Peanut-specific type 1 regulatory T cells induced in vitro from allergic subjects are functionally impaired.

BACKGROUND: Peanut allergy (PA) is a life-threatening condition that lacks regulator-approved treatment. Regulatory T type 1 (TR1) cells are potent suppressors of immune responses and can be induced in vivo upon repeated antigen exposure or in vitro by using tolerogenic dendritic cells. Whether oral immunotherapy (OIT) leads to antigen-specific TR1 cell induction has not been established. OBJECTIVES: We sought to determine whether peanut-specific TR1 cells can be generated in vitro from peripheral blood of patients with PA at baseline or during OIT and whether they are functional compared with peanut-specific TR1 cells induced from healthy control (HC) subjects. METHODS: Tolerogenic dendritic cells were differentiated in the presence of IL-10 from PBMCs of patients with PA and HC subjects pulsed with the main peanut allergens of Arachis hypogaea, Ara h 1 and 2, and used as antigen-presenting cells for autologous CD4+ T cells (CD4+ T cells coincubated with tolerogenic dendritic cells pulsed with the main peanut allergens [pea-T10 cells]). Pea-T10 cells were characterized by the presence of CD49b+ lymphocyte-activation gene 3 (LAG3)+ TR1 cells, antigen-specific proliferative responses, and cytokine production. RESULTS: CD49b+LAG3+ TR1 cells were induced in pea-T10 cells at comparable percentages from HC subjects and patients with PA. Despite their antigen specificity, pea-T10 cells of patients with PA with or without OIT, as compared with those of HC subjects, were not anergic and had high TH2 cytokine production upon peanut-specific restimulation. CONCLUSIONS: Peanut-specific TR1 cells can be induced from HC subjects and patients with PA, but those from patients with PA are functionally defective independent of OIT. The unfavorable TR1/TH2 ratio is discussed as a possible cause of PA TR1 cell impairment.

Elimination diet and the development of multiple tree-nut allergies.

BackgroundDespite its high prevalence, relatively little is known about the characteristics of patients with multiple tree-nut allergies.MethodsPatients (n=60, aged 4-15 years), recruited for a multiple food (tree nuts, peanut, milk, egg, soy, sesame, and wheat) oral immunotherapy (OIT) study, filled a questionnaire on their initial allergy evaluation. Medical records were reviewed. At OIT enrollment (median interval, 7.5 years), patients underwent oral food challenges (OFCs) to foods still eliminated.ResultsThere was significantly less evidence for eliminating tree nuts compared with other foods, as reflected by a lower rate of acute reaction to the offending food, either as the trigger for initial allergy evaluation (5.9% for tree-nuts vs. 20-40% for other foods, respectively P<0.001) or later in life (14.5% vs. 38-75%, respectively P=0.001), and a higher rate of negative skin prick test (SPT)/specific IgE (sIgE) at initial diagnosis (25% vs. <10%, P<0.001). SPT/sIgE increased significantly from past initial levels to present for tree nuts (P<0.001) and peanut (P=0.001) but not for other foods, and most OFCs performed at present were positive.ConclusionsTree nuts are often eliminated from the diet of multiple-food-allergic patients, despite their low probability for allergy. Sensitization and allergy to most tree nuts exist years later, suggesting that it developed during the period of elimination.

Children with type 2 diabetes mellitus and the prevalence of psychiatric disorders.

