Pollen Food Allergy Syndrome in Southern European Adults: Patterns and Insights

Abstract

Oral Allergy Syndrome (OAS) is an allergic reaction that occurs upon contact of the mouth and throat with food, leading to symptoms primarily affecting the oral mucosa. In patients with allergic rhinitis, OAS may develop due to cross-reactivity between the pollen allergens responsible for allergic rhinitis, and specific plant-derived foods. This particular type of OAS is known as Pollen Food Allergy Syndrome (PFAS). The difference in prevalence of PFAS across different regions of the world is attributed to various factors, including environmental exposure and dietary habits. Southern Europe’s temperate climate favors the blooming of many allergenic plants, making respiratory allergies and PFAS significant public health concerns. There is a regional variation in pollen in Southern Europe, contributing to differences in the presence of panallergens—such as profilins, pathogenesis-related class 10 (PR-10) proteins and lipid transfer proteins (LTPs)—which mediate PFAS. In order to examine the epidemiology, pathogenesis, and diagnostic approaches of OAS and PFAS, focusing on their prevalence and impact in Southern European adults, a narrative review was performed. Data from Portugal, Spain, France, Italy, Albania, Greece, and Türkiye were retrieved. The main outcome of this review was that the frequency of PFAS varies across studies, not only between countries but also within the same country, due to vegetation variability across regions as well as methodological differences and the year of study. However, despite these differences, PFAS emerges as a common issue in Southern Europe, underscoring the need for effective diagnosis and management.

1. Introduction

Food allergy is a significant global public health concern, affecting approximately 8% of children and 10% of adults worldwide [1]. This condition not only impacts the individuals diagnosed but also affects their families, influencing daily life and overall well-being [1,2]. In Europe, Immunoglobulin E (IgE)-mediated food allergy remains a significant clinical issue, with a pooled point prevalence of 2.7% (95% CI: 1.7–3.7). Recent findings suggest that food allergies might be more common in adults than previously recognized, with numerous cases of adult-onset allergies being reported [3].

IgE-mediated food allergy is defined as the presence of symptoms combined with a positive IgE response to at least one food [2]. The ability of linear or conformational epitopes of food allergens to elicit, and bind to elicited IgE immunoglobulins, is the cornerstone of IgE-mediated food allergies. Linear epitopes, typically associated with the life-threatening reactions of food allergies, are continuous stretches of amino acids. In contrast, conformational epitopes, which are implicated in the development of Pollen Food Allergy Syndrome (PFAS), are formed by protein folding that brings distally located amino acids or peptides into spatial proximity.

The term Oral Allergy Syndrome (OAS) was initially used in the 1980s to describe the oral mucosal symptoms caused by the cross-reactivity of airborne allergens and food allergens [4,5]. PFAS is currently used to better describe the (mainly located to) oropharynx symptoms due to a cross-reaction of allergens present in both pollen and plant foods [6]. The primary sensitization to these allergens is occurring in the respiratory system and leads to the development of allergic rhinitis [6,7]. The elicitation of symptoms after the ingestion of homologous food proteins (called also panallergens) usually involves the oral cavity. Nevertheless, there are cases of PFAS that are also involving the skin, gastrointestinal tract, and the respiratory system [8]. Systemic reactions depend on the allergenicity of the involved food but are also influenced by certain risk factors and cofactors, such as the liquid form of the food, its quantity consumed, and fasting [9].

A wide variation in the incidence of PFAS is noticed around the globe, attributed to factors such as differences in climate and vegetation, dietary habits, the prevalence of atopy in each country, and the syndrome’s registration by healthcare professionals [10]. The aim of the present review is to present current insights on PFAS in Southern Europe. This review assesses epidemiological data on PFAS in adults and the key panallergens in the Mediterranean and Southern European region, providing a comprehensive analysis of this emerging concern.

2. Materials and Methods

The current study employed a mixed review approach. A comprehensive systematic review was conducted to identify studies on PFAS in adults from Southern European countries, using predefined inclusion criteria (studies on adults, geographical area, each country by name, PFAS, OAS). The initial search focused on studies published within the last decade; however, due to limited data, this research was expanded without restrictions on the year of publication. Literature searches were performed in PubMed and Scopus. The search was performed by two independent reviewers, and any discrepancies were resolved through discussion. Identified articles were managed using reference management software, and duplicates were removed. Although studies involving children were excluded, studies including data on both children and adults were considered. In addition to the comprehensive systematic review, a descriptive review was carried out to provide a broader contextual analysis, including studies on panallergens in the Mediterranean/Southern European region.

