Is age a critical factor for the diagnosis of peanut allergy in children?

Abstract

Background

Peanut allergy (PA) is a significant health concern. Some children with PA may present with a relatively high reaction threshold. However, even in this group the chances of spontaneous resolution are low and there is significant impairment in the quality of life. Newer data suggest that treatment protocols in this group are safer and easier to implement.

Objective

This study aims to identify clinical factors influencing reaction threshold and challenge outcomes in PA children, assisting physicians to estimate the allergic threshold and improving the chances to diagnose children with high threshold PA.

Methods

A retrospective study, collecting and analyzing data of challenge-proven PA children under 12 years of age, from our pediatric food allergy center, where all children with suspected PA are offered a diagnostic challenge. The data included demographics, medical history, skin test and oral food challenge results.

Results

A total of 194 children under 12 years of age (mean 43 months, 95% CI 38.9–47.1) with challenge-proven PA were enrolled in the study. Children with low threshold PA (threshold less than 100 mg) were older (52.5 months % vs 33.6 months, p < 0.001) and had larger wheal size during skin prick tests (11.2 mm vs 8.3 mm, p < 0.001).

In girls an additional predictor of low threshold was a previous systemic/anaphylactic reaction (p < 0.001).

Using exploratory machine-driven decision tree analysis, an age of 18 months or younger yielded a negative predictive value of over 94% for developing respiratory reactions and a markedly lower incidence of anaphylaxis compared with older children.

Conclusion

Since an oral food challenge is the gold standard for the diagnosis of PA, performing a diagnostic challenge at a young age, may optimize the chance to diagnose PA with a relatively high threshold, increasing the safety and outcomes of potential interventions. Therefore, the early referral of young patients for a diagnostic workup is strongly recommended.

Introduction

Peanut allergy (PA) is one of the most prevalent food allergies, affecting 2.2% of the children in the United States (US)¹ and accounts for the highest rate of emergency department (ED) visits for food-induced anaphylaxis.² In contrast to other food allergies such as milk, egg, and wheat, PA usually persists into adulthood with a resolution rate estimated between 2% and 20%.3, 4, 5

While prevention, if feasible, is recommended,⁶ dietary avoidance may be challenging with up to 40% of patients reporting at least 1 allergic reaction leading to an ED visit.⁷ Immunotherapy, nowadays a recommended option for the treatment of PA,⁸ is purposed for increasing the tolerated dose and therefore decreasing the incidence of life-threatening accidental reactions. However, long treatment protocols, requiring significant medical resources and expertise, along with a list of relatively frequent side effects, has rendered this option limited to a minority of peanut allergic patients and families.^9,10

Oral food challenge is the gold standard for diagnosis of PA as well as identifying significant standardized doses (Fig. 1), such as the single highest tolerated dose (SHTD),^11,12 also named the allergic threshold.¹³ Another important measure is the cumulative dose of allergic proteins ingested during the test, including the dose eliciting an allergic reaction, also known as the cumulative reactive dose (CRD).^11,12

Fig. 1.

Demonstration of an oral food challenge. The patient had an allergic reaction after ingesting a 100 mg dose. The highest dose ingested without eliciting any symptoms was 50 mg and the total amount of proteins ingested during the test was 176 mg. Abbreviations: CRD, cumulative reactive dose; SHTD, single highest tolerated dose

To date, most studies on the treatment of PA enrolled children with a relative low threshold, namely a SHTD lower than 100 mg of peanut protein (ie, less than 1/3 of a peanut).^5,9,14 These children are indeed at high risk for severe allergic reactions following minor accidental exposures¹⁵ and are even less likely to naturally outgrow the allergy. Therefore, treating children with low threshold peanut allergy (LTPA), using oral immunotherapy, has become a viable therapeutic option, despite its limitations.⁵