OBJECTIVE: Type 2 diabetes is a common disease, afflicting more than 20 million Americans. Psychiatric disorders, particularly depression, have been previously correlated with diabetes. METHODS: The objectives of this study were to determine the frequency of psychiatric illnesses in a type 2 pediatric diabetic cohort and to examine if there were any significant demographic differences between diabetic children with psychiatric disorders and diabetic children without psychiatric disorders. A retrospective chart review was performed on patients from two southeastern children's hospitals. RESULTS: In our study, 26.2% (67 of 256) of diabetic patients were diagnosed with neuropsychiatric disorders (NPD). A comparison between gender frequencies of affected and unaffected patients suggested a statistical difference (P = 0.009). It appears that pediatric diabetic males are affected with NPD to a greater extent than females. Patients diagnosed with neurological disorders showed a body mass index average of 39.03, which was statistically different from non-diagnosed NPD patients (P = 0.0313). CONCLUSIONS: To our knowledge, this is the first report to demonstrate the frequency of psychiatric disorders in a cohort of pediatric type 2 diabetics in the southeastern US. This study provides information regarding children afflicted with type 2 diabetes mellitus and the frequency of neuropsychiatric morbidities. This information may be useful for crafting future health policies and quality improvement interventions.

Changing Patient Mindsets about Non-Life-Threatening Symptoms During Oral Immunotherapy: A Randomized Clinical Trial.

BACKGROUND: Oral immunotherapy (OIT) can lead to desensitization to food allergens, but patients can experience treatment-related symptoms of allergic reactions that cause anxiety and treatment dropout. Interventions to improve OIT for patients are needed. OBJECTIVE: To determine whether fostering the mindset that non-life-threatening symptoms during OIT can signal desensitization improves treatment experience and outcomes. METHODS: In a randomized, blinded, controlled phase II study, 50 children/adolescents (28% girls, aged 7-17 years, M = 10.82, standard deviation = 3.01) completed 6-month OIT for peanut allergies. Patients and their parent(s) had monthly clinic visits at the Sean N. Parker Center for Allergy and Asthma Research between January 5, 2017, and August 3, 2017. All families received identical symptom management training. In a 1:1 approach, 24 patients and their families were informed that non-life-threatening symptoms during OIT were unfortunate side effects of treatment, and 26 patients and their families were informed that non-life-threatening symptoms could signal desensitization. Families participated in activities to reinforce these symptom mindsets. RESULTS: Compared with families informed that symptoms are side effects, families informed that symptoms can signal desensitization were less anxious (B = -0.46, 95% confidence interval [CI]: -0.76 to -0.16; P = .003), less likely to contact staff about symptoms (5/24 [9.4%] vs 27/154 [17.5%] instances; P = .036), experienced fewer non-life-threatening symptoms as doses increased (BInteraction = -0.54, 95% CI: -0.83 to -0.27; P < .001), less likely to skip/reduce doses (1/26 [4%] vs 5/24 [21%] patients; P = .065), and showed a greater increase in patient peanut-specific blood IgG4 levels (BInteraction = 0.76, 95% CI: 0.36 to 1.17; P < .001). CONCLUSIONS: Fostering the mindset that symptoms can signal desensitization improves OIT experience and outcomes. Changing how providers inform patients about non-life-threatening symptoms is a promising avenue for improving treatment.

Anti-IgE treatment with oral immunotherapy in multifood allergic participants: a double-blind, randomised, controlled trial.

