Allergy to Plant-Based Panallergens LTPs in Children: A Scoping Review

Abstract

Introduction: Lipid Transfer Proteins (LTPs) are plant-derived panallergens that have emerged as significant allergens in Mediterranean populations. Though less common in children, LTP allergies represent a critical consideration for physicians diagnosing plant food allergies in this demographic. Methodology: PRISMA-ScR guidelines were followed. A search with specific terms was performed in searchable databases. Two of the authors extracted and evaluated the data. Results: A total of 21 original studies and 6 case reports focusing on LTP allergies in the paediatric population met the inclusion criteria. Diagnostic tools, predictive markers and management options for LTP allergies were examined. Allergens, clinical presentation and history were the diagnostic tools investigated. The clinical and laboratory phenotypes of the patient were considered possible predictive markers for the evaluation and progression of LTP allergies. Lastly, dietary modifications and sublingual immunotherapy were identified as the main focus of LTP allergy management. Discussion: A summary of the results is presented, and at the same time, questions concerning the nature of LTP allergies and their management are raised. Conclusions: LTP allergy in children is something physicians should be aware of. Further research is needed to establish the differences in LTP allergies in children and adults and the effectiveness of immunotherapy in paediatric populations.

1. Introduction

Allergies represent a major health concern amongst children. In particular, food allergies carry a significant impact, with a meta-analysis revealing that the lifetime risk of physician-diagnosed food allergies in European children is 9.28% [1].

The interest of researchers has recently been attracted by Lipid Transfer Proteins (LTPs), panallergens found in plant foods. LTPs are plant-derived proteins which have emerged as important allergens in countries of the Mediterranean Basin [2]. More specifically, a study conducted by Scala et al. examined 23.077 Italian subjects with IgE to at least 1 of 75 allergenic molecules and concluded that the prevalence of LTP sensitisation was 15% in individuals aged 15–25 years [3]. Thus, while LTPs are not the most common allergens in children, they should always be considered by physicians when investigating plant food allergies, especially in populations of Mediterranean origin.

After an extensive search of the literature, no reviews were found on LTP allergies in children. For this reason, a scoping review was conducted, in order to establish the diagnostic tools, the predictive markers and the proper management of LTP allergies in children.

2. Materials and Methods

2.1. Protocol

This study was designed in accordance with the protocol Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) [4].

2.2. Literature Search and Study Selection

A comprehensive review was performed in searchable databases, i.e., Medline (through PubMed) and Scopus, using common keywords and Medical Subject Headings (MeSH) and the logical terms AND/OR, i.e., [“Allergy” OR “Anaphylaxis”] AND [“LTP”(Title) OR “Lipid transfer protein”(Title) OR “Lipid transfer proteins”(Title)]. Only original research studies that included paediatric subjects in their population were considered. Moreover, the references of the selected studies were reviewed to identify any additional relevant studies.

It was decided to include only studies published after 2009. This was because, to our knowledge, the first case report on immunotherapy for LTP allergy was published in 2009. Immunotherapy has changed the way physicians approach LTP allergy, while it has also prompted researchers to investigate the pathology more thoroughly and systematically.

2.3. Inclusion and Exclusion Criteria

Inclusion criteria: (i) sample size consisting of at least 10% of the target population (aged from infancy up to 18 y.o.); (ii) published from 1 January 2009 to March 2024 (date of the most recent study the time the search was conducted); (iii) evaluation of LTP allergies. In studies investigating immunotherapy treatment, the population was mainly composed of young adults. However, most of these patients had been diagnosed and monitored by paediatricians, with their follow-up data available for several years prior to starting treatment. Consequently, it was deemed prudent to include them in this review.

Exclusion criteria: (i) non-original articles; (ii) non-English articles; (iii) publications in non-peer-reviewed journals.

2.4. Data Extraction

Two reviewers (D.K. and N.P.) extracted data from the results of the aforementioned search independently. Data were charted independently by using the following: publication year, study design, sample size and age, and LTP allergy evaluation.

Case reports were charted separately by using the following: patient’s age and gender, allergen, clinical presentation, co-factors and management.

2.5. Study Evaluation

Each of the two authors carefully examined each study and extracted data related to the diagnostic tools, the predictive markers and the treatment of LTP allergies in children. They also carefully examined the strengths and weaknesses of each study to assess their reliability. For the final selection of the studies, the two authors compared and discussed their findings, until a consensus was reached.

2.6. Synthesis of Results

The studies were grouped as “Evaluating diagnostic tools”, “Evaluating predictive markers” and “Evaluating management options”. Each group was further sub-grouped as “Diagnostic tools: Allergens”, “Diagnostic tools: Clinical presentation” and “Diagnostic tools: History”; “Predictive markers: Clinical phenotype” and “Predictive markers: Laboratory phenotype”; and finally, “Management options: Dietary modifications” and “Management options: Sublingual Immunotherapy (SLIT)”, respectively.