High threshold peanut allergy (HTPA) is defined as a challenge-proved threshold equal to or higher than 100 mg of peanut protein. Despite still being at risk of allergic reactions, children with a relatively high threshold are less likely to have severe reactions at very low doses in accidental exposures, compared to those with low threshold. However, the impact on quality of life, health resource utilization and lifestyle limitations are the same.¹⁶ Overall, HTPA accounts for 25–70% of children with PA17, 18, 19, 20 but the usage of oral immunotherapy for this group is not well established, both due to lack of studies addressing this group and due to the risk of adverse events related to current published oral immunotherapy protocols. However, the few published studies, suggest that treating this group is both effective and has a significantly improved safety profile.^20,21

Notably, PA threshold may significantly change under the influence of many factors such as exercise and sleep deprivation,²² time,²³ medication and illness²⁴ or the composition of the food.^25,26 Unsurprisingly, subsequent real-life allergic reactions to a previously challenge-proven tolerated dose have been documented.^20,27

Another major factor affecting PA is age. Previous studies have suggested that older age is related with a lower reaction threshold²⁸ and a higher risk of severe anaphylactic reaction. However, predictors of peanut allergy threshold and challenge outcomes are not well established across different populations.

Therefore, we aimed to identify potentially modifiable risk factors, such as age, that may predict peanut allergy threshold and challenge outcomes in children.

Methods

Study design & patients

We performed a retrospective study including challenge-proven PA children seen at an outpatient hospital bases allergy clinic as well as a community-based food allergy clinic in the same geographical area. As a policy, all children referred to the allergy clinic with a suspected PA were offered a diagnostic food challenge, regardless of the severity of the suspected reaction or the results of PA skin/Specific IgE testing. All patients in the study are on long term follow-up for their food allergy and have expressed verbal agreement for participating. The study was approved by the Sheba Medical Center review board (SMC-0457-13).

Data collection

Data was collected from the medical center’s electronic medical record system. The data included demographic characteristics (age, gender), atopy-related medical conditions (previous allergic reactions, additional diagnoses such as asthma, atopic dermatitis, and other allergies), and data from the patient’s skin prick test (SPT) and oral food challenge (OFC).

SPT – Skin prick tests were performed during the patient’s visit, using single-head lancets on the forearms of children with histamine (1 mg/ml) as positive control, glycerinated saline as negative control and whole-peanut extract (ALK- Abelló, Denmark).

OFC - All challenges were performed under expert medical supervision following previously published protocols.^20,29 The OFCs to peanut were performed using a commercial preparation of “Bamba” (Osem, Israel), a common snack containing 50% puffed maize and 50% peanut (Approximately 100 mg of peanut protein/piece). A portion of 21 Bamba pieces is equivalent to approximately 2.0 g of peanut protein. The OFC began with a smear of Bamba applied to the buccal mucosa of the lower lip. Subsequently, at 20-min intervals, doses of ¼, ½, 1, 2, 6, and 12 snack pieces were given. A peanut oral food challenge was considered positive (failed) when objective allergic symptoms occurred during the challenge. Objective symptoms included significant urticaria, angioedema, vomiting, wheezing, hypoxia, hypotension, or anaphylaxis. Mild, isolated, or transient findings, such as 1 or 2 localized urticarial lesions, mild rhinorrhea, or cough without objective respiratory compromise, were not considered sufficient to define a positive challenge unless persistent, progressive, or accompanied by additional objective findings. Challenge interpretation and stopping decisions were made in accordance with the updated AAAAI–EAACI PRACTALL recommendations.

Participants who developed allergic reactions were diagnosed as peanut allergic and included in the study. If no reaction occurred during the full challenge and observation period, the participant was considered tolerant and excluded from the analysis. Using the single highest tolerated dose (SHTD), children were classified as having low-threshold peanut allergy (SHTD <100 mg) or high-threshold peanut allergy (SHTD ≥100 mg).

Statistical analysis

Demographic and clinical data of children with HTPA were compared with those of the group of children with LTPA, diagnosed by the same methodology. For all tests, a p-value of <0.05 was considered statistically significant. Continuous variables were described as mean ± 95% confidence interval (CI), and categorical variables as percentages. Comparison of means of continuous and distribution of categorical variables was performed using analysis of variance.

