Tolerance induction through non-avoidance to prevent persistent food allergy (TINA) in children and adults with peanut or tree nut allergy: rationale, study design and methods of a randomized controlled trial and observational cohort study.

BACKGROUND: Peanuts (PN) and tree nuts (TN) are among the most frequent elicitors of food allergy and can lead to life-threatening reactions. The current advice for allergic patients is to strictly avoid the offending food independently of their individual threshold level, whereas sensitized patients without allergic symptoms should frequently consume the food to avoid (re-)development of food allergy. The aim of this trial is to investigate (I) whether the consumption of low allergen amounts below the individual threshold may support natural tolerance development and (II) to what extent regular allergen consumption in sensitized but tolerant subjects prevents the (re-)development of PN or TN allergy. METHODS: The TINA trial consisting of (part I) a randomized, controlled, open, parallel group, single-center, superiority trial (RCT), and (part II) a prospective observational exploratory cohort study. Children and adults (age 1-67 years) with suspected or known primary PN and/or TN allergy will undergo an oral food challenge (OFC) to determine their clinical reactivity and individual threshold. In the RCT, 120 PN or TN allergic patients who tolerate ≥100 mg of food protein will be randomized (1:1 ratio) to consumption of products with low amounts of PN or TN on a regular basis or strict avoidance for 1 year. The consumption group will start with 1/100 of their individual threshold, increasing the protein amount to 1/50 and 1/10 after 4 and 8 months, respectively. The primary endpoint is the clinical tolerance to PN or TN after 1 year assessed by OFC. In the cohort study, 120 subjects sensitized to PN and/or TN but tolerant are advised to regularly consume the food and observed for 1 year. The primary endpoint is the maintenance of clinical tolerance to PN and/or TN after 1 year assessed by challenging with the former tolerated cumulative dose. DISCUSSION: This clinical trial will help to determine the impact of allergen consumption versus avoidance on natural tolerance development and whether the current dietary advice for PN or TN allergic patients with higher threshold levels is still valid. TRIAL REGISTRATION: German Clinical Trials Register; ID: DRKS00016764 (RCT), DRKS00020467 (cohort study). Registered on 15 January 2020, http://www.drks.de .

Multicentre Double-Blind Placebo-Controlled Food Challenge Study in Children Sensitised to Cashew Nut.

BACKGROUND: Few studies with a limited number of patients have provided indications that cashew-allergic patients may experience severe allergic reactions to minimal amounts of cashew nut. The objectives of this multicentre study were to assess the clinical relevance of cashew nut sensitisation, to study the clinical reaction patterns in double-blind placebo-controlled food challenge tests and to establish the amount of cashew nuts that can elicit an allergic reaction. METHODS AND FINDINGS: A total of 179 children were included (median age 9.0 years; range 2-17 years) with cashew nut sensitisation and a clinical history of reactions to cashew nuts or unknown exposure. Sensitised children who could tolerate cashew nuts were excluded. The study included three clinical visits and a telephone consultation. During the first visit, the medical history was evaluated, physical examinations were conducted, blood samples were drawn and skin prick tests were performed. The children underwent a double-blind placebo-controlled food challenge test with cashew nut during the second and third visits. The study showed that 137 (76.5%) of the sensitised children suspected of allergy to cashew nut had a positive double-blind placebo-controlled food challenge test, with 46% (63) manifesting subjective symptoms to the lowest dose of 1 mg cashew nut protein and 11% (15) developing objective symptoms to the lowest dose. Children most frequently had gastro-intestinal symptoms, followed by oral allergy and skin symptoms. A total of 36% (49/137) of the children experienced an anaphylactic reaction and 6% (8/137) of the children were treated with epinephrine. CONCLUSION: This prospective study demonstrated a strikingly high percentage of clinical reactions to cashew nut in this third line population. Severe allergic reactions, including anaphylaxis requiring epinephrine, were observed. These reactions were to minimal amounts of cashew nut, demonstrated the high potency of this allergens. TRIAL REGISTRATION: www.ncbi.nlm.nih.gov/pubmed NTR3572.

Safety, clinical, and immunologic efficacy of a Chinese herbal medicine (Food Allergy Herbal Formula-2) for food allergy.