3. Results

3.1. Selection of Studies

A total of 21 original studies and 6 case reports were considered for this analysis. When the searched terms mentioned in the previous section were used, a total of 455 studies were found. The selection process included the removal of duplicates, the application of the inclusion and exclusion criteria, and the consideration of the titles and abstracts. Nineteen of the studies and six of the case reports were found with the original search, and two of the studies were cross-references. In two of the studies, the population examined consisted of young adults instead of including infants, children, or adolescents (as explained in Section 2.3. The selection process is presented in Figure 1, and the studies analysed are presented in

Table 1. Populations of studies considered.

First Author	Date of Publication (DoP)	Sample Size [N]	Ages [y.o.]	LTP Allergy Evaluation
Akkerdaas, J. [5]	2011	10	6–48	This study examined the lentil Len c 3 allergen.
Arkwright, P. [6]	2013	192	2–10	This study examined peanut Ara h 9, its association with bronchospasm and possible predictive markers.
Asero, R., Aruanno, A. [7]	2021	244	6–68	This study examined two different peach extracts for SPT.
Asero, R., Piantanida, M. [8]	2018	67	6–56	This study examined how allergens, history, predictive markers and dietary modifications can enhance LTP allergy follow-ups.
Barradas Lopes, J. [9]	2023	26	<18	This study examined the characteristics of and diagnostic tools for LTP allergy.
Basagaña, M. [10]	2018	84	3–62	This study examined the presentation, history and predictive markers of LTP allergy.
Beitia, J.M. [11]	2021	29	5–43	This study examined LTP allergens and Pru p 3 SLIT in LTP allergy.
Bernardi, M.L. [12]	2011	1003	n/a	This study examined the kiwi Act d 10 and Act c 10 allergens.
Betancor, D. [13]	2021	151	n/a	This study examined the diagnostic tools, clinical phenotype and follow-up in LTP allergy.
Boyano-Martinez, T. [14] A	2013	51	2–17	This study examined dietary modifications in Pru p 3 allergy.
Deng, S. [15]	2019	148	3–46	This study examined mugwort LTP pollen allergy and its correlation with the history and laboratory phenotype of LTP food allergy.
Gadermaier, G. [16]	2011	n/a	n/a	This study examined celery Api g 2, its cross-reactivity and laboratory phenotype in LTP allergy.
Gomez, F. [17] A,B	2017	48	21–38	This study examined the effects of SLIT with Pru p 3 on peach and peanut allergy.
González-Mancebo, E. [18]	2011	430	n/a	This study examined the characteristics and diagnostic tools of LTP and profilin allergy.
Lisiecka, M.Z. [19]	2023	284	3–55	This study examined the diagnostic tools and laboratory markers in LTP allergy.
Lisiecka, M.Z. (children model) [19]	2023	126	3–14	Same as above.
Mota, I. [20]	2018	43	3–52	This study examined the history and predictive markers of patients presenting with LTP-induced anaphylaxis.
Palomares, F. [21] B	2021	20	22–49	This study examined SLIT and its effects on innate lymphoid cells type 2.
Pascal, M. [22]	2016	130	<18	This study examined LTP allergies and their predictive markers in asymptomatic patients.
Pastorello, E.A. [23]	2014	3	n/a	This study examined wheat Tri a 14 and Tri a 14-induced FDEIA.
Romano, A. [24]	2012	82	9–47	This study examined LTP-induced FDEIA and its history.
Scala, E. [25]	2015	568	1–84	This study examined the characteristics, allergens, history and predictive markers of LTP allergy.

^A: Studies considered cross-references from other studies; see Section 2.2. ^B: Studies whose population consisted of young adults; see Section 2.3.

.

It is of note that only 5 out of the 21 original studies focused exclusively on children. These have been separately analysed, and the results are shown in Supplementary Table S1.

3.2. Diagnostic Tools

3.2.1. Allergens

A total of 15 out of 21 studies [5,7,8,9,10,11,12,13,15,16,18,19,22,23,25] investigated the epidemiology of sensitisation to different LTP allergens.

The prevalence of sensitisation to reported allergens was studied in seven articles [7,9,10,13,15,18,19]. In all of them (100%), fruits and more specifically peach were the most common foods to be reported as a cause of clinically evident allergy. Tree nuts were the second most common reported allergen in four studies [8,9,13,19] and apples in one study [15]. Peanuts [8,9,13,15], hazelnuts [13,15] and oranges [19] were other frequent allergens. Interestingly, Asero R et al. described tomato as the most prominent allergen in Food-Dependent Exercise-Induced Anaphylaxis (FDEIA) [8]. The molecular components of each allergen involved in a specific IgE (sIgE)-mediated response was measured in four different studies [10,13,22,25]. The most frequent sensitiser in all the studies (100%) was the peach LTP Pru p 3, with a sensitisation rate of 70.3–96.9%. The second most frequent food-derived sensitiser was walnut Jug r 3 in all of the studies. Betancor D. et al. described that a pollen LTP, plane tree Pla a 3, is a more common sensitiser than Jug r 3 [13]. It should be noted that sensitisation to Cor a 8 and Ara h 9 occurred in patients allergic to Pru p 3 and Jug r 3, indicative of the fact that Pru p 3 acts as the primary sensitiser [22]. Research findings support the theory of Pru p 3 acting as the primary sensitiser [16,23]. Lastly, skin prick testing (SPT) suggests that peach is the most common food allergen, followed by peanuts and nuts [11].