Classification tree analysis was performed to identify predictors of the categorical outcome variable using a machine learning–based approach. The model was constructed using the CHAID algorithm with predefined stopping criteria, including a minimum node size of 10 and a maximum tree depth of 3. The tree-building process enabled identification of the most statistically significant and clinically relevant predictive variables from the full set of variables collected in the study. Model validation was conducted using cross-validation, and classification accuracy was used to assess model performance.

Statistical analyses were performed using SPSS 32.0 (IBM SPSS Statistics, Armonk, New York).

Results

A total of 194 patients with challenge confirmed peanut allergy under the age of 12 and CRD lower than 2 g, were enrolled to the study between January 2019 and February 2023. The mean age was 43 months (95% CI: 38.9–47.1), and 66% were boys (Table 1). Most of the patients had additional atopy related medical conditions such as atopic dermatitis (58%), asthma (25%) or additional food allergies (49%). Using OFC results, the children were divided into 2 groups. Ninety-seven children (50%) were diagnosed with LTPA and another ninety-seven children (50%) with HTPA. As a group, children with LTPA were older, with a mean age of 52.5 months vs 33.6 months in HTPA children (p < 0.001), in addition, children with LTPA were also significantly more likely to be over the age of 4 years (49% vs 21%, p < 0.001). In our population of children under 4 years of age the prevalence of HTPA was 61% while in children 4 years of age or older the prevalence was 29% (p < 0.001, see Fig. 2).

Table 1.

Characteristics of 194 patients with challenge-proven peanut allergy.

Characteristic	Total (N = 194)	LTPA (N = 97)	HTPA (N = 97)	P. Value
Age mean – months (95% CI)	43 (38.9–47.1)	52.5 (46.2–58.8)	33.6 (29–38.1)	<0.001
Age ≥4 years – no. (%)	68 (35)	48 (49)	20 (21)	<0.001
Sex – no. (%)				0.88
Male	129 (66)	65 (67)	64 (66)
Female	65 (34)	32 (33)	33 (34)
Coexisting conditions – no. (%)
Atopic dermatitis	113 (58)	52 (54)	61 (63)	0.19
Additional Food Allergies	96 (49)	43 (44)	53 (55)	0.15
Nuts Allergy	51 (26)	27 (28)	24 (25)	0.63
Sesame Allergy	48 (25)	19 (20)	29 (30)	0.1
Eggs Allergy	32 (16)	16 (16)	16 (16)	1.00
Asthma	48 (25)	25 (26)	23 (24)	0.74
First Exposed Age – months (95% CI)	9.1 (7.7–10.6)a	10.5 (7.7–13.4)b	7.8 (7–8.5)c	0.06
Skin test (peanut) size – mm (95% CI)	9.8 (9–10.5)	11.2 (10.1–12.3)	8.3 (7.4–9.3)	<0.001

Abbreviation: LTPA, low threshold peanut allergy; HTPA, high threshold peanut allergy; CI, confidence interval.

Bold represents P value <0.05.

^aOut of 106 patients with data including first exposure age.

^bOut of 52 LTPA patients with data including first exposure age.

^cOut of 54 HTPA patients with data including first exposure age.

Fig. 2.

(A) The distribution of age in children with low threshold peanut and children with high threshold peanut allergy. (B) The prevalence of different peanut allergy thresholds in children older and younger than 4 years of age. Abbreviations: HTPA, high-threshold peanut allergy; LTPA, low-threshold peanut allergy

Children with LTPA showed a trend towards delayed first exposure to peanuts, 10.5 vs 7.8 months (p = 0.06). Although all children had positive skin tests for peanut allergy, skin test results of children in the LTPA group had significantly larger wheal size (11.2 mm vs 8.3 mm; p < 0.001).

The mean single highest tolerated dose for LTPA was 21.4 mg compared to the 227.2 mg in the HTPA group (p value < 0.001) (Table 2). The most common clinical presentation during the oral food challenge was cutaneous reaction (92%). Compared to HTPA, Children with LTPA were more likely to have other types of reactions, eg, respiratory reactions 37% vs 23% (p = 0.028), GI reactions 40% vs 18% (p < 0.001) and anaphylactic reaction 51% vs 32% (p = 0.006).

