Update on Tree Nut and Seed Allergies: Prevalence, Clinical Characteristics, Diagnosis, and Management

Abstract

Tree nut (TN) and seed allergies have become increasingly recognized as important global health concerns, paralleling rising consumption driven by dietary trends. These allergies are often severe, typically develop in childhood, and may persist throughout life. Recent population-based studies show rising prevalence, particularly for TNs and sesame, with substantial regional variability. Clinical outcomes are strongly influenced by the underlying sensitization profile: storage proteins and lipid transfer proteins are associated with systemic reactions and anaphylaxis, whereas sensitization to pathogenesis-related group 10 and profilins usually results in milder manifestations including pollen-food syndrome. Co-sensitization among TNs and seeds occurs frequently; however, clinical co-allergy is observed to a lesser degree, with the highest overlap reported between cashew–pistachio and walnut–pecan. Advances in diagnosis, including component-resolved diagnostics and the basophil activation test, improve discrimination between clinical allergy and asymptomatic sensitization or mild localized reactions, and help minimize the need for oral food challenges. Acute management aligns with standard principles for immunoglobulin E-mediated food allergy, with prompt intramuscular epinephrine being the first-line treatment for anaphylaxis. Long-term management emphasizes accurate allergen identification, pragmatic dietary recommendation that supports inclusion of tolerated nuts, and preparedness with epinephrine for accidental exposure. Emerging data support the use of oral immunotherapy for selected TNs and sesame, with promising desensitization rates. Regulatory progress in allergen labeling and targeted education in high-risk settings, such as schools, restaurants, and air travel, are essential for prevention. Further studies are required to clarify natural history, to optimize immunotherapy, and to refine management for better supporting affected individuals across the lifespan.

INTRODUCTION

Tree nuts (TNs) and seeds are considered healthy foods due to their high nutritional value; therefore, their consumption has increased. The types of TNs and seeds most commonly consumed vary by region and culture.¹,² In parallel with this rising consumption, TN and seed allergies have also increased in prevalence over the past 2 decades and are recognized as potentially life-threatening diseases.³,⁴ The term “TN” is commonly used to include nuts that come from trees even when they do not strictly meet the botanical definition. Nine nuts account for most TN allergies: walnut, almond, pistachio, cashew, pecan, hazelnut, macadamia, Brazil nut, and pine nut.¹,⁴ Popular specialty seeds include black cumin, chia, flax, hemp, perilla, pumpkin, quinoa, and sesame, and allergies to these seeds have been increasing.² TN and/or seed allergies are relatively common, typically develop early in life, are rarely outgrown, and often persist as lifelong conditions. However, data on TN and seed allergies remain limited.³,⁵,⁶

TN and seed allergies are major causes of severe allergic reactions, including anaphylaxis. The principal allergenic components have been identified and are used for diagnosis, management, and patient education regarding TN and seed allergies. Sensitization to storage proteins or nonspecific lipid transfer proteins (LTPs) is generally associated with severe clinical reactions, whereas sensitization to cross-reactive homologues related to pollen is typically linked to mild symptoms and pollen-food syndrome (PFS).³,⁴,⁷,⁸ Co-allergy, co-sensitization, and cross-reactivity are common and represent important considerations in dietary elimination for patients with TN and seed allergies; however, these distinctions are not always clear or easily defined.³,⁴,⁸,⁹,¹⁰

The prevalence of TN and seed allergies appears to be increasing and has emerged as an important clinical concern over the past several decades. Several systematic reviews and meta-analyses have reported the overall prevalence, sensitization rates, and oral food challenge (OFC)-proven prevalence of TN or seed allergies.⁴,⁸,¹¹ Specific studies have focused on individual nuts and seeds, such as hazelnut, walnut, cashew, pistachio, almond, macadamia, sesame, perilla, sunflower, and other seed allergies.⁴,⁹,¹⁰,¹¹,¹²,¹³,¹⁴,¹⁵ In this review, we summarize the most recent literature and update the evidence on prevalence and time trends, clinical characteristics and allergenic components, diagnostic advancements, and current therapeutic approaches for TN and seed allergies.

GLOBAL PREVALENCE AND TIME TREND

In the first half of the 20th century, nut allergies were described mainly in anecdotal case reports, while peanut and TN allergies have been increasingly reported only during the last quarter of the century.⁴,¹¹,¹⁶,¹⁷ Using random-digit-dial telephone surveys conducted in 1999, 2002, and 2008, the self-reported prevalence of peanut and/or TN allergy in the general U.S. population was estimated. Among adults, the prevalence rates of peanut or TN allergy were 1.4%, 1.2%, and 1.4% in 1999, 2002, and 2008, respectively, with no significant difference across these time points. However, among children younger than 18 years, the prevalence increased significantly from 0.6% in 1999 to 1.2% in 2002 and 2.1% in 2008.¹⁶,¹⁷ In U.S. children, TN allergy prevalence specifically rose from 0.2% in 1997 to 0.5% in 2002 and 1.1% in 2008. In this series of studies, data on seed allergies were limited; only sesame allergy was reported in 2008, with prevalence being 0.1%.¹⁷ In a later set of population-based surveys conducted in the U.S. between 2015 and 2016, parent- and self-reported prevalence rates of TN and sesame allergies were similar for both children and adults, at 1.2% and 0.2%, respectively. These findings were consistent with the survey data from 2009–2010.¹⁸,¹⁹

A nationwide, population-based survey conducted in 2015 among Korean schoolchildren reported an overall prevalence of 0.32% for TN allergy and 0.05% for sesame allergy, with anaphylaxis rates of 0.12% and 0.01%, respectively.²⁰ In a longitudinal study from Israel, the OFC-proven prevalence of TN and sesame allergies increased from 0.02% and 0.18% in 2000 to 0.57% and 0.93% in 2018, respectively. In this study, the overall prevalence of food allergy (FA) also rose over time, and sesame allergy remained more common than TN allergy.¹¹