Betancor, D. et al. measured the sensitisation rate of symptomatic and non-symptomatic patients sensitised to LTPs in various allergens. Pru p 3 was the most common sensitiser in both groups. More specifically, the sensitisation rate against Pru p 3 was 80.6% in the symptomatic group and 70.3% in the asymptomatic group. In the group of asymptomatic patients, Pru p 3 was followed by Art v 3 and Cor a 8 [13].

Forms of co-sensitisation are mentioned in most of the studies. Adverse reactions to more than one plant food were described in up to 70% of the population [9,22] diagnosed with LTP allergy. On the other hand, Lisiecka, M.Z. et al. documented that as few as 28% of the children diagnosed with LTP allergy may present adverse reactions to more than one plant food [19]. It is important to note that LTP allergens were found to have a positive association with each other [12]. Additionally, Asero, R. et al. [8] and González-Mancebo, E. et al. [18] documented co-sensitisation to profilins at 15% and 23%, respectively, in subjects allergic to LTPs. Co-sensitisation was seen in allergens of the same type of species, more specifically, Act c 10 and Act d 10, deriving from green (Actinidia deliciosa) and gold (Actinidia chinensis) kiwifruit, respectively [12].

More in-depth analysis of allergens was also performed. Akkerdaas, J. et al. described the process of extraction (nLen c 3) and synthesis (rLen c 3) of two different forms of the lentil Len c 3 allergen. It was reported that both forms are closely homologous with respect to each other [5]. Additionally, as expected, Act c 10 and Act d 10, two allergens from different species of kiwifruits, were very similar in laboratory analysis [12]. Gadermaier, F. et al. reported that Pru p 3 is more resistant to heat, pH changes and proteolytic activity compared with other LTP allergens. Moreover, all proteins studied had four distinct peptide clusters at similar locations, with different degrees of amino acid agreement [16]. A study by Bernardi, M.L. et al. supports these findings [12]. Pru p was also reported to be digested by trypsin [12]. Scala, E. et al. investigated the sensitisation of an Italian population to seven different LTPs, suggesting that Pru p 3 may not contain all the LTP binding epitopes. However, they proposed that all LTPs must have epitope co-recognition to an extent [25].

3.2.2. Clinical Presentation and Course

A total of 9 out of 21 studies [6,9,10,13,18,19,20,23,24] investigated the clinical presentation and course of LTP allergies.

Six studies investigated the presentation of patients with LTP allergy. In three of them, the manifestations were classified as Local, Systemic or Mixed (findings are presented in

Table 2. Prevalence of reaction types to LTP allergens in 3 different studies.

First Author	Local	Systemic	Local + Systemic
Barradas Lopes, J. [9]	15% (n = 4/27)	58% (n = 15/27)	27% (n = 7/27)
Betancor, D. [13] (all)	24.8% (n = 28/113)	75.2% (n = 85/113)	n/a
Betancor, D. [13] (not Pru p 3)	80% (n = 9/14)	20% (n = 5/14)	n/a
González-Mancebo, E. [18]	86% (18/21)	0	14.3% (n = 3/21)

) [9,13,18]. Lisiecka, M.Z. et al. reported that 42% of the children examined presented with two or more clinical manifestations [19]. Another study revealed that contact with Ara h 9 led to respiratory symptoms or reduced the level of consciousness in 63% of the sensitised patients [6]. Mota, I. et al. stated that the severity of a patient’s reaction to foods may differ, depending on the allergen involved. More specifically, 43 patients with food-induced anaphylaxis (FIA) were investigated. FIA was reported in 70.9% of the fruit-allergic patients (N_F = 31), 94.7% of the nut-allergic patients (N_N = 19) and 71.4% of the peanut-allergic patients (N_P = 14) [20]. However, it should be noted that González-Mancebo, E. et al. documented that only 37.7% of patients sensitised to LTPs developed symptoms when consuming plant foods [18].

FDEIA was another implication of the LTP allergies studied. One study investigated the correlation between LTP sensitisation and FDEIA. It was documented that the prevalence of LTP sensitisation in a mixed (children + adults) population of 82 subjects who presented with FDEIA was higher compared with the prevalence of LTP sensitisation in an allergic population not exclusively presenting with FDEIA. Accordingly, patients with LTP allergy are more likely to present with FDEIA [24]. Moreover, Pastorello, E.A. et al. examined three patients diagnosed with FDEIA from wheat LTPs. They were all co-sensitised to maize and rice LTPs. Maize and rice induced a different reaction in each of the three patients [23].