Table 2.

Outcomes of open peanut challenge among 194 Patients with Peanut Allergy.

Type	Total (N = 194)	LTPA (N = 97)	HTPA (N = 97)	P. Value
SHTD – mg (95% CI)	124.3 (101–147.6)	21.4 (17.7–25.1)	227.2 (190.7–263.6)	<0.001
CRD - mg (95% CI)	268.5 (199–338.1)	75.7 (64.5–86.9)	731.38 (567.4–895.4)	<0.001
Oral food challenge reaction – no. (%)
Cutaneous	178 (92)	86 (89)	92 (95)	0.12
Respiratory	58 (30)	36 (37)	22 (23)	0.028
Gastrointestinal	56 (29)	39 (40)	17 (18)	<0.001
Anaphylaxis	80 (41)	49 (51)	31 (32)	0.006

Abbreviation: LTPA, low threshold peanut allergy; HTPA, high threshold peanut allergy; CI, confidence interval; SHTD, single highest tolerated dose; CRD, cumulative reactive dose.

Bold represents P value <0.05.

In a sub analysis according to gender, we found some variation in the factors associated with PA threshold (Table 3). For boys (129/194), an older age (p < 0.001) and a larger skin test (p = 0.008) were the main factors that seemed to determine the observed threshold.

Table 3.

Characteristics and peanut challenge results among 194 children with Peanut Allergy with gender separation.

		Total (N = 129)	LTPA (N = 65)	HTPA (N = 64)	P. Value
Boys	Age – months (95% CI)	45 (39.7–50.2)	54.1 (45.9–62.2)	35.7 (29.6–41.8)	<0.001
	Oral food challenge reaction – no. (%)
	Cutaneous	115 (89)	55 (85)	60 (94)	0.1
	Respiratory	42 (33)	24 (37)	18 (28)	0.29
	Gastrointestinal	39 (30)	24 (37)	15 (23)	0.1
	Anaphylaxis	57 (44)	30 (46)	27 (42)	0.53
	Skin test (peanut) size – mm (95% CI)	9.7 (8.8–10.6)	10.9 (9.5–12.2)	8.5 (7.3–9.6)	0.008
		Total (N = 65)	LTPA (N = 32)	HTPA (N = 33)	P. Value
Girls	Age – months (95% CI)	39.2 (33–45.5)	49.3 (39.5–59.2)	29.4 (22.9–35.9)	<0.001
	Oral food challenge reaction – no. (%)
	Cutaneous	63 (97)	31 (97)	32 (97)	0.98
	Respiratory	16 (25)	12 (38)	4 (12)	0.017
	Gastrointestinal	18 (28)	16 (50)	2 (6)	<0.001
	Anaphylaxis	23 (35)	19 (59)	4 (12)	<0.001
	Skin test (peanut) size – mm (95% CI)	10 (8.7–11.4)	12 (10–14)	8.1 (6.5–9.7)	0.003

Abbreviation: LTPA, low threshold peanut allergy; HTPA, high threshold peanut allergy; CI, confidence interval.

Bold represents P value <0.05.

For girls (65/194), In addition to younger age and skin test size, the clinical manifestation of the allergic response to peanuts seemed to be an influencing factor, with LTPA girls more likely to have respiratory (38% vs 12% p = 0.017), GI (50% vs 6% p < 0.001) and anaphylactic reactions (59% vs 12% p < 0.001).

To maximize discrimination between groups and to construct a model for a priori risk stratification of respiratory reactions and anaphylaxis during peanut oral food challenge, an exploratory classification tree analysis was performed (Fig. 3).

Fig. 3.