Prevalence of individual TN allergies

Data from a recent European systematic review and meta-analysis reported the estimated prevalence and sensitization rates for specific TN allergies, although no data were available for macadamia nut.⁴ This update included 32 studies published between 2000 and 2021, incorporating 17 studies from 2012–2021 in addition to the 15 studies covered in the 2014 European Academy of Allergy & Clinical Immunology (EAACI) report (based on data from 2000–2012). Across this large-scale, 22-year dataset, allergy or sensitization to individual TNs was investigated in 29 studies for hazelnut, 12 for walnut, 9 for almond, 5 for cashew, 4 for Brazil nut, 3 for pistachio, and 1 each for chestnut, pecan, and pine nut, with none for macadamia nut. The overall lifetime and point prevalence rates of self-reported hazelnut allergy were 0.8% (95% confidence interval [CI], 0.5–1.1) and 4.0% (95% CI, 2.9–5.2), respectively. The lifetime prevalence of self-reported, physician-diagnosed hazelnut allergy was 0.8%, while the point prevalence of sensitization to hazelnut was 8.1% (95% CI, 4.6–11.6). The point prevalence of hazelnut allergy and sensitization was higher in adults than in children, whereas the lifetime prevalence of self-reported hazelnut allergy was higher in children than in adults. The overall lifetime and point prevalence rates of self-reported walnut allergy were 0.3% (95% CI, 0.2–0.9) and 1.8% (95% CI, 1.1–2.5), respectively. The point prevalence of sensitization to walnut was 4.1% (95% CI, 2.2–5.9) for specific immunoglobulin E (sIgE) positivity and 2.7% (95% CI, 0.3–5.6) for skin prick test (SPT) positivity. The point prevalence of walnut allergy was higher in adults than in children. The overall point prevalence rates of self-reported almond allergy and sensitization were 2.0% (95% CI, 1.1–2.9) and 3.6% (95% CI, 2.6–4.6), respectively. The corresponding point prevalence rates of self-reported cashew, Brazil nut, and pistachio allergies were 0.7% (95% CI, 0.65–0.77), 3.4% (95% CI, 2.0–4.9), and 0.6% (95% CI, 0.3–0.9), respectively. Overall, the point prevalence of individual TN allergies was higher when assessed by sensitization measures.⁴

In a large-scale, population-based survey on FA conducted between 2015 and 2016 among U.S. children, the parent-reported prevalence rates of walnut, almond, hazelnut, pecan, cashew, and pistachio allergies were 0.6%, 0.7%, 0.6%, 0.6%, 0.7%, and 0.5%, respectively.¹⁸ In a similar population-based survey conducted during 2015–2016 among U.S. adults, the self-reported prevalence rates of walnut, almond, hazelnut, pecan, cashew, and pistachio allergies were 0.6%, 0.7%, 0.6%, 0.5%, 0.5%, and 0.4%, respectively.¹⁹ A nationwide, population-based survey conducted in 2015 among Korean schoolchildren reported a prevalence of 0.32% for TN allergy and a prevalence of 0.12% for TN-induced anaphylaxis. No data were available for individual TN allergies.²⁰ In a longitudinal population-based study examining TN sensitization and allergy patterns, the prevalence of parent-reported TN allergy was 0.1% at age 1, while OFC–proven TN allergy at age 6 was 3.3%. Cashew was the most common TN allergy among the nuts investigated (cashew, almond, and hazelnut).⁹ The reported prevalences of TNs and seeds have been summarized in Table 1.⁴,⁸,⁹,¹¹,¹³,¹⁵,¹⁶,¹⁷,¹⁸,¹⁹,²⁰,²¹

Table 1. Summary of the prevalence and temporal trend of TN and seed allergies.

Study/Source	Period	Region/Population	Main findings (prevalence)
Random-digit-dial telephone surveys	1999, 2002, 2008	US general population	Adults: Peanut or TN allergy 1.4%, 1.2%, 1.4% (no significant change)
			Children: 0.6% → 1.2% → 2.1%
			TN-specific: 0.2% (1997) → 0.5% (2002) → 1.1% (2008)
			Sesame: 0.1% (2008)
National survey (2015–2016)	2015–2016	US (children & adults)	TN: 1.2%; Sesame: 0.2%
Nationwide survey	2015	Korea (schoolchildren)	TN: 0.32%, Sesame: 0.05%
Longitudinal population-based study	2000–2018	Israel	OFC-proven prevalence: TN 0.02% → 0.57%, Sesame 0.18% → 0.93%
EAACI systematic review/meta-analysis	2000–2021	Europe	Hazelnut: lifetime 0.8%, point 4.0%
			Walnut: lifetime 0.3%, point 1.8%
			Almond: point 2.0%, sensitization 3.6%
			Cashew: 0.7%; Brazil nut: 3.4%; pistachio: 0.6%
US national survey	2015–2016	Children	Walnut 0.6%, almond 0.7%, hazelnut 0.6%, pecan 0.6%, cashew 0.7%, pistachio 0.5%
		Adults	Walnut 0.6%, almond 0.7%, hazelnut 0.6%, pecan 0.5%, cashew 0.5%, pistachio 0.4%
Longitudinal population-based	Age 1–6 years	Australia	Parent-reported TN allergy 0.1% (age 1); OFC-proven 3.3% (age 6)
			Cashew most common
Prospective cross-sectional	2017–2018	Israel (infants)	Sesame: 0.7–0.93%
Population-based, cross-sectional birth cohort	2007–2011	Australia (infants)	Sesame: 0.4–0.8%
Retrospective cohort study	1995–2021	US (children)	Sunflower seed: 0% → 0.38% (2021), odds ↑ 21% per year
			Mustard seed: 0% → 0.14% (2020), odds ↑ 9% per year

Data summarized from reference #^{4, 8, 9, 11, 13, 15},¹⁶,¹⁷,¹⁸,¹⁹,²⁰,²¹.

TN, tree nut; OFC, oral food challenge; EAACI, European Academy of Allergy & Clinical Immunology.

Prevalence of individual seed allergies

Population-based data on seed allergies are limited, and most available information pertains to sesame allergy. The OFC-proven prevalence of sesame allergy is higher among children in countries with high sesame consumption, ranging from 0.4% to 0.8% in Australia and 0.7% to 0.93% in Israel, whereas lower prevalence rates have been reported in Canada, Europe, and Mexico (0.1%–0.2%).¹¹,¹³,²¹ The prevalence of parent- or self-reported sesame allergy was 0.2% among U.S. children and adults between 2015 and 2016 and 0.05% among Korean schoolchildren in 2015.¹⁸,¹⁹,²⁰ In a retrospective cohort study of sunflower seed allergy conducted between 1995 and 2021 using 2 data-mining programs (Hound Dog and i2b2) in a pediatric allergy clinic, the incidence of sunflower seed allergy ranged from 0% (1995–1999, 2001–2004, and 2006) to 0.38% (2021), with the odds of diagnosis increasing annually by 21%. In the same study, mustard seed allergy was analyzed as a reference seed allergy. Its incidence ranged from 0% (1995–1996, 1999–2001, and 2004) to 0.14% (2020), with the odds of diagnosis increasing annually by 9%.¹⁵

