Discussion
We were able to show that peanut-sensitized infants and toddlers are often co-sensitized to tree nuts and their 2S albumins. Regarding co-existing tree nut allergy among peanut-allergic children several observational studies have been conducted. In the population-based Australian HealthNuts study cohort of 5,276 participants, 27% (95% CI: 16.1%, 39.7%) of children with peanut allergy at the age of one year had tree nut allergy at 6 years of age (19). The authors of the SchoolNuts study, a cohort of 9816 school children aged 10–14 years, reported that tree nut allergy co-existed in 41.5% of peanut-allergic children (18). Moreover, our data indicates that even very young peanut-sensitized children below 2 years of age may frequently be sensitized to tree nuts and their seed storage proteins. Calculating the likelihood of clinical relevance, we could show that many of these infants and toddlers would present allergic symptoms.
Almost all of the children included in our analysis (98%) suffered from eczema, which is known to be a major risk factor for sensitization and the development of food allergy (3). In the HEAP study, we observed that 65% of infants with eczema were sensitized to hen´s egg at the early age of 4 to 6 months compared to only 9% of sensitized infants without eczema (22). It seems that low-dose concentrations of food allergens in the environment, for example in house dust, can penetrate a disrupted skin barrier, ultimately leading to Th2-response and IgE production (2). In this context, results from the PreventADALL birth cohort showed that a high transepidermal water loss, a marker for impaired skin barrier function, is able to predict sensitization at 6 months of age with 61.7% sensitivity and 78.1% specificity (8). Moreover, we have observed that food allergens like peanut and hen´s egg proteins can be detected in house dust and that they even can be found in the infant´s bed after consumption in the eating area (5, 6). These findings reflect the dual-allergen-hypothesis proposing that an early cutaneous exposure to allergens in children with eczema occurring before the first oral intake enhances the risk for sensitization but also allergy to these foods (2). Thus, Martin et al. demonstrated that infants with eczema had an 11 times higher risk to develop peanut allergy and were 6 times more likely to have hen´s egg allergy by the age of 12 months compared to infants without eczema (23). Finally, a recently published meta-analysis concluded that the overall prevalence of challenge-proven food allergy among patients with eczema is 40%, whereby the association between eczema and food allergy was stronger in children (3). In our study, peanut-allergic as well as peanut-tolerant patients were at equal risk to be sensitized to tree nuts and its seed storage proteins, highlighting that eczema itself is a major risk factor for the sensitization to food allergens.
Even though the household consumption of tree nuts of the families taking part in our study is unknown, tree nuts in general are becoming more present in many households and are highly potent allergens (11, 13). In principal, experts tending to argue against pre-emptive testing of additional allergens (24). Nevertheless, our analysis has revealed that peanut-sensitized infants and young children were already sensitized to the 2S albumins of tree nuts to a high extent. Being sensitized to 2S albumins is associated with allergic reactions (14). More than 15% of our peanut-sensitized infants and toddlers were very likely to be allergic to hazelnut and/or cashew and 32.7% had a more than 50% probability, according to probability curves outlined in literature (15, 16). Given these findings, it should be considered to test peanut-sensitized infants and toddlers also for sensitization to tree nuts if tree nuts are not already part of their diet. This might become more relevant if specific recommendations not only for the prevention of peanut but also tree nut allergy will come into place. So far it has been shown in the LEAP trial that the early introduction of peanut significantly reduces the risk for developing peanut allergy (25). Therefore, international guidelines suggest introducing peanuts into the infant´s diet in an age-appropriate form as part of complementary feeding in order to prevent peanut allergy in infants and young children in populations where there is a high prevalence of peanut allergy. As Germany is not a country with high prevalence of peanut allergy our S3 guideline states that introduction and regular consumption of peanuts in an age-appropriate form may be considered in infants with atopic dermatitis living in families with regular peanut consumption, however, peanut allergy should first be ruled out, especially in infants with moderate to severe atopic dermatitis (7) as it had been performed in the LEAP trial (25). Due to a lack of interventional trials, so far, no specific recommendations for tree nuts have been formulated. However, in the HealthNuts study, none of the children who consumed cashew by the age of 12 months developed cashew allergy (0%; 95% CI, 0%-2.6%), compared with 3.6% (95% CI, 2.9%-4.4%) of those that had not eaten cashew by one year of age (26). Nevertheless, further randomized-controlled trials are needed to observe the effectiveness regarding allergy prevention and safety of an early introduction of tree nuts into the infant´s diet.
Limitations of our study have to be mentioned. As this was a retrospective analysis of stored serum samples, we had no data on the clinical relevance of the tree nut sensitization. Therefore clinical reactivity could only be estimated using probability curves published in literature.
In conclusion our study demonstrates that a very high proportion of peanut-sensitized infants and toddlers are already co-sensitized to tree nuts with a high likelihood of clinical relevance in many of them. These findings should be considered for future strategies in screening, diagnostics and the prevention of tree nut allergy in children.