Validation of the NUT CRACKER Diagnostic Algorithm and Prediction for Cashew and Pistachio Co-Allergy.

BACKGROUND: Because of the high cross-sensitization among tree nuts, the NUT CRACKER (Nut Co-reactivity-Acquiring Knowledge for Elimination Recommendations) study proposed a diagnostic algorithm to minimize the number of required oral food challenges (OFCs). OBJECTIVE: To validate the algorithm for cashew and pistachio allergy and determine markers for allergic severity. METHODS: Patients (n = 125) with a median age of 7.8 (interquartile range, 5.9-11.2) years with suspected tree nut allergy were evaluated prospectively with decision tree points on the basis of skin prick test (SPT), basophil activation test (BAT), and knowledge of the coincidence of allergies. Validation of allergic status was determined by OFC. Markers of clinical severity were evaluated using the combined original and prospective cohort (n = 187) in relationship to SPT, BAT, and Ana o 3-sIgE. RESULTS: Reactivity to cashew in SPT, BAT, and Ana o 3-sIgE and the incidence of abdominal pain on challenge were significantly higher in dual-allergic cashew/pistachio patients (n = 82) versus single cashew allergic patients (n = 18) (P = .001). All 3 diagnostic tests showed significant inverse correlation with log10 reaction doses for positive cashew OFC. The algorithm reduced overall the total number of OFCs by 72.0%, with a positive predictive value and negative predictive value of 93.0% and 99.0%, respectively. Cashew false-positives were observed primarily in hazelnut-allergic patients (P = .026). In this population, Ana o 3-specific IgE could diagnose cashew allergy with a sensitivity of more than 90% and a specificity of more than 95%. CONCLUSIONS: The NUT CRACKER diagnostic algorithm was validated and reduced the number of diagnostic OFCs required. Markers for severity phenotypes may guide oral immunotherapy protocols, improving the risk/benefit ratio for patients.

Sesame eliciting and safe doses in a large sesame allergic population.

BACKGROUND: Sesame is a significant food allergen causing severe and even fatal reactions. Given its increasing prevalence in western diet, sesame is listed as an allergenic food requiring labeling in the United States and EU. However, data on the population reaction doses to sesame are limited. METHODS: All sesame oral food challenges (OFCs), performed either for diagnosis or for threshold identification before the beginning of sesame oral immunotherapy (OIT) between November 2011 and July 2021 in Shamir medical center were analyzed for reaction threshold distribution. Safe-dose challenges with 90-120 min intervals were also analyzed. RESULTS: Two hundred and fifty patients underwent 338 positive OFCs, and additional 158 safe-dose OFCs were performed. The discrete and cumulative protein amounts estimated to elicit an objective reaction in 1% (ED01) of the entire cohort (n = 250) were 0.8 mg (range 0.3-6.3) and 0.7 mg (range 0.1-7.1), respectively, and those for 5% of the population (ED05) were 3.4 mg (range 1.2-20.6) and 4.5 mg (range 1.2-28.8), respectively. Safe-dose OFCs showed similar values of ED01 (0.8, 0.4-7.5 mg) and ED05 (3.4, 1.2-22.9 mg). While doses of ≤1 mg sesame protein elicited oral pruritus in 11.6% of the patients, no objective reaction was documented to this amount in any of the challenges, including safe-dose OFCs. CONCLUSIONS: This study provides data on sesame reaction threshold distribution in the largest population of allergic patients studied, with no right or left censored data, and with validation using a safe-dose OFC. It further supports the current methods for ED determination as appropriate for establishing safety precautions for the food industry.

Severe Anaphylactic Reactions to Home Doses of Oral Immunotherapy for Food Allergy.