3. Results

3.1. Pathogenesis of PFAS

PFAS typically involves “Class 2” food allergens, such as pathogenesis-related class 10 (PR-10) proteins and profilins, which are conformational epitopes, meaning their three-dimensional structure is crucial for their activity. These proteins are sensitive to heat and gastric acid, which can cause them to lose their structural integrity during cooking or digestion [11,12]. As a result, when these allergens are ingested, their ability to trigger an allergic reaction is typically limited to the oropharynx, and the structural changes often prevent them from interacting with specific IgE antibodies in other parts of the body.

These panallergens are contained in pollen but also in plant foods, like fruits and vegetables [13]. When a pollen-sensitized person eats raw plant foods containing the same panallergen to pollen, cross-reaction is observed, triggering PFAS symptoms [6,14]. Symptoms appear immediately or within 5–10 min after ingestion of the implicated food and usually subside gradually, within 30 min [15,16]. For instance, a patient with pollen allergy to Birch, who has developed antibodies against the Bet v 1 allergen (a PR-10 protein), may experience PFAS following the ingestion of an apple containing the same allergen. Notably, in extremely rare cases, PFAS may progress to anaphylactic reactions [15,17].

In contrast, linear epitopes of plant-origin food allergens (“Class 1” food allergens) are typically sensitizing directly via ingestion [18]. These allergens are composed of a continuous stretch of amino acids, as opposed to conformational epitopes, and they remain resistant to heat and gastrointestinal pH fluctuations, properties that enable them to be absorbed intact by the intestinal epithelium and cause systemic allergic reactions [12,18]. The nsLTP proteins is an example of Class 1 food allergens, affecting adolescents and adults mainly in the Mediterranean area, with those who were not pollen-sensitized typically experiencing more severe reactions [19]. Although sensitization to nsLTP is mainly performed via ingestion, it may also occur via inhalation [13].

3.2. Epidemiology of PFAS/OAS

There is a wide variety of PFAS prevalence in different geographical regions. Rates between 4.7% and more than 20% have been reported in children, and 13% to 53.8% in adults [20]. Studies aiming to determine the prevalence of PFAS often begin with populations that include individuals with allergic rhinitis, and sensitivities to aeroallergens associated with PFAS. This selection bias may lead to artificially elevated prevalence rates. Additionally, epidemiological studies face limitations such as varying definitions of PFAS and OAS, the underreporting of symptoms that do not significantly affect the daily quality of life, and underdiagnosis in individuals often labeled as ‘picky eaters’.

In Asia, South Korea is the country with apparently the highest prevalence of PFAS (42.7%) [21], followed by Japan (34.6%) [22]. However, differences in study methodologies, including the use of the ImmunoCAP ISAC (ImmunoSolid-phase Allergy Chip, Thermo Fisher Scientific, Uppsala, Sweden) in the Japanese study and skin prick tests/specific IgE in the South Korean study, may contribute to these variations rather than reflecting true regional differences. In a study performed in Armenia, its prevalence in young adults was 13% [23]. PFAS appears to be less widespread in the USA; a previous study, conducted using a mailed questionnaire, reported median estimates of the prevalence of OAS among the patients with pollen allergy were 5% among children and 8% in adults [24]. In Australia, the outcomes of a study performed in children and adolescents showed that the prevalence of OAS was 14.7%, while that of PFAS was 4.9% [25].

In Europe, particularly in central and northern areas, sensitization to the Bet v 1 allergen contained in Birch pollen is the main cause of seasonal allergic rhinitis, as well as of PFAS, elicited by the ingestion of plant foods containing Bet v 1-homologous PR-10 proteins, such as Mal d1 in apple and Cor a1 in hazelnut [20,26]. In Europe, PFAS also occurs in allergic rhinitis patients who have been sensitized to panallergens present in the pollen of Grass or Ragweed. The rise in temperatures due to the climate change is leading to a lengthening of the pollen season, increasing the prevalence of allergic rhinitis and therefore growing the prevalence of PFAS [16].

There is a higher incidence of PFAS in countries of Northern Europe, compared to the southern ones. The influence of Birch and Ragweed on the prevalence of PFAS in Europe is evident, with reports indicating a prevalence of 40–50% among patients with pollen allergies [4,27]. In contrast, the prevalence is approximately 20% in the Mediterranean region, which is free of this pollen [28]. In pediatric studies performed in Sweden and the United Kingdom, the prevalence of PFAS was estimated to be 25% and 48%, respectively [29,30]. As far as the pediatric population in the Mediterranean area of South Europe is regarded, the prevalence of PFAS is estimated as follows: 35.9% in an Italian population, while another one estimated it in 27% of the ones with seasonal allergic rhinitis [10,31], 29.7% in Croatia [32], 16% in French children with asthma [33], and 3.3% in Turkish children with respiratory allergies [34].

3.3. PFAS in Adults of Southern Europe

Several studies show that the prevalence of PFAS varies significantly across Mediterranean countries, ranging from approximately 7.5% to 41.4% of the general population. Variability is observed in the age of symptom onset, seasonality, and frequency of symptoms, severity, and the occurrence of comorbidities [10]. Additionally, multisensitization to various pollen associated with PFAS distinguishes Mediterranean countries from those in Central and Northern Europe.