CLINICAL CHARACTERISTICS

General clinical features of TN allergy

In immunoglobulin E (IgE)-mediated TN allergy, several clinical phenotypes have been described according to symptom severity, the type of sensitization (primary or secondary), and the presence of co-allergic reactions. In a nationwide U.S. registry-based report of 5,149 voluntarily registered TN allergy cases in 2001, the general clinical characteristics were analyzed.²² The median age at first known exposure to TNs was 24 months (mean, 48 months), whereas the first allergic reaction occurred at a median age of 36 months (mean, 77 months). In this study, a single TN accounted for 54% of reactions, while the remaining cases involved exposure to more than one type. Walnut was the most frequently reported allergen (34% of registrants), followed by cashew (20%), almond (20%), pecan (15%), pistachio (9%), and hazelnut (7%), with Brazil nut, pine nut, macadamia, and hickory each accounting for less than 5%. Approximately 68% of participants reported that their first allergic reaction occurred upon initial exposure. Ingestion was the most common mode of exposure (80%), followed by skin contact (9%) and airborne exposure (3%).²² In a prospective study analyzing 1,013 OFC-confirmed TN allergy cases, skin symptoms were reported in 78% of reactions, followed by gastrointestinal (47%), upper respiratory (42%), and lower respiratory (32%) symptoms. Cardiovascular symptoms were observed in 6% of cases, and in three-quarters of the reactions, more than one organ system was involved.²³ In another OFC-confirmed Northern European cohort of 70 positive challenges in 40 children and young adults, oral symptoms followed by skin reactions were the most common manifestations. Cashew was distinguished as the allergen causing reactions at the lowest dose. Multiorgan involvement was frequent, whereas cardiovascular and neurologic symptoms were not identified.²⁴

Phenotypes and related allergens of TN allergy

Peanut and TNs account for 70%–90% of reported anaphylaxis fatalities, and TNs alone are responsible for 18%–40% of anaphylaxis triggers. In a hospital-based, multicenter retrospective study, 43.5% of walnut-allergic and 57.7% of pine nut-allergic children experienced anaphylaxis.³,²⁵ The severity of allergic reactions is related to the specific allergenic components of TNs, and the major allergen components associated with each clinical phenotype are summarized in Table 2.⁵,¹¹,¹²,¹³,¹⁴,²⁶,²⁷,²⁸,²⁹ Seed storage proteins—namely 11S globulins, 2S albumins, and 7S globulins—and LTPs are key contributors to severe allergic reactions. The following storage proteins have been identified as being associated with severe TN allergies or as differentiating markers between allergic and tolerant individuals: Cor a 9, Cor a 11, and Cor a 14 of hazelnut; Jug r 1, Jug r 2, and Jug r 4 of walnut; Ana o 1, Ana o 2, and Ana o 3 of cashew; Pru du 6 of almond; Pin p 1 of pine nut; Ber e 1 and Ber e 2 of Brazil nut; Pis v 1, Pis v 2, Pis v 3, and Pis v 5 of pistachio; and Mac i 1 of macadamia.³,⁸,¹²,²⁶ LTPs also act as elicitors of anaphylaxis to plant-derived food allergens. Hazelnut (Cor a 8), walnut (Jug r 3), and almond (Pru du 3) have been reported as major elicitors in LTP allergy. However, the severity of reactions to LTPs varies across geographic regions, and LTP sensitization is not always predictive of anaphylaxis.³,⁸ Sensitization to pathogenesis-related protein 10 (PR-10) and profilins is generally associated with milder, localized reactions. Individuals sensitized to these proteins may develop PFS upon ingestion of raw TNs—most commonly hazelnuts, almonds, and walnuts—whereas macadamia, cashew, and pistachio are unlikely to trigger PFS.³,⁵,⁷,¹²,¹³

Table 2. Allergenic components of TNs and seeds.

Common name		Plant family	Seed storage proteins			nsLTP	PR-10	Profilin	Oleosin
			2S albumin	7S globulin (vicilin-like)	11S globulin (legumin-like)
Tree nuts
	Almond	Rosaceae			Pru d 6	Pru du 3	Pru du 1	Pru du 4
	Hazelnut	Betulaceae	Cor a 14	Cor a 11	Cor a 9	Cor a 8	Cor a 1	Cor a 2	Cor a 12, Cor a 13, Cor a 15
	Cashew	Anacardiaceae	Ana o 3	Ana o 1	Ana o 2
	Pistachio	Anacardiaceae	Pis v 1	Pis v 3	Pis v 2, Pis v 5
	Walnut	Juglandaceae	Jug r 1	Jug r 2, Jug r 6	Jug r 4	Jug r 3	Jug r 5, Jug r 8	Jug r 7
	Pecan	Juglandaceae	Car i 1	Car i 2	Car i 4
	Brazil nut	Lecythidaceae	Ber e 1		Ber e 2
	Macadamia	Proteaceae		Mac i 1	Mac i 2
	Pine nut	Pinaceae	Pin p 1	Pin p 4
Seeds
	Sesame	Pedaliaceae	Ses i 1, Ses i 2	Ses i 3	Ses i 6, Ses i 7				Ses i 4, Ses i 5
	Sunflower	Asteraceae				Hel a 3
	Poppy	Papaveraceae		Pap s 1.0101	Pap s 2.2021
	Flax	Linaceae
	Pomegranate	Punicaceae	Pun g 2S-A1, Pun g 2S-A2
	Cotton	Malvaceae		C72 vicilin	C72 legumin
	Perilla	Lamiaceae							Perilla oleosin fraction

Data summarized from reference #5, 11-14, 26-29.

TN, tree nut; nsLTP, nonspecific lipid transfer protein; PR-10, pathogen-related protein 10.

Co-allergy among TNs and seeds

A high degree of sequence identity exists among TNs and also between TNs, peanuts, and seeds, resulting in a high rate of reported co-sensitization. However, the rate of co-sensitization is typically higher than that of clinically confirmed co-allergic reactions. Several studies have analyzed TN co-allergy based on sensitization data, retrospective clinical records, prospective cohort findings, OFC-confirmed data, and systematic reviews.³,⁵,⁸,⁹,¹⁰,¹²,¹³,²³,²⁴,³⁰ In the population-based HealthNuts study from Australia, among 154 children aged 6 years with any TN allergy (almond, Brazil nut, cashew, hazelnut, macadamia, pecan, pistachio, or walnut allergy), 52.2% were allergic to only 1 TN, 26.7% to 2 TNs, 12.4% to 3 TNs, and 8.7% to more than 3 TNs. Among those with each TN allergy, co-allergy rates ranged from 2.4% to 92.5% across specific TN pairs.⁹ In the Pronuts study—a prospective, multicenter European study that evaluated co-allergy through sequential OFCs—61% of children were allergic to more than one nut or seed. Sesame seed allergy was found to co-occur with pine nut and Brazil nut allergies, whereas hazelnut and macadamia nut allergies showed co-occurrence with sesame seed allergy.¹⁰ Similarly, the NutCracker study, a prospective single-center cohort study from Israel, reported that although most patients were sensitized to multiple TNs, more than half were clinically allergic to only one or two TNs.³⁰ In an OFC-confirmed Northern European cohort, allergy to 2 or more TNs was observed in most cases.²⁴ The patterns of co-reactivity were strongest among phylogenetically related TNs, whereas the relationships among other TNs and seeds were more variable.

