy: a Current Perspective.

Purpose of the ReviewPeanut oral immunotherapy (OIT) is one of the most studied experimental therapies for food allergy. With the recently FDA-approved peanut product, Palforzia, the goal of this article is to review the most recent data from clinical trials, discuss recent trends, and anticipate future developments.Recent FindingsThe latest research suggests that peanut OIT could be a promising option for peanut-allergic patients, with the majority of participants in research studies achieving the primary efficacy endpoint of desensitization, as well as sustained unresponsiveness in select populations. Some studies also showed improvements in food allergy-related quality of life. However, peanut OIT is not without risk or side effects, including potentially serious allergic reactions.SummaryFuture research will need to evaluate the short- and long-term effectiveness of the therapy in the real-world setting, predictors of important treatment outcomes, and the use of adjunctive therapies that may mitigate some of these allergic reactions.

Low-dose peanut challenges can facilitate infant peanut introduction regardless of skin prick test size

The Learning Early About Peanut Allergy (LEAP) trial and other studies recommend early peanut introduction to prevent peanut allergy in at-risk infants. 1 Du Toit G. Roberts G. Sayre P.H. et al. Randomized trial of peanut consumption in infants at risk for peanut allergy. N Engl J Med. 2015; 372: 803-813 Crossref PubMed Scopus (1239) Google Scholar ,2 Perkin M.R. Logan K. Tseng A. et al. Randomized trial of introduction of allergenic foods in breast-fed infants. N Engl J Med. 2016; 374: 1733-1743 Crossref PubMed Scopus (497) Google Scholar In addition, peanut oral immunotherapy (OIT) shows increased rates of sustained unresponsiveness in children younger than 5 years with known peanut allergy, 3 Vickery B.P. Berglund J.P. Burk C.M. et al. Early oral immunotherapy in peanut-allergic preschool children is safe and highly effective. J Allergy Clin Immunol. 2017; 139: 173-181.e8 Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar suggesting better outcomes with early exposure. The LEAP trial excluded infants with skin prick tests (SPTs) greater than 4 mm. 1 Du Toit G. Roberts G. Sayre P.H. et al. Randomized trial of peanut consumption in infants at risk for peanut allergy. N Engl J Med. 2015; 372: 803-813 Crossref PubMed Scopus (1239) Google Scholar The guidelines recommend peanut introduction or oral food challenge (OFC) only in infants who have SPTs less than or equal to 7 mm and do not specifically address management of infants with SPTs greater than 7 mm (or high peanut IgE levels). 4 Togias A. Cooper S.F. Acebal M.L. et al. Addendum guidelines for the prevention of peanut allergy in the United States: report of the National Institute of Allergy and Infectious Diseases-sponsored expert panel. J Allergy Clin Immunol. 2017; 139: 29-44 Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar Data suggest that patients with peanut SPT greater than 7 mm are likely to react, 4 Togias A. Cooper S.F. Acebal M.L. et al. Addendum guidelines for the prevention of peanut allergy in the United States: report of the National Institute of Allergy and Infectious Diseases-sponsored expert panel. J Allergy Clin Immunol. 2017; 139: 29-44 Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar ,5 Roberts G. Lack G. Diagnosing peanut allergy with skin prick and specific IgE testing. J Allergy Clin Immunol. 2005; 115: 1291-1296 Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar but most reference values for SPT and peanut IgE levels are not standardized for infants. 5 Roberts G. Lack G. Diagnosing peanut allergy with skin prick and specific IgE testing. J Allergy Clin Immunol. 2005; 115: 1291-1296 Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar ,6 Hill D.J. Heine R.G. Hosking C.S. The diagnostic value of skin prick testing in children with food allergy. Pediatr Allergy Immunol. 2004; 15: 435-441 Crossref PubMed Scopus (201) Google Scholar It is unknown whether infants with SPT greater than 7 mm may tolerate and benefit from early peanut exposure. Given the potential long-term benefits of tolerating peanut, we sought to offer peanut OFCs to a wider population of sensitized infants.

Food allergy immunotherapy: Oral immunotherapy and epicutaneous immunotherapy.