An effort to describe the occurrence of PFAS in the adult population of Southern Europe is outlined next. A multicenter study conducted in the region (Figure 1) has provided valuable insights on this topic [10].

3.3.1. Portugal

A study conducted in Portugal using telephone interviews reported a self-reported prevalence of OAS in adults, at 16.6%. However, after medical assessment and IgE testing, food allergies (including OAS) were confirmed in fewer than 0.71% of the cases [35]. In data referring to the Portuguese population in the Porto area, it was observed that allergic symptoms typically begin at a very young age (around 7 years), and PFAS occurred in 23.5% [10]. Atopic dermatitis was found to be a common concomitant atopic disease, affecting 11 out of 24 patients.

More than half of the surveyed patients with PFAS (13 out of 24) reported experiencing at least one systemic symptom, with profilin identified as the predominant panallergen associated with PFAS symptoms. Grass, Olive, Parietaria and Mugwort were identified as the predominant sensitizing pollen in Portugal [10]. Most pollen (Graminaceae, Artemisia vulgaris, Olea europea) may act as primary sensitizers for profilin [36,37]. The foods most commonly causing PFAS in Portugal are kiwi, melon, peach, apricot, apple, banana and watermelon [10].

3.3.2. Spain

In an older study conducted in Spain, 6.51% of adolescent and adult patients referred to an Allergy Unit were diagnosed with OAS, representing 46.5% of those with a food allergy [38]. In a cross-sectional study, involving a mixed (children and adults) population, OAS was estimated to be present in 33.6% of individuals who visited an allergologist [39]. PFAS was observed in 14.1% of a Spanish cohort from the Valencia area, with atopic dermatitis reported as a common concomitant atopic disease among them [10].

Data from the @IT.2020 study reported sensitivity to nsLTP in 4 out of 10 patients studied [10]. Sensitization to Pru p3, a nsLTP protein, is notable in many areas of Spain [40]. In contrast to PFAS, primary food sensitization to an nsLTP epitope, such as Pru p3 found in peaches, and Mal d3, found in apples, can lead to systemic anaphylaxis after their ingestion [41].

Significant variability in sensitizations of adult patients is observed in Spain, influenced by geographic region, which in turn affects the occurrence of PFAS. For instance, there is a higher frequency of sensitizations to Graminaceae in the south-western region near Portugal, to Olea europea in the southern region, to Salsola kali in central-eastern region, and to Plantago lanceolata in the center-western region [28,40]. Notably, central Spain is home to the largest Quercus ilex (oak) forest area in the world, which may cause sensitization to Que i1, a PR-10 allergen responsible for PFAS [39].

The foods most commonly causing PFAS in Spain appear to be peach, almond, kiwi, pear, cherry, and melon [10,42].

3.3.3. France

Few data on PFAS in French adults exist. In the @IT.2020 study, patients from Marseille presented the lowest incidence of PFAS (7.5%) within the studied cohort [10]. All French PFAS patients had moderate/severe allergic rhinitis. PR-10 was the prevalent panallergen in this patient cohort, and PFAS-associated foods were mainly kiwi, almond, sesame, watermelon, apple, banana, and peach.

In another study conducted in France, patients who tested SPT-positive for Birch, and had pollinosis, reacted to rBet v 1 (a PR-10 allergen), while sensitization to rBet v 2 (a Birch-pollen profilin) may have also resulted from cross-sensitization to other pollen, such as Grass [43]. Allergies to apples, cherries, and hazelnuts were observed in these Birch-sensitized patients. In Southern France, allergy to Cypress pollen has been connected to PFAS after peach and citrus ingestion, through sensitization to a Snakin/gibberellin-regulated protein sensitization [44].

3.3.4. Italy

In a large multicenter study performed in Italy, it was calculated that 57% of adults visiting allergy clinics presented with “Type-2 food allergy”. In addition to PFAS (present in 97% of patients with Type-2 food allergy), latex-fruit allergy syndrome (3%), and Mugwort-Celery-Spice syndrome (<1%) were recorded. PFAS patients had only mild symptoms; however, 5% of them reported systemic symptoms [45]. Regarding the geographical distribution of PFAS, a progressive decrease was registered southbound. The same southbound decrease was noticed for Birch pollen sensitization [45,46].

A paradox that has been observed in the adult population of Genoa, located in Northern Italy, is that, although there is a high percentage of Bet v 1-positive patients, they have a low occurrence of OAS. This is explained by the fact that they live in a Birch-free area, and positive Bet v 1 sensitization is due to cross-reaction with Ost c1, the homologous allergen identified in hop-hornbeam (Ostrya carpinifolia), which has a wide distribution in the area [46].