BACKGROUND: Food Allergy Herbal Formula-2 (FAHF-2) is a 9-herb formula based on traditional Chinese medicine that blocks peanut-induced anaphylaxis in a murine model. In phase I studies FAHF-2 was found to be safe and well tolerated. OBJECTIVE: We sought to evaluate the safety and effectiveness of FAHF-2 as a treatment for food allergy. METHODS: In this double-blind, randomized, placebo-controlled study 68 subjects aged 12 to 45 years with allergies to peanut, tree nut, sesame, fish, and/or shellfish, which were confirmed by baseline double-blind, placebo-controlled oral food challenges (DBPCFCs), received FAHF-2 (n = 46) or placebo (n = 22). After 6 months of therapy, subjects underwent DBPCFCs. For those who demonstrated increases in the eliciting dose, a repeat DBPCFC was performed 3 months after stopping therapy. RESULTS: Treatment was well tolerated, with no serious adverse events. By using intent-to-treat analysis, the placebo group had a higher eliciting dose and cumulative dose (P = .05) at the end-of-treatment DBPCFC. There was no difference in the requirement for epinephrine to treat reactions (P = .55). There were no significant differences in allergen-specific IgE and IgG4 levels, cytokine production by PBMCs, or basophil activation between the active and placebo groups. In vitro immunologic studies performed on subjects' baseline PBMCs incubated with FAHF-2 and food allergen produced significantly less IL-5, greater IL-10 levels, and increased numbers of regulatory T cells than untreated cells. Notably, 44% of subjects had poor drug adherence for at least one third of the study period. CONCLUSION: FAHF-2 is a safe herbal medication for subjects with food allergy and shows favorable in vitro immunomodulatory effects; however, efficacy for improving tolerance to food allergens is not demonstrated at the dose and duration used.

Ten-year review reveals changing trends and severity of allergic reactions to nuts and other foods.

AIM: Over the past few decades, the incidence of food allergies has risen and Sweden has increased its import of peanuts and exotic nuts, such as cashew nuts, which may cause severe allergic reactions. This study aimed to retrospectively investigate paediatric emergency visits due to food reactions over a 10-year period, focusing on reactions to peanuts and tree nuts. METHODS: Emergency visits to Uppsala University Children's Hospital, Sweden, between September 2001 and December 2010, were reviewed, and cases containing diagnostic codes for anaphylaxis, allergic reactions or allergy and hypersensitivity not caused by drugs or biological substances were retrieved. RESULTS: We analysed 703 emergency visits made by 578 individuals with food allergies. Peanuts and tree nuts accounted for 50% of the food allergies and were more frequently associated with adrenaline treatment and hospitalisation than other foods. Cashew nut reactions increased over the study period, and together with peanuts, they were responsible for more anaphylactic reactions than hazelnuts. CONCLUSION: Peanut and tree nut reactions were more likely to result in adrenaline treatment and hospitalisation than other food reactions. Peanut and cashew nut reactions were more likely to cause anaphylaxis than hazelnuts. Cashew nut reactions increased during the study period.

Basophil CD203c levels are increased at baseline and can be used to monitor omalizumab treatment in subjects with nut allergy.

RATIONALE: Basophils contribute to anaphylaxis and allergies. We examined the utility of assessing basophil-associated surface antigens (CD11b/CD63/CD123/CD203c/CD294) in characterizing and monitoring subjects with nut allergy. METHODS: We used flow cytometry to analyze basophils at baseline (without any activation) and after ex vivo stimulation of whole blood by addition of nut or other allergens for 2, 10, and 30 min. We also evaluated whether basophil expression of CD11b/CD63/CD123/CD203c/CD294 was altered in subjects treated with anti-IgE monoclonal antibody (omalizumab) to reduce plasma levels of IgE. RESULTS: We demonstrate that basophil CD203c levels are increased at baseline in subjects with nut allergy compared to healthy controls (13 subjects in each group, p < 0.0001). Furthermore, we confirm that significantly increased expression of CD203c occurs on subject basophils when stimulated with the allergen to which the subject is sensitive and can be detected rapidly (10 min of stimulation, n = 11, p < 0.0008). In 5 subjects with severe peanut allergy, basophil CD203c expression following stimulation with peanut allergen was significantly decreased (p < 0.05) after 4 and 8 weeks of omalizumab treatment but returned toward pretreatment levels after treatment cessation. CONCLUSIONS: Subjects with nut allergy show an increase of basophil CD203c levels at baseline and following rapid ex vivo stimulation with nut allergen. Both can be reduced by omalizumab therapy. These results highlight the potential of using basophil CD203c levels for baseline diagnosis and therapeutic monitoring in subjects with nut allergy.

Good prognosis, clinical features, and circumstances of peanut and tree nut reactions in children treated by a specialist allergy center.

