Editorial: With tree nut sensitization, take the current when it serves, or lose our ventures

Tree nut allergy affects approximately 1.4%-2.3%, depending on the study methodology, patient age, and region in which the study was conducted.1, 2 Tree nut allergy can be severe and tends to persist throughout life.1, 3 Tree nut is not a singular allergen like the other allergens—we use the term “tree nut” to refer to these items, but in essence, it can refer to one nut, 8 nuts, or as per the US Food and Drug Agency classification, on the order of 19 items.1, 4 Older, more conservative practice is to treat one nut as “all nuts,” and instruct avoidance of all tree nuts where there is a clinical allergy proven to just one. This is often supported by high rates of co-sensitization, which is frequently observed among tree nuts because of structural similarity, and fueled concerns of cross-contamination, proper identification, or labeling confusion.1, 5 Tree nut sensitization is quite common, influenced by cross-reactive proteins with tree pollen (which may vary depending on where one may reside).5-7 But to what extent is this sensitization clinically relevant for our patients, truly necessitating avoidance? Few studies have been conducted that provide a robustly (and oral challenge) proven rationale for widespread avoidance of “all” tree nuts due to allergy to just one or multiple sensitizations to others that have never been ingested.8-10 This creates knowledge gaps, needs for best practice strategies, and risks contributing to poor quality of life. Therefore, a pressing clinical question remains whether such widespread avoidance as a matter of routine is really the best advice we can (and should) provide our patients. A recent single-center US study of 159 tree nut challenges performed in either tree nut-sensitized but unexposed individuals or individuals sensitized to multiple tree nuts but only allergic to one noted 76% were tolerant of at least one other nut when challenged, with no co-allergy noted to almond. These findings may suggest there is significant opportunity to prevent over-restrictive management in the setting of multiple tree nut sensitization.9 The NUTCRACKER study by Elizur et al11 further probes this theme and adds much needed additional support to the notion that selected tree nut avoidance, as opposed to widespread avoidance of all tree nuts, is safe and practical. In this study, they conducted multiple tree nut challenges in 83 patients known to be allergic to at least one tree nut and were avoiding other tree nuts based on sensitization alone (which averaged avoidance of approximately 5-6 nuts). Challenges were conducted to these other nuts so long as there was not a documented reaction in the previous 2 years. They demonstrated a challenge-proven rate of co-allergy to more than one tree nut to be less than 30%, and the highest rate of allergy noted to walnut (74.6%) and cashew (65.6%) (and one single case of almond allergy). Certain patterns emerged that may allow focusing on co-allergy that is more likely, such as a 66% rate of challenge-proven co-allergy between walnut and pecan, and between cashew and pistachio. Interestingly, all pecan- and pistachio-allergic patients were allergic to walnut and cashew, showing an interesting pattern of directionality to this mix. Elizur et al additionally utilized basophil activation testing (BAT) in combination with skin test results to help identify those who could have selected tree nuts introduced at home rather than in office. This approach correctly differentiated allergic vs tolerant patients sensitized to walnut (87%), pecan (66%), cashew (71%), and pistachio (79%). Although the BAT is still primarily a research test, these results represent a promising potential future clinical application for its future use. These findings, in context with other similar work, hold significant potential value for changing the paradigm of how to optimally manage the tree nut-sensitized/allergic population. Elizur et al publish challenge-proven co-allergy rates significantly lower than prior reported estimates and rates that may be predicted based on co-sensitization alone.5-7 Given recent data suggesting that peanut-sensitized children without tree nut exposure have some likelihood of developing tree nut sensitization, with adoption of early peanut introduction guidelines in multiple nations there is a distinct possibility children develop incidental tree nut sensitization as an unintended trade-off for preventing peanut allergy.12 Thus, it becomes up to us as a field as to how we handle this situation— conservatively, fearing the potential that sensitization without a clinical context denotes a likely allergic reality, or more rationally, utilizing the NUTCRACKER data to optimally manage such children to help prevent unnecessary avoidance.11 The field of food allergy has evolved rapidly, but it is unknown the extent that inertia may exist toward more aggressive practices in cases of potentially incidental tree nut sensitization. Well-intended instincts may recommend too much avoidance than is warranted. However, this is not necessarily the right thing for our patients. While striving to do no harm, we must consider the inadvertent harm caused by questionable avoidance, and the potential benefit in offering challenge to validate the necessity of such avoidance. There is a real opportunity provided by the NUTCRACKER data as a practical example to how mismanagement can potentially be avoided. We as a field just have to be willing to seize such opportunity. The authors declare that they have no conflicts of interest. Dr. Greenhawt is supported by grant #5K08HS024599-02 from the Agency for Healthcare Quality and Research; is an expert panel and coordinating committee member of the NIAID-sponsored Guidelines for Peanut Allergy Prevention; has served as a consultant for the Canadian Transportation Agency, Thermo Fisher, Intrommune, and Aimmune Therapeutics; is a member of physician/medical advisory boards for Aimmune Therapeutics, DBV Technologies, Nutricia, Kaleo Pharmaceutical, Nestle, and Monsanto; is a member of the scientific advisory council for the National Peanut Board; has received honorarium for lectures from Thermo Fisher, Before Brands, multiple state allergy societies, the ACAAI, the EAACI; is an associate editor for the Annals of Allergy, Asthma, and Immunology; and is a member of the Joint Taskforce on Allergy Practice Parameters.

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