Regarding allergenic foods in Italy, fruits and vegetables were the most commonly reported ones. Although this can be explained by the high occurrence of PFAS, no parallel increase in sensitization to them was noticed northbound [45]. The epidemiological registration of foods connected to PFAS in Italian adults remains an unmet need. Data from pediatric populations indicate that kiwi and peach are the main fruits causing PFAS in Italy [31].

3.3.5. Albania

According to the outcomes of the @IT.2020 study, in Albania, 14% of the patients visiting an Allergy Center are presenting PFAS. These individuals are mainly sensitized to PR-10, and they present moderate/severe allergic rhinitis [10]. The most frequent PFAS reactions were triggered by almond, followed by cherry, apple, melon, banana, and sesame. Despite the valuable data reported in this multicenter study, a comprehensive publication specifically addressing PFAS prevalence and its association with various pollen and foods exclusively in the Albanian population is still lacking.

3.3.6. Greece

In the Greek population, the high frequency of allergic rhinitis is connected to a high occurrence of PFAS [10]. An online survey on self-reported OAS found that nearly 26% of the adult population experienced relevant symptoms [47]. The data from the @IT.2020 study showed no PR-10 sensitivity but a low occurrence of sensitization to nsLTP and profilin [10]. In a study performed in atopic adult population, the prevalence of profilin was found to be 11%. In the same study, OAS (mainly PFAS) was reported by 29.9% of the examined cohort, with no statistically significant correlation found between sensitization to profilin and OAS [48]. PFAS in Greece is mainly attributed to the ingestion of peach, kiwi, melon, banana, almond, and walnut [10,48]. Culprit foods may pose the suspicion of primary sensitization to PR-10 and PR-5 allergens; however, Greece has limited vegetation consisting of trees or plants that produce PR-10 homologs, whereas the vegetation of plants that produce PR-5 homologs is more prevalent [48].

3.3.7. Türkiye

In Türkiye, studies conducted in Ankara, Izmir, and Istanbul have reported similar outcomes, indicating that approximately 14% of adult patients with allergic rhinitis present with PFAS [10,49]. The age of onset of PFAS symptoms is relatively late, around 26 years, and there is a low incidence of comorbidities. PR-10 is not detected in pollen-allergic patients [10]. Most adults with allergic rhinitis and PFAS are sensitized to Grasses and Weeds; however, sensitization to tree pollen is associated with the highest rates of PFAS [49,50]. The foods that most frequently induce PFAS are kiwi, peach, tomato, apricot, eggplant, walnut, sesame, melon, and watermelon [10,49,50].

3.4. Allergens Causing PFAS in South Europe

3.4.1. Profilins

Profilins are one of the main causes of PFAS in the South European area. They are monomeric proteins with a primary physiological role in regulating actin filaments within the cytoskeleton of eukaryotic cells. The first profilin identified as an allergen was Bet v 2 (in Birch) [51].

Profilins like Phl p12 in Timothy grass, Art v4 in Mugwort, Pla a3 in Plane tree, and Ole e2 in Olive tree can serve as the primary sensitizers in the Southern European area [48,52]. Sensitization in them may trigger PFAS in about 50% of sensitized patients, with foods like melon, watermelon, citron fruits, banana, pineapple, tomato, zucchini, mustard, hazelnut, tomato, persimmon, muskmelon, Apiaceae (celery, carrot, fennel), and Rosaceae (apple, pear, peach, apricot, plum) [15,52,53].

3.4.2. Pathogenesis-Related Class 10 Proteins

The PR-10 proteins are also a major cause of PFAS in the region. They belong to the broader family of pathogenesis-related proteins and play a role is host defense against phytopathogens, like fungi, in several plant species. Additionally, they contribute to protection against biotic stress induced by environmental factors, such as UV-B radiation and ozone [54].

Allergenicity is not observed in all PR-10 proteins [55]. Sensitization to PR-10-like proteins is mainly caused by the pollen of Fagales, like Birch, Hazel, Chestnut, Beech, Oak and Alder [56]. Bet v 1 is the major pollen allergen of Birch and represents the archetype of all PR-10-like allergens [57]. Although PR-10-like allergens are among the most significant causes of PFAS in Europe, sensitization to Fagales is not observed in the Mediterranean coastal regions, since they do not grow in this region. In contrast, individuals residing in more central parts of the Southern European countries can be sensitized to their pollen and manifest PFAS in up to 70% of cases after consuming fruits and vegetables of the Rosaceae (e.g., apple, peach), Actinidiaceae (kiwi), Corylaceae (e.g., hazelnut), Fabaceae (e.g., soy, peanut), and Apiaceae (e.g., celery, carrot) families. The similarity of Bet v 1 with the food allergens Cor a 1, Ara h 8, Gly m 4, Mal d 1, and Pru p 1 explains this cross-reactivity [55].

