The current food allergy guidelines suggest that performing OFCs, aimed to document tolerance to the food, once the FSIgE value is ≤2 kUa/L to milk, egg, and peanut (or ≤5 kUa/L for sensitization only to peanut) is appropriate because it is associated with ~50% likelihood of negative OFC.3
Our study confirmed these recommendations by showing that the proportions of negative OFCs while using these cutoffs were 58% to milk, 42% to egg, and 63% to peanut. Moreover, we showed that incorporating clinical and laboratory data into regression models and using FSIgE values in a continuous range rather than single cutoff value can identify subgroups of children who have increased likelihoods for negative OFCs. Overall, we identified combinations of factors that in our cohort resulted in proportions of negative OFCs of 83, 75, and 75% to milk, egg, and peanut, respectively.
Our models identified several independent factors associated with increased likelihoods of negative OFCs. We found that even within the range of FSIgE of ≤2 kUa/L, lower levels of FSIgEs were associated with increased likelihoods of negative OFC to milk, egg, and peanut. Higher total IgE was associated with increased likelihood of negative milk OFCs. We do not fully understand the mechanism behind this finding, but similar (albeit not significant) trends were previously reported in statistical models that were designed to predict results of OFC to milk.13
Eating egg as an ingredient in baked goods was common among our egg-allergic children (42%) and was the factor most strongly associated with negative OFC to egg. This finding is consistent with recent data suggesting that, in a subset of egg-allergic children, ingestion of heated egg is well tolerated and might facilitate tolerance.17,18
In addition, although negative skin tests (egg and peanut) were significantly associated with negative OFCs in the univariate analyses, they were not significant in the regression models, likely because of collinearity of skin test results with FSIgE values.
We intentionally selected patients with FSIgE of ≤2 kUa/L because these are the children defined by the current clinical recommendations as the most appropriate candidates for OFC aimed to document tolerance to food.3
Our goal was to maximize the proportion of negative OFCs within this group. A previous study13
reported negative OFCs among children with higher FSIgE values. DunnGalvin et al.13
sought to develop a model that might replace OFCs in diagnosing food allergy. Their models were developed retrospectively and then validated in an independent cohort. These models addressed a different clinical question, namely establishing the diagnosis of food allergy. Thus, DunnGalvin's13
population included children with higher mean FSIgE and a wider range of FSIgE values. In contrast, the aim of our OFCs was mainly to document resolution of food allergy. As a result, our study population is confined to the lower end of the FSIgEs range. These major differences in aims and, subsequently, in study population are likely to explain why the main predictors in the DunnGalvin's model (e.g.
, severity scores of previous reaction and skin tests results) were not shown to be significant in our cohort. We suggest that the severity of clinical reaction at the initial event and positive skin test findings are informative in establishing a diagnosis of food allergy (as reported by DunnGalvin13
), but may be less informative in a child already diagnosed with food allergy and presenting to investigate whether he/she developed resolution of food allergy.
Retrospective data collection is a limitation of our study. However, retrospective data collection was used in most previous studies aimed to predict outcomes of OFC,10,12,13
which were later validated in prospective independent cohorts.9,13
In addition, we took several measures to minimize bias in our study and to increase the validity of our findings. To minimize potential selection bias, we established clearly defined inclusion/exclusion criteria that assured that we identified the population of interest: children presenting for OFC based on a predefined set of clinical and laboratory characteristics. To minimize potential measurement bias, data were collected by a trained research assistant using a predefined questionnaire. Finally, we did not perform double-blind placebo-controlled OFCs because graded OFCs are considered to be an adequate and cost-effective method in the clinical setting,3,4,19
and we took efforts to minimize potential measurement bias resulting from nonobjective symptoms during the challenge, as described in the Methods section. Moreover, to minimize potential false negative results of the graded challenge, each negative graded challenge was followed by an open consumption of a meal-sized portion of the food. However, a recent report20
suggested that a small proportion of children who had a negative graded challenge may react to the food if the open challenge is performed a day after the graded challenge. It is not known from that report if similar findings will occur if a similar dose of food will be given at the same day after the graded challenge rather than a day later. While reactions to food on the days after negative challenge are not commonly reported, we did not directly assess for such reactions in our study.
In summary, we have confirmed that the currently recommended FSIgE cutoffs to guide the decision to perform OFC aiming to document resolution or allergy to milk, egg, and peanut3
result in rates of negative OFCs of ~50%. We identified food-specific clinical factors that were independently associated with greater likelihood of negative OFC and identified combinations of factors that were associated with increased likelihood of negative OFCs in our population. These findings will need to be validated in a different population and if confirmed, then clinicians will be able to use this information to better estimate the risk-to-benefit ratio of each challenge.