BACKGROUND: Severe anaphylactic reactions to home doses may occur during food allergy oral immunotherapy (OIT). OBJECTIVE: To study the rate and risk factors for such reactions. METHODS: We studied all patients aged greater than 3.5 years who completed OIT in a single center between April 2010 and January 2020. All home epinephrine-treated reactions (HETRs) were identified. High-grade HETRs (HG-HETRs) were defined as HETRs involving respiratory (SpO2 of 94% or less), cardiovascular (low blood pressure), or central nervous system impairment (loss of consciousness). We investigated the rate and risk factors for HG-HETRs. RESULTS: A total of 1,637 OIT treatments were studied: milk (880), peanut (346), tree nuts (221), sesame (115), and egg (75). Of 390 identified HETRs, 30 HG-HETRs occurred during 27 treatments (1.65% of all treatments). Nearly all (26 of 30) were during milk OIT in patients with house dust mite (HDM) sensitization and asthma (26 of 30 each). Of the 30 patients with HG-HETRs, 21 recovered with one or two epinephrine treatments, but nine (0.55% of all treatments) did not respond to a second dose of epinephrine and were deemed to have refractory anaphylaxis. Three patients required intensive care unit admission and three received epinephrine drip, but none required ventilatory support. Risk factors for HG-HETRs included milk OIT (P = .031), asthma (P = .02) and HDM sensitization (P = .02). No specific triggers for HG-HETR were identified. Of patients with HG-HETRs, 25.9% were fully desensitized, including the four non-milk treated patients; 22.2% were partially desensitized; and 51.9% failed. CONCLUSIONS: High-grade HETRs are uncommon, particularly refractory anaphylactic reactions to home OIT doses. Although milk OIT, asthma, and HDM sensitization are the main risk factors for such reactions, identification of patients who are at risk is challenging.

Factors associated with home epinephrine-treated reactions during peanut and tree-nut oral immunotherapy.

BACKGROUND: Home reactions requiring epinephrine administration, a marker of their severity, restrict the widespread use of oral immunotherapy (OIT), but their risk factors are largely not known. OBJECTIVE: To identify risk factors for such reactions during OIT to most allergenic foods. METHODS: All patients who began OIT for peanut, tree nuts, sesame, or egg allergy at the Shamir Medical Center between April 2010 and January 2020 were enrolled. The patients were instructed to use their epinephrine autoinjectors during reactions consisting of severe abdominal pain, significant shortness of breath, or lethargy, or whenever in uncertainty of reaction severity. Patients with and without home epinephrine-treated reactions (HETRs) were compared. RESULTS: A total of 757 OIT treatments for peanut (n = 346), tree nuts (n = 221; walnut n = 147, cashew n = 57, hazelnut n = 16, almond n = 1), sesame (n = 115), and egg (n = 75) allergies were administered to 644 patients. Eighty-three (10.9%) patients experienced HETRs. The highest rate of HETRs was experienced during walnut (20.4%) or hazelnut (25%) OIT, followed by peanut (9.8%), sesame (6.1%), egg (6.7%), and cashew (5.3%) OIT. Risk factors for HETRs included a reaction treated in an emergency department (ER) (P = .005) before starting OIT and a reaction treated with epinephrine during in-clinic induction (P < .001). Significantly fewer patients with (73.6%) than without (88.3%) HETRs achieved full desensitization (P = .001), but only a few patients with HETRs (8.4%) failed treatment. CONCLUSION: Previous reaction severity is the main predictor for HETRs during OIT. These reactions are more frequent during walnut and hazelnut OIT than during OIT for other foods studied. Most patients experiencing HETRs achieved desensitization.

Informing Risk Management for Patients With Cow's Milk Allergy Based on Threshold Dose Distributions Using Low-Dose Food Challenges.

BACKGROUND: The safe consumption of foods depends on their allergen content in relation to patients' lowest observed adverse effect level (LOAEL) and no observed adverse effect level (NOAEL), as well as other factors. In the case of milk, data on LOAEL and NOAEL are limited and conflicting. OBJECTIVE: To determine the threshold dose distribution and the lowest individual eliciting dose (ED) for milk in a large group of milk-allergic patients METHODS: Individuals with confirmed cow's milk allergy who underwent a diagnostic or pre-oral immunotherapy open milk oral food challenge at the Institute of Allergy, Immunology, and Pediatric Pulmonology at Shamir Medical Center between 2010 and 2015 were included. A subgroup of patients with severe milk allergy underwent a modified challenge with a 90- to 120-minute interval after a starting dose of 0.3 mg cow's milk protein. RESULTS: A total of 866 participants (193 with diagnostic challenges and 673 with pre-oral immunotherapy challenges) were included in the study. The discrete ED01 and ED05, or values derived in which 1% or 5% of the respective allergic population would be predicted to experience an allergic reaction, were 1.1 to 1.9 and 4.7 to 5.6 mg milk protein, respectively, and values for cumulative doses for ED01 and ED05 were 0.9 to 1.8 and 5.2 to 6.2 mg milk protein, respectively. No patients, including the most severely milk-allergic individuals who underwent the modified challenge, reacted to the first 0.3 mg protein dose. CONCLUSION: This report provides valuable information about milk NOAELs, LOAELs, and EDs that might assist regulators in decisions about food labeling in general, and milk in particular.