3.4.3. Thaumatin-like Proteins

Several members of the Thaumatin-like proteins (TLPs) are related to the pathogenesis-related-5 (PR-5) family and play an important role in the plant’s defense against pathogens. The TLP family has been identified as major allergens in Cupressaceae pollen, such as Jun a 3, Cup a 3, and Cry j 3, as well as in plant foods such as cherry, apple, kiwi, banana, grape, sapodilla, and bell pepper. Recombinant TLPs have been characterized as important allergens of bell pepper, several fruits (kiwi, apple, cherry, and grape), as well as of pollen of cypress, mountain cedar, and Japanese cedar. Despite the vast experimental data, the clinical relevance of TLPs is still debated [41,58].

3.4.4. Non-Specific Lipid Transfer Proteins (nsLTPs)

Non-specific lipid transfer proteins are small proteins (with a molecular weight of 9 kDa) that perform various functions in plants, including as the inhibition of plant pathogens, seed development, and germination [59]. Their highly conserved conformational structure, a basic isoelectric point (pI) between 9 and 11, and high stability against denaturant agents, heat, and proteases are characteristics useful for their functions in plants but are also associated with the clinical symptoms that they cause.

Sensitization to nsLTPs can lead to clinical symptoms ranging from localized manifestations of PFAS to anaphylaxis. Sensitization typically occurs through the ingestion of foods containing these proteins (e.g., peach, walnut, hazelnut, apple) [60], although sensitization via inhalation is also possible in some cases [61,62]. NsLTPs are significantly more resistant to heat and gastric enzymes than profilins and PR-10s, which explains why LTPs are responsible for most cases of systemic reactions following sensitization via the gastrointestinal tract [61,62].

They are considered one of the causes of PFAS in Southern Europe and the Mediterranean area. Allergens of the nsLTP family are found in the pollen of Parietaria, Artemisia, Platanus, and Olea but show limited (Artemisia and Platanus) or absent (Parietaria and Olea) cross-reactivity with Pru p 3 due to lower sequence identity (<35%) and difference in length [63]. Many patients experience food allergy symptoms after ingestion of the skin of fruits of the Rosaceae family (Mal d 3-apple, Pru p 3-peach) but also with peanut, soybean, walnut, and wheat [20]. It has been proposed that the severity of nsLTP-related allergic reactions is related to concomitant allergies to three or more plant food groups [64].

3.4.5. Gibberellin-Regulated Protein (GRP)

Of specific interest for Southern Europe is well-documented PFAS that has been observed between peach and Cypress pollen. The culprit allergens belong to the Gibberellin-regulated protein (GRP) family, specifically BP14 from cypress pollen and Pru p 7 from peach [65].

3.5. Cross-Reactivity Between Aeroallergens and Food Allergens in Southern Europe

PFAS is clearly influenced by local airborne allergens, which act as primary sensitizers, as well as by the dietary habits of the local population. The Mediterranean climate, characterized by mild winters and dry summers with relatively high temperatures, supports a diverse range of vegetation typical of Southern Europe. Common plants in this area include Grass, Olive, and Cypress, as well as weeds like Parietaria (Wall-pellitory), Plantago (Plantain), Chenopodium (Goosefoot), Salsola kali, Artemisia (Mugwort), and Ambrosia (Ragweed).

The aerobiological sampling of pollen concentrations in Mediterranean cities has identified three distinct “pollen seasons” [66]:

• Mild winter season (December–March) with Cypress as the prevailing pollen.
• Spring–Summer season (March–July) with Grass, Olive, and weeds as prevailing pollen.
• Autumn period with Parietaria and Artemisia.

An interesting review on the topic highlights numerous associations between aeroallergens and foods of plant origin within this geographical area, many of them implicated in PFAS. The region is particularly known for Olive tree growing, and sensitization to the Olive profilin Ole e2 has been linked to PFAS to peach (Prunus persica), pear (Pyrus communis), melon (Cucumis melo), and kiwi (Actinidia deliciosa) [67]. The profilin Cyn d 12 from Cynodon dactylon (Bermuda grass) is cross-reactive with profilins from tomato (Sola l1) and cantaloupe (Cuc m2) [68]. On the other hand, the profilin of Mugwort (Art v4) is associated with PFAS involving Apiaceae foods such as celery (Api g4), carrot (Dau c4), and various spices, a cross-reaction often referred to as Celery-Mugwort-Spice syndrome [67,69].

Fruits of the Cucurbitaceae family—including watermelon, cantaloupe, honeydew melon, zucchini, and cucumber—are widely consumed during summer in South Europe. PFAS to Cucurbitaceae as well as to Musaceae family (e.g., bananas), is commonly observed in individuals sensitized to Ambrosia artemisifolia, a phenomenon known as the Ragweed–melon–banana association [67,69,70]. PFAS to melon, banana, and peach has also been linked to respiratory sensitization to the profilin of Chenopodium album, while sensitization to Plantago lanceolata pollen has also been associated with PFAS to melon [67,69].