(A) Classification tree analysis for the predication of respiratory reaction during oral food challenge, using demographic data. The model yields a negative predication value of 94.9% for children 18 months old or younger. (B) Classification tree analysis for the prediction of anaphylactic reactions during peanut oral food challenge. Age emerged as the primary discriminatory variable, with younger children demonstrating a lower probability of anaphylaxis during challenge and negative predictive value of 84.6% for children aged 18 months or younger

In the model predicting respiratory reactions (Fig. 3A), the overall prediction accuracy was 73.7%. Among all demographic and clinical variables evaluated, age emerged as the sole discriminatory factor. Notably, 94.9% of peanut-allergic children challenged at or before 18 months of age did not develop respiratory symptoms during the challenge.

In the anaphylaxis model (Fig. 3B), age likewise emerged as the primary discriminatory variable. Children aged ≤18 months demonstrated a relatively low incidence of anaphylaxis (15.4%), whereas the proportion of anaphylactic reactions increased with age.

Discussion

Peanut allergy prevalence seems to have risen significantly, all over the western world^30,31 with a prevalence of 2.2%¹ in children from the United States, 3.5% in Canada,³² 1.7% in Scandinavian countries,³³ and 1.85–2.5% in the United Kingdom.^31,34 The current recommended diagnostic pathway³⁵ includes a thorough medical history and examination, with the addition of skin testing and/or specific IgE blood tests to peanut proteins, that are limited due to the low predictive value of the commercially available skin tests.^29,36 Even with the introduction of additional diagnostic tools, such as the epitope and peptide specific serum IgE, OFC remains the only gold standard for both diagnosis and threshold estimation in PA. The decision of where and when to perform such a challenge is dependent on many factors, including the estimated chances of spontaneous resolution (low for peanut allergy), the available facilities and medical expertise of the allergy team, the availability of an oral immunotherapy program etc. Challenging small children and treating the resulting potentially severe allergic reactions is limited due to the requirement of highly experienced teams and patient/family worries due to recent real-life exposure/reactions.

Our study results may help estimate PA threshold and type of allergic reaction a priori to the challenge and may benefit decision making for both physicians and parents toward the setting, timing and protocol of the challenge. We found age (p. value < 0.001), and skin test results (as a surrogate for the IgE reaction to peanuts, see Table 1, p < 0.001) as significant predictors for PA threshold. Additionally, for girls, a previously reported anaphylactic reaction or any clinical reaction to peanuts other than in the skin, was also a significant risk factor for LTPA (Table 3). Our study also suggests that earlier exposure to peanuts correlates with relatively higher threshold (mean age for HTPA was 7.8 vs 10.5 months in LTPA, p = 0.06).

Machine-driven decision tree analysis identified age as the primary factor for a priori risk stratification during peanut challenge, with children ≤18 months demonstrating a very low risk of respiratory reactions and a markedly lower incidence of anaphylaxis compared with older children (Fig. 3). In subanalysis according to gender, prior respiratory, GI or anaphylactic reaction were significant risk factors for LTPA in girls.

Data from previous studies, estimates that 25%–70% of the children with PA having a high threshold phenotype.17, 18, 19, 20 Our study had 50% of the children with HTPA, that variability may derive from a different average age of the study population, as studies with older population showed lower prevalence of the milder phenotype.

The finding that LTPA is more common in older ages is in concordance with previous studies, showing that ingesting small amounts of peanut intermittently (such as repeated accidental exposures over time), is considered to be sensitizing,³⁷ explaining higher sensitization to peanuts at an older age.

Additionally, previously published studies suggested that children with HTPA may be easier to treat, using a milder and safer oral immunotherapy/reintroduction protocols.^20,21 Taken together, these findings support the potential value of performing diagnostic peanut challenges earlier in the course of disease, particularly to identify children who may benefit from early peanut OIT, especially when low-risk populations can be defined prior to challenge.

Early introduction to peanuts followed by continuous exposure, is now recommended to prevent the development of peanut allergy.38, 39, 40 Interestingly, our study showed that earlier exposure to peanuts in patients who ultimately developed PA showed a trend (p = 0.06) toward a relatively higher threshold phenotype, another argument to emphasize the importance of the early introduction policy.

