Threshold dose for peanut: Risk characterization based upon published results from challenges of peanut-allergic individuals
Population thresholds for peanut are unknown. However, lowest- and no-observed adverse effect levels (LOAELs and NOAELs) are published for an unknown number of peanut-allergic individuals. Publications were screened for LOAELs and NOAELs from blinded, low-dose oral challenges. Data were obtained from 185 peanut-allergic individuals (12 publications). Data were analyzed by interval-censoring survival analysis and three probability distribution models fitted to it (Log-Normal, Log-Logistic, and Weibull) to estimate the ED10. All three models described the data well and provided ED10's in close agreement: 17.6, 17.0, and 14.6 mg of whole peanut for the Log-Normal, Log-Logistic, and Weibull models, respectively. The 95% lower confidence intervals for the ED10's were 9.2, 8.1, and 6.0 mg of whole peanut for the Log-Normal, Log-Logistic, and Weibull models, respectively. The modeling of individual NOAELs and LOAELs identified from three different types of published studies – diagnostic series, threshold studies, and immunotherapy trials – yielded significantly different whole peanut ED10's of 11.9 mg for threshold studies, 18.0 mg for diagnostic series and 65.5 mg for immunotherapy trials; patient selection and other biases may have influenced the estimates. These data and risk assessment models provide the type of information that is necessary to establish regulatory thresholds for peanut.
Peanut and tree nut consumption during pregnancy and allergic disease in children—should mothers decrease their intake? Longitudinal evidence from the Danish National Birth Cohort
Background: The relation between maternal peanut intake during pregnancy and allergic disease development in children has been controversial.
Objective: We used data from the Danish National Birth Cohort to examine associations between maternal peanut and tree nut intake during pregnancy and allergic outcomes in children at 18 months and 7 years of age.
Methods: We estimated maternal peanut and tree nut intake (n = 61,908) using a validated midpregnancy food frequency questionnaire. At 18 months, we used parental report of childhood asthma diagnosis, wheeze symptoms, and recurrent wheeze (>3 episodes). We defined current asthma at 7 years as doctor-diagnosed asthma plus wheeze in the past 12 months and allergic rhinitis as a self-reported doctor's diagnosis. We also used alternative classifications based on registry-based International Classification of Diseases, Tenth Revision, codes and drug dispensary data. We report here odds ratios (ORs) comparing intake of 1 or more times per week versus no intake.
Results: We found that maternal intake of peanuts (OR, 0.79; 95% CI, 0.65-0.97) and tree nuts (OR, 0.75; 95% CI, 0.67-0.84) was inversely associated with asthma in children at 18 months of age. Compared with mothers consuming no peanuts, children whose mothers reported eating peanuts 1 or more times per week were 0.66 (95% CI, 0.44-0.98) and 0.83 (95% CI, 0.70-1.00) times as likely to have a registry-based and medication-related asthma diagnosis, respectively. Higher tree nut intake was inversely associated with a medication-related asthma diagnosis (OR, 0.81; 95% CI, 0.73-0.90) and self-reported allergic rhinitis (OR, 0.80; 95% CI, 0.64-1.01).
Conclusions: Our results do not suggest that women should decrease peanut and tree nut intake during pregnancy; instead, consumption of peanuts and tree nuts during pregnancy might even decrease the risk of allergic disease development in children.
Antigen-fixed leukocytes tolerize th2 responses in mouse models of allergy
Allergic diseases; including asthma and food allergies; are an increasing health concern. Immunotherapy is an effective therapeutic approach for many allergic diseases but requires long dose escalation periods and has a high risk of adverse reactions; particularly in food allergy. New methods to safely induce Ag-specific tolerance could improve the clinical approach to allergic disease. We hypothesized that Ag-specific tolerance induced by the i.v. injection of Ags attached to the surface of syngeneic splenic leukocytes (Ag-coupled splenocytes [Ag-SPs]) with the chemical cross-linking agent ethylene-carbodiimide; which effectively modulate Th1/Th17 diseases; may also safely and efficiently induce tolerance in Th2-mediated mouse models of allergic asthma and food allergy. Mice were tolerized with Ag-SP before or after initiation of OVA/alum-induced allergic airway inflammation or peanut-induced food allergy. The effects on disease pathology and Th2-directed cytokine and Ab responses were studied. Ag-SP tolerance prevented disease development in both models and safely tolerized T cell responses in an Ag-specific manner in presensitized animals. Prophylactically; Ag-SP efficiently decreased local and systemic Th2 responses; eosinophilia; and Ag-specific IgE. Interestingly; Ag-SP induced Th2 tolerance was found to be partially dependent on the function of CD25(+) regulatory T cells in the food allergy model; but was regulatory T cell independent in the model of allergic airway inflammation. We demonstrate that Ag-SP tolerance can be rapidly; safely; and efficiently induced in murine models of allergic disease; highlighting a potential new Ag-specific tolerance immunotherapy for Th2-associated allergic diseases.
