Biomarkers of severity and threshold of allergic reactions during oral peanut challenges

Abstract

Background Oral food challenge (OFC) is the criterion standard to assess peanut allergy (PA), but it involves a risk of allergic reactions of unpredictable severity. Objective Our aim was to identify biomarkers for risk of severe reactions or low dose threshold during OFC to peanut. Methods We assessed Learning Early about Peanut Allergy study, Persistance of Oral Tolerance to Peanut study, and Peanut Allergy Sensitization study participants by administering the basophil activation test (BAT) and the skin prick test (SPT) and measuring the levels of peanut-specific IgE, Arachis hypogaea 2–specific IgE, and peanut-specific IgG4, and we analyzed the utility of the different biomarkers in relation to PA status, severity, and threshold dose of allergic reactions to peanut during OFC. Results When a previously defined optimal cutoff was used, the BAT diagnosed PA with 98% specificity and 75% sensitivity. The BAT identified severe reactions with 97% specificity and 100% sensitivity. The SPT, level of Arachis hypogaea 2–specific IgE, level of peanut-specific IgE, and IgG4/IgE ratio also had 100% sensitivity but slightly lower specificity (92%, 93%, 90%, and 88%, respectively) to predict severity. Participants with lower thresholds of reactivity had higher basophil activation to peanut in vitro . The SPT and the BAT were the best individual predictors of threshold. Multivariate models were superior to individual biomarkers and were used to generate nomograms to calculate the probability of serious adverse events during OFC for individual patients. Conclusions The BAT diagnosed PA with high specificity and identified severe reactors and low threshold with high specificity and high sensitivity. The BAT was the best biomarker for severity, surpassed only by the SPT in predicting threshold. Nomograms can help estimate the likelihood of severe reactions and reactions to a low dose of allergen in individual patients with PA.

Basophil activation test: mechanisms and considerations for use in clinical trials and clinical practice

“…Two recent studies of peanut allergy found a relationship of reactivity and symptom severity 25,33 ; however, in a study of wasp venom allergy, basophil reactivity to wasp allergen extract could not predict patients symptom severity 34 . The latter study set the scene for developing methods to assess basophil sensitivity 35 , that has been shown to be useful in the diagnosis of allergic asthma 36 , rhinitis 37 , food allergy 33,[38][39][40] , allergen immunotherapy [41][42][43][44][45] and anti-IgE therapy 46-48 . Basophil sensitivity refers to the allergen concentration eliciting half-maximal basophil activation and can be expressed as EC 50 that decreases with increasing severity 42,45 , or CD-sens which is the inverse of EC 50 multiplied by 100 and can be calculated based on the slope of the dose-response curve 25,35 . CD-sens increases with the severity of allergic reactions 35 .…”

“…One cause of non-responsiveness is a low level of Syk phosphatase [21][22][23] , possibly in combination with elevated amounts of CD45 13 . The non-responder phase is transient; a patient may revert to a responsive state within months 24,25 . The nonresponder state has also been reversed experimentally in vitro by culturing basophils in the presence of IL-3 26 .…”

“…The degree of reactivity at each allergen concentration is plotted against allergen concentration, and both maximal reactivity and half-maximal reactivity are determined by fitting a non-linear curve to the dose-response. Basophil sensitivity correlates with the patient s sensitivity to allergen at the clinical level, both in respiratory 36,49 and in food allergies 25,[38][39][40]50 and changes in sensitivity reflect the clinical improvement in allergic rhinitis 41,42,44,45,51,52 . Basophil reactivity and basophil sensitivity appeared to be distinct parameters of activation 53,54 ; however, systematic analyses of signalling molecules in the pathway leading from IgE crosslinking to degranulation show that are interdependent and regulated by syk 55,56 .…”

Molecular approach to a patient’s tailored diagnosis of the oral allergy syndrome

“…However, this procedure is contraindicated in patients with past severe food responses because it can cause allergic reactions of unpredictable severity. Basophil activation test (BAT) is a functional test useful for the diagnosis of pollen and food allergy and can be used to evaluate the possibility of more severe allergic reactions in patients with OAS [12,13]. Actually, BAT is reported to be quite specific and able to estimate the threshold of allergic reactions, as well as to discriminate between sensitized and symptomatic patients.…”

Advances and novel developments in molecular allergology

“…Clinically relevant hymenoptera allergy in patients with double sensitization to honeybee and vespid venoms was best diagnosed using BAT, thereby reducing the need for double venom immunotherapies 48 . A post hoc analysis including 3 peanut allergy cohorts concluded that BAT performs best to predict disease severity and the threshold of consumable peanut during oral food challenge (OFC) 49 . Interestingly, a study of 70 SLIT patients showed discrepancies between the use of whole peanut extract or Ara h 2 in BAT to predict the eliciting dose in double‐blinded OFC 50 .…”