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 is 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 4/2016-12/2019. 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 protein cashew 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: 44 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 3 patients were desensitized to 1200 mg cashew protein and 3 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 4 of 8 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. https://doi.org/10.1111/all.15212
Open‐label follow‐on study evaluating the efficacy, safety, and quality of life with extended daily oral immunotherapy in children with peanut allergy.
Background: The benefit of daily administration of Peanut (Arachis hypogaea) Allergen Powder-dnfp (PTAH)-formerly AR101-has been established in clinical trials, but limited data past the first year of treatment are available. This longitudinal analysis aimed to explore the impact of continued PTAH therapeutic maintenance dosing (300 mg/day) on efficacy, safety/tolerability, and food allergy-related quality of life. Methods: We present a subset analysis of PALISADE-ARC004 participants (aged 4-17 years) who received 300 mg PTAH daily for a total of ~1.5 (Group A, n=110) or ~2 years (Group B, n=32). Safety assessments included monitoring the incidence of adverse events (AEs), accidental exposures to food allergens, and adrenaline use. Efficacy was assessed by double-blind, placebo-controlled food challenge (DBPCFC); skin prick testing; peanut-specific antibody assays; and Food Allergy Quality of Life Questionnaire (FAQLQ) and Food Allergy Independent Measure (FAIM) scores. Results: Continued maintenance with PTAH increased participants' ability to tolerate peanut protein: 48.1% of completers in Group A (n=50/104) and 80.8% in Group B (n=21/26) tolerated 2000 mg peanut protein at exit DBPCFC without dose-limiting symptoms. Immune biomarkers showed a pattern consistent with treatment-induced desensitisation. Among PTAH-continuing participants, the overall and treatment related exposure-adjusted AE rate decreased throughout the intervention period in both groups. Clinically meaningful improvements in FAQLQ and FAIM scores over time suggest a potential link between increased desensitisation as determined by the DBPCFC and improved quality of life. Conclusions: These results demonstrate that daily PTAH treatment for peanut allergy beyond 1 year leads to an improved safety/tolerability profile and continued clinical and immunological response. https://doi.org/10.1111/all.15027
Accurate and reproducible diagnosis of peanut allergy using epitope mapping
Background: Accurate diagnosis of peanut allergy is a significant clinical challenge. Here, a novel diagnostic blood test using the peanut bead-based epitope assay ("peanut BBEA") was developed utilizing the LEAP cohort and then validated using two independent cohorts. Methods: The development of the peanut BBEA diagnostic test followed the National Academy of Medicine's established guidelines with discovery performed on 133 subjects from the non-interventional arm of the LEAP trial and an independent validation performed on 82 subjects from the CoFAR2 and 84 subjects from the POISED study. All samples were analyzed using the peanut BBEA methodology, which measures levels of IgE to two Ara h 2 sequential (linear) epitopes and compares their combination to a threshold pre-specified in the model development phase. When a patient has an inconclusive outcome by skin prick testing (or sIgE), IgE antibody levels to this combination of two epitopes can distinguish whether the patient is "Allergic" or "Not Allergic." Diagnoses of peanut allergy in all subjects were confirmed by double-blind placebo-controlled food challenge and subjects' ages were 7-55 years. Results: In the validation using CoFAR2 and POISED cohorts, the peanut BBEA diagnostic test correctly diagnosed 93% of the subjects, with a sensitivity of 92%, specificity of 94%, a positive predictive value of 91%, and negative predictive value of 95%. Conclusions: In validation of the peanut BBEA diagnostic test, the overall accuracy was found to be superior to existing diagnostic tests for peanut allergy including skin prick testing, peanut sIgE, and peanut component sIgE testing.
https://doi.org/10.1111/all.14905
Basophil activation test shows high accuracy in the diagnosis of peanut and tree nut allergy: The Markers of Nut Allergy Study.
Background: Peanut and tree nut allergies are the most important causes of anaphylaxis. Co-reactivity to more than one nut is frequent, and co-sensitization in the absence of clinical data is often obtained. Confirmatory oral food challenges (OFCs) are inconsistently performed. Objective: To investigate the utility of the basophil activation test (BAT) in diagnosing peanut and tree nut allergy. Methods: The Markers Of Nut Allergy Study (MONAS) prospectively enrolled patients aged 0.5-17 years with confirmed peanut and/or tree nut (almond, cashew, hazelnut, pistachio, walnut) allergy or sensitization fromCanadian (n=150) and Austrian (n=50) tertiary pediatric centers. BAT using %CD63+ basophils (SSClow/CCR3pos) as outcome was performed with whole blood samples stimulated with allergen extracts of each nut (0.001-1000ng/mL protein). BAT results were assessed against confirmed allergic status in a blinded fashion to develop a generalizable statistical model for comparisonto extract and marker allergen-specificIgE. Results: A mixed effect model integrating BAT results for 10 and 100 ng/mL of peanut and individual tree nut extracts was optimal. The area under the ROC curve (AUROC) was 0.98 for peanut, 0.97 for cashew, 0.92 for hazelnut, 0.95 for pistachio, and 0.97 for walnut. The BAT outperformed sIgE testing for peanut or hazelnut and was comparable for walnut (AUROC 0.95, 0.94, 0.92) ina sub-analysis in sensitized patients undergoing OFC. Conclusions: BAT can predict allergic clinical status to peanut and tree nuts in multi-nut sensitized children and may reduce the need for high-risk OFCs in patients.