LTP allergy progression was examined by three different studies. The rate of new allergies emerging in each population ranged from 26.5 to 28% [10,13,19]. Furthermore, Basagaña, M. et al. suggested that the natural course of LTP allergy is not only towards sensitisation to more allergens but also towards more pronounced reactions [10]. On the other hand, Betancor, D. et al. documented that sensitised but non-allergic patients presented with less notable evolution, with less sensitisation and milder reactions [13].

3.2.3. History of LTP-Allergic Patients

A total of 11 out of 21 studies [6,8,9,10,13,15,18,19,20,24,25] investigated the history of patients with LTP allergy.

Age and gender were two important aspects of a patient’s history. Many children experienced their first reaction before the age of 3 years [9]. Additionally, anaphylactic episodes have been described in children as young as 2 y.o. [20]. Therefore, clinicians should consider LTP allergy in their differential diagnosis when the presentation is consistent with it. Conflicting evidence has been reported, as far as the association of age and disease activity is concerned (results presented in

Table 3. Results of studies examining the age of patients.

First Author	Parameters Studied	Results
Arkwright, P. [6]	Age and bronchospasm	Older subjects were more prone to acute bronchospasm
Asero, R. [8]	Age, gender, number of foods sensitised and severity of presentation	No associations were described
Barradas Lopes, J. [9]	Age, gender, number of foods sensitised and anaphylaxis	No associations were described
Basagaña, M. [10]	Age and severity of presentation	Younger subjects were less prone to clinically evident allergy
Lisiecka, M.Z. [19]	Age and mode of LTP sensitisation	Adults were more prone to LTP sensitisation by inhalation
Romano, A. [24]	Age, gender and FDEIA	Male subjects were younger

). The progress of LTP allergies was not altered in different subgroups of patients [8]. Gender was not linked with IgE levels against LTPs [25]. Moreover, LTP allergy was also reported in Northern European populations [6].

Another important aspect of the history of LTP sensitised patients was the conditions in which allergy was elicited. Ara h 9-allergic patients were studied, and it was found that sensitisation via ingestion was more common than other possible routes [6]. Additionally, three studies reported that co-factors needed to be present [9,13,24]. Factors described were Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) [9,24], exercise [9], seasonal rhinitis (worsening of symptoms), menstruation, stress and climatic conditions [24]. Romano, A. et al. performed a throughout investigation of patients with FDEIA. The time between consumption of allergen and symptoms was 30–240 min, the duration of exercise before symptoms appeared was 10–50 min, and the intensity of exercise ranged from walking to running [24].

Co-morbidities also represented a topic of interest amongst studies. Atopy was the most common condition investigated. Its prevalence ranged from 61% to 95% [6,9,13,20] (refer to Figure 2 for a more detailed presentation of the results). Moreover, clinical manifestations of LTP allergies may have a surge in pollen season [15]. Despite that, one study stated that no associations were found between LTP allergy and other allergic diseases [18]. Additionally, Romano A. et al. remarked that 19.5% of patients diagnosed with FDEIA had no history of allergies or allergic-like diseases [24]. Eosinophilic esophagitis coexisted with LTP allergy in two independent studies [9,20].

3.3. Predictive Markers

3.3.1. Clinical Phenotype

A total of 7 out of 21 studies [6,8,10,13,20,22,25] investigated the predictive value of the clinical phenotype of LTP patients.

A major predictive marker for the severity of LTP allergy is the co-sensitisation with other allergens. Four studies examined the role of PR-10 and/or profilin sensitisation (results presented in

Table 4. Associations of co-sensitisation with LTP allergy presentation.

First Author	Allergen	Association with LTP
Asero, R. [8]	Profilins and PR-10	Co-sensitisation was not associated with anaphylaxis or more severe progress
Mota, I. [20]	Profilins and PR-10	Co-sensitisation was associated with less severe reactions *
Pascal, M. [22]	Profilins and PR-10	Co-sensitisation was not associated with anaphylaxis
Scala, E. [25]	Profilins and PR-10	Co-sensitisation was associated with less systematic reactions **

* n = 8/35, non-conclusive; ** p < 0.001.

). Two studies supported that it had no association with anaphylaxis [8,22], while two other studies supported that it was associated with less severe reactions [20,25]. Additionally, two independent studies revealed that co-sensitisation with storage proteins was associated with a higher chance of anaphylaxis [10,22] Other allergens studied were CCD [25] and Pru p 1 [22]. Neither of them was associated with different clinical outcomes. González-Mancebo, E. et al. calculated the odds ratios (ORs) for LTP allergy in plant food-allergic patients and pollen-allergic patients, which were 6.6 and 2.4, respectively [18].