Finally, pistachio (Pistacia vera), a popular tree nut in Italy, Greece, Türkiye, and Cyprus has been implicated in PFAS due to cross-reactivity to Parietaria sensitization [71].

4. Diagnostic Tools for the Assessment of PFAS

In vitro and in vivo IgE-detection is the cornerstone of daily allergy practice. Skin Prick Testing (SPT) is a practical, fast, and cost-effective method for assessing allergen sensitivity. The use of raw extracts in food allergies can indicate sensitization by food allergens but does not identify the allergen molecules (components) responsible for symptoms. In contrast, SPT extracts containing panallergens, like profilin, can be a useful tool. A study analyzing commercial SPT extracts of food and pollen (including a profilin extract) using SDS-PAGE, revealed inconsistent profilin content across pollen SPT extracts, and its absence in peach SPT extracts from two different suppliers [72]. This suggests that SPT has limited utility in detecting PFAS.

The in vitro detection of specific IgE (sIgE) with extract-based diagnostics, is considered slightly less sensitive than SPT and cannot distinguish between multiple genuine sensitizations and cross-sensitizations. However, component-resolved diagnostics (CRDs) have been developed to detect allergenic molecules. The CRD enhances the accuracy of PFAS diagnosis by identifying primary sensitizations from cross-reactivity. Incorporating molecular diagnostics and CRDs into routine clinical practice is critical for improving diagnostic precision and effectively managing complex multisensitization profiles [73].

In the era of CRDs, IgE microarrays containing many different allergen components can provide information on the whole IgE sensitization pattern and help the clinician in the diagnosis of components responsible for PFAS. The ImmunoCAP ISAC test is the most used and studied multiplex array to date, offering 112 molecular components. The ALEX² multiplex array is a relatively new multiplex allergy test that analyzes more than 120 allergen extracts and 170 molecular components [74]. Advanced tools of informatics, called expert systems, have been developed to support the interpretation of allergy tests based on microarray technology [75]. Such state-of-the-art technology can assist allergy diagnosis of cross-reactions in polysensitized patients [67].

Region-specific diagnostic and therapeutic approaches are essential for managing PFAS. In Mediterranean countries, molecular diagnostics targeting nsLTPs (e.g., Pru p3)—which are strongly associated with systemic reactions—along with profilins and PR-10 proteins, should be prioritized. Updated knowledge about regional exposomes is crucial for the development of newer, improved, versions of microarrays. Given the current product characteristics, if a comparison should be made, the ISAC is highly reliable but may not cover as many allergens as the ALEX² multiplex array and tends to focus more on inhalant allergens than food allergens. ALEX² appears to be a preferred method for establishing the diagnosis of PFAS.

Biotechnology plays a crucial role in diagnosing PFAS; however, the clinician’s ability to establish clinical suspicion and set the final diagnosis remains essential, particularly in areas where there is no access to CRDs. A validated questionnaire can be a valuable tool for allergologists [76]. By combining a patient’s anamnesis with available diagnostic methods, clinicians can provide accurate information and guidance to the patient.

5. Treatment of PFAS

The symptoms of PFAS are usually confined to the oral cavity and are not life-threatening unlike other types of food allergy. Avoidance of the raw form of the culprit food is recommended, particularly for the patients with a history of systemic reaction [77]. Furthermore, given the typically mild nature of most PFAS reactions, tailored suggestions can be offered through shared decision making with the patient.

Reactions are often self-limiting, and the use of antihistamines is an effective treatment [78]. However, the severity of reactions after ingestion of plant foods may vary. For individuals with PFAS, consuming peeled and deseeded fruits and vegetables is often sufficient to prevent a reaction [78,79]. Nevertheless, certain plant foods associated with PFAS—such as nuts, soy milk, and smoothies or fresh juices—may trigger systemic reactions, especially if consumed rapidly or in large quantities [77]. For patients with a history of anaphylaxis, training in the management of systemic reactions and the use of an emergency kit, including epinephrine, are essential.

A recently published international Delphi consensus provides practical guidance for clinicians managing PFAS patients [77]. The consensus aimed to establish standardized recommendations for PFAS management. The international panel of experts emphasized the importance of counseling patients on the nature of PFAS, recognizing the rare risk of severe systemic reactions, and avoiding only the specific raw food that triggers symptoms rather than all cross-reactive foods. In accordance with an EAACI Position paper, authors also concluded that the role of allergen immunotherapy in PFAS remains unclear and should not be considered a primary treatment [13].

