Tree Nut Storage Proteins Better Than Tree Nut Extract for Predicting Allergy

Heidi Splete

August 31, 2021

Childhood sensitization to tree nut storage protein is a stronger predictor of tree nut allergy symptoms than sensitization to tree nut extract, according to data from 2215 young adults.

Dr Jessica Bager

The prevalence of tree nut allergy ranges from 0.05% to 4.9% worldwide. It remains a significant health problem for those affected, write Jessica Bager, MD of the Karolinska Institutet, Stockholm, Sweden, and colleagues.

Molecular allergy diagnostics allow for more accurate prediction of the severity of a reaction to a particular food, and studies of children have shown an association between increasing age and increased polysensitization to different nuts, the researchers note. "The clinically most relevant tree nut allergen molecules are storage proteins, resistant to both heating and gastrointestinal digestion," they write. They note that the relationship between the prevalence of tree nut sensitization and clinical symptoms has not been well studied.

In a study published in Clinical and Experimental Allergy, the researchers reviewed data from 2215 children born in Stockholm, Sweden, between 1994 and 1996. The data came from the Swedish birth cohort BAMSE (Barn/Children Allergi/Allergy Miljö/Milieu Epidemiologi/Epidemiology Stockholm). Questionnaires that elicited information about allergies and certain lifestyle and environmental exposures were completed by parents for the participants at ages 1, 2, 4, 8, 12, and 16 years, and self-reports were gathered at 24 years. Blood samples were taken and lung function tests were administered at 4, 8, 16, and 24 years.

The overall prevalence for tree nut extract sensitization was 21.2%; 7.9% of these individuals were both symptomatic and sensitized. The most common sensitization was to hazelnut (20.6%). The most common phenotype in the 217 participants with tree nut symptoms was to all tree nuts, followed by hazelnut. The prevalence of tree nut sensitization in the 1996 individuals who reported no tree nut allergy symptoms was 14.6%. "Thus, the majority of tree nut–sensitized individuals in the cohort did not report any tree nut symptoms," the researchers note.

Among the participants, 3.5% were found to have sensitization to any of the tree nut storage proteins, and 2.1% of individuals had storage protein sensitization and reported symptoms. The highest prevalence was for hazelnut storage protein (specifically, Cor a 1), at