**4. Discussion**

To our knowledge, this is the first Italian study to provide a comprehensive characterization of children with nut allergies [15], although a Turkish study has recently been published on the same topic [22]. Indeed, most of the studies about nut allergies have focused on a single type of nut, especially peanut, walnut, or hazelnut, or summarized the main characteristics of nut allergies without making a distinction between the various kinds of nuts [11,23–26]. Conversely, we retrospectively analyzed the demographic, clinical, and allergological characteristics of Italian children with nut allergies and compared them.

From our experience, in Italian children, nut allergies are more common in male subjects, and allergies to hazelnuts and walnuts were the most observed nut allergies, as stated by a previous Spanish study [27]; peanut allergies were frequently observed as well. Furthermore, most of the first nut reactions occurred between 2 and 5 years (mean age 4.7 ± 3.6 years), which is later in comparison with those in the available literature [13,22]. The underlying reason for a later age of onset of the signs and symptoms may be due to the high percentage of familial history of allergy in our population, which leads the parents to introduce the nuts in the diet later for the fear of possible allergic reaction. The mean age of the first nut reaction was statistically higher for pine nuts (8.6 ± 3.7 years) when compared with the other nuts except for cashews (8.5 ± 5.9 years). On the contrary, in the hazelnut group, the mean age of the first nut reaction (3.7 ± 3.2 years) was lower than with other nuts, even without a statistical significance. These differences may be related to the low

number of patients included in the study. The majority of patients in our population had a familiar history of allergy (75%) and/or concomitant allergic disorders (68%), including asthma, atopic dermatitis, and allergic rhinitis. Among these, allergic rhinitis was the most common allergic disorder (43%), followed by atopic dermatitis (41%). The percentage of children with allergic rhinitis and a concomitant food allergy is in line with the literature (33–40%) [28].

In subjects with food co-allergies, the most frequent foods involved were egg (50%), milk (41%), and concomitant egg and milk allergies (32%), according to the literature [22]. Most of our patients (over 75% in each group) reported a single nut allergy, and the remaining subjects had at least one nut co-allergy. A coexistent nut allergy was also described in several studies [29]. Sicherer et al. reported that 34% of patients allergic to peanuts or nuts might present with multiple nut allergies [30]; however, further studies reported a large variation in the proportion of patients reacting to multiple nuts, ranging from 12% to 96.7% [31]. We found more single nut allergies because our population is younger (median age of 3.5 years) than the other ones. In particular, the studies of Sicherer et al., Maloney et al., Mc William et al., and Brough et al. found values of coallergies and median age, respectively, as follows: 34% and 3.6 years, 34% and 6.1 years, 47.8% and 6 years, and 60.7% and 5.5 years [29,30,32,33]. The only study that showed a lower percentage of co-allergy (12%) has a younger population (1.3 years) [34]. It seems that the percentage of the co-allergy increases with the increasing age of the studied population. In our study, the most common co-allergy was hazelnut, mainly represented in the group of patients allergic to walnut. These data could depend on the high prevalence of hazelnut allergy in continental Europe, in which it represents the most frequent nut allergy [8].

Anaphylaxis as the first clinical manifestation of nut allergy occurred in over 40% of our population, similarly to the Turkish study [22]. In agreement with the literature, the most common presenting signs and symptoms at initial diagnosis of nut allergy were skin manifestations (62%), including hives, itching, flushing, and/or rash [35,36]. The cutaneous involvement was followed by gastrointestinal (39%) and respiratory (2%) ones. In the same way, the characteristic of the population (gender, familiar history of allergic diseases, concurrent allergic diseases, food and/or nut co-allergy) did not differ between the various nuts, except for the mean age of the first nut reaction, as previously mentioned. Finally, we were unable to find a statistical association between the severity of nut reaction (first one in chronological order according to clinical history and during OFC), the mean values of allergological tests (PbP, s-IgE, molecular components), and the type of nut involved.

Among positive nut OFCs, we observed 22 severe reactions (19%). However, none of these required the injection of epinephrine, hospitalization, or intensive care assistance and the clinical manifestations resolved with oral antihistamines and corticosteroids. In the literature, the occurrence of anaphylaxis during the OFC depends on the type of food tested and, for TN and peanut, it ranges from 8% to 70% according to the different studies [37–39]. In the remaining population (81%), clinical manifestations during the OFC involved a single system (mainly the gastrointestinal one), according to different experiences carried out on a wide range of foods [40], and resolved spontaneously, confirming the safety of the OFC in children with suspected food allergies [36,38,39]. Thus, the clinical features, the severity of the reactions during the OFC, and the need for therapy did not depend on the type of nuts tested. Conversely, the mean dose of nut proteins ingested differed according to the severity of reactions during the OFC, with a lower threshold of doses observed in severe reactions.

The limitation of this observational study is the heterogeneous number of children retrospectively recruited for each kind of nut. These data could hide real differences between the various nut groups, but they could be informative as well, strictly connected to the characteristics of children with a nut allergy referred to our center, a tertiary-care pediatric hospital. However, as this study was carried out in a single allergy unit, the reference center for the region, our results could have limited applicability to other centers and regions. Another limitation is the lack of a complete molecular analysis of patients

before the OFC was performed per clinical criteria. Therefore, only 64% of the eligible population received a molecular analysis; for this reason, it was not possible to clearly discriminate patients with primary nut allergy versus PFS/OAS. Finally, due to the small number of patients in the cashew and pistachio groups, the results concerning them should be interpreted with caution.

On the other hand, the strength of this study is the clear-cut selection of the studied population with an OFC-confirmed nut allergy and the summary of the main characteristics of the nut allergy, taking into account differences between the various kind of nuts. Finally, our study also confirmed the safety of an OFC performed by experienced personnel on selected subjects.