The Global Burden of Illness of Peanut Allergy: A Comprehensive Literature Review.
Peanut allergy (PA) currently affects approximately 2% of the general population of Western nations and may be increasing in prevalence. Patients with PA and their families/caregivers bear a considerable burden of self-management to avoid accidental peanut exposure and to administer emergency medication (adrenaline) if needed. Compared with other food allergies, PA is associated with higher rates of accidental exposure, severe reactions, and potentially fatal anaphylaxis. Approximately 7-14% of patients with PA experience accidental peanut exposure annually, and one-third to one-half may experience anaphylaxis, although fatalities are rare. These risks impose considerably high healthcare utilisation and economic costs for patients with PA and restrictions on daily activities. Measures to accommodate patients with PA are often inadequate, with inconsistent standards for food labelling and inadequate safety policies in public establishments such as restaurants and schools. Children with PA are often bullied, resulting in sadness, humiliation, and anxiety. These factors cumulatively contribute to significantly reduced health-related quality of life for patients with PA and families/caregivers. Such factors also provide essential context for risk/benefit assessments of new PA therapies. This narrative review comprehensively assessed the various factors comprising the burden of PA.
Identification of Pru du 6 as a potential marker allergen for almond allergy.
Background: Oral food challenges have demonstrated that diagnosis of almond allergy based on extract-sIgE tests display low specificity. Molecular allergy diagnosis is expected to improve accuracy, but its value in diagnosing almond allergy remains unknown. Objective: To identify relevant almond allergens and examine their ability to improve almond allergy diagnosis. Methods: IgE-reactive proteins were purified from almond kernels. IgE-binding to almond extract and the allergens was analyzed by quantitative ELISA using sera from 18 subjects with a proven almond allergy. The control group consisted of sera from 18 subjects allergic to peanut and/or tree nuts but tolerant to almond. Results: Three IgE-binding proteins were identified: legumin (Pru du 6), alpha-hairpinin (Pru du 8) and mandelonitrile lyase (Pru du 10). Positive IgE (≥0.35 kU/L) to almond extract showed 94% sensitivity but only 33% specificity. IgE to Pru du 6 maintained high sensitivity (83%) and provided superior specificity (78%). Sera from almond-allergic subjects had significantly higher IgE levels to almond extract (P<0.0001) and Pru du 6 (P<0.0001) than sera from tolerant donors. Sensitization to Pru du 6 was highly specific for almond allergy, while frequencies of sensitization to legumins from peanut, walnut, hazelnut, and cashew were similar in both groups. IgE to Pru du 8 and Pru du 10 was less sensitive (41% and 67%), but showed specificities of 100% and 61%. Conclusion: The use of almond allergens markedly increases the diagnostic specificity compared to the extract. Pru du 6 is a potential new molecular marker for almond allergy.
APPEAL‐1: A multiple country European survey assessing the psychosocial impact of peanut allergy.
Background: Peanut allergy (PA) is a common, potentially life-threatening, and typically lifelong condition with a significant burden of illness. However, information is lacking on how persons with PA (PwPA) and their caregivers perceive the psychosocial impact of living with PA. The Allergy to Peanuts imPacting Emotions And Life study 1 (APPEAL-1) survey, conducted across Europe, investigated the experience and impact of living with PA. Here, we report data evaluating the psychosocial impact of PA on PwPA and their caregivers. Methods: APPEAL-1 was an online survey conducted in 8 European countries. Representatives of 8 patient advocacy groups and 5 healthcare-research specialists developed the survey. Eligible respondent groups included: adults diagnosed with PA (self-report); parent/nonparent caregivers (proxy-report for a child with PA); and parent/nonparent caregivers (self-report of PA impact on themselves). Results: Of 1846 total study respondents, 419 were adults with PA (self-report); 546 were parents/ caregivers (proxy-report) ; 881 were parents/caregivers (self-report). Most respondents reported lifestyle restrictions regarding food (84-93%) and additional domains including parties and socializing, holiday activities and destinations, and taking public transport (53-89%). Approximately 40% rated themselves as "very" frustrated and "very" stressed. Two-thirds (65%) felt socially isolated; 43% were bullied. Less than half felt confident in knowing when to use an adrenaline autoinjector. Several intercountry differences were observed such as high levels of uncertainty and stress in respondents from Ireland, highest rates of anxiety in respondents from Germany, and social exclusion and isolation most common in respondents from France. Conclusions: PA imposes an adverse psychosocial impact on patients and caregivers, leading to frustration, stress, and isolation. Attention to the impact of PA is needed in research and clinical practice to improve PA healthcare and public education programs.