Characteristics of patients diagnosed as non-allergic following food allergy oral immunotherapy referral.

BACKGROUND: Ascribing food allergy diagnosis to patients who are not allergic is well described, but its implications on oral immunotherapy (OIT) have not been studied. The aim was to study non-allergic patients referred for OIT. METHODS: All patients who began OIT at Shamir Medical Center between November 2015 and August 2020 were included. Medical records were reviewed, and skin prick tests (SPT) and/or specific IgE were measured. Patients were challenged to the index food. Allergic and non-allergic patients were compared. RESULTS: A total of 1073 patients were studied (milk, n = 327; egg, n = 41; peanut, n = 272; sesame, n = 130; and tree nuts, n = 303) and 87 (8.1%) were found non-allergic (milk, n = 21; egg, n = 6; sesame, n = 5; peanut, n = 29; tree nuts, n = 26). Predictors of being not allergic were no previous reaction to the index food (OR = 3.3, p = 0.001), not having asthma (OR = 2.4, p = 0.001), or HDM sensitization (OR = 2.0, p = 0.007), male sex (OR = 2.3, p = 0.004), and a smaller SPT wheal size (OR = 1.5, p < 0.001). CONCLUSIONS: A substantial number of patients referred for OIT are mislabeled with food allergy, suffer from unjustly food limitations and impairments in quality of life, and "take up" OIT places of true allergic patients. Awareness of OIT centers to this phenomenon is important. IMPACT: A significant number (8.1%) of patients referred for OIT are found not allergic to the food they intended to treat. This study characterizes non-allergic patients referred for OIT (a lack of previous reaction to the index food, a smaller or negative SPT wheal size, and less atopic co-morbidities) and discusses the implications of such referrals. Increased awareness by OIT centers to potential non-allergic patients referred for OIT is required, including screening of patients before treatment initiation, to minimize unnecessary treatments of non-allergic patients.

Efficacy and safety of food allergy oral immunotherapy in adults.

BACKGROUND: Oral immunotherapy (OIT) is an emerging method for treating food allergy in children. However, data regarding adults undergoing this process are lacking. METHODS: We retrospectively analyzed the medical records of patients with food allergy aged ≥17 years who completed OIT treatment between April 2010 and December 2020 at Shamir Medical Center. Data were compared with that of children aged 4 to <11 years and adolescents aged ≥11 to 17 treated during the same time period. RESULTS: A total of 96 adults at a median age of 22.3 years who underwent OIT for milk (n = 53), peanut (n = 18), sesame (n = 7), egg (n = 5), and tree nuts (n = 13) were analyzed and compared with 1299 children and 309 adolescents. Adults experienced more adverse reactions requiring injectable epinephrine, both during in-clinic up-dosing (49% vs. 15.9% and 26.5% for children and adolescents, respectively, p < 0.0001) and during home treatment (22.9% vs. 12.4%, p = 0.007 for children, and 17.5%, p = 0.23 for adolescents). Most adults (61.5%) were fully desensitized, but the rates of full desensitization were significantly lower than children (73.4%, p = 0.013). Significantly more adults (28.3%) undergoing milk OIT failed treatment than children (14.3%, p = 0.015) and adolescents (14.1%, p = 0.022), while failure rates in adults undergoing OIT for other foods were low (9.3%) and comparable with children and adolescents. CONCLUSIONS: OIT is successful in desensitizing most adults with IgE-mediated food allergy. Adults undergoing milk OIT are at increased risk for severe reactions and for OIT failure while failure rates in adults undergoing OIT for other foods are low.

Cashew oral immunotherapy for desensitizing cashew-pistachio allergy (NUT CRACKER study).