BACKGROUND: Despite progress in single food oral immunotherapy, there is little evidence concerning the safety and efficacy of treating individuals with multiple food (multifood) allergies. We did a pilot study testing whether anti-IgE (omalizumab) combined with multifood oral immunotherapy benefited multifood allergic patients. METHODS: We did a blinded, phase 2 clinical trial at Stanford University. We enrolled participants, aged 4-15 years, with multifood allergies validated by double-blind, placebo-controlled food challenges to their offending foods. Inclusion criteria included a positive skin prick test of 6 mm or more (wheal diameter, above the negative control), a food-specific serum IgE concentration of more than 4 kU/L for each food, or both, and a positive double-blind, placebo-controlled food challenge at 500 mg or less of food protein. Exclusion criteria included eosinophilic oesophagitis and severe asthma. Participants were randomised (3:1) with a block size of four, to receive multifood oral immunotherapy to two to five foods, together with omalizumab (n=36) or placebo (n=12). 12 individuals who fulfilled the same inclusion and exclusion criteria were included as controls. These individuals were not randomised and received neither omalizumab nor oral immunotherapy. Omalizumab or placebo was administered subcutaneously for 16 weeks, with oral immunotherapy starting at week 8, and was stopped 20 weeks before the exit double-blind, placebo-controlled food challenge at week 36. The primary endpoint was the proportion of participants who passed double-blind, placebo-controlled food challenges to at least two of their offending foods. This completed trial is registered with ClinicalTrials.gov, number NCT02643862. FINDINGS: Between March 25, 2015, and Aug 18, 2016, 165 participants were assessed for eligibility, of whom 84 did not meet the inclusion criteria and 21 declined to participate. We enrolled and randomised 48 eligible participants and the remaining 12 patients were included as nonrandomised, untreated controls. At week 36, a significantly greater proportion of the omalizumab-treated (30 [83%] of 36) versus placebo (four [33%] of 12) participants passed double-blind, placebo-controlled food challenges to 2 g protein for two or more of their offending foods (odds ratio 10·0, 95% CI 1·8-58·3, p=0·0044). All participants completed the study. There were no serious or severe (grade 3 or worse) adverse events. Participants in the omalizumab group had a significantly lower median per-participant percentage of oral immunotherapy doses associated with any adverse events (27% vs 68%; p=0·0082). The most common adverse events in both groups were gastrointestinal events. INTERPRETATION: In multifood allergic patients, omalizumab improves the efficacy of multifood oral immunotherapy and enables safe and rapid desensitisation. FUNDING: US National Institutes of Health (NIH).

Observational long-term follow-up study of rapid food oral immunotherapy with omalizumab.

BACKGROUND: A number of clinical studies focused on treating a single food allergy through oral immunotherapy (OIT) with adjunctive omalizumab treatment have been published. We previously demonstrated safety and tolerability of a rapid OIT protocol using omalizumab in a phase 1 study to achieve desensitization to multiple (up to 5) food allergens in parallel, rapidly (7-36 weeks; median = 18 weeks). In the current long-term, observational study, we followed 34 food allergic participants for over 5 years, who had originally undergone the phase 1 rapid OIT protocol. METHODS: After reaching the maintenance dose of 2 g protein for each of their respective food allergens as a part of the phase 1 study, the long-term maintenance dose was reduced for some participants based on a pragmatic team-based decision. Participants were followed up to 62 months through standard oral food challenges (OFCs), skin prick tests, and blood tests. RESULTS: Each participant passed the 2 g OFC to each of their offending food allergens (up to 5 food allergens in total) at the end of the long-term follow-up (LTFU) study. CONCLUSION: Our data demonstrate the feasibility of long-term maintenance dosing of a food allergen without compromising the desensitized status conferred through rapid-OIT. Trial registration Registry: Clinicaltrials.gov. Registration numbers: NCT01510626 (original study), NCT03234764 (LTFU study). Date of registration: November 29, 2011 (original study); July 26, 2017 (LTFU study, retrospectively registered).

Feasibility of sustained response through long-term dosing in food allergy immunotherapy.

BACKGROUND: Clinical trials using oral immunotherapy (OIT) for the treatment of food allergies have shown promising results. We previously demonstrated the feasibility of desensitization for up to 5 food allergens simultaneously through OIT. In this observational study, we report the findings of long-term follow-up (LTFU) of the participants treated through a single site OIT phase 1 trial. METHODS: The participants (n = 46) were followed up to 72 months since the time they reached 2 g maintenance dose per food in the initial phase 1 trial. During the long-term maintenance dosing, participants continued or reduced the initial maintenance dose of food allergen protein to high (median 2 g protein) vs. low (median 300 mg protein). Participant follow-up included clinical monitoring, standardized OFCs, and in some cases, skin prick tests and measurement of allergen-specific IgE and IgG4. RESULTS: Irrespective of the high vs. low long-term maintenance dose during LTFU, all participants were able to ingest 2 g protein of each food allergen protein during OFCs performed at the end of our LTFU. CONCLUSION: Our LTFU cohort of food OIT participants from a single site, phase 1 OIT study, supports the feasibility of sustained desensitization through long-term maintenance dosing. Trial registration Registry: Clinicaltrial.gov. Registration numbers: NCT01490177 (original study); NCT03234764 (LTFU study). Date of registration: November 29, 2011 (original study); July 26, 2017 (LTFU study, registered).