In patients with pollinosis and PFAS, the use of pollen extracts for sublingual and subcutaneous immunotherapy appears effective for treating allergic rhinitis, but its efficacy in treating PFAS is not established [13,78]. Alternatively, studies on food desensitization, particularly for apple, show promising results [80,81]. In cases of apple-related PFAS, tolerance can be induced through a slow gradual increase in its consumption, with a favorable safety profile. However, maintaining tolerance depends on the continued consumption of apples, and relapse has been observed after discontinuation [80].

An alternative treatment of PFAS using local nasal immunotherapy with a Birch pollen–galactomannan conjugate (BP-GMC) ointment has been introduced [82]. The results demonstrated that the BP-GMC was well tolerated, with no significant adverse effects, and, at the end of the study, patients were able to consume up to 64 g of apples without symptoms, suggesting a potential therapeutic benefit.

Omalizumab is a biologic globally used for the treatment of asthma and chronic urticaria. It has been used to reduce reactions following incidental exposure in food-allergic individuals and has also been administered in a few cases of PFAS. Although its efficacy is time-limited, it may be useful in cases of children where antihistamines fail to alleviate symptoms [83].

6. Discussion

The reported prevalence of PFAS in Europe varies significantly across studies due to differences in study design, population selection, and diagnostic methods. Most available data on adult populations with PFAS originate from allergy clinics, which introduce selection bias, as these settings assess individuals already suspected of having allergic conditions and do not represent the general population. Additionally, some studies rely on self-reported data, while others use allergy tests, further contributing to variability. Even among test-based studies, methodologies differ; some utilize skin testing, whereas others employ molecular allergy diagnostics.

Another contributing factor to the inconsistencies in epidemiological data is the underestimation of the condition, which partly explains the observed differences in prevalence between children and adults. Furthermore, PFAS appears to be less severe in Southern Europe compared to Central and Northern Europe [45]. This disparity may be attributed to the limited blooming of the Betulaceae family, particularly Birch trees, in coastal Southern Europe [26,84].

The prevalence of PFAS in adult populations across Southern Europe shows significant variation (

Table 1. Data from studies performed on national level in Southern European countries.

Country	Sample size/Population	Major Findings	Food Allergens	Limitations	Author; Year [Reference]
Portugal	1436 adults/general population	IgE-mediated food allergy was confirmed in less than 0.71% of the 840 patients that were investigated (with skin-tests/sIgE/provocation)	Fruits, not specified which ones	Clear information on the number of OAS patients is missing	Lozoya-Ibáñez, C et al.; 2016 [35]
Spain	506 adolescents and adults/mixed population	33 out of 506 adolescents/adults (6.51%) had OAS	Not specified	Missing data on PFAS	Alvarado, M. I.; Pérez, M.; 2006 [38]
France	51 adults/sensitized to Betulaceae	47 patients reacted to rBet v 1 (nsLTP) and 10 to rBet v 2 (profilin). Sensitization to rBet v 2 was related to grass and weed (no Birch) pollinosis	Apples, cherries, hazelnuts (in Bet v 1-sensitized)	Missing data on PFAS Study restricted to Betulaceae	Pauli, G.; et al.; 1996 [43]
France	16 adults/mixed population with allergy to Cypress	Sensitization to Cypress pollen can be connected to PFAS	Peach, citrus	Study restricted in sensitization to Snakin/GRPs	Sénéchal, H.; et al.; 2018 [44]
Italy	25,601 adults/mixed-ages, general population	IgE-mediated food allergy was diagnosed in 1079 patients. PFAS was diagnosed in 598 (2.33%) out of the screened population	The type-2 food allergy allergens were not specified	Recruitment was performed from patients visiting allergy clinics	Asero, R.; et al.; 2009 [45]
Italy	854 adults/Birch-allergic patients	Frequency of OAS in Birch allergic patients is 33.5% in Genoa, 76.9% in Northern, 62.5% in Central, and 66.07% in Southern regions of Italy	Apple, apricot, cherry, peach	Retrospective study restricted in Birch-allergic patients	Ciprandi, G.; et al.; 2016 [46]
Greece	3673 adults/general population	25.9% reported itching of lips, tongue and oral cavity, suggestive of OAS	Foods causing symptoms suggestive of OAS were not specified	Data based on online study. Self-reported symptoms, not confirmed by in vivo or in vitro allergy testing	Kalogeromitros, D.; et al.; 2013 [47]
Greece	264 adults/atopic patients	79/264 (29.9%) atopic patients reported OAS after consuming fruits, vegetables, or tree nuts Sensitization to profilin was detected in 10.9% of the atopic patients	Peach, walnut, kiwi, banana, hazelnut, peanut, eggplant, apricot, melon, strawberry, almond, cherry, cabbage, tomato, watermelon, apple, pineapple, grape, orange, peanut, spinach, sesame seed, sunflower seed, pear, cashew, Brazilian nut, lemon, cucumber, pepper, mustard, chestnut, fig, papaya, plum, onion, lentil, peas	Patients were recruited among the ones visiting an allergy clinic. Diagnosis was based on SPT, not confirmed with in vitro testing Study was focused on profilin-sensitization	Iliopoulou, A.; et al.; 2018 [48]
Türkiye	256 adults/patients with pollen sensitizations	49/256 (19.3%) self-reported PFAS	Kiwi, peach, tomato, melon, watermelon, plum, apricot, hazelnut, cucumber, orange, cherry, banana, black pepper, sunflower seed, onion, zucchini, celery, almond, apple, caraway, dill	Retrospective study, based on patients with allergic rhinitis There was a discordance of foods reported to cause PFAS and SPT results	Özdemir, S.K.; Ö zgüçlü, S.; 2018 [50]
Türkiye	222 adults/patients with seasonal allergic rhinitis	31/222 (14%) reported PFAS symptoms	Eggplant, tomato, potato, walnut, kiwi, peach, plum, apricot, melon, watermelon, sunflower seed, onion, garlic, peanut, arugula, cress, grapes	Retrospective study, based on patients with allergic rhinitis	Özdemir, E.; et al.; 2023 [49]