BACKGROUND: Oral immunotherapy (OIT) is a treatment option for patients with milk, egg, and peanut allergy, but data on the efficacy and safety of cashew OIT are limited. METHODS: A cohort of 50 cashew-allergic patients aged ≥4 years, who were consecutively enrolled into cashew OIT (target dose 4000 mg protein) between 4/2016 and 12/2019. Fifteen cashew-allergic patients who continued cashew elimination served as observational controls. Co-allergy to pistachio and walnut was determined. Full desensitization rate and associated immunological changes in both groups were compared. Patients fully desensitized to cashew were instructed to consume a dose of 1200 mg cashew protein for 6 months and were then challenged to a full dose. Patients with co-allergy to pistachio or walnut were challenged to the respective nut. RESULTS: Forty-four of 50 OIT-treated patients (88%) compared to 0% in controls tolerated a dose of 4000 mg cashew protein at the end of the study (odds ratio 8.3, 95% CI 3.9-17.7, p < 0.001). An additional three patients were desensitized to 1200 mg cashew protein, and three patients stopped treatment. Three patients (6%) were treated with injectable epinephrine for home reactions. Desensitized patients had decreased SPT, sIgE, basophil reactivity, and increased sIgG4, following treatment. Following cashew desensitization, all pistachio (n = 35) and four of eight walnut co-allergic patients were cross-desensitized to the respective nut. All (n = 44) patients consuming a low cashew dose for ≥6 months following desensitization passed a full-dose cashew OFC. CONCLUSIONS: Cashew OIT desensitizes most cashew-allergic patients and cross-desensitizes to pistachio. Safety is similar to OIT for other foods.

Triggers for Home Epinephrine-Treated Reactions During Oral Immunotherapy for Food Allergy.

BACKGROUND: Home reactions requiring epinephrine treatment represent a significant obstacle to oral immunotherapy (OIT) and impair treatment outcome. OBJECTIVE: To identify potential triggers for such reactions for improvement of patient safety. METHODS: All patients aged older than 3.7 years who began an open-label OIT treatment program to milk, peanut, egg, sesame, or tree nuts in the Institute of Allergy, Immunology, and Pediatric Pulmonology at Shamir Medical Center between April 2010 and March 2018 were enrolled. Information on home epinephrine-treated reactions (HETRs) during the up-dosing phase of OIT was collected from the documentation in patients' files and the reports were transmitted by email and via a web reporting system. RESULTS: A total 1,270 OIT treatments were included (milk 780; peanut 256; egg 63; sesame 72; and tree nuts 99). Home epinephrine was administered in 200 treatments (15.7%) and in 70 of them a second epinephrine-treated reaction occurred. The leading identified triggers for HETRs were physical exercise temporally associated with administration of home dose (20%), and dose consumption during infectious disease (16.7%), or when fatigued (13.8%). The rate of first HETRs was highest (10.1%) to doses of 500 mg protein or less and particularly to 300 mg or less. The occurrence of first HETRs was highest (35.5%) during the first and decreased to 13.8% by the last of the 4-week home-treatment phase. Second HETRs occurred in a similar rate throughout these 4 weeks. The incidence of HETRs was highest during pollen season and vacation months. CONCLUSIONS: The identification of factors, some protocol-dependent, that trigger HETRs should assist in improving OIT safety.

Combinatorial advantage of Ses i 1-specific IgE and basophil activation for diagnosis of sesame food allergy.

BACKGROUND: The prevalence of sesame food allergy (SFA) is increasing worldwide with the potential of anaphylactic reactions upon exposure. Utility of specific component IgE testing as an alternative to the oral food challenge (OFC), the diagnostic standard, is being investigated. METHODS: Patients (n = 42) with suspected SFA completed an open OFC to sesame. Diagnostic testing included serum levels of Ses i 1-specific IgE, skin prick test with high-protein extract, and basophil reactivity (% induced CD63 expression) for each patient. The diagnostic utility of these tests was evaluated at a 95% sensitivity, with the outcome measure being the number of OFCs required. RESULTS: Twenty-seven patients (64%) were diagnosed with SFA. Ses i 1 IgE differed significantly between allergic and tolerant patients (p = .0001). ROC curve analysis for Ses i 1 IgE yielded an AUC of 0.88 ± 0.05. Levels of Ses i 1 IgE correlated to induced CD63+ expression on basophils (p = .0001). Ses i 1 IgE was not sufficiently robust as a single step for diagnosis. Used concurrently, BAT and Ses i 1 IgE yielded correct positive classifications for 25 of 27 sesame-allergic patients with two false positives (93% PPV). Both tests were negative in 5 non-allergic patients. Patients with divergent Ses i 1 IgE and BAT results required OFC (n = 10, 24% of patients). Alternatively, sequential use of BAT, ruling in SFA followed by Ses i 1 IgE diagnosing non-allergic patients, yielded a 89% PPV, with 19% requiring OFC. CONCLUSION: Ses i 1 IgE and BAT used together can decrease the need for OFC in most SFA patients. A prospective cohort trial is necessary to validate these results.

