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.

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.

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.

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.

Proton pump inhibitors in eosinophilic esophagitis (EoE) related to oral immunotherapy: is it as effective as in other EoE?

Oral immunotherapy (OIT) may induce eosinophilic esophagitis (EoE). Proton pump inhibitors (PPIs) are an effective treatment for EoE. However, the effect of PPI treatment is not well established in patients with EoE induced by OIT. Our primary aim was to compare the clinical, endoscopic, and histological response rates to PPIs in children with EoE induced by OIT (EoE+OIT) versus EoE patients without OIT (EoE-OIT). The secondary aims are to describe the clinical and histological features of EoE+OIT. Demographic, clinical, endoscopic, and histological findings of patients with EoE in the gastroenterology clinic at Shamir Medical Center between March 2015 and December 2022 were collected. Comparisons were performed between EoE+OIT and EoE-OIT patients. The study included 42 children (74% male, mean age 11.2), of whom 31 had EoE-OIT and 11 had EoE+OIT. There were no significant differences between groups regarding sex, comorbidities, symptoms, or endoscopic and histological characteristics at diagnosis. All 42 children were treated with PPIs after diagnosis with or without diet changes. The rates of any clinical response were 83.9% and 90.1% in the EoE-OIT group and EoE+OIT group, respectively (p = 1.0). The rate of any endoscopic response was 74.2% for EoE-OIT and 81.8% for EoE+OIT (p = 0.54). Histologically, PPIs were even more effective in the EoE+OIT group, where only 18.2% had no histological response at all compared to 51.6% in the EoE-OIT group (p = 0.1). CONCLUSION: PPI treatment is as effective in EoE with OIT as it is in EoE due to other etiologies. WHAT IS KNOWN: • Proton pump inhibitor (PPI) treatment is effective for achieving clinical response and histologic remission in some patients with eosinophilic esophagitis (EoE). • EoE has also been reported to be triggered by oral immunotherapy (OIT). WHAT IS NEW: • PPI treatment in EoE with OIT is as effective as treatment for EoE due to other etiologies.

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.

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.

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.

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.

Quality of life of children aged 8-12 years undergoing food allergy oral immunotherapy: Child and parent perspective.

BACKGROUND: Oral immunotherapy (OIT) for food allergy improves the quality of life (QOL) of children from parental perspective but little is known about the child perception. METHODS: The Food Allergy Quality of Life Questionnaire-Child Form (FAQLQ-CF) was administered to children aged 8-12 years, and the FAQLQ-Parent Form (FAQLQ-PF) was administered to their parents at the start of OIT for milk, egg, peanut, sesame, or tree nuts, at the end of up-dosing, and after 6 months of follow-up. Food-allergic children not undergoing OIT served as controls. Children QOL scores were compared to their parents. RESULTS: The total FAQLQ-CF score of 103 children undergoing OIT improved significantly from start of OIT (median (IQR); 4.8, 3.8-5.7) to end of up-dosing (3.9, 3-5.2) (P < .001). A greater improvement was noted in the 56 children who reached a follow-up visit, from 5.0 (3.7-5.8) at OIT start to 3.1 (1.8-5.0) on follow-up, (P < .001). In contrast, FAQLQ-CF scores of control patients improved mildly and nonsignificantly between the two time points from 5.3 (4.3-5.7) to 4.8 (3.6-6.0), (P = .13). The improvement in the total FAQLQ-CF scores from OIT start to follow-up was significantly greater compared to the change in control patients during observation (P = .015). Parents reported better QOL scores compared to their children at all stages of OIT (start 4.0, 3.2-5, P = .004; end of up-dosing 2.9, 1.9-4.7, P = .04; follow-up 2.2, 1.6-3.6, P = .003). CONCLUSIONS: QOL of food-allergic children undergoing OIT improves significantly compared to controls. Parents perceive QOL to be better than the perception of the children.

Efficacy of omalizumab treatment for pediatric chronic spontaneous urticaria: A multi-center retrospective case series.