The highest clinical co-allergic reaction rates are observed between cashew and pistachio (family Anacardiaceae) and between walnut and pecan (family Juglandaceae). Nearly all (97%–100%) individuals allergic to pecan or pistachio are also allergic to walnut and cashew, respectively. Conversely, 65%–83% of cashew-allergic patients are allergic to pistachio, and 64%–75% of walnut-allergic patients are allergic to pecan.¹⁰,³⁰ Moderate to high co-allergy rates with cashew allergy have been reported for macadamia (36%–75%), hazelnut (36%–73%), pecan (28%–63%), walnut (31%–64%), almond (60%–80%), and Brazil nut (40%–85%). Fewer than 5% of patients with any TN allergy reported allergy to pine nuts, and overall, co-allergy among any TNs was reported in 48% of cases.⁸ These co-allergy patterns have important clinical implications and can guide clinicians in determining the need for OFCs with specific TN pairs.³⁰,³¹

Sesame and other reported seed allergies

Several popular specialty seeds include black cumin, chia, flax, hemp, perilla, pumpkin, quinoa, and sesame.² Seed allergies have gained increasing attention in recent years, primarily due to the rising incidence of sesame allergy, which has been associated with severe and even fatal reactions in Western countries. However, research on other seed allergies remains limited. Previously recognized and recently identified seed allergens are summarized in Table 2.⁵,¹¹,¹²,¹³,¹⁴,²⁶,²⁷,²⁸,²⁹

Sesame is a potent allergen capable of triggering severe allergic reactions, and its prevalence varies by geographic region and the level of sesame consumption.¹³ Sensitization may occur without clinical symptoms, and co-allergy with TNs and peanuts has been documented in prospective OFC studies involving children and adolescents. The odds ratios for co-allergy between sesame and pine nut, macadamia, Brazil nut, and hazelnut were 9.1, 8.8, 4.8, and 3.6, respectively.¹⁰,¹³ Both protein and lipid (oleosin) components in sesame seed can elicit allergic responses, and seven specific sesame allergens have been identified. The storage proteins Ses i 1 and Ses i 2 are associated with a higher risk of severe allergic reactions. Several sesame components share structural similarity with allergens found in peanuts (legumes) and TNs—such as hazelnut, walnut, cashew, macadamia, and pistachio—leading to observed co-sensitization.¹³ In a study of 341 children with OFC-confirmed sesame allergy, co-sensitization to peanuts and TNs was reported in 62% of cases, whereas co-sensitization to other seeds (mustard, sunflower, flaxseed, poppy, and chia) was below 9%. Among OFC-positive participants, 22% experienced anaphylaxis, accounting for 7% of all OFCs conducted.³² The substantial risk of accidental sesame exposure and its potential for severe reactions have prompted mandatory sesame labeling in several countries, including the US, Canada, EU, UK, Australia, and New Zealand.³³

Several recent studies have examined seed allergies other than sesame. Perilla seed, known as a specialty health food, has seen increasing consumption in Korea. In a multicenter, hospital-based, retrospective study investigating anaphylaxis caused by peanut, TN, and seed allergies in 126 Korean children, perilla seed was identified as the most common seed trigger (3.2%), followed by sunflower seed (1.6%) and sesame (0.8%).³⁴ In a clinical and immunological study of 21 children with IgE-mediated perilla seed allergy, diagnosed through clinical reactions and SPT, the median age at first reaction was 3 years. The most common modes of exposure were boiled seed flour used in soups or porridges (42.9%), roasted seed (33.3%), unspecified forms (19%), and oil (4.8%). Anaphylaxis occurred in 28.5% of cases, and TN co-allergy was identified in 19% of participants. Oleosin homologues are suspected to be major allergens, although their complete characterization has not yet been performed.¹⁴ In a recent retrospective cohort study involving 235 patients with sunflower seed allergy, the median age at diagnosis was 3.9 years. The most frequent exposure form was sunflower seed butter (54.8%), followed by whole seed (26.3%), and oil (4.0%). Approximately half of the reactions (52.8%) were classified as Grade 1 or involved mild skin, mucosal, and gastrointestinal symptoms, while 25.9% of reactions were anaphylactic. In this study, the cumulative incidence of sunflower seed allergy increased sharply between 1995 and 2021, whereas the slope of increase for mustard seed allergy was comparatively mild.¹⁵ Sunflower LTP (Hel a 3) is currently recognized as a clinically relevant allergen, although the allergenicity of several storage proteins remains to be fully evaluated.²⁷ Poppy seed can cause severe allergic reactions, particularly in patients with concurrent TN and other seed allergies. In a molecular study involving 36 children with OFC-confirmed poppy seed allergy, four novel poppy seed allergens—Pap s 1 (vicilin), Pap s 1 (27–424) (α-hairpinin), Pap s 2 (legumin), and Pap s 3 (small hydrophilic seed protein)—were identified, and sIgE binding to α-hairpinin effectively distinguished allergic from tolerant individuals. Poppy seed vicilin and legumin demonstrated strong cross-reactivity with hazelnut allergens, whereas α-hairpinin cross-reacted with almond.²⁸ Flaxseed LTP has been suggested as a clinically relevant allergen capable of inducing anaphylaxis. More recently, storage proteins—specifically 2S albumin and 11S globulin—have also been identified as major allergens responsible for severe reactions. These flaxseed LTPs and storage proteins have been associated with co-allergy to TNs and other seeds.³⁵,³⁶ Additionally, several allergens from pomegranate seed and cottonseed with relevant clinical implications have been reported.²⁹,³⁷

UPDATES IN DIAGNOSIS

The diagnosis of TN and seed allergies relies on a combination of clinical history, testing to identify IgE sensitization, and/or OFC, similar to the diagnostic approach used for other IgE-mediated FAs. In TN and seed allergies, the rate of co-sensitization is higher than that of true clinical co-allergy, which may lead to unnecessary dietary restrictions in patients sensitized to multiple nuts. Therefore, a key diagnostic challenge is differentiating between clinical co-allergy and co-sensitization. In this section, we review the recently updated diagnostic methods and algorithms for TN and seed allergies, as illustrated schematically in Fig. 1.

Fig. 1. Diagnostic approach for IgE-mediated tree nut and seed allergies. The algorithm outlines a structured approach incorporating focused clinical assessment, sensitization testing, molecular allergology, and basophil activation test to assess clinical relevance and co-allergy. This integrated workflow supports accurate diagnosis and rational use of oral food challenge.

IgE, immunoglobulin E; SPT, skin prick test; sIgE, specific immunoglobulin E; CRD, component-resolved diagnostics; OFC, oral food challenge; BAT, basophil activation test.