Home epinephrine-treated reactions in food allergy oral immunotherapy: Lessons from the coronavirus disease 2019 lockdown.

BACKGROUND: Oral immunotherapy (OIT) is effective in desensitizing patients with food allergy but adverse reactions limit its use. OBJECTIVE: To study the effect of the coronavirus disease 2019 lockdown in Israel between March 15, 2020, and April 30, 2020, on the incidence of home epinephrine-treated reactions. METHODS: All patients who were in the up-dosing phase of OIT for greater than or equal to 1 month during the lockdown, or a respective period in years 2015 to 2019, were studied. The incidence of home-epinephrine treated reactions during the 2020 lockdown was compared with that in the respective period in 2015 to 2019 and to periods before and after the lockdown. RESULTS: A total of 1163 OIT treatments were analyzed. Two epinephrine injections occurred during 2020 (0.7%) compared with 29 injections (3.28%) during 2015 to 2019 (P = .03). Patients treated in 2020 were older (8.1 vs 7 years, P < .01) and had a significantly lower single highest tolerated dose (12 vs 20 mg protein, P < .01). The rate of milk-OIT was lower (P = .01), but the total number of milk treatments was higher (99 vs 71 to 82) in 2020 compared with 2015 to 2019. On multivariate analysis, treatments during the 2020 lockdown were performed in older patients (P = .001), primarily for nonmilk (P = .03), began with a lower single highest tolerated dose (P = .006), and were associated with significantly less home epinephrine-treated reactions (P = .05) compared with those in 2015 to 2019. Patients treated in 2020 experienced more epinephrine-treated reactions in adjacent periods before (n = 8) and after (n = 6) the lockdown. CONCLUSION: The lower rate of home epinephrine-treated reactions during the coronavirus disease 2019 lockdown in Israel suggests that potentially avoidable triggers contribute significantly to the rate of adverse reactions during OIT.

Characteristics and associated morbidities of young adults with misconceived food allergy: A cross-sectional study.

BACKGROUND: Many patients with self-reported food allergy are not allergic but suffer from similar burdens. We aimed to characterize young adults with misconceived food allergy. METHODS: A cross-sectional study of individuals (n = 12,592) aged 17-18 years, recruited to the Israel Defense Forces (IDF) at a single urban-area recruitment center over a six month-period. All participants underwent a comprehensive medical and psychological evaluation. Cognitive tests were performed and a Combined Intellectual-Education score assigned. Participants who reported food elimination due to allergy were skin-tested and underwent oral food challenges, when indicated. The characteristics, psychological evaluation and cognitive tests of individuals with no reported food allergy (n = 12,444), misconceived food allergy (n = 64) and true food allergy (n = 84) were compared. FINDINGS: The prevalence of atopic co-morbidities was higher in recruits reporting compared to those not reporting food allergy while the rate of other co-morbidities was comparable. Anxiety disorder was diagnosed significantly more in individuals who reported food allergy (4·1%) compared to those who did not (1·7%) (p = 0·04). Further analysis revealed that this diagnosis was concentrated in individuals with misconceived (8/64, 12·5%) compared to true food allergy (2/84, 2·4%), (p = 0·02). Patients with misconceived food allergy were mostly of female sex, had lower Combined Intellectual-Education scores compared to patients with true (p = 0·001) and no reported food allergy (p = 0·01), and required the longest mean evaluation time (147·6 ± 109·4 days). INTERPRETATION: Patients with misconceived food allergy have higher rates of anxiety disorder and are often from a lower educational level and of female sex. Medical and educational attention is required to improve care of this specific population. FUNDING: The research reported in this publication was supported by the Israel Defense Forces (IDF) Medical Corps and Directorate of Defense Research & Development, Israeli Ministry of Defense (IMOD DDR&D).