Interestingly, three studies [6,10,25] indicated the degree of LTP sensitisation as a predictive marker for the risk of severe reactions. Basagaña, M. et al. documented that sensitisation to the pollen LTP allergens Pla a 3 and Art v 3 was positively correlated with food allergy. Thus, they can be used as markers indicative of food allergies [10]. Additionally, Ara h 9 sensitisation was positively linked with bronchospasm in peanut-allergic patients when compared with other peanut allergens. The researchers concluded that Ara h 9 can be used as a predictive marker for the severity of reactions in peanut-allergic patients [6]. Scala, E. et al. described that sensitisation to more than five LTP allergens was associated with a higher risk of systematic reactions compared with sensitisation to only one or two LTP allergens [25]. The findings of Basagaña et al. support these results [10].

It should be mentioned that research has expanded beyond the qualitive investigation of the predictive value of allergens, also including the quantitative investigation of their predictive value. Arkwright, P et al. documented that no correlation was found between the amount of consumed peanut-containing food and the severity of the reaction [6].

Comorbidities can also affect the manifestation of LTP allergy, as observed in two studies [6,25] (results presented in

Table 5. Studies investigating comorbidities.

Pathology	Arkwright, P. et al. [6]	Scala, E. et al. [25]
Asthma	(+) association with bronchospasm	No associations
Rhinoconjunctivitis	(+) association with pharyngeal oedema	(+) association with Art v 3 and Pla a 3, (−) association with Pru p 3
Atopy (atopic dermatitis, asthma and allergic rhinoconjunctivitis)	(+) association with LTP allergy (1/3: 88%; 2/3: 40%; 3/3: 20%)	n/a

).

One study investigated the correlation between LTP allergy and co-factors. Pascal, M. et al. observed that only 3 out of 130 children (2.3%) needed co-factors to display symptoms, significantly less than the 40% in the adult population [22].

3.3.2. In Vitro and In Vivo Tests

A total of 9 out of 21 studies [6,7,8,15,16,19,20,22,25] examined the predictive value of the laboratory phenotype of LTP patients.

Regarding the prognostic value of sIgE levels for systemic reactions, results were inconsistent. No difference was observed in Pru p 3 levels in patients reporting systematic or local symptoms [8]. This is in agreement with Pascal, M. et al., who documented that peach, walnut and peanut sIgE levels had no difference between patients presenting with or without anaphylaxis [22]. On the contrary, Scala, E. et al. reported that systemic reactions were more common in patients with higher sIgE levels. An exception was sIgE against Tri a 14 [25]. Deng S. et al. reported mixed results [15]. Total IgE was also examined. It did not correlate with sIgE levels or the progress or severity of the disease [8,15]. Interestingly, Gadermaier, G. et al. determined that sIgE affinity is more important than sIgE levels concerning the severity of reactions. Patients allergic to celery Api g 2 were examined. More specifically, their self-inhibition against Api g 2 was measured. Symptoms occurred more often in patients with stronger self-inhibition. Moreover, patients sensitised to Pru p 3 and Art v 3 exhibited weaker self-inhibition against Api g 2 even if in vivo cross-reactivity was achieved. Thus, symptoms occurred less often [16].

sIgE levels could be indicative of allergic disease. One study compared the levels of sIgE against food allergens between tolerant and non-tolerant children. The levels of sIgE against Pru p 3 and Ara h 9 were the only ones to differ between the two populations [22]. Additionally, Deng, S. et al. suggested that sIgE against Art v 3 could be used as a marker for food allergy. Specifically, a cut-off value of 1.25 kUA/L was proposed [15]. This evidence was supported by other studies, which linked pollen LTP sensitisation with food allergy [15,25].

Generally, according to Scala E. et al., high-risk patients for systematic reactions were patients with (i) more than five LTP allergies; (ii) no sensitisation to PR-10, profilins, or Par j 2; and (iii) higher sIgE values [25].

Pru p 3 sIgE was also studied as a marker for polysensitisation. Asero, R. et al. described that lower Pru p 3 sIgE levels were found in monosensitised patients compared with polysensitised ones [8]. However, other researchers documented no correlation between its levels and the number of plant foods sensitised [22]. Additionally, another independent study revealed that no linear association was found between number of sensitising foods and Pru p 3 sIgE [22].

Laboratory findings of LTP-allergic patients also correlated with comorbidities. Reactivity to Par j 2 was associated with bronchial asthma [25], while reactivity to Ara h 9 was not [6]. Moreover, sIgE against Ara h 9 did not associate with the severity of respiratory symptoms nor with the loss of consciousness in anaphylaxis [6]. Ara h 9 was also found to be an inadequate marker for predicting allergy to peanuts, since only 20% of peanut-allergic patients were sensitised against Ara h 9 [6].

Age was also a parameter studied. Lisiecka M. et al. documented that sIgE levels were higher in older populations [19].