SPT and serologic tests

TN-specific SPT and serum sIgE testing to crude extracts are established markers of sensitization and can assist in diagnosis when interpreted alongside clinical history.³ Numerous studies have proposed diagnostic thresholds for these tests; overall, an SPT wheal diameter of ≥ 8 mm or a TN sIgE level of ≥ 15 kU_A/L generally indicates a high likelihood of clinical allergy.³,⁸ However, these parameters should be interpreted with caution, as both false-negative and false-positive results are possible due to variations in extract composition, patient reactivity, and testing technique. In a retrospective analysis of open TN OFCs, many patients with TN sensitization—with or without a prior history of TN reactivity—successfully passed the OFC despite having an SPT wheal of ≥ 3 mm or an sIgE level of ≥ 2 kU_A/L.³⁸

This finding highlights that sensitization alone does not equate to clinical allergy. The advent of component-resolved diagnostics (CRD) has markedly improved the precision of TN and seed allergies diagnosis by enhancing prediction of clinical reactivity and reaction severity. As discussed in the clinical characteristics section of this review, primary sensitization to storage proteins or LTPs is associated with severe systemic reactions and distinguishes true allergy from asymptomatic sensitization to crude extracts. Conversely, isolated sensitization to PR-10 proteins or profilins is typically associated with milder localized reactions or PFS. The relevant allergenic components are listed in Table 2.⁵,¹¹,¹²,¹³,¹⁴,²⁶,²⁷,²⁸,²⁹ Several studies have proposed diagnostic cut-off values for individual components; however, these thresholds are not yet validated for routine clinical application.³,⁸,¹⁰,¹²,²⁶ The chip-based multiplex assay provides semi-quantitative estimates of IgE antibody levels based on interpolated calibration curves, though its analytical sensitivity is generally lower than that of singleplex assays.

The median thresholds associated with clinical reactivity were as follows: for SPT (measured as wheal diameter in millimeters), hazelnut, cashew, and sesame were 5, 5, and 8 mm, respectively; for sIgE (kU_A/L, ImmunoCAP; Thermo Fisher Scientific, Uppsala, Sweden) to crude extracts of hazelnut, cashew, walnut, almond, and sesame, the respective cut-offs were 2.34, 1.1, 2.8, 3.4, and 7.5.³⁹ In subpopulations of TN-allergic patients—particularly those sensitized to multiple TNs—determining clinical reactivity remains challenging and requires integration of additional diagnostic modalities. Reported cut-off values for major allergens as well as relevant allergen components are summarized in Table 3.³,⁸,³⁹

Table 3. Reported diagnostic cutoff values for SPT and sIgE in major TN and seed allergies.

Allergen (TN/seed)	Test type	Cut-off value
General TN	SPT (wheal diameter)	8 mm
	sIgE to crude extract	15 kUA/L
Hazelnut	SPT	5 mm
	sIgE to crude extract	2.34 kUA/L
	Component sIgE (Cor a 9)	0.83 kUA/L
	Component sIgE (Cor a 14)	0.64 kUA/L
Cashew	SPT	5 mm
	sIgE to crude extract	1.1 kUA/L
	Component sIgE (Ana o 3)	0.4 kUA/L or 0.32 kUA/L
Walnut	sIgE to crude extract	2.8 kUA/L
	Component sIgE (Jug r 1)	0.2 kUA/L
Almond	sIgE to crude extract	3.4 kUA/L
Sesame	SPT	8 mm
	sIgE to crude extract	7.5 kUA/L
	Component sIgE (Ses i 1)	2.0 kUA/L

Data summarized from reference #3, 8, 39.

SPT, skin prick test; sIgE, specific immunoglobulin E; TN, tree nut.

Basophil activation test in TN and seed allergies

The basophil activation test (BAT) is an in vitro assay that measures the percentage of CD63⁺ basophils following allergen stimulation. Recently, BAT has been investigated as a diagnostic tool for peanut and TN allergies. BAT may help determine clinical reactivity in patients with suspected TN or seed allergy, as well as in co-sensitized or multi-nut-allergic individuals. Studies suggest that BAT can effectively reduce the need for OFCs in the diagnosis of TN allergies.³⁰,³¹,⁴⁰ In the Markers of Nut Allergy Study, BAT was performed in 200 Canadian and Australian pediatric patients with peanut and/or TN (almond, cashew, hazelnut, pistachio, walnut) allergies to evaluate its diagnostic utility and accuracy. BAT results were assessed against confirmed allergic status in a blinded manner to develop a generalized statistical model for comparison with extract-based and component-sIgE results. The area under the receiver operating characteristic curve (ROC) was 0.97 for cashew, 0.95 for pistachio, and 0.97 for walnut. BAT outperformed sIgE testing for hazelnut and was comparable to sIgE for walnut in a sub-analysis of sensitized patients who underwent OFCs. These findings demonstrate the potential utility of BAT in predicting clinical reactivity to TNs in multi-nut–sensitized children and in reducing the need for high-risk OFCs in diagnostic evaluation.⁴⁰

In a study conducted to investigate the coexistence of allergies among different TNs and to improve diagnostic testing while minimizing the need for OFCs, 83 patients were prospectively evaluated for TN (walnut, pecan, cashew, pistachio, hazelnut, and almond) allergy using clinical history, SPTs, BATs, and OFCs in a subgroup of patients. Although most participants were sensitized to 5 or 6 TNs, more than 50% were clinically allergic to 1 or 2. Two-thirds of patients allergic to walnut and cashew were also allergic to pecan and pistachio, respectively. ROC analysis demonstrated that both SPT and BAT performance was TN-dependent, with areas under the curve ranging from 0.75 to 0.94. The combination of SPT and BAT accurately distinguished allergic from tolerant patients for walnut (87%), pecan (66%), cashew (71%), and pistachio (79%). These findings support the utility of combining SPT and BAT to differentiate between allergic and tolerant individuals, thereby reducing the need for OFCs and facilitating appropriate dietary elimination recommendations. This diagnostic algorithm was subsequently validated in further studies.³⁰,³¹

OFC in TN and seed allergies: dosing schedules

Although the OFC remains the gold standard for diagnosing FAs, it is time-consuming, resource-intensive, and carries a risk of anaphylaxis. More than half of TN- and seed-allergic patients are co-sensitized or co-allergic to multiple TNs or seeds, necessitating several OFCs for accurate diagnosis in some individuals. This requirement presents a major barrier and often leads to unnecessary dietary restrictions in the absence of confirmed clinical reactivity. Unlike other FAs such as cow’s milk, hen’s egg, and wheat, standardized protocols for TN and seed OFCs have not yet been established, and only a limited number of studies have addressed TN and seed OFC procedures to date.

The American Academy of Allergy, Asthma & Immunology-EAACI PRACTALL guideline was recently updated to standardize OFC procedures for common FAs, including TNs and seeds.³⁹ In diagnosing IgE-mediated FAs, the dosing schedule generally includes 3 to 6 incremental steps, with a maximum dose typically corresponding to an age-appropriate serving size. Recommended age-appropriate serving portions for TNs are as follows: (1) for children aged 4–8 years, 11 almonds, 10 cashews, 3 tablespoons (tbsp) of hazelnuts, 10–25 pecan halves, 3 tbsp of pine nuts, 20 pistachios, and 10 walnut halves; (2) for individuals aged 9 years and older, the same portions are recommended for almond, cashew, hazelnut, pistachio, and walnut, while the portions increase to 25 pecan halves and 3–4 tbsp of pine nuts. However, it is essential to distinguish between dosing schedules designed for different clinical purposes—such as diagnosing FA, conducting an OFC before initiating oral immunotherapy (OIT), determining reaction thresholds, and performing clinical trials—because the total dose and stepwise increments may vary accordingly.