IgE-mediated food allergy remains a significant and growing problem across the globe. Of the various treatment modalities, oral immunotherapy (OIT) and epicutaneous immunotherapy (EPIT) have been the best studied. Across various studies of OIT for egg, milk, and peanut allergy, strong levels of desensitization have been shown. With egg and peanut OIT, a limited remission, or sustained unresponsiveness (SU), has further been demonstrated. These advances have been further validated by successful phase 2 and phase 3 studies of peanut OIT. EPIT, using daily administrations of a proprietary patch, demonstrated efficacy as well as safety and tolerability in parallel phase 2 studies; however, its phase 3 study did not meet its primary efficacy outcome. Despite its good track record of desensitization, the safety and tolerability of OIT has remained a question. EPIT, on the other hand, has proven safe and tolerable; however, the adequacy of its desensitization has remained to be determined. As OIT and EPIT continue their march toward regulatory review, optimizations for immunotherapy and novel therapies continue to be developed providing hope for food allergy patients everywhere.

Sustained outcomes in oral immunotherapy for peanut allergy (POISED study): a large, randomised, double-blind, placebo-controlled, phase 2 study

Dietary avoidance is currently recommended for peanut allergies. We evaluated sustained effects of treating peanut allergy with oral immunotherapy (OIT) in the first phase 2 randomized-controlled long-term study in adults and children. In a double-blind, placebo-controlled, randomized study, 120 peanut-allergic participants (7-53 years old) received up to 4 g of peanut protein or placebo daily for 3 years. Participants received placebo (N=25) or peanut protein (N=95) over 104 weeks; 60 then discontinued (peanut-0) while 35 received 300 mg daily (peanut-300). Double-blind, placebo-controlled food challenges (DBPCFCs) to 4 g peanut protein were conducted at baseline, week 104, and every 13 weeks thereafter for one year. The primary endpoint was reached at week 117 after 3 months of discontinuation (testing sustained unresponsiveness): 21/60 (35%) peanut-0 participants passed the challenge with no reaction versus 1/25 (4%) placebo (primary endpoint, P=0.002). Time to failure was significantly longer in peanut-300 vs. peanut-0 vs. placebo arms (P<0.0001). The percentage of participants passing DBPCFCs in peanut-300 declined significantly (weeks 104 vs. 156; 83% vs. 37%, P<0.001). Adverse allergic reactions decreased over time in all arms. Peanut-specific IgG4/IgE levels were higher (P<0.001), and Ara h 2-specific IgE (P<0.001) and basophil activation responses (P=0.037) were lower, at baseline in those achieving sustained unresponsiveness at week 117. Peanut OIT desensitizes most peanut-allergic individuals to 4 g peanut protein but discontinuation, or even a reduction to 300 mg daily, increases the likelihood of regaining clinical reactivity to peanut. Baseline blood tests correlate with week 117 treatment outcomes.

The Efficacy and Safety of Probiotic and Peanut Oral Immunotherapy for inducing Desensitization and Sustained Unresponsiveness: Results from a Phase 2b Multi-center Randomized Trial (PPOIT-003)

The Efficacy and Safety of Probiotic and Peanut Oral Immunotherapy for inducing Desensitization and Sustained Unresponsiveness: Results from a Phase 2b Multi-center Randomized Trial (PPOIT-003)

A 5-year summary of real-life dietary egg consumption after completion of a 4-year egg powder oral immunotherapy (eOIT) protocol

The majority of children with sustained unresponsiveness after extended egg OIT are able to successfully introduce dietary egg. OIT outcome may be predictive of frequency, type (concentrated, baked), and quantity of egg ingested in the long term.