Gender-related differences in prevalence and clinical manifestations of allergies are not new to the field, however a clear-cut impact of the previous clinical presentation on the PA threshold, seen only in girls, is a new finding of our study. Using clinical data available to the pediatrician, enabling the attending physician to appropriately refer these high-risk children for a diagnostic challenge within a high risk/tertiary center.

From the machine learning analysis in our limited database, it is difficult to ascertain a high precision tool for the prediction of high-risk patients apriori to the challenge. However, it appears that children aged 18 months or younger have a greater than 94% chance of not experiencing a respiratory reaction during oral peanut challenge and were also less likely to experience anaphylaxis during challenge compared with older age groups. There may be more significant additional factors that have not been analyzed in our study such as IgG4, gut microbiome etc., that may enable better predictive tools for other populations of children.

Further, longitudinal research is needed to determine how these factors affect a child’s PA threshold over time, and specifically what would be the optimal age for PA diagnostic challenge in different populations.

In this work, additional food allergies such as sesame or nuts did not have a significant impact on the threshold of PA. This is consistent with published data showing that though allergenic peanut proteins are similar to walnut allergenic proteins they do not share significant IgE-binding epitopes.⁴¹

There are some limitations to our study, derived from its design. Retrospective study may have inherent biases, such as selection bias, often because of choosing less severe patients. However, as a policy during the study period all children with suspected PA were referred to a diagnostic challenge irrespective of their age, gender, or presentation mitigating this limitation.

Another limitation of this study relates to its aim to be broadly applicable across clinicians from different medical disciplines. While multiple studies have shown that sIgE levels and component-resolved diagnostics such as Ara h 2 are more discriminatory than skin prick testing in predicting peanut allergy outcomes, these tests are not universally available in many clinical settings. Consequently, clinicians often must decide whether a child requires an oral food challenge, and in what clinical setting it should be performed, without access to these more advanced diagnostic tools.

The open label OFC protocol employed in our study, though previously published,^15,20,28 is not a standardized protocol, recommended for clinical studies of oral immunotherapy. As opposed to double blind placebo-controlled food challenges, open challenges may be biased by the family/caregiver’s expectations, causing increased rates of false positive diagnoses or a potentially falsely decreased threshold dose, if standard diagnostic criteria are not strictly followed. However, in this instance, the consistent ability of the protocol to identify both peanut tolerant children²⁹ as well as HTPA and LTPA phenotypes²⁰ has been well established.

Another aspect of this type of study is that one might argue that young patients with HTPA may represent a group on their way to natural resolution, which may explain why there are less HTPAs in the older age groups. However, this argument is not supported by the findings of consistent prevalence of peanut allergy in the pediatric population, regardless of age in Europe⁴² and the adult population in the United States.⁴³

The main limitation of the predictive model is derived from a retrospective discovery population, thus, it is exploratory. Exploratory models should be verified in a larger independent population of patients. Further, longitudinal research is needed to determine how these factors affect a child’s PA threshold over time, and specifically what would be the optimal age for PA diagnostic challenge in different populations.

The study was performed in 1 center with a relatively homogenous population. The question of whether data from 1 study/center can be reproducible in other environments and whether any of the published knowledge can be generalized as a universal take home message, is still a subject of intense debate in the scientific community. To mitigate this, we have presented a series of statements, as a formal application of Meaning Equivalence Reusable Learning Objects (MERLO) statements to define a boundary of meaning (BOM) representing a generalizability of findings in this paper.⁴⁴ The BOM represents what can and what cannot be inferred from the study and enables researchers to design studies that are capable of challenging or reproducing the published results (Table 4).

Table 4.