Medical clown support is associated with better quality of life of children with food allergy starting oral immunotherapy.

BACKGROUND: The start of oral immunotherapy (OIT) for food allergy is a critical period in the treatment process, with a potential to influence patient quality of life (QOL) and subsequently treatment outcome. The association of medical clowning with QOL at OIT initiation was examined. METHODS: Children aged 4-12 years supported by a medical clown (MC) during the induction week of OIT for food allergy were studied. Children in the same age range starting OIT without the support of a MC served as controls. Parents of all children completed the Food Allergy Quality of Life Questionnaire-Parent Form (FAQLQ-PF), and children aged 8-12 years completed the Food Allergy Quality of Life Questionnaire-Child Form (FAQLQ-CF). QOL scores of parents and children with and without a MC support were compared. RESULTS: Children with (n = 88) and without (n = 212) the support of a MC were comparable in demographics and clinical characteristics. The study group had a significantly lower single highest tolerated dose compared to controls (57 ± 83 vs 162 ± 274 mg protein, respectively, P < .001). Parental perception of the QOL of children was not associated with a MC support (P = .81) but rather with previous reaction severity (P < .01). In contrast, the QOL of children aged 8-12 years (n = 119) was positively associated primarily with a MC support, total score 3.7 ± 1.1 vs 4.6 ± 1.3 (P < .001). CONCLUSIONS: While the perception of QOL of parents of children with food allergy at OIT initiation is mainly associated with previous reaction severity, the QOL of the children themselves is primarily positively associated with MC support.

Patient Characteristics and Risk Factors for Home Epinephrine-Treated Reactions During Oral Immunotherapy for Food Allergy.

BACKGROUND: Oral immunotherapy (OIT) is effective in desensitizing food-allergic patients but adverse events limit its applicability. OBJECTIVE: To identify risk factors for home epinephrine-treated reactions during the build-up phase of OIT. METHODS: A retrospective cohort study of patients older than 3.7 years undergoing OIT for food allergy at Shamir Medical Center between April 2010 and March 2019. All patients with a final disposition of full desensitization, partial desensitization, or failure were analyzed. Risk factors and outcome of home epinephrine-treated reactions were examined. RESULTS: A total of 1037 patients (mean age, 8.4 years) who underwent 1100 OIT treatments (milk, n = 710; peanut, n = 213; egg, n = 50; sesame, n = 57; and tree nuts, n = 70) reached a final disposition and were analyzed. Full desensitization was achieved in 763 (69.4%) treatments, partial desensitization in 219 (19.9%), and 118 (10.7%) failed. Epinephrine was administered to 121 patients (11.7%) during 10.8% of treatments. Milk OIT was a significant risk factor both for epinephrine-treated reactions (odds ratio, 2.15; 95% CI, 1.25-3.68) and for low rate of full desensitization following such reactions compared with nonmilk OIT (18.2% vs 73.9%, respectively; P < .0001). Risk factors during milk OIT included asthma, pre-OIT reaction severity, lower tolerated dose, and epinephrine-treated reactions during clinic updosing, whereas risk factors during nonmilk OIT were male sex and lower tolerated dose. CONCLUSIONS: Milk OIT poses a significant risk for home epinephrine-treated reactions during OIT and for poor outcome following such reactions. Together with the additional risk factors described for both milk and nonmilk OIT, this information may assist in patient selection for treatment.

A Prospective Validation of the NUT CRACKER Diagnostic Algorithm for Walnut and Pecan Allergy with Prediction of Severity.