Immunotherapy and Oral Immunotherapy with Omalizumab for Food Allergies

Food allergy is potentially life-threatening and has a major impact on quality of life. Avoidance is currently the only approved therapy, and, although effective, avoidance diets can be difficult and may also put children at risk of nutritional deficiencies and impaired growth. At least 80% of milk and egg-allergic children are expected to achieve natural tolerance to these foods by adulthood, and 15–20% of peanut or tree nut-allergic individuals ‘outgrow’ their allergies. Effective therapies for food allergies are therefore highly desirable. There have been several immunotherapies for food allergy such as oral immunotherapy (OIT), sublingual immunotherapy (SLIT), epicutaneous immunotherapy (EPIT), and OIT combined with anti-IgE monoclonal antibodies (omalizumab [OMB]). However, efficacy and safety have only been demonstrated in one large Phase III trial for peanut allergies. Additionally, there have only been three randomised, controlled studies of OMB–OIT combination and these were low-powered, single-centre trials; therefore, evidence levels were low in these trials. Studies that included long-term follow-up observations and clinical tolerance are rare. Additionally, clinical tolerance is not well-defined and remains unknown. Therefore, several problems remain to be resolved, but hopefully OIT in combination with OMB will resolve these problems in the future. Although there are only three randomised, controlled trials of OMB–OIT, the combination therapy enabled high dose desensitisation for a short duration without any adverse events, resulting in the sustained unresponsiveness in IgE-related food allergy. It is speculated that this combination therapy will be the most effective immunotherapy in the future.

Sustained successful peanut oral immunotherapy associated with low basophil activation and peanut-specific IgE

Oral immunotherapy (OIT) can successfully desensitize many peanut-allergic subjects, but clinical tolerance diminishes over time on discontinuation, or low-dose maintenance, of peanut. Therefore, to improve the efficacy and sustainability of such therapy, we sought to identify biomarkers and clinical tools that can predict therapeutic outcomes and monitor treatment responses. We evaluated whether basophil activation in whole blood, and plasma levels of peanut-specific immunoglobulins, are useful biomarkers for peanut OIT. We longitudinally measured, before, during, and after OIT, basophil activation in whole blood exvivo in response to peanut stimulation, and peanut-specific IgE (sIgE) and peanut-specific IgG4 (sIgG4), in a large, single-site, double-blind, randomized, placebo-controlled, phase 2 peanut OIT study. We compared basophil responsiveness and peanut-specific immunoglobulins between those who were clinically reactive and those who were tolerant to peanut oral challenges. Peanut OIT significantly decreased basophil activation, peanut sIgE, Ara h 1, Ara h 2, and Ara h 3 IgE levels, and sIgE/total IgE, but increased sIgG4/sIgE. Participants who became reactive to 4 g of peanut 13 weeks off active OIT exhibited higher peanut-induced basophil activation exvivo and higher peanut sIgE levels and sIgE/total IgE, but lower sIgG4/sIgE. Notably, participants entering the study with low basophil responsiveness were more likely to achieve treatment success. Substantial suppression of basophil activation was required to maintain long-term clinical tolerance after peanut OIT. Assessments of peanut-induced basophil activation and peanut-specific immunoglobulins can help to predict treatment outcomes, and to differentiate transient desensitization versus sustained unresponsiveness after OIT.

Real–World Experience With Peanut Oral Immunotherapy: Lessons Learned From 270 Patients

This retrospective record review reports observations on the treatment of 270 patients with peanut allergy with peanut oral immunotherapy (POIT).The study included 270 patients between the ages of 4 and 18 years who received POIT in a single practice between 2009 and 2017. A total of 96.7% of patients had a history of an immunoglobulin E–mediated reaction, 70.7% had experienced anaphylaxis, 26% had a peanut-specific immunoglobulin E (PSIgE) concentration of >100 kU/mL, and 9.6% had a positive peanut challenge result within 2 years of inception of POIT. No patient was excluded on the basis of severity of previous reaction(s) or PSIgE concentration. Patients with a history of eosinophilic esophagitis or gastroenteritis were excluded.The treatment protocol began with 2.5 µg of peanut protein. Dose increases were administered under direct observation. Patients reached a target dose of 3000 mg of peanut protein, underwent a 6000-mg challenge, and then began a 2000-mg maintenance dose administered at home 1 to 2 times per day for a minimum of 3 years. The treatment team made dose adjustments and decisions regarding discontinuation of therapy on the basis of collaborative clinical judgment. Patients and caregivers were instructed to report any adverse reactions more significant than transient, self-limited oral pruritis or abdominal discomfort.A total of 214 of 270 patients (79%) completed POIT dose escalation. Age (P < .001) and PSIgE (P < .001) correlated inversely with completion of dose escalation. For each year increase in patient age after 5, there was a 17% decrease in the odds ratio of reaching the escalation target (P < .001). One hundred epinephrine-treated reactions occurred in 63 patients (23%) during escalation. Intermittent asthma and higher PSIgE levels increased the risk of epinephrine-treated reactions (P = .035 and .019, respectively). Eosinophilic esophagitis–like oral immunotherapy–related syndrome occurred in 37 patients (13.7%). Intermittent asthma and higher PSIgE levels increased the risk of eosinophilic esophagitis–like oral immunotherapy–related syndrome (P = .014 and <.001, respectively). After 3 years of maintenance treatment, 14 patients were able to achieve sustained peanut unresponsiveness, defined as tolerance of 6000 mg of peanut protein after avoiding peanut for 30 days. The best predictors of sustained unresponsiveness were a pretreatment PSIgE level <20 kU/L and a prechallenge PSIgE level <1 kU/L.In an allergy office practice, 79% of patients were able to complete a POIT desensitization protocol and maintain a desensitized state with daily peanut dosing.This study demonstrates that patients can achieve successful peanut desensitization despite a history of previous reaction(s) or markedly elevated PSIgE levels. Epinephrine-treated reactions did occur during POIT, demonstrating that risk of significant allergic reactions was not eliminated. Reduced likelihood of achieving the target dose with increasing age makes early intervention attractive. Additional future studies are necessary to improve risk assessment and identification of patients likely to achieve sustained unresponsiveness.