BACKGROUND: Chronic urticaria is defined by the presence of itchy wheals, sometimes accompanied by angioedema, lasting for at least 6 weeks. In children, most cases occur without an eliciting factor and are defined as chronic spontaneous urticaria (CSU). CSU affects up to 0.75% of children with a negative impact on quality of life and school performance. CSU is treated in adults with second-generation antihistamines, increased up to four times normal doses for second-line treatment. Omalizumab (a monoclonal antibody to IgE) may be recommended as third-line therapy. A similar protocol is used in children, yet little is known of its efficacy and safety. OBJECTIVES: To summarize our multi-center experience in treating children with recalcitrant CSU with omalizumab. METHODS: A retrospective multi-center case series conducted in 5 tertiary care centers in Israel. Patients included were children <18 years old diagnosed with recalcitrant CSU who were treated with omalizumab. Patients were followed up throughout the duration of omalizumab therapy/symptom remission. Patients' electronic medical records were used to gather data. RESULTS: Nineteen participants (11 F; 8 M) presented with CSU between ages 6 and 16.9 years. Sixteen (84%) responded to omalizumab, including children <12 years old, although two became non-responsive after 6-12 months of therapy. Another three patients (16%) were resistant to treatment, achieving remission through fourth-line (Cyclosporine A) or other therapies. CONCLUSION: Children with recalcitrant CSU, even those <12 years old, respond well to standard-dose, third-line omalizumab therapy at rates similar to adults. Yet, some cases may become non-responsive with ongoing treatment.

Risk factors for reduced bone mineral density measurements in milk-allergic patients.

BACKGROUND: Earlier studies noted that young adults with IgE-mediated cow's milk allergy (IgE-CMA) have significantly lower bone mineral density (BMD) than age- and gender-matched controls. We sought to identify additional risk factors contributing to the low BMD in IgE-CMA patients. METHODS: Postpubertal (defined by Tanner stage V) IgE-CMA patients (n = 78; 16- to 30-year-old females and 17.5- to 30-year-old males) were evaluated prospectively for BMD using a DXA scan, serum values of bone turnover factor, and dietary and lifestyle questionnaires. Patients receiving > 2 short courses of systemic steroid treatments were excluded. RESULTS: Abnormal BMD measurements (T- or Z-scores < -1.0) of the lumbar vertebrae, femoral neck, or hip were noted in 60 patients, while normal BMD values were present in 18 patients, despite similarly decreased calcium intakes between the groups (P = 0.92). Patients with abnormal BMD were more likely to be asthmatic (P = 0.014), have a lower weight z-score (P = 0.007), have a decreased percent caloric intake derived from fat (P = 0.01), and have an increased carbohydrate intake (P = 0.03), in comparison with the normal-BMD group. Serum values of bone turnover were similar between the groups. On multivariate regression analysis, only asthma significantly (P = 0.006) increased the risk for osteopenia and osteoporosis (OR 38.5, 95% CI 2.8-500). Fitting continuous z-scores into a regression model, both asthma and weight z-score were significant (adjusted r2  = 0.272). Asthma was significantly overrepresented in osteopenic and osteoporotic subpopulations while decreased weight only in patients with osteoporosis. CONCLUSIONS: In the context of a low calcium intake, asthma and weight are independent risk factors for decreased BMD in IgE-CMA patients.

Patient quality of life following induction of oral immunotherapy for food allergy.

BACKGROUND: Patient quality of life improves following successful completion of oral immunotherapy (OIT), but the process itself might have undesirable effects. We aimed to evaluate patient quality of life following OIT initial induction. METHODS: The Hebrew version of the Food Allergy Quality of Life Questionnaire-Parental Form (FAQLQ-PF) was validated and administered to the parents of children following the first week of OIT for food allergy (n = 119). Patient demographics and clinical history as well as the course of initial induction week were reviewed. RESULTS: Pre-OIT severity of food allergy, defined as severity of reactions due to accidental exposure to the allergenic food (anaphylactic reactions, p = 0.017; epinephrine use, p = 0.049; emergency room referrals p = 0.003; and hospital admissions, p = 0.015) and a lower number of tolerated doses during initial induction, reflective of a lower maximal tolerated dose for the different allergens (p = 0.011) were associated with worse total FAQLQ-PF scores. The number of tolerated doses during induction and pre-OIT emergency room referrals remained significantly associated with worse total score of the FAQLQ-PF on multivariate analysis (p = 0.016 and p = 0.005, respectively). The correlation between the number of tolerated doses and quality of life scores was moderate-strong primarily in children aged 6-12 years (Total score, r = -0.41, p = 0.001; Emotional Impact r = -0.42, p = 0.001; Food Anxiety, r = -0.38, p = 0.002; Social and Dietary Limitations, r = -0.33, p = 0.009). CONCLUSIONS: Pre-OIT reaction severity affects quality of life in both preschool and school-aged food-allergic children. In contrast, a lower maximal tolerated dose during OIT induction is associated with worse indices of quality of life primarily in children aged 6-12 years.