Association of Clinical Reactivity with Sensitization to Allergen Components in Multifood-Allergic Children.

BACKGROUND: Thirty percent of children with food allergies have multiple simultaneous allergies; however, the features of these multiple allergies are not well characterized serologically or clinically. OBJECTIVE: We comprehensively evaluated 60 multifood-allergic patients by measuring serum IgE to key allergen components, evaluating clinical histories and medication use, performing skin tests, and conducting double-blind, placebo-controlled food challenges (DBPCFCs). METHODS: Sixty participants with multiple food allergies were characterized by clinical history, DBPCFCs, total IgE, specific IgE, and component-resolved diagnostics (IgE and IgG4) data. The food allergens tested were almond, egg, milk, sesame, peanut, pecan, walnut, hazelnut, cashew, pistachio, soy, and wheat. RESULTS: Our data demonstrate that of the reactions observed during a graded DBPCFC, gastrointestinal reactions occurred more often in boys than in girls, as well as in individuals with high levels of IgE to 2S albumins from cashew, walnut, and hazelnut. Certain food allergies often occurred concomitantly in individuals (ie, cashew/pistachio and walnut/pecan/hazelnut). IgE testing to components further corroborated serological relationships between and among these clustered food allergies. CONCLUSIONS: Associations of certain food allergies were shown by DBPCFC outcomes as well as by correlations in IgE reactivity to structurally related food allergen components. Each of these criteria independently demonstrated a significant association between allergies to cashew and pistachio, as well as among allergies to walnut, pecan, and hazelnut.

Diagnosis of Food Allergy.

The prevalence of food allergies has been on the increase over the last 2 decades. Diagnosing food allergies can be complicated, as there are multiple types that have distinct clinical and immunologic features. Food allergies are broadly classified into immunoglobulin E (IgE)-mediated, non-IgE-mediated, or mixed food allergic reactions. This review focuses on the clinical manifestations of the different categories of food allergies and the different tests available to guide the clinician toward an accurate diagnosis.

Two year effects of food allergen immunotherapy on quality of life in caregivers of children with food allergies.

BACKGROUND: Food allergy (FA) can have serious psychosocial and economic repercussions on food-allergic children and their caregivers and be associated with negative effects on their quality of life. Food allergen immunotherapy (IT) is a promising experimental therapy but can be linked to anxiety. This study investigated the effects of IT on FA-specific health-related quality of life (HRQL) over a 24 month-follow-up in caregivers of children with single and multiple food allergies. We hypothesized that characteristics such as age, asthma at baseline and respiratory allergic reactions during therapy were key characteristics that influenced HRQL scores. METHODS: A validated Food Allergy Quality of Life - Parental Burden Questionnaire (FAQL-PB) was used to assess HRQL. It was randomly distributed to and filled out by caregivers of 57 food-allergic children enrolled in clinical trials of IT. The same parent answered the FABQL-PB questionnaire at baseline and for 6-month, 12- month, 18- month, and 24-month time points on IT. RESULTS: Caregiver HRQL improved significantly (change < - 0.5, p <0.0001) at each follow-up time point compared to baseline. The percentages of caregivers with improvement in HRQL progressively increased (92% at 24 month-follow-up time point compared to baseline). HRQL improved more in caregivers of participants older than 10 years or desensitized to more than 4 food allergens than those who were not (p <0.0001). Caregivers of participants with pre-existing asthma or dose-related respiratory allergic reactions had less improvement in HRQL than those who did not (p <0.01). CONCLUSION: IT lead to improvement in caregiver HRQL. Certain characteristics were associated with greater improvements in caregiver HRQL.