Food allergy immunotherapy: OIT and EPIT.
IgE mediated food allergy remains a significant and growing problem across the globe. Of the various treatment modalities, oral immunotherapy (OIT) and epicutaneous immunotherapy (EPIT) have been the best studied. Across various studies of OIT for egg, milk and peanut allergy, strong levels of desensitization have been shown. With egg and peanut OIT, a limited remission, or sustained unresponsiveness (SU), has further been demonstrated. These advances have been further validated by successful phase 2 and phase 3 studies of peanut OIT. EPIT, using daily administrations of a proprietary patch, demonstrated efficacy as well as safety and tolerability in parallel phase 2 studies, however its phase 3 study did not meet its primary efficacy outcome. Despite its good track record of desensitization, the safety and tolerability of OIT has remained a question. EPIT, on the other hand, has proven safe and tolerable, however the adequacy of its desensitization has remained to be determined. As OIT and EPIT continue their march towards regulatory review, optimizations for immunotherapy and novel therapies continue to be developed providing hope for food allergy patients everywhere.
Recent developments and highlights in food allergy.
The achievement of long lasting, safe treatments for food allergy is dependent on the understanding of the immunological basis of food allergy. Accurate diagnosis is essential for management. In recent years, data from oral food challenges have revealed that routine allergy testing is poor at predicting clinical allergy for tree nuts, almonds in particular. More advanced antigen-based tests including component resolved diagnostics and epitope reactivity may lead to more accurate diagnosis and selection of therapeutic intervention. Additional diagnostic accuracy may come from cellular tests like the basophil activation test or mast cell approaches. In the context of clinical trials, cellular tests have revealed specific T-cell and B-cell populations that are more abundant in food allergic individuals with distinct mechanistic features. Awareness of clinical markers, such as the ability to eat baked forms of milk and egg, continue to inform the understanding of natural tolerance development. Mouse models have allowed for investigation into multiple mechanisms of food allergy including modification of epithelial metabolism, the induction of regulatory cell subsets and the microbiome. Increasing numbers of children who underwent food immunotherapy enlarged the body of evidence on mechanisms and predictors of treatment success. Experimental immunological markers in conjunction with clinical determinants such as lower age and lower initial specific IgE appear to be of benefit. More research on the optimal dose, preparation, and route of application integrating a high-level safety and efficacy is demanded. Alternatively, biologics blocking TSLP, IL-33, IL4 and IL13, or IgE may help to achieve that.
Clinical Factors Associated with Peanut Allergy in a High Risk Infant Cohort.
BACKGROUND: Prognostication of peanut allergy (PNA) is relevant for early interventions. We aimed to determine baseline parameters associated with development of PNA in 3-15 month olds with likely egg and/or milk allergy, and/or moderate-severe atopic dermatitis (AD) and a positive egg/milk skin prick test (SPT), but no known PNA. METHODS: The primary endpoint was PNA [confirmed/convincing diagnosis or last classified as serologic PNA (<2 yrs, ≥5 kUA/L, otherwise ≥14 kUA/L, peanut-IgE)] among 511 participants (median follow-up, 7.3 years). Associations were explored with univariate logistic regression; factors with p<0.15 were analyzed by stepwise multiple logistic regression, using data stratified by PNA status and randomly assigned to development and validation datasets. RESULTS: 205/511 (40.1%) had PNA. Univariate factors associated with PNA (p<0.01) included: increased AD severity, larger egg and peanut SPT, greater egg, milk, peanut, Ara h1-h3 IgE, higher peanut IgG and IgG4, and increased pregnancy peanut consumption. P-values were between 0.01 and 0.05 for younger age, non-white race, lack of breastfeeding, and increased lactation peanut consumption. Using a development dataset, the multivariate model identified younger age at enrollment, greater peanut and Ara h2 IgE, and lack of breastfeeding as prognosticators. The final model predicted 79% in the development and 75% in the validation dataset (AUC=0.83 for both). Models using stricter or less strict PNA criteria both found Ara h2 as predictive. CONCLUSIONS: Key factors associated with PNA in this high risk population included lack of breastfeeding, age, and greater Ara h2 and peanut-specific IgE, which can be used to prognosticate outcomes.