Beta-lactam antibiotics administration among adult inpatients with a beta-lactam allergy label: incidence, predictors, and outcomes.

Background: A beta-lactam antibiotics (BLA) allergy label is common, resulting in disadvantageous outcomes due to the usage of second-line antimicrobial agents. Noncontrolled case-series analyses report low rates of hypersensitivity reactions, following intentional/non-intentional BLA challenges among labeled inpatients. The study aims were to explore predictors and outcomes associated with hypersensitivity reactions following BLA challenge among BLA-allergic labeled inpatients. Methods: Retrospective cohort study (2019-2020) of adult (≥18 years) inpatients (Shamir Medical Center, Israel), labeled as allergic to ≥1 BLA, who received ≥1 dose/s of BLA during their stay. Independent predictors to develop allergic reactions and the independent associations of allergic reactions with clinical outcomes were queried by logistic and Cox regressions. Results: Of 9,670 inpatients (14,088 hospitalizations), 3,570 (37%) were labeled as allergic to ≥1 BLA. Of those, 1,171 (33%) patients received ≥1 BLA. The majority were women (67%), and the mean age was 69.3 ± 19.4 years. Only 30 patients (2.6%) developed a reaction, all mild. Independent predictors to develop an allergic reaction were documented reactions in the past, atopic background, antihistamines administration prior to the BLA challenge, and high risk for cross-reactivity, based on the BLA side chains, between the labeled and the challenged agents. Reaction upon the BLA challenge was not independently associated with any worse outcome. Conclusions: Despite the commonality of allergy labeling, and the commonality of BLA administration to labeled inpatients, hypersensitivity reactions were mild and rare. Interventional stewardship strategies for active BLA de-labeling among low-risk patients should be promoted, to improve patients' and institutional health and fiscal outcomes.

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.

Eosinophil-Associated Gastrointestinal Manifestations During OIT.

Gastrointestinal adverse events are common during oral immunotherapy (OIT) for food allergy and range from immediate IgE-mediated reactions to non-anaphylactic clinical presentations. This review aims to summarize recent findings on non-anaphylactic eosinophil-associated gastrointestinal adverse events during OIT. Two clinical presentations of non-anaphylactic eosinophil-associated gastrointestinal adverse events during OIT are identified, each with a different paradigm for treatment, and distinguished by their time of onset. In the first clinical entity, characterized by its onset early in the course of treatment, patients present with abdominal pain, nausea, and/or vomiting. The symptoms become evident typically within weeks to months of starting OIT. These symptoms, however, are not temporally related to the time of dose administration, as in the case of immediate IgE-mediated anaphylactic reactions. While esophageal biopsies, when performed, can demonstrate eosinophilic esophagitis (EoE), baseline esophageal eosinophilia has also been observed in food allergic patients prior to OIT. A potential non-invasive biomarker, the peripheral absolute eosinophil count (AEC), often rises during these reactions and subsides after dose reduction and subsequent resolution of symptoms. OIT can usually then be resumed, albeit at a slower pace, without a recurrence of symptoms. Risk factors for development of symptoms early during OIT include a high starting dose and a baseline AEC of greater than 600. The second, and much less frequently encountered, non-anaphylactic gastrointestinal adverse event related to OIT, presents months to years after initiating OIT. In this latter group, patients present with the classical clinical symptoms and endoscopic findings of EoE. In contrast to the acute onset group, peripheral eosinophilia is usually not observed in these cases. This OIT-associated EoE has shown good response to standard EoE treatment approaches of proton pump inhibitors or swallowed steroids. Most patients with eosinophil-associated adverse reactions are able to continue OIT and remain desensitized. Treatment approaches depend on the specific subtype of these reactions and relate to the stages of OIT treatment.

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.

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.