BACKGROUND: The diagnosis of nut allergy causes anxiety. Few studies exist that estimate risk of reactions and inform management. OBJECTIVE: To describe frequency and circumstances of reactions after the institution of a management plan. METHODS: Prospective study of children with peanut/nut allergy with an allergist's management plan. Severity and circumstances of worst reaction before diagnosis (index) and follow-up reactions were evaluated. RESULTS: A total of 785 children were followed for 3640 patient-years from diagnosis. Index reactions were mild in 66% (516), moderate in 29% (224), and severe in 5% (45). Fourteen percent (114/785) had follow-up reactions (3% annual incidence rate). Ninety percent had the same/reduced severity grade, and 1 of 785 (0.1%) had a severe reaction. Preschool children (n = 263) had a low incidence of reactions, and none were severe. There was a 3-fold reduction in injected epinephrine use from that used in the index reaction, required in 1 severe reaction, never twice; 14% (16/114) required no medication, 78% only oral antihistamines. Forty-eight percent reacted to the index nut type, 19% to a different nut (55% sensitized at diagnosis, 14% not sensitized, 31% not tested). Accidental versus index reactions were 4-fold more likely to be a result of contact exposure rather than ingestion. Contact reactions were always mild. Most (53%) reactions occurred at home, 5% in school, 21% at other sites (21% not recorded). The nut was given by a parent/self in 69 (61%) reactions or teacher in 5 (4%). CONCLUSION: With a comprehensive management plan, accidental reactions were uncommon and usually mild, most requiring little treatment; 99.8% self-treated appropriately and 100% effectively.

Reported food allergy to peanut, tree nuts and fruit: comparison of clinical manifestations, prescription of medication and impact on daily life.

BACKGROUND: Peanut (PN), tree nuts (TN) and fruits are frequent causes of food allergy (FA). Peanut and TN are believed to cause more severe reactions than fruits. However, there are no studies comparing the severity of PN, TN and fruit allergy within one patient group. METHODS: Four-hundred and eleven adult patients referred to our tertiary allergy center with suspicion of FA completed a standardized questionnaire. Patients with a typical history of immunoglobulin E (IgE)-mediated allergy, e.g. oropharyngeal symptoms to PN, TN (hazelnut, walnut, cashew nut) or fruit (apple, kiwi, peach, pear and cherry) were recruited (218/411). The objective was to evaluate differences in clinical severity between PN, TN and fruit allergy and how this was reflected by prescription of emergency medication and impact on daily life. RESULTS: Eighty-two percent of the included 218 patients were sensitized to the respective foods. The percentages of severe symptoms (i.e. respiratory or cardiovascular symptoms) in PN, TN and fruit allergic patients were respectively 47%, 39% and 31% (respiratory) and 11%, 5.0% and 3.4% (cardiovascular). Prescription and use of emergency medication (epinephrine, antihistamines and steroids) did not differ among the three groups. The majority of patients with a PN or TN allergy (72%) and fruit allergy (62%) reported that FA influences their daily life considerably. CONCLUSIONS: Fruit allergy causes less severe symptoms than TN and especially PN allergy. However, this is not reflected in the prescription or use of emergency medication. This may indicate that physicians are not fully acquainted with the guidelines for prescription of emergency medication. A high impact on daily life was found both in PN, TN and in fruit allergy.

Peanut and tree nut allergy in childhood.

Peanut and tree nut allergies present multiple challenges in their presentation and management. These challenges have become increasingly relevant in recent years, as these allergies appear to have become more common. An estimated 1-2% of the population in the USA is allergic to peanut or tree nuts. Peanut allergy typically presents with symptoms in one of the first few exposures to peanut. Diagnosis is based on clinical history along with skin prick test, or quantitation of allergen-specific immunoglobulin E (IgE), and oral food challenges when indicated. Once the diagnosis is confirmed, the only current management approach is strict avoidance of the food. This is clearly an imperfect option as it can be difficult to avoid completely peanut and tree nuts and accidental exposures are not uncommon. Only about 20% of those with peanut allergy, and <10% of those with tree nut allergy, are reported to acquire tolerance. Additionally, peanut allergy can recur, with one study finding a recurrence rate of 8%. Peanut and tree nuts are the foods most frequently associated with fatal episodes of anaphylaxis. This is of particular concern in adolescents and young adults, among whom life-threatening and fatal food allergy-related reactions are most common.

Anaphylaxis to foods.

Three crucial areas of the management of anaphylaxis due to food allergy are discussed: making a diagnosis, deciding who needs a self-injectable adrenaline device and spotting the novel allergen. Managing children and teenagers with anaphylaxis is challenging due to the lack of available evidence that specific addresses these issue. The available evidence is presented and discussed.

Cashew nut causes more severe reactions than peanut: case-matched comparison in 141 children.

