To the Editor,
1.
Data regarding resolution of tree nut allergy are mostly derived from population level questionnaires [1], or retrospective analysis of clinical records. Cashew nut allergy diagnosis may be simply based on sensitization, or on sensitization combined with reaction history [2], and in some cases on a positive challenge [3]. Resolution in tree nut allergy is suggested to be 9%–14% [1, 3].
The aim of the study was to investigate the natural resolution of confirmed cashew allergy and predictors for recovery. In a previous study, 72/106 (68%) children reacted during the cashew nut challenge (aged 1–16‐years, median age 5.04 years). Methods and baseline characteristics are presented in a previous article [4]. Fifty‐nine cashew allergic children participated in the follow‐up study, and rechallenges were performed a median 3.26 years after primary diagnosis, out of whom 31/59 (53%) were female. Median age (range) at primary challenge was 4.45 (1.19–14.81) years [4]. Eight children (14%) passed the rechallenge, with 5 (63%) being female. Median age was 8.4 years in the positive rechallenge group and 8.2 years in the negative rechallenge group. The flow chart and baseline characteristics at rechallenge are shown in Figure S1 and Table S1.
IgE to cashew nut and its storage protein, Ana o 3, skin prick test (SPT) to cashew, and basophil activation test (BAT) were assessed before primary challenge and rechallenge. BAT result was reported as percentage of activated CD63+ basophils (BAT%). Challenge outcome was based on PRACTALL guidelines [5] and anaphylaxis was defined by EAACI 2014 criteria [6].
Median IgE to cashew nut and Ana o 3, BAT%, and SPT to cashew in the follow‐up population were statistically similar between primary challenge and rechallenge values (p = 0.178, p = 0.343, p = 0.283, and p = 0.658, respectively). Median cashew‐IgE, Ana o 3‐IgE, and BAT% were significantly lower among those with a negative rechallenge compared with those reacting in the rechallenge (p < 0.001*, p < 0.001*, and p = 0.005*). Median SPT did not differ significantly between those with a negative or positive rechallenge (p = 0.123).
Children who recovered had a significantly greater percentage decrease in cashew nut‐IgE, Ana o 3‐IgE, and BAT% (p < 0.001*, p < 0.001*, and p = 0.008*, respectively) than persistently allergic children. Percentage change in SPT to cashew did not differ significantly between the allergic and tolerant patients. Data is shown in Figure S2. The median percent values for allergic versus tolerant groups were: 13.9% versus −53.8% for BAT%, −15.0% versus −81.2% for IgE to cashew, and −13.1% versus −85.4% for Ana o 3‐IgE (Figure 1). The optimal cutoff for percentage change in Ana o 3‐IgE was −50%, which yielded 100% specificity and 76% sensitivity for predicting a negative rechallenge. Percentage change in SPT did not effectively predict clinical resolution (area under the curve 0.436). Optimal cutoffs for percent change in IgE to cashew and Ana o 3 and BAT% in predicting negative rechallenge are demonstrated in Table 1. Specific IgE to cashew nut and Ana o 3, SPT to cashew, and BAT% at primary challenge and rechallenge among tolerant are presented in Table S2.
FIGURE 1.
Median percent change in basophil activation test (BAT%), cashew nut‐IgE, and Ana o 3‐IgE between primary challenge and rechallenge among tolerant and persistently allergic children.
TABLE 1.
Optimal cutoffs for percent change in IgE to cashew nut and Ana o 3 and BAT% in predicting a negative cashew nut rechallenge.
| Cutoff | Specificity | Sensitivity | PPV | NPV | AUC | 95% CI | |
|---|---|---|---|---|---|---|---|
| Cashew‐IgE | −70% | 75% | 88% | 96% | 50% | 0.856 | 0.727–0.986 |
| Ana o 3‐IgE | −50% | 100% | 76% | 100% | 40% | 0.912 | 0.832–0.993 |
| BAT% | −10% | 86% | 80% | 97% | 40% | 0.805 | 0.611–0.999 |
Note: Youden method was used to define the optimal cutoffs.
Abbreviations: AUC, area under the curve; BAT%, percentage of activated CD63+ basophils; CI, confidence interval; NPV, negative predictive value; PPV, positive predictive value.
Median cumulative reactive dose was significantly higher in children reacting in the primary challenge compared with children with a positive rechallenge (80 mg [4] vs. 30 mg, p = 0.012*). Among persistently allergic, 26/51 (51%) experienced anaphylaxis, and adrenalin was required in 33/51 (65%) of the positive rechallenges.
In conclusion, only 14% of children with confirmed cashew nut allergy achieved tolerance, which suggests consideration of early cashew immunotherapy to prevent development of potentially persistent cashew nut allergy. The most reliable predictor of potential resolution may be a marked decrease in IgE to cashew nut and Ana o 3 and BAT%. Anaphylaxis rate remained high and cumulative reactive dose decreased significantly after follow‐up, underlining the high potency of cashew nut in inducing severe reactions even after years of avoidance.
Ethics Statement
The study followed the principles of the Declaration of Helsinki. The study protocol was approved by the ethics committee at the Helsinki University Hospital of Children and Adolescents, according to which one of the parents and children aged ≥ 6 years provided written informed consent.
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
Figure S1: Flow chart of study design.
Figure S2: Median percent change in (A) skin prick test (SPT), (B) basophil activation test (BAT%), (C) cashew nut‐IgE, and (D) Ana o 3‐IgE between primary challenge and rechallenge between those with negative rechallenge and positive rechallenge. In the positive rechallenge groups, two outliers were excluded from (B, D) and one outlier from (C).
Data S1.
Table S1.
Table S2.
Acknowledgements
Open access publishing facilitated by Helsingin yliopisto, as part of the Wiley ‐ FinELib agreement.
Funding: This work was supported financially by Helsinki University Hospital Research Funds, Sigrid Jusélius Foundation, Pediatric Research Foundation, Finnish Allergy Research Foundation, and Finnish Society of Allergology and Immunology.
Data Availability Statement
Research data are not shared.
References
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Associated Data
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Supplementary Materials
Figure S1: Flow chart of study design.
Figure S2: Median percent change in (A) skin prick test (SPT), (B) basophil activation test (BAT%), (C) cashew nut‐IgE, and (D) Ana o 3‐IgE between primary challenge and rechallenge between those with negative rechallenge and positive rechallenge. In the positive rechallenge groups, two outliers were excluded from (B, D) and one outlier from (C).
Data S1.
Table S1.
Table S2.
Data Availability Statement
Research data are not shared.