The eliciting dose of peanut in double-blind; placebo-controlled food challenges decreases with increasing age and specific IgE level in children and young adults.
Background: Several risk factors for severe anaphylactic reactions to food in daily life are known. However; to date; it is not possible to predict the severity of allergic reactions to food in the individual patient with accuracy. Some studies show that a history of severe reactions is associated with a lower eliciting dose in double-blind; placebo-controlled food challenges (DBPCFCs). Therefore; in this study; the eliciting dose was used as a measure of clinical sensitivity. Objectives: To study whether risk factors for severe allergic reactions to food in daily life such as age; degree of sensitization; and coexistent atopic disease influence the eliciting dose in DBPCFCs in children allergic to peanut. Methods: Data from children who had clinical reactions to peanut during DBPCFCs at the University Medical Center Groningen (2001-2009) were analyzed. A Cox regression model was used to analyze the association of the determinants with the eliciting dose. Results: One hundred twenty-six positive DBPCFCs with peanut were analyzed. Age older than 10 years; a specific IgE level above the lowest tertile (=5.6 kU/L); and the absence of atopic dermatitis were associated with reactions to lower doses: respective hazard ratios 1.89 (95% CI; 1.28-2.81; P = .001); 2.03 (95% CI; 1.37-3.00; P < .0001); and 0.45 (95% CI; 0.29-0.71; P = .001) present versus absent. No significant associations with the eliciting dose were found for sex; the presence of asthma and rhinitis; and the severity of food reactions by history. Conclusions: Using the eliciting dose as a measure of clinical sensitivity; greater clinical sensitivity in DBPCFCs to peanut was found to be associated with increasing age; higher specific IgE level; and the absence of atopic dermatitis. This finding may explain why adolescents experience severe allergic reactions in daily life to peanut more often than do younger children.
Efficacy and safety of high-dose peanut oral immunotherapy with factors predicting outcome.
Background: Peanut allergy is severe and rarely resolves. Objective: To test the efficacy and safety of a new oral immunotherapy (OIT) protocol for peanut allergy. Method Twenty-two peanut-allergic children underwent oral challenge. OIT was administered by gradual updosing with 2-weekly increments (8-38 weeks) to 800 mg of protein (5 peanuts/day) followed by 30-week maintenance. Oral challenge was repeated after 6 and 30 weeks maintenance. Results Twenty-two children (median 11 years) had positive challenges (threshold 1-110 mg). Nineteen of 22 (86%) tolerated updosing and maintenance at 800 mg protein/day. One of 22 dropped out; 2/22 tolerated updosing and maintenance at 200-400 mg protein. Reactions; mostly mild; occurred in 86% during immunotherapy; adrenaline was not required. Eight of 8 with pre-immunotherapy peanut IgE<27.3 kU/L required no dose adjustment compared with 5/13 with pre-immunotherapy peanut IgE27.3 kU/L. Twelve of 22 (54%) required a transient dose reduction because of reactions possibly related to extrinsic factors: tiredness; infection and exercise. After 6 weeks; 12/22 (54%) had no reaction to a 2.6 g protein challenge. After 30 weeks; 14/22 (64%) tolerated 6.6 g protein. The median tolerated peanut dose increased 1000-fold following immunotherapy; from 6 to 6459 mg of protein. Conclusions and Clinical Relevance: We used a novel protocol using gradual updosing; and higher maintenance dose resulting in a better outcome compared with rush protocols. There was a 1000-fold increase in the amount of peanut tolerated with a good safety profile. No serious adverse events occurred. Most subjects tolerated five peanuts and all were protected against amounts likely during accidental ingestion. New information is provided on 'extrinsic factors'; updosing method and factors associated with success (trial registration http://ClinicalTrials.gov- ID number NCT01259804).