Generalization of conclusions

Target statement	Meaning equivalence included in BOM	Surface similarity not included in BOM
Statement 1: The gold standard for the diagnosis of PA in children is an oral peanut challenge.	Most children with a suspected PA should be challenged under supervision of a highly trained medical team in an appropriate facility to both confirm the diagnosis and establish a threshold.	All children with suspected PA should be challenged.
Statement 2: The purpose of a diagnostic challenge is also to establish the PA threshold.	Establishing a threshold should inform a patient/family oriented, management and treatment decisions.	If a child’s threshold is high during an oral challenge, it means that this child will not have life threatening reactions to peanuts.
Statement 3: A subgroup of peanut allergic children displays a peanut allergy phenotype with a relative high threshold. The prevalence of this group decreases in older children.	In a subgroup of peanut allergic children, the single highest tolerated dose may be equal or higher than 100 mg. In this subgroup, Oral immunotherapy has been proven feasible and safe solution.
Statement 4: The prevalence of high threshold PA is significantly higher in children younger than 4 years of age.	A diagnostic/threshold finding challenge performed earlier, may enable the identification of this milder food allergy phenotype together with the safe reintroduction of peanut containing foods into child’s diet.	Older children do not have severe PA. If a child develops an allergic reaction at a higher dose, it means they should not worry or carry an EpiPen.
Statement 5: In girls, a prior systemic allergic reaction to peanuts is a risk factor for low PA threshold.	A girl with documented systemic reactions to peanuts is at higher risk for a more severe phenotype of PA with a relative low threshold.	A girl with a previous systemic reaction to peanut must have low threshold PA.

Using Meaning Equivalence Reusable Learning Objects statements, we define a BOM of findings in this paper. BOM represents what can and what cannot be inferred from the study and enables researchers to challenge or reproduce the published results.

Abbreviations: BOM, boundary of meaning; PA, peanut allergy.

Conclusions

In a large group of peanut allergic children under the age of 12, children older than 4 years were more likely to have an LTPA phenotype compared to younger children.

Older age and for girls, reactions other than skin seem to be strong predictors of LTPA phenotype. This information may help Pediatricians and allergists estimate the child’s allergic threshold before deciding where and when to perform a diagnostic challenge. In addition, diagnostics at a younger age may increase our chances of finding a relatively high threshold PA, with safer and easier treatment protocols.

Ethics statement

The study was reviewed and approved by the Sheba Medical Center institutional review board. All research was conducted in accordance with the 1964 Declaration of Helsinki and its later amendments. Informed consent was obtained from all individual participants included in the study. For participants under the age of 16, consent was obtained from a parent or legal guardian. All participants were informed of the study’s purpose, process, and their right to withdraw at any time without consequence. No interventions were done in the research process.

Submission declaration

All authors have reviewed this manuscript and consent to its submission and publication.

All authors agreed to be accountable for all aspects of the work.

Author contribution statement

Omer Bondorevsky designed the data collection instruments, collected data, carried out the initial analyses, authored and critically reviewed and revised the manuscript.

Prof Mona Kidon conceptualized and designed the study, drafted the initial manuscript, and critically reviewed and revised the manuscript.

Prof Nancy Agmon-Levin, Ran Hovav, Dr Yulia Lifshitz-Tunitsky, Dr Irena Offengenden and Dr Ramit Maoz-Segal critically reviewed and revised the manuscript.

Dr Soad Haj Yahia, Dr Ronen Shavit, Dr Diti Machness-Maayan ,Dr Stanley Niznik, Dr Anne Ari, Dr Amarilla Bernadett Mandola, Dr Shirly Frizinsky and Alona Falach-Malik contributed data collection, patient care, follow-up and responsibility.

Ron Kenett conceptualized and designed the study and statistical validation and analysis of important intellectual content.

Disclosure of the use of generative AI and AI-assisted technologies

Generative AI and AI-assisted tools were used solely to improve readability and language during manuscript preparation. These tools were not used to compose the manuscript, generate scientific or medical insights, provide clinical recommendations, draw scientific conclusions, or create or modify figures, images, or artwork. All content was reviewed, edited, and approved by the authors, who take full responsibility for the manuscript.

Funding source

This study was funded by Sheba Medical Center research and innovation foundation and the Sheba Arrow program. The funding sources had no involvement in study design, in the collection, analysis and interpretation of data, in the writing of the report, in the decision to submit the article for publication or such.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.