TREATMENT AND NATURAL COURSE

Fundamental strategies in the management of TN and seed allergies

The acute management of TN and seed allergies follows the same principles as that applied to other IgE-mediated FAs. Intramuscular epinephrine remains the first-line treatment for anaphylaxis and should be administered immediately once systemic symptoms develop. Adjunctive medications, such as antihistamines and corticosteroids, may help alleviate symptoms, but must never delay the administration of epinephrine. Anaphylaxis has been reported in over 40% of walnut and pine nut allergy cases and in up to 68.9% of sesame seed allergy cases, with these rates considerably higher than those typically observed in other FAs.¹³,²⁵ Sunflower seed (approximately 25%) and perilla seed (28.6%) allergies exhibit anaphylaxis rates comparable to other plant-derived food allergens, but still require careful clinical monitoring.¹⁴,¹⁵ These findings emphasize the critical importance of rapid symptom recognition and the need for all patients with TN and seed allergies to be prescribed an epinephrine auto-injector (EAI) and to receive comprehensive education on its proper use.

Long-term management of TN and seed allergies centers on accurate allergen identification and continuous patient education to prevent recurrence and accidental exposure. Key components include counseling on allergen avoidance, early symptom recognition, and emergency preparedness. Regular follow-up is essential to monitor clinical progress and sensitization patterns, supporting decisions regarding possible reintroduction through supervised OFCs. For selected patients, particularly those with persistent allergies or a high risk of accidental exposure, OIT can be considered based on individualized risk assessment and patient preference.

Subsequent sections will discuss long-term management in greater depth, including context-specific strategies for schools, restaurants, and air travel; guidance on allergen labeling; and the scope and duration of dietary avoidance in light of the natural disease course. Fig. 2 presents an overview of the comprehensive treatment framework.

Fig. 2. Comprehensive management strategies for TN and seed allergies. This figure illustrates key elements of acute and long-term management in TN and seed allergies. Acute treatment focuses on prompt epinephrine use, while long-term management requires a multidisciplinary approach across various settings, including reassessment, OIT, school-based care, and practical safety strategies for eating out and air travel.

TN, tree nut; OIT, oral immunotherapy; EAI, epinephrine auto-injector; IgE, immunoglobulin E; SPT, skin prick test.

The scope of TN and seed avoidance

Dietary avoidance of TNs and seeds should be individualized according to each patient’s clinical reactivity and specific sensitization profile. Although co-sensitization among TNs is common, true clinical co-allergy occurs much less frequently. The NutCracker study reported that multiple TN allergy was present in approximately 30% of individuals with confirmed TN allergy.³⁰ Furthermore, the likelihood of a positive OFC to an additional TN among patients with established TN allergy has been estimated at about 14%.³⁸

A key consideration in managing TN and seed allergies is determining the appropriate extent of dietary avoidance. Regardless of clinical history, avoidance of all TNs may simplify management and reduce the risk of cross-contact; however, this approach is often impractical due to unnecessary dietary restriction and potential nutritional compromise. Instead, including TNs that patients have been clinically proven to tolerate is widely regarded as a more practical and evidence-based strategy. The management of untried TNs that the patient has neither consumed nor undergone OFC testing remains particularly challenging. One approach is to avoid all untried TNs without further testing, thereby minimizing the burden and risk associated with OFCs. However, this strategy may unnecessarily limit dietary variety, reduce quality of life, and increase the risk of developing new sensitizations during prolonged avoidance. Alternatively, conducting OFCs to untried TNs allows for broader dietary inclusion, but is time- and resource-intensive and adds complexity in differentiating between multiple nuts.³ Clinical decisions should be individualized, taking into account the specific TNs involved, the degree of sensitization, and patient preferences. From a clinical standpoint, co-allergy rates are particularly high between cashew and pistachio, as well as between walnut and pecan.³⁰ Therefore, avoiding these pairs together is generally recommended for both clinical safety and practicality. Conversely, certain TN pairs, such as pecan–pistachio, cashew–hazelnut, and pistachio–hazelnut, have demonstrated lower co-allergy rates (<20%) and may be considered for dietary inclusion in carefully selected cases. Almond consistently shows low co-allergy rates across multiple studies and may also be cautiously included in the diet.³⁰

Although data are limited, available studies suggest that certain seeds may exhibit cross-reactivity with other seeds or tree nuts. For instance, sesame seeds may cross-react with poppy seeds, and sunflower seeds with mustard seeds. These potential cross-reactions should be taken into account when formulating dietary

TN and seed allergen labeling: current practices and challenges

TNs are included among the “Big Eight” major food allergens for which allergen labeling is mandatory in most countries. Particular caution is required for high-risk foods such as chocolate, confectionery, and cereal bars, which frequently involve cross-contact with TNs. Labeling practices differ across regions: some countries list individual TNs, whereas others use the broader category of “tree nuts.” In Korea, allergen labeling is mandatory for prepackaged foods, with walnut and pine nut designated as mandatory allergens since 2015 and 2020, respectively. In Japan, only walnut labeling is required, while almonds and cashews are recommended. In the U.S., sesame was officially designated the ninth major allergen under the Food Allergy Safety, Treatment, Education, and Research Act and has been required on food labels since January 2023. It is also mandatory in Canada, the UK, Australia, and New Zealand, whereas sesame labeling remains nonmandatory in several other countries, including Japan, Korea, Argentina, Brazil, and South Africa. In the European Union, sesame and mustard are among the seeds subject to mandatory allergen labeling.³³

Precautionary allergen labeling (PAL)—such as “may contain” statements—is used in several countries to indicate the possibility of cross-contamination. However, such labeling may create confusion among consumers. In a UK study, most adults with peanut or TN allergy reported distrust toward PALs, citing their perceived overuse and their function as legal disclaimers rather than reliable safety guidance.⁴¹ Implementing a standardized evidence-based system, such as Japan’s threshold-based model, may improve both clarity and consumer confidence. Furthermore, allergen labeling regulations should be regularly updated to reflect regional dietary trends and the identification of emerging allergens. Because ingredient lists in prepackaged foods can change over time, continued vigilance is recommended when purchasing or consuming such products.

Strategies for managing TN and seed allergies in schools

According to a Korean multicenter registry, 7.8% of pediatric anaphylaxis cases occurred in schools, with an additional 9% reported in preschools.⁴² Another study found that 18% of food-allergic children experienced reactions at school, and these reactions were generally more severe than those occurring at home.⁴³,⁴⁴ Furthermore, 39% of schools reported at least 1 food-allergic reaction within the preceding 2 years.⁴⁵ These findings underscore the need for effective TN and seed allergy management in schools, where children spend a substantial portion of their day under the supervision of caregivers with varying levels of allergy awareness and training.