Two studies examined the diagnostic potential of SPT. Asero, R. et al. compared two different peach extracts, used in SPT (namely, Lofarma and ALK-Abell). The two extracts were found to be in almost complete accordance. It is noteworthy that both tests screened peach-allergic patients sensitised to a peach allergen different from Pru p 3 [7]. Mota, I. et al. studied a population with a clinical history of anaphylaxis. Out of the 43 subjects who took part in the study, 36 were tested with sIgE assay and SPT. All of them (36/36) came back positive for sIgE, and 35/36 tested positive in SPT. sIgE, as expected, proved to be a more sensitive, while SPT was also a reliable diagnostic method [20].

3.4. Management of LTP Allergy

3.4.1. Dietary Modifications

A total of 3 out of 21 studies [8,13,14] examined the importance of dietary modifications.

It has been described that the peel of peach contains approximately eight times more Pru p 3 compared with peach pulp. Specifically, the freeze-dried extract from yellow peach peel contains 15.48 mg of Pru p 3, compared with 2.25 mg in the freeze-dried extract from yellow peach pulp. Similarly, the freeze-dried extract from red peach peel contains 14.67 mg of Pru p 3, while red peach pulp extract contains 1.84 mg [14]. Consequently, many individuals who are allergic to Pru p 3 can still consume peach pulp without issues. While it is often possible to identify and avoid the specific food triggering a reaction, it is not always possible to pinpoint the responsible food, particularly when reactions involve composite foods or co-factors. Asero’s study noted that individuals who initially had localised reactions to certain foods began developing systemic symptoms upon their continued consumption. Accordingly, avoiding foods that trigger milder immune responses should be considered [8]. Additionally, Rosaceae/Prunoideae family’s fruit, nuts and peanuts constitute the most common long-term triggers for developing new food allergies. Therefore, the decision to exclude these foods from a patient’s diet at baseline should be taken into account and be carefully individualised [8]. Moreover, evidence suggests that one-third of individuals with LTP allergy may develop new reactions and sensitisation to LTP allergens over the years, including substances that were previously tolerated and safely consumed [13]. Thus, regular follow-ups are crucial.

3.4.2. SLIT: An Emerging Therapeutic Approach

A total of 3 out of 21 studies [11,17,21] investigated SLIT for managing LTP allergy. One study included children, adolescents and young adults [11], while the other two focused exclusively on young adults [17,21].

SLIT has been considered a safe alternative for managing food allergies and may become a significant treatment option in the coming years [17]. Given the complex nature of LTP allergy management, it is not surprising that there is growing interest in developing SLIT for treating LTP allergy.

Beitia, J.M. et al. investigated the effectiveness of Pru p 3 SLIT in LTP allergy at a Spanish hospital from 2011 to 2018. The study involved 29 patients, aged from childhood to young adulthood, who were treated with SLIT and later underwent oral food challenges (OFCs) to test for the development of tolerance. A control group of 13 patients with LTP allergy who did not receive SLIT was also observed. After one year of SLIT, 73% of patients demonstrated tolerance to peaches, and this rate increased to 95% after two years. Additionally, 69% of patients exhibited tolerance to nuts and peanuts. In contrast, the control group experienced worsening symptoms and new food reactions. Overall, SLIT using Pru p 3 proved to be both effective and safe, leading to a reduction in dietary limitations for patients with LTP allergy [11].

The two other studies [17,21] focused on young adult populations and their immune response after SLIT.

Palomares, F. et al. carried out a controlled clinical trial, dividing participants into three groups, i.e., those allergic to peaches who underwent Pru p 3-enriched SLIT, untreated peach-allergic patients and a control group, for 1 year. Only the SLIT-treated patients exhibited a noteworthy reduction in allergen-specific effector T cells, a decrease in the maturation status of monocyte-derived dendritic cells, and an elevation in regulatory T (Treg) cells. These Treg cells exhibited increased expression of Programmed Death-Ligand 1 (PD-L1) and elevated production of Interleukin-10 (IL-10), suggesting that these alterations could serve as potential biomarkers during SLIT. Additionally, other indicators, such as the IgE/IgG4 ratio, may also be relevant [21].

Gomez, F. et al. conducted a one-year clinical trial on Pru p 3-allergic participants undergoing SLIT. The treated subjects were divided into peanut-allergic (Group A), sensitised (Group B) and tolerant (Group C) categories. SLIT resulted in reduced SPT reactions and an increased peach threshold (p < 0.001). In peanut-allergic individuals (Group A), significant declines in peanut SPT weal area and increases in peanut threshold were observed (p < 0.001). The treated patients showed immunological shifts, including decreased sIgE levels, increased sIgG4 and sIgG4/sIgE ratio and enhanced basophil reactivity for Pru p 3 and Ara h 9. Pru p 3 SLIT demonstrated desensitisation and immunological changes for various food allergens, including potentially severe ones, like peanut [17].