BACKGROUND: Cashew nut allergy is becoming common, but the risk of severe reactions in comparison with peanut allergy is unknown. METHOD: A case-matching study of children with a recent history of a reaction after definite nut ingestion, with positive skin prick test. Children whose worst ever reaction was to cashew nut (cashew group), were matched with two children each whose worst ever reaction was to peanut (peanut group) for sex, age of reaction and presentation, amount ingested, and asthma. Severity of the worst clinical reactions to date was compared. RESULTS: A total of 47 children in the cashew group were matched to 94 in the peanut group. There were no differences in clinical features between groups for matching criteria, except asthma (more prevalent in the peanut group). Wheezing and cardiovascular symptoms were reported more frequently during reactions in the cashew compared with the peanut group: odds ratios (OR) 8.4 (95% CI: 3.2-22.0) and 13.6 (95% CI: 5.6-32.8), respectively. The cashew group received intramuscular adrenaline more frequently: OR 13.3 (95% CI: 5.5-32.2). Overall, the OR for a severe reaction (severe dyspnoea and/or collapse) in the cashew group was 25.1 (95% CI: 3.1-203.5). CONCLUSIONS: Previous studies show cashew nut can cause severe reactions; this is the first study to show by case-matching that severe clinical reactions occur more frequently in cashew compared with peanut allergy. The nut type which caused the worst reaction to date should be considered when providing emergency medication.

[Anaphylaxis in two children caused by peanut and nut allergies; recommendations for treatment]. / Anafylaxie door pinda- en notenallergie bij 2 kinderen; aanbevelingen voor beleid.

Two girls aged 12 and 7 years with asthma and peanut and nut allergy developed anaphylactic shock after ingestion of peanuts and nuts from an unreported source. They were both given intramuscular epinephrine. The 12-year-old girl was treated clinically for shock and after two days was discharged from hospital. The 7-year-old girl died. Risk factors for life-threatening anaphylactic reactions are adolescent to young adult age, asthma, previous severe anaphylactic reactions to the food in question, previous reaction to small dose of the food in question and allergy to peanuts or tree nuts. A double-blind, placebo-controlled food challenge should be carried out to document the culprit food. The most important therapeutic intervention is the intramuscular administration of epinephrine. For patients with two or more risk factors the prescription of an epinephrine auto-injector should be considered.

Differences in race, ethnicity, and socioeconomic status in schoolchildren dispensed injectable epinephrine in 3 Massachusetts school districts.

BACKGROUND: Published surveys depicting the increase in the incidence of food allergy, especially peanut or tree nut allergy, in children have not reported any differences in race, ethnicity, or socioeconomic status. OBJECTIVE: To analyze the demographics of schoolchildren with diverse racial, ethnic, and socioeconomic characteristics dispensed injectable epinephrine. METHODS: School nurses in 44 schools enrolling 21,875 students recorded the characteristics of students dispensed injectable epinephrine in the 2003-2004 school year. Surveyed school districts included 2 affluent suburban districts enrolling 5,855 students (> 92% white) and 1 urban district enrolling 16,020 students (60% nonwhite). RESULTS: A total of 181 students in all 3 districts were dispensed injectable epinephrine; 118 of these children had peanut or tree nut allergy. Males were more likely to be dispensed injectable epinephrine than females (odds ratio [OR], 1.44; P < .02). Whites were more likely to have been dispensed injectable epinephrine than nonwhites (OR, 4.76; P < .001). Whites were nearly 5 times more likely to be dispensed injectable epinephrine for peanut or tree nut allergy than nonwhites (OR, 4.5; P < .001). Most students (75%) dispensed injectable epinephrine for peanut or tree nut allergy were enrolled in prekindergarten through grade 5 (P < .001). Whites were more likely than nonwhites to be dispensed injectable epinephrine for stinging insect allergy (OR, 8.7; P < .001). CONCLUSIONS: This study found significant racial, ethnic, and socioeconomic differences in the prevalence of childhood allergic disorders, especially peanut or tree nut allergy, requiring prescribed injectable epinephrine in a school setting. Additional studies are needed to determine whether minority children are being underdiagnosed or undertreated for allergic disorders requiring injectable epinephrine or whether they truly have a lower incidence of such allergic disorders.

Anaphylaxis induced by pine nuts in two young girls.

Pine nuts are the seeds of Pinus pinea. There are few reported cases of allergy to pine nut. We describe two young girls with anaphylaxis caused by small amounts of pine nuts. Specific IgE to pine nut was demonstrated by skin prick tests and RAST but no IgE to other nuts and pine pollen was detected. The patients had IgE against a pine nut protein band with apparent molecular weights of approximately 17 kDa that could be considered as the main allergen. Our patients were monosensitized to pine nut and the 17-kDa protein could be correlated with the severe clinical symptoms.

Adrenaline autoinjectors and schoolchildren: a community based study.

Sixty schoolchildren prescribed adrenaline autoinjectors were identified by surveying schools in Hounslow, London; the 25 families who consented were interviewed. There was inconsistency in prescription and use of autoinjectors with poor training, absence of written instructions, and lack of follow up. It is recommended that national guidelines should be developed.