Although formal school-based allergy management guidelines exist in several countries, including the US, Canada, and Australia, many schools still lack comprehensive allergy management systems.⁴⁶ While evidence supporting allergen-free policies remains limited, increasing awareness and improving staff training through collaboration among families, schools, and healthcare providers are essential. Brief educational interventions have been shown to enhance anaphylaxis recognition and correct EAI use, although the optimal frequency and structure of such training remain uncertain.⁴⁷ Physicians play a pivotal role in counseling families, prescribing EAIs for school use, and providing individualized allergy action plans. These plans may use broader labeling categories, such as “TNs”, rather than listing specific nuts (e.g., “cashew”), to simplify management and reduce cross-contact risk.⁴⁸ While EAIs provide reassurance to caregivers and school staff, some children report anxiety about carrying the device, and studies indicate that 28%–49% of those aged 10–14 years do not consistently carry their EAIs.⁴⁹ Because TN allergy often persists into late childhood and adolescence, continuous education and psychosocial support are particularly important during this transitional period.

Precautions and strategies for eating out

Accidental ingestion of TNs in restaurants remains a major cause of food-induced anaphylaxis. In the UK, 59% of hospitalizations for food-related anaphylaxis occurred in restaurant settings, while data from a Korean multicenter registry indicated that 9% of pediatric anaphylaxis cases and 5% of adult anaphylaxis cases were linked to restaurant exposure.⁴²,⁵⁰ Key contributing factors include hidden allergens, cross-contact, and inadequate communication with restaurant staff. Among individuals aged 14 years and older, 22.4% of reactions were attributed to hidden allergens, and 53.9% of restaurant-related reactions occurred despite prior disclosure of the allergy.⁵¹,⁵² Various seeds, such as pumpkin, sunflower, flaxseed, hemp, and chia, are increasingly incorporated into modern diets due to their perceived health benefits and may serve as hidden allergens, particularly in bakery and health-oriented food products. This trend warrants heightened vigilance among individuals with known TN or seed allergies. Preventive strategies should target both patients and food service providers. From the patient perspective, effective precautions include avoiding high-risk venues, such as bakeries where TN exposure is more likely, using verbal or written tools (e.g., chef cards or mobile applications) to communicate allergies, dining during off-peak hours, carrying emergency medication, and inquiring about preparation methods. From the food service perspective, establishments should adopt formal allergen management protocols, provide clear menu labeling, and ensure that staff receive basic allergy training to recognize and respond appropriately to allergen risks. The best practices include preparing allergen-free meals first, maintaining rigorous kitchen hygiene, and remaking any dish suspected of cross-contact contamination.⁵³ Sustained improvements depend on system-wide measures encompassing kitchen safety, transparent labeling, ongoing staff education, and the implementation of supportive institutional policies.

In-flight considerations for individuals with TN and seed allergies

Management of TN and seed allergies during air travel requires targeted, proactive precautions. Current evidence indicates that allergen exposure on airplanes is more likely to occur through surface contamination, such as on tray tables and armrests, than through airborne transmission via ventilation systems.⁵⁴ Therefore, patients are strongly advised to clean tray tables, armrests, and seat-back screens with detergent-based sanitizing wipes at the beginning of the flight and to wash their hands with soap and water afterward, as these methods provide more effective allergen removal than alcohol-based gels or plain wet wipes.⁵⁵ Patients should carry their EAIs during air travel and ensure they remain readily accessible at all times, rather than stored in overhead compartments. Airlines, in turn, are encouraged to establish and clearly communicate transparent allergen management policies, either on their websites or on passenger request. Although not yet a universal practice, the inclusion of general-use EAIs within in-flight emergency medical kits may further enhance passenger safety. With appropriate personal precautions, careful environmental cleaning, and cooperative airline policies, the risk of allergic reactions during air travel can be substantially reduced.

Changes in TN allergenicity after processing

Roasting is well known to increase allergenicity in peanuts; however, in certain TNs, such as hazelnut and almond, it may actually reduce allergenic potential by diminishing PR-10 protein reactivity.⁵⁶ Conversely, other studies have reported that roasting may increase TN allergenicity under specific conditions.⁵⁷ Recent findings indicate that allergenic proteins in hazelnut, pistachio, and cashew can be hydrolyzed by specific proteases, and that combining enzymatic treatment with pressure heating may significantly reduce their allergenic potential.⁵⁸ Boiling has been shown to markedly alter the protein profile of walnut, although certain proteins, particularly prolamins, remain stable even after boiling or dry-frying.⁵⁹ In sesame seed, processing methods can also influence allergenicity. Roasting may either enhance or reduce IgE-binding capacity, whereas boiling generally decreases allergenicity by promoting protein unfolding and solubilization. Fermentation and enzymatic hydrolysis of sesame seed may further lower allergenic potential, although these effects are highly condition-dependent.⁵⁸,⁵⁹,⁶⁰ In contrast, the impact of food processing on the allergenicity of other seeds remains largely unexplored and warrants further investigation. Given that the effects of processing on TNs and seeds have not been studied as extensively as for cow’s milk or egg—where heating is known to significantly reduce allergenicity—such assumptions should not be directly extrapolated to TNs or seeds without supporting evidence.

Clinical course and reassessment in TN and seed allergies

The natural history of TN allergy remains relatively underexplored. Although TN allergy was traditionally regarded as a lifelong condition, emerging evidence indicates that resolution is possible in a subset of patients. A widely cited 2005 study reported a resolution rate of 8.9% among children with confirmed clinical reactivity and sensitization to TNs.⁶¹ In a parental report-based survey, 14% of children were reported to have outgrown their TN allergy, whereas an OFC-based study examining both peanut and TN allergy observed a higher resolution rate of 39%.⁴³,⁶² Persistence of TN allergy appears more likely in individuals with atopic dermatitis and coexisting FAs. Laboratory parameters may assist in evaluating readiness for reintroduction. For instance, one study found that children with TN-sIgE levels below 1 kU_A/L achieved an 89% OFC pass rate, with a mean SPT wheal size of 4.8 mm among those who passed.³⁸ Furthermore, evidence suggests that patients aged ≥ 4 years with TN-sIgE levels ≤ 5 kU_A/L may be considered eligible for challenge.⁶¹

The natural course of sesame allergy has been most extensively studied in Israel. A retrospective study involving 45 sesame-allergic patients followed for six years reported that 20% developed tolerance. A more recent analysis of 190 children found a spontaneous resolution rate of 32.1% over a mean follow-up of 3.86 ± 4.43 years.⁶³ However, the natural history of seed allergies other than sesame remains poorly characterized and requires further longitudinal research.