Skin prick testing and peanut-specific IgE can predict peanut challenge outcomes in preschoolchildren with peanut sensitization.
BACKGROUND: The rise in peanut allergy is a source of considerable burden in the community. A growing number of pre-schoolchildren have been identified as peanut sensitized in the course of investigation of other allergic conditions. Although many have never knowingly ingested peanuts and their clinical reactivity is not known; it has been common practice to place these children on avoidance diets for many years. OBJECTIVE: To determine the utility of skin prick tests (SPT) and fluorescent-enzyme immunoassays (FEIA) for identifying either peanut allergy or tolerance in pre-schoolchildren with peanut sensitization. METHODS: Forty-nine pre-schoolchildren (<5 years of age) with peanut sensitization (SPT 2 mm or peanut-specific IgE 0.35 kU/L) but unknown clinical reactivity had graded open peanut challenges reaching a total of 11g. A positive challenge was defined as an objective IgE-mediated reaction during challenge or the 2-h observation. Results Forty-nine percent (24/49) of children had positive challenges. An SPT of > 7 mm on the day of challenge predicted a positive challenge with a sensitivity of 83% and a negative predictive value (NPV) of 84%. An FEIA of > 2.0 kU/L showed a sensitivity of 79% and an NPV of 80%. Predicting challenge outcome from a combination of SPT and FEIA (SPT > 7 and/or FEIA > 2 is positive) increased sensitivity to 96% and NPV to 95%. CONCLUSION AND CLINICAL RELEVANCE: At least half of pre-schoolchildren with peanut sensitization and no antecedent history of peanut ingestion can tolerate peanuts. A SPT<7 mm and FEIA < 2 kU/L identify children most likely to tolerate peanut; with only a 5% likelihood of failing an oral challenge. This study assists clinicians considering challenges in very young peanut-sensitized children.
A randomized controlled study of peanut oral immunotherapy: Clinical desensitization and modulation of the allergic response
Abstract BACKGROUND: Open-label oral immunotherapy (OIT) protocols have been used to treat small numbers of patients with peanut allergy. Peanut OIT has not been evaluated in double-blind; placebo-controlled trials. OBJECTIVE: To investigate the safety and effectiveness of OIT for peanut allergy in a double-blind; placebo-controlled study. METHODS: In this multicenter study; children ages 1 to 16 years with peanut allergy received OIT with peanut flour or placebo. Initial escalation; build-up; and maintenance phases were followed by an oral food challenge (OFC) at approximately 1 year. Titrated skin prick tests (SPTs) and laboratory studies were performed at regular intervals. RESULTS: Twenty-eight subjects were enrolled in the study. Three peanut OIT subjects withdrew early in the study because of allergic side effects. During the double-blind; placebo-controlled food challenge; all remaining peanut OIT subjects (n = 16) ingested the maximum cumulative dose of 5000 mg (approximately 20 peanuts); whereas placebo subjects (n = 9) ingested a median cumulative dose of 280 mg (range; 0-1900 mg; P < .001). In contrast with the placebo group; the peanut OIT group showed reductions in SPT size (P < .001); IL-5 (P = .01); and IL-13 (P = .02) and increases in peanut-specific IgG(4) (P < .001). Peanut OIT subjects had initial increases in peanut-specific IgE (P < .01) but did not show significant change from baseline by the time of OFC. The ratio of forkhead box protein 3 (FoxP3)(hi): FoxP3(intermediate) CD4+ CD25+T cells increased at the time of OFC (P=04) in peanut OIT subjects. CONCLUSION: These results conclusively demonstrate that peanut OIT induces desensitization and concurrent immune modulation. The current study continues and is evaluating the hypothesis that peanut OIT causes long-term immune tolerance.