3.5. Case Report Analysis

A total of six case reports were examined. Moreover, Pastorello, E.A. et al. documented FDEIA by Tri a 14, a wheat-derived LTP allergen, in three patients. We considered the results of each patient as a case report and listed them separately [23]. A cumulative analysis of the seven case reports is presented in

Table 6. Characteristics of patients from the 7 case reports studied.

First Author (DoP)	Patient’s Age, Gender	Allergen	Clinical Presentation	Co-Factors	Management
Almeida, E.A. (2013) [26]	18 y.o., female	1st reaction: apple ingestion 2nd reaction: apple ingestion 3rd reaction: pear juice consumption 4th reaction: ingestion of a pomegranate—2 isoforms of LTP allergens Causative food: pomegranate (cross-reaction with peach)	1st reaction: angiooedema and urticaria 2nd reaction: angiooedema and urticaria 3rd reaction: urticaria, abdominal pain and angio-oedema 4th reaction: angiooedema, generalised urticaria, glottis oedema, vomiting, abdominal pain and malaise	-	Rosaceae- and pomegranate-free diet
Gandolfo-Cano, M. (2012) [27]	15 y.o., female	1st reaction: omelette made with peeled zucchini 2nd reaction: melon pulp ingestion 3rd reaction: contact with melon peel Causative food: melon peel	1st reaction: labial angioedema 2nd reaction: oral pruritus and labial angioedema 3rd reaction: palpebral angioedema and conjunctivitis	-	Parental consent for allergy workup
Jiang, N. (2023) [28]	12 y.o., female	Breakfast (including milk, egg, wheat bread and blueberry) Causative food: blueberry	Anaphylaxis	Walking (exercise), menstruation	Epinephrine and fluid therapy Adrenaline auto-injector prescription Suggestion of avoiding the consumption of relevant fruits (blueberries, cherries, kiwifruits, pears)
Murad, A. (2016) [29]	12 y.o., female	1st reaction: consumption of apple puree, prepared by blending whole apples 2nd reaction: consumption of whole, seedless and green grapes Causative food: apple	1st reaction: generalised urticaria, hypotension and angioedema of the lips and tongue. 2nd reaction: facial angiooedema and hypotension	2nd reaction: walking (exercise)	Avoidance of grape and apple seed as well as seeds of other fruits Avoidance of pomegranates and cumin (wheal size on SPT) Prescription of adrenaline auto-injector and anaphylaxis action plan
Nemni, A. (2023) [30]	7 y.o., female	Ingestion of cow’s milk, Cereals containing barley malt Causative food: barley	Abdominal pain with vomiting and anaphylactic reaction	-	Adrenaline IV and anti-histaminic administration
Queirós Gomes, J. (2022) [31]	1st reaction: 7 mo; 2nd reaction: 18 mo; 3rd reaction: 21 mo; male	1st reaction: milk-containing baby food 2nd reaction: ham (ham stored with cheese) 3rd reaction: peach Causative food: peach	1st reaction: Perioral urticaria and lip swelling 2nd reaction: Generalised urticaria and conjunctivitis 3rd reaction: Facial and abdominal urticaria, along with oedema of the lips and eyelids	-	1st and 2nd reactions: milk avoidance 3rd reaction: oral corticosteroids and antihistamines Peach, apricot and nectarine avoidance Peeled apple
Pastorello, E.A. (2014)—1st case [23]	17 y.o., male	No clear association to any foods or exercise. Causative food: wheat	Numerous anaphylaxis episodes since infancy	Dancing and performing CRP at work	n/a
Pastorello, E.A. (2014)—2nd case [23]	15 y.o., male	Prunoideae fruit consumption Eating any kind of cereal Causative food: wheat	OAS, then frequent episodes of severe anaphylaxis	Dancing and performing CRP at work	n/a
Pastorello, E.A. (2014)—3rd case [23]	21 y.o., female	1st reaction: peach consumption 2nd reaction: maize consumption 3rd reaction: pizza consumption Causative food: wheat	1st reaction: Severe OAS 2nd reaction: Anaphylaxis 3rd reaction: Anaphylaxis	Performing CRP at work	n/a

.

4. Discussion

The epidemiology and clinical presentation of LTP allergies were explored in this systematic review, highlighting peach as the most common allergen source, followed by tree nuts and apples [8,9,10,11,13,15,16,18,19,22,25]. Sensitisation to LTPs, particularly peach Pru p 3, was significant across studies, with co-sensitisation to multiple plant foods reported in up to 70% of patients [9,22]. Interestingly, in a study, LTP sensitisation was associated with garlic and onion sensitisation. Immunodetection suggested the existence of a non-cross-reactive LTP in these foods [32]. Clinical manifestations varied, with systemic reactions being more common than local ones [9,13,18]. A link with FDEIA was noted, particularly with certain allergens, like wheat LTP [23]. Predictive markers for severe reactions included co-sensitisation to storage proteins and multiple LTP allergens, while sensitisation to pollen LTPs indicated a higher risk of food allergies. On the contrary, PR-10 and/or profilin sensitisation indicated a negative predictive value for experiencing severe allergic reactions to LTPs [20,22,25]. Additionally, the presence of comorbidities such as asthma, rhinoconjunctivitis and atopy influenced the clinical manifestations of LTP allergy [6,25]. The need for co-factors to trigger symptoms was significantly lower in children compared with adults. Laboratory studies on LTP patients show conflicting results on the prognostic value of specific IgE (sIgE) levels for systemic reactions, with no consistent correlation with disease severity or allergen sensitisation, though higher sIgE affinity may be more critical for reaction severity [7,14,21,24]. SPT and sIgE testing offer varying diagnostic reliability, with sIgE being slightly more consistent [7].