Current evidence and considerations for TN and seed OIT

OIT for TN and seed allergies remains less extensively investigated compared with OIT for egg, peanut, or cow’s milk. Nevertheless, emerging evidence indicates promising desensitization outcomes for certain TNs. Walnut OIT has demonstrated a desensitization rate of 89%, with reported cross-desensitization effects to pecan and, in some instances, hazelnut.⁶⁴ A single-center study on cashew OIT reported a 91% desensitization rate, although 33% of participants experienced adverse reactions during treatment. Similarly, another cashew OIT study involving children with a median age of 8 years showed an 88% desensitization rate, with 52% experiencing reactions during home dosing and 6% requiring epinephrine for those reactions.⁶⁵,⁶⁶ Hazelnut OIT has demonstrated variable but encouraging outcomes across studies, with desensitization rates ranging from 34% at a maintenance dose of 1,635 mg to 96.7% at 1,200 mg, and another study reporting approximately 51% desensitization to 120 mg after one year, with a safety profile comparable to that of other nut OITs.⁶⁷,⁶⁸,⁶⁹,⁷⁰ Notably, hazelnut OIT did not induce desensitization to other TNs, whereas cashew OIT successfully induced desensitization to pistachio.⁵ Recent studies on sesame OIT involving young children, typically aged 2 to 3 years, have shown desensitization rates ranging from approximately 65% to 88%, with allergic reactions occurring in about 30% to 40% of participants, most of which were mild in severity.⁷¹,⁷²,⁷³ A case report also documented successful desensitization using sunflower seed butter OIT.⁷⁴

A systematic review encompassing 3 sublingual immunotherapy trials, 5 single-TN OIT studies, and 6 multi-TN OIT studies demonstrated that TN OIT achieves efficacy comparable to peanut OIT, although safety profiles varied depending on the specific nut.⁷⁵ In a recent safety analysis of 92 preschool-aged children (median age: 35 months) undergoing TN OIT, 38% experienced grade 1 reactions and 32.6% experienced grade 2 reactions during the buildup phase, while no grade 3 or 4 reactions were reported.⁷⁶ Table 4 summarizes TN OIT outcomes and the reported proportions of allergic reactions during treatment from studies published within the last 5 years⁶⁴,⁶⁶,⁶⁷,⁶⁸,⁶⁹,⁷⁰,⁷¹,⁷²,⁷³,⁷⁶; studies involving fewer than 10 participants were excluded. TN OIT represents a viable therapeutic option for selected patients but requires individualized risk–benefit assessment, consideration of underlying conditions, target TN selection (single or multiple), maintenance dosing strategy, and potential adjunctive use of biologics such as omalizumab. Further studies are needed to optimize protocols and long-term outcomes of TN and seed OIT.

Table 4. Summary of recent OIT studies for TN and seed allergies.

Study, year	OIT food	OIT food material	No.	Age	Dose escalation schedule	Maintenance dose	Maximal target dose	Desensitization rate	Adverse event
Elizur et al., 202567	Hazelnut	< 80 mg hazelnut protein: hazelnut flour; ≥ 120 mg hazelnut protein: whole hazelnuts	30	Median 9.7 yr	Monthly escalation		4,000 mg	96.7% (4,000 mg)	Any reaction in 63.3% during home doses; 16.7% treated with epinephrine for home reactions
Shah et al., 202572	Sesame	Crushed sesame seeds or tahini	84	Median 2 yr	Up-dosing at ≥ 2-week intervals	1,000 mg		65% (1,000 mg)	29.8% experienced allergic reactions, mostly grade 1
Chua et al., 202473	Sesame	50 mg sesame protein: sesame flour; 80 mg sesame protein: tahini	28	Median 33.5 mon	Up-dose every 2–4 weeks	200 mg	2,000 mg	85.7% (2,000 mg)	39.3% grade 2 reactions during buildup; 3.6% received epinephrine during buildup
Erdle et al., 202376	Cashew	TN flour or TN milk	58	Median 35 mon*	Up-dose every 2-4 weeks	300 mg	300 mg	96.7% (300 mg)	70.6% experienced symptoms (all grade 1 or 2); 2.53% received epinephrine during buildup
	Walnut		19
Nachshon et al., 202370	Walnut	Not specified	147	Median 6.8 yr	Initial dose escalation for 3–4 days, followed by monthly escalation	300 mg	3,900 mg for TNs, 4,000 mg for sesame	86.70%	HETRs experienced in 20.4%, 5.3%, 25%, and 6.1%, respectively
	Cashew		57
	Hazelnut		16
	Sesame		115
Sabouraud et al., 202268	Hazelnut	Raw hazelnut powder in capsules for OFC; Cooked hazelnut from the market for OIT	70	Median 10 yr	Up-dose over 6 months	Individualized	Individualized	51.4% (120 mg) at 1 year	57.1% experienced at least 1 adverse effect at home; 2.9% experienced systemic allergic reactions at home
Elizur et al., 202266	Cashew	< 144 mg cashew protein: cashew flour; ≥ 144 mg cashew protein: whole cashew nuts	50	Median 8 yr	Initial dose escalation for 3 days, followed by monthly escalation	1,200 mg	4,000 mg	88% (4,000 mg)	Any reaction in 52% during home doses; 6% treated with epinephrine for home reactions
Moraly et al., 202069	Hazelnut	Ground hazelnut	100	Median 5 yr	Monthly escalation	416 mg	1,635 mg	34% (1,635mg)	Mild reactions in 30%, no EoE
Elizur et al., 201964	Walnut	< 120 mg walnut protein: walnut flour; ≥ 150 mg walnut protein: regular walnuts	55	Median 7.9 yr	Initial dose escalation for 4 days, followed by monthly escalation	1,200 mg	4,000 mg	89.0% (4,000 mg)	85% had an adverse reaction (mostly grade 1 or 2) during up-dosing in the clinic; 14.5% required epinephrine at home
Nachshon et al., 201971	Sesame	< 240 mg sesame protein: liquid form; ≥ 240 mg sesame protein: raw tahini	60	Median 7.5 yr	Monthly escalation	1,200 mg	4,000 mg	88.3% (4,000 mg)	Any reaction in 65% during home doses; 8.3% treated with epinephrine for home reactions

Data summarized from references #64, 66-73, 76.

OIT, oral immunotherapy; TN, tree nut; HETR, home epinephrine-treated reaction; OFC, oral food challenge; EoE, eosinophilic esophagitis.

^*Median age including hazelnut, macadamia, and multi-TN OIT patients with fewer than 10 cases each.

CONCLUSION

TN and seed allergies are rising globally and impose substantial, lifelong burdens. Precision diagnostics, particularly CRD and BAT, better distinguish clinically relevant allergy from sensitization, guiding selective avoidance, targeted challenges, and readiness with epinephrine. Pragmatic, patient-centered care that supports inclusion of tolerated nuts, along with education and preparedness in high-risk settings, can reduce morbidity without undue restriction. OIT for selected TNs and sesame is promising, yet key gaps remain in optimal protocols, long-term outcomes, cross-desensitization, and the management of multi-sensitized patients.