BACKGROUND: We previously devised an algorithm using skin prick tests (SPT), basophil activation tests (BAT), and co-allergy status to reduce the need for oral food challenges (OFCs) in 63 patients with suspected walnut/pecan allergies. OBJECTIVE: To validate prospectively the NUT CRACKER (Nut Co-Reactivity-Acquiring Knowledge for Elimination Recommendations) diagnostic algorithm in a new cohort of patients (n = 120) and to study the utility of SPT and BAT in predicting walnut-pecan allergy severity in both groups (n = 183). METHODS: Patients (n = 183) aged 8 (6-11) years, median (interquartile range), with suspected tree nut allergy were studied. SPT used ground nut extract (10 mg/mL), and BAT assessed allergen-induced basophil CD63 expression. Allergy was determined based on a recent reaction or a positive OFC, and tolerance was defined by regular consumption or a negative OFC. RESULTS: Walnut BAT was significantly higher in walnut/pecan dual compared with single walnut allergy (P = .003) and predicted the need for epinephrine during positive walnut OFCs (P = .009). Results of walnut and pecan BAT correlated with the corresponding nut eliciting dose (P = .014 and P < .001, respectively). Receiver operating curves for walnut and pecan allergy in the prospective cohort yielded area under the curves ranging from 0.87 to 0.93 for SPT and BAT. Concordant with the original study, pecan-allergic patients were all co-allergic for walnut. The algorithm decreased the need for OFCs by 78.8 % with 6 of 240 (2.5%) falsely positives and no false negatives. CONCLUSION: The algorithm was validated prospectively and awaits broader testing across other populations. The use of BAT further associates with severity in walnut/pecan allergy.

Subjective oral symptoms are insufficient predictors of a positive oral food challenge.

BACKGROUND: Subjective oral symptoms, especially if recurrent, might lead to termination of an oral food challenge (OFC) for fear of a subsequent severe reaction. METHODS: In a single-center retrospective cohort study, oral food challenges to milk, egg, peanut, sesame, or tree nuts performed between January 2016 and January 2018 in patients aged ≥3 years, at the Institute of Allergy, Immunology and Pediatric Pulmonology in Shamir Medical Center, were analyzed. Subjective oral symptoms during the challenge were documented, and their association with the challenge outcome was examined. RESULTS: A total of 323 patients underwent 652 oral food challenges to the investigated foods (milk, 71; egg, 22; peanut, 48; sesame, 24; and tree nuts, 487). Subjective oral symptoms were experienced in 237 (36.3%) of all OFCs performed, and their rate was comparable across most foods tested. The rate of positive challenges was significantly higher when subjective oral symptoms were experienced during the challenge than when they were not (69.6% vs 30.4%, respectively, P < .001). However, the false-positive rate of such symptoms in predicting a positive food challenge was 30.3% for all foods; peanut, 40%; sesame, 27.3%; milk, 35.5%; egg, 33%; and tree nuts, 28.4%. Overall, subjective oral symptoms (SOS) provided sensitivity of 56.7, specificity 80.4, PPV 69.6, and NPV 69.0 for predicting OFC outcome. Importantly, reactions during positive challenges with and without subjective oral symptoms were comparable to severity. CONCLUSIONS: Continuing OFCs with subjective oral symptoms is recommended for it will prevent false-positive results in a third of cases without increasing patients' risk.

Microbial signature in IgE-mediated food allergies.

BACKGROUND: Multiple studies suggest a key role for gut microbiota in IgE-mediated food allergy (FA) development, but to date, none has studied it in the persistent state. METHODS: To characterize the gut microbiota composition and short-chain fatty acid (SCFAs) profiles associated with major food allergy groups, we recruited 233 patients with FA including milk (N = 66), sesame (N = 38), peanut (N = 71), and tree nuts (N = 58), and non-allergic controls (N = 58). DNA was isolated from fecal samples, and 16S rRNA gene sequences were analyzed. SCFAs in stool were analyzed from patients with a single allergy (N = 84) and controls (N = 31). RESULTS: The gut microbiota composition of allergic patients was significantly different compared to age-matched controls both in α-diversity and ß-diversity. Distinct microbial signatures were noted for FA to different foods. Prevotella copri (P. copri) was the most overrepresented species in non-allergic controls. SCFAs levels were significantly higher in the non-allergic compared to the FA groups, whereas P. copri significantly correlated with all three SCFAs. We used these microbial differences to distinguish between FA patients and non-allergic healthy controls with an area under the curve of 0.90, and for the classification of FA patients according to their FA types using a supervised learning algorithm. Bacteroides and P. copri were identified as taxa potentially contributing to KEGG acetate-related pathways enriched in non-allergic compared to FA. In addition, overall pathway dissimilarities were found among different FAs. CONCLUSIONS: Our results demonstrate a link between IgE-mediated FA and the composition and metabolic activity of the gut microbiota.