Despite increasing reports of LTP sensitisation and associated food allergies in regions like China [33], Australia [29] and Central Europe [34,35,36], LTP syndrome is predominantly observed in the Mediterranean, particularly in Italy, Spain and Greece [37]. Positive SPT responses to peach Pru p 3 were found in 60–90% of Spanish patients with peach allergy [38,39]. Discrepancies in sensitisation rates among different countries highlight this issue: only 3% of German patients were sensitised to cherry Pru av 3 compared with 100% of Italian patients [34]. Furthermore, SPT confirmed cherry allergy, showing 4% positivity in a Swiss group versus 88% in a Spanish group [40]. The reasons for this geographical distribution remain unclear but may relate to the higher consumption of raw LTP-containing foods like peaches and apricots in the Mediterranean diet. In contrast, the cooler climate makes fruits like apples and stone fruits less common, leading to lower LTP exposure. LTPs in pollen of various wind-pollinated plants [35] have prompted investigations into cross-reactivity with food LTPs and the hypothesis of airway sensitisation due to local pollen allergens. This connection is unproven, although a stronger association with mugwort pollen allergy has been noted in China [33]. A case study of a 21-year-old woman working in a wholesale fruit warehouse in Southern Italy revealed that her severe perennial rhinitis improved after leaving work for over five days but recurred upon her return, supporting the possibility of sensitisation to LTP via the inhalation of airborne food particles [41]. Additionally, high rates of contact urticaria among fruit workers in peach-growing regions imply dermal sensitisation may also play a role [42]. Unfortunately, these data mostly concern the adult population, further reenforcing the need for more research in the paediatric population.

As with all food allergies, the management of LTP allergies requires personalised dietary guidance to eliminate food triggers and prevent nutritional deficits. As shown in De Agrela-Mendes’ study, children sensitised to LTPs demonstrated high tolerance rates for peanuts (98.6%), hazelnuts (97.7%) and walnuts (84.3%), suggesting that most patients could safely consume these nuts. Therefore, it is important to conduct individualised tolerance assessments (oral provocation tests) to avoid unnecessary dietary restrictions [43]. Moreover, due to the varied nature of LTP syndrome, dietary advice must be tailored to individual reactions, co-factors, common foods and taste preferences [44]. In addition to dietary management, educating patients and caregivers about the use of epinephrine auto-injectors is crucial, as these devices are essential to treating anaphylaxis. Both patients and their support network, including family and school personnel, must be trained in proper administration techniques [45]. Labelling and food choices are complex, as there is no established threshold for nsLTP allergens, and reactions to trace amounts are not well documented. Therefore, while individuals might not need to avoid foods with precautionary labels, they should be guided on foods likely to trigger reactions. Superfoods and common dietary items, such as nuts, dried fruits and energy bars, often contain nsLTP allergens and should be carefully considered [44].

In this context, the following question emerge: is oral immunotherapy (OIT) as effective as SLIT in treating peach allergy and generally LTP allergies? Further research is essential to compare SLIT and OIT, particularly focusing on safety, efficacy, sustained desensitisation, tolerance induction and improvements in quality of life. It should also address adverse effects, their severity, cost-effectiveness and ease of application, especially concerning specific allergens contributing to LTP allergies.

Strengths and Limitations

The two main strengths of this study are that (i) two independent researchers examined the databases separately and compared their results and that (ii) the topic of LTP allergy in children, to our knowledge, has not been studied before.

However, as any body of work, this study comes with some limitations. The main limitation would be that not all studies included in the analysis covered an exclusively paediatric population.

5. Conclusions

LTPs are significant allergens, particularly amongst children from Mediterranean regions, posing unique diagnostic and management challenges. While not the most common allergen, LTP sensitisation, especially to fruits like peach and nuts, is crucial to consider in paediatric food allergies. Sensitisation, clinical presentation and history are the cornerstones of the diagnostic process. The phenotype of the patient, based on clinical and laboratory findings, is a way of predicting the nature and evolution of LTP allergies. Dietary avoidance of foods and emerging therapies like SLIT show promise. However, further research is needed focusing on paediatric populations, as data are lacking, to optimise treatment and develop precise predictive markers. Overall, LTP allergy in children requires increased awareness and careful management to protect at-risk populations and enhance their quality of life.