Biomarkers in Food Allergy Immunotherapy.

Investigational allergen immunotherapies (AITs) including oral immunotherapy (OIT), sublingual immunotherapy (SLIT), and epicutaneous immunotherapy (EPIT) have proven to increase allergen thresholds required to elicit an allergic reaction in a majority of subjects. However, these studies lack consistent biomarkers to predict therapy outcomes. Here, we will review biomarkers that are currently being investigated for AIT. The mechanisms underlying the therapeutic benefit of AIT involve various cell types, including mast cells, basophils, T cells, and B cells. Skin prick and basophil activation tests assess effector cell sensitivity to allergen and are decreased in subjects on AIT. Allergen-specific IgE increases initially and decreases with continued therapy, while allergen-specific IgG and IgA increase throughout therapy. Allergen-induced regulatory T cells (Tregs) increase throughout therapy and were found to be associated with sustained unresponsiveness after OIT. Subjects on OIT and SLIT have decreased Th2 cytokine production during therapy. Although trends have been reported, a common limitation of these biomarkers is that none are able to reproducibly predict prognosis during AIT. Further studies are needed to expand the currently available biomarker repertoire to provide personalized approaches to AIT.

M110 SIGNIFICANTLY INCREASED THRESHOLD DOSE AFTER LONG-TERM PEANUT EPICUTANEOUS IMMUNOTHERAPY AND DAILY ORAL PEANUT INTAKE

While research has demonstrated the efficacy and safety of epicutaneous immunotherapy (EPIT) for peanut allergy, questions still exist regarding its ability to induce sustained unresponsiveness (SU) and maintained desensitization once achieved. We describe a patient with significantly increased threshold dose to peanut following EPIT despite inconsistent oral ingestion – evidence of a real-world situation.

Transcriptome analysis and safety profile of the early-phase clinical response to an adjuvanted grass allergoid immunotherapy