), with reported rates ranging from 7.5% in France to nearly 30% in Greece and as high as 57% in Italy among patients attending allergy outpatient clinics [10,45,48]. These discrepancies underscore the need for well-designed, population-based studies to accurately assess the true prevalence of PFAS in Southern Europe.

Southern Europe’s unique aeroallergen exposure—dominated by Oleaceae, Cupressaceae, Poaceae, Urticaceae, Chenopodiaceae, Plantaginaceae, and Asteraceae—plays a crucial role in the pathogenesis of PFAS [84]. The prevalence and clinical manifestations of PFAS are shaped by both local airborne allergens, which act as primary sensitizers, and the dietary habits of the population [10,20]. The pattern of sensitization varies across different regions in Southern Europe. For example, in Rome, patients tend to be highly polysensitized, whereas, in Marseille, monosensitization to specific allergens like Cup a 1 is more common [85]. This interaction between environmental and dietary allergens is central to the distinct manifestation of PFAS in Mediterranean populations. Sensitization to specific allergens in Southern Europe leads to unique cross-reactions between aeroallergens and common foods. For instance, the profilin of Phleum pratense Phl p12 is implicated in PFAS reactions to peach, melon, and kiwi, while the profilin Cyn d 12 from Bermuda Grass is cross-reactive with tomato [24,57].

Climate change is emerging as a contributing factor to the rising prevalence of PFAS. Extended pollen seasons, shifts in vegetation patterns (notably the spread of Ragweed), and increased aeroallergen exposure may exacerbate both the incidence and severity of PFAS in Southern Europe, highlighting the need for ongoing surveillance and adaptive healthcare strategies [86,87].

Rising temperatures and other environmental changes are key characteristics of climate change, with various effects on public health. One of the consequences of climate change is the prolonged pollen season for some allergens, leading to an extended period of pollinosis [88]. Environmental factors, such as air pollutants, can enhance the allergenicity of specific pollen species. For example, long-term exposure to high levels of NO₂ in urban areas is associated with the increased allergenicity of Birch pollen, though a similar effect has not been observed for Olive or Grass pollen [86,89,90]

The combined exposure to air pollutants and allergens can have a synergistic effect on respiratory allergies and may also contribute to the prevalence of PFAS. A study focusing on Ragweed has predicted that, under a moderate greenhouse gas emissions scenario, sensitization to this allergen is projected to increase significantly by 2041 in European countries, including the Mediterranean basin, where it is now uncommon [86]. This projected increase in Ragweed sensitization is expected to further raise the prevalence of PFAS.

This review provides a focused analysis of PFAS in Southern Europe, considering the influence of climate and vegetation on allergen exposure, while also addressing its prevalence in adults. The applicability of our review lies in the potential for public health policies to be designed to promptly detect changes in the prevalence of PFAS that could be driven by factors such as climate change and the introduction of new allergenic plants. A key contribution of our work is also the identification of methodological biases in current epidemiological studies, as most are not derived from the general population. This limitation underscores the need for well-designed, population-based studies to obtain a more accurate understanding of PFAS prevalence. By synthesizing current knowledge and highlighting research gaps, this review aims to support future studies that can better assess the true burden of PFAS in Southern Europe.

In conclusion, PFAS in this region is shaped by distinct aeroallergen profiles, dietary habits, and environmental factors. The significant variability in PFAS prevalence across and within countries underscores the influence of both regional differences and study methodologies. Addressing these gaps through more comprehensive epidemiological research and the integration of advanced molecular diagnostic tools could improve both the understanding and management of PFAS, ultimately enhancing patient outcomes in this region.