BackgroundSpecific immunotherapy is the only type of disease-modifying treatment, which induces rapid desensitization and long-term sustained unresponsiveness in patients with seasonal allergic rhinoconjunctivitis. The safety and tolerability of a new cumulative dose regimen of 35600 SU Grass MATA MPL for subcutaneous immunotherapy were assessed in pre-seasonal, single-blind, placebo controlled Phase I clinical study. Underlying immunological mechanisms were explored using transcriptome analysis of peripheral blood mononuclear cells. MethodsStudy subjects with a history of moderate to severe seasonal allergic rhinitis and/or conjunctivitis (SAR) due to grass (Pooideae) pollen exposure were randomized on a 1:1 ratio to receive either six 1.0 mL injections of cumulative dose regimen 35600 SU of Grass MATA MPL or placebo. The study consisted of three periods: screening, randomization and treatment and End of Study period. Blood samples were taken for clinical safety laboratory assessments and for the assessment of gene expression analysis during screening visit and End of Study visit. The safety statistics was calculated using Fisher's exact test. Delta Delta Ct method analysis of RT2 Profiler PCR Array gene expression results was used to calculate changes in gene expression level. Genes with the absolute value of log2 fold change greater than ±1.1 and p-value less than 0.05 were identified as differentially expressed and underwent IPA data analysis. ResultsThe results of the study indicated that the higher cumulative dose regimen of the immunotherapy was well-tolerated. Changes in gene expression profile were associated with early immune responses implicating innate and adaptive immune mechanisms. Pathways and mechanistic network analysis via IPA mapped differentially expressed genes onto canonical pathways related to T cell differentiation, cytokine signalling and Th1/Th2 activation pathways. The transcriptome findings of the study could be further verified in large-scale field studies in order to explore their potential as predictive markers of successful immunotherapy. ConclusionsThe higher dose cumulative regime 35600 SU of Grass MATA MPL vaccine was well tolerated and safe. Molecular markers IL-27, IL-10, IL-4, TNF, IFNγ, TGFβ and TLR4 were the main predicted molecular drivers of the observed gene expression changes following early stages of SIT with Grass MATA MPL immunotherapy.

IgE binding to linear epitopes of Ara h 2 in peanut allergic preschool children undergoing oral Immunotherapy.

For patients with peanut allergy, there are currently no methods to predict who will develop sustained unresponsiveness (SU) after oral immunotherapy (OIT). Assess IgE binding to peanut (PN), Ara h 2, and specific linear epitopes of Ara h 2 as predictors of the important clinical parameters: eliciting dose threshold and attainment of SU following OIT. Samples and clinical data were collected from children undergoing OIT. PN- and Ara h 2-sIgE were quantified by ImmunoCAP® . IgE binding to linear peptides of Ara h 2 and Ara h 6 was measured with peptide microarrays. Values of PN-sIgE correlated with eliciting dose (P=.001) and with a higher likelihood of achieving SU (P<.0001), but these relationships were lost at higher values for PN-sIgE (≥14kIU for eliciting dose and ≥35kIU/L for SU). In subjects with PN-sIgE≥14kIU/L, binding of IgE to epitopes 5 and 6 of Ara h 2 was associated with a lower eliciting dose at baseline challenge (P<.001; Pc <.02). In subjects with PN-sIgE≥35kIU/L, a combined model of IgE binding to epitopes 1, 5 and 6 with PN-sIgE was highly predictive of attainment of SU (AUC of 0.86; P=.0067). In young patients with peanut allergy, measurement of PN-sIgE and IgE binding to specific linear epitopes of Ara h 2 in baseline samples may allow stratification of patients regarding sensitivity to challenge and outcome of OIT.

Intranasal nanoemulsion vaccine confers long-lasting immunomodulation and sustained unresponsiveness in a murine model of milk allergy.

Immunotherapy for food allergy requires prolonged treatment protocols and, in most cases, does not lead to durable modulation of the allergic immune response. We have demonstrated an intranasal (IN) nanoemulsion adjuvant that redirects allergen-specific Th2 responses toward Th1 and Th17 immunity, and protects from allergen challenge after only 2-4 monthly administrations. Here, we investigate the ability of this technology to provide long-term modulation of allergy in a murine model of cow's milk allergy. Six weeks after sensitization to bovine casein, mice received four, monthly IN immunizations with nanoemulsion formulated with casein. Protection from casein challenge was assessed at 4 and 16weeks after the final vaccine administration. The NE vaccine significantly blunted the physiological responses to allergen challenge, and this effect persisted for at least 16weeks. The protection from challenge was associated with the suppression of casein-specific Th2 immunity and induced Th1 and Th17 cytokines as well as induction of IL-10. Of interest, while immunized animals showed significantly decreased Th2 cytokine responses, cow's milk-specific IgE remained elevated in the serum at levels associated with reactivity in control sensitized animals. Protection was associated with suppressed mast cell activation and markedly reduced mast cell infiltration into the small intestine. The sustained unresponsiveness of at least 16weeks after vaccination suggests that the nanoemulsion vaccine alters the allergic phenotype in a persistent manner different from traditional desensitization, and this leads to long-term suppressive effects on allergic disease without eliminating serum IgE.

The clinical and immune outcomes after food allergen immunotherapy emphasizing the development of tolerance.

The present review serves to outline the direction of food allergy immunotherapy research with an emphasis on clinical and immunologic outcomes. It helps to delineate sustained unresponsiveness achieved from food immunotherapy as the clinical outcome most similar to immune tolerance. We will discuss the difference between immune tolerance, desensitization, and sustained unresponsiveness in relation to food immunotherapy by discussing the clinical and immunologic changes which have been recently discovered. Research has recently shown that oral immunotherapy is most efficacious clinically at achieving desensitization to a food and sustained unresponsiveness.

Sustained unresponsiveness in peanut oral immunotherapy

Peanut allergy is a potentially life-threatening disease with substantial impact on the quality of life of patients and carers.1 Many initiatives are underway to develop treatment alternatives for strict peanut avoidance. Subcutaneous immunotherapy with aqueous peanut extract was found to be too dangerous.2 Alternatives such as sublingual, epicutaneous, and oral immunotherapies are being tested. So far, oral immunotherapy (OIT) has proved most effective in achieving meaningful desensitisation while on therapy.

Sustained outcomes in oral immunotherapy for peanut allergy (POISED study): a large, randomised, double-blind, placebo-controlled, phase 2 study

Dietary avoidance is recommended for peanut allergies. We evaluated the sustained effects of peanut allergy oral immunotherapy (OIT) in a randomised long-term study in adults and children. In this randomised, double-blind, placebo-controlled, phase 2 study, we enrolled participants at the Sean N Parker Center for Allergy and Asthma Research at Stanford University (Stanford, CA, USA) with peanut allergy aged 7-55 years with a positive result from a double-blind, placebo-controlled, food challenge (DBPCFC; ≤500 mg of peanut protein), a positive skin-prick test (SPT) result (≥5 mm wheal diameter above the negative control), and peanut-specific immunoglobulin (Ig)E concentration of more than 4 kU/L. Participants were randomly assigned (2·4:1·4:1) in a two-by-two block design via a computerised system to be built up and maintained on 4000 mg peanut protein through to week 104 then discontinued on peanut (peanut-0 group), to be built up and maintained on 4000 mg peanut protein through to week 104 then to ingest 300 mg peanut protein daily (peanut-300 group) for 52 weeks, or to receive oat flour (placebo group). DBPCFCs to 4000 mg peanut protein were done at baseline and weeks 104, 117, 130, 143, and 156. The pharmacist assigned treatment on the basis of a randomised computer list. Peanut or placebo (oat) flour was administered orally and participants and the study team were masked throughout by use of oat flour that was similar in look and feel to the peanut flour and nose clips, as tolerated, to mask taste. The statistician was also masked. The primary endpoint was the proportion of participants who passed DBPCFCs to a cumulative dose of 4000 mg at both 104 and 117 weeks. The primary efficacy analysis was done in the intention-to-treat population. Safety was assessed in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT02103270. Between April 15, 2014, and March 2, 2016, of 152 individuals assessed, we enrolled 120 participants, who were randomly assigned to the peanut-0 (n=60), peanut-300 (n=35), and placebo groups (n=25). 21 (35%) of peanut-0 group participants and one (4%) placebo group participant passed the 4000 mg challenge at both 104 and 117 weeks (odds ratio [OR] 12·7, 95% CI 1·8-554·8; p=0·0024). Over the entire study, the most common adverse events were mild gastrointestinal symptoms, which were seen in 90 of 120 patients (50/60 in the peanut-0 group, 29/35 in the peanut-300 group, and 11/25 in the placebo group) and skin disorders, which were seen in 50/120 patients (26/60 in the peanut-0 group, 15/35 in the peanut-300 group, and 9/25 in the placebo group). Adverse events decreased over time in all groups. Two participants in the peanut groups had serious adverse events during the 3-year study. In the peanut-0 group, in which eight (13%) of 60 participants passed DBPCFCs at week 156, higher baseline peanut-specific IgG4 to IgE ratio and lower Ara h 2 IgE and basophil activation responses were associated with sustained unresponsiveness. No treatment-related deaths occurred. Our study suggests that peanut OIT could desensitise individuals with peanut allergy to 4000 mg peanut protein but discontinuation, or even reduction to 300 mg daily, could increase the likelihood of regaining clinical reactivity to peanut. Since baseline blood tests correlated with week 117 treatment outcomes, this study might aid in optimal patient selection for this therapy. National Institute of Allergy and Infectious Diseases.

Long-term sublingual immunotherapy for peanut allergy in children: Clinical and immunologic evidence of desensitization

Peanut sublingual immunotherapy (SLIT) for 1year has been shown to induce modest clinical desensitization in allergic children. Studies of oral immunotherapy, epicutaneous immunotherapy, and SLIT have suggested additional benefit with extended treatment. We sought to investigate the safety, clinical effectiveness, and immunologic changes with long-term SLIT in children with peanut allergy. Children with peanut allergy aged 1 to 11years underwent extended maintenance SLIT with 2mg/d peanut protein for up to 5years. Subjects with peanut skin test wheals of less than 5mm and peanut-specific IgE levels of less than 15 kU/L were allowed to discontinue therapy early. Desensitization was assessed through a double-blind, placebo-controlled food challenge (DBPCFC) with up to 5000mg of peanut protein after completion of SLIT dosing. Sustained unresponsiveness was further assessed by using identical DBPCFCs after 2 to 4weeks without peanut exposure. Thirty-seven of 48 subjects completed 3 to 5years of peanut SLIT, with 67% (32/48) successfully consuming 750mg or more during DBPCFCs. Furthermore, 25% (12/48) passed the 5000-mg DBPCFC without clinical symptoms, with 10 of these 12 demonstrating sustained unresponsiveness after 2 to 4weeks. Side effects were reported with 4.8% of doses, with transient oropharyngeal itching reported most commonly. Side effects requiring antihistamine treatment were uncommon (0.21%), and no epinephrine was administered. Peanut skin test wheals, peanut-specific IgE levels, and basophil activation decreased significantly, and peanut-specific IgG4 levels increased significantly after peanut SLIT. Extended-therapy peanut SLIT provided clinically meaningful desensitization in the majority of children with peanut allergy that was balanced with ease of administration and a favorable safety profile.

Early decrease in basophil sensitivity to Ara h 2 precedes sustained unresponsiveness after peanut oral immunotherapy

Only some patients with peanut allergy undergoing oral immunotherapy (OIT) achieve sustained clinical response. Basophil activation could provide a functional surrogate of efficacy. We hypothesized that changes in basophil sensitivity and area under the curve (AUC) to the immunodominant allergen Ara h 2 correlate with clinical responses to OIT. Children with peanut allergy aged 7 to 13years were enrolled in a single-center, open-label peanut OIT trial. Levels of specific immunoglobulins were measured throughout OIT. Peripheral blood from multiple time points was stimulated invitro with peanut allergens for flow cytometric assessment of the percentage of CD63hi activated basophils. Twenty-two of 30 subjects were successfully treated with OIT; after avoidance, 9 achieved sustained unresponsiveness (SU), and 13 had transient desensitization (TD). Basophil sensitivity, measured by using the dose that induces 50% of the maximal basophil response, to Ara h 2 stimulation decreased from baseline in subjects with SU (after OIT, P=.0041; after avoidance, P=.0011). At 3months of OIT, basophil sensitivity in subjects with SU decreased from baseline compared with that in subjects with TD (median, 18-fold vs 3-fold; P=.01), with a receiver operating characteristic of 0.84 and optimal fold change of 4.9. Basophil AUC to Ara h 2 was suppressed after OIT equally in subjects with SU and those with TD (P=.4). After avoidance, basophil AUC rebounded in subjects with TD but not those with SU (P<.001). Passively sensitized basophils suppressed with postavoidance SU plasma had a lower AUC than TD plasma (6.4% vs 38.9%, P=.03). Early decreases in basophil sensitivity to Ara h 2 correlate with SU. Basophil AUC rebounds after avoidance in subjects with TD. Therefore, different aspects of basophil activation might be useful for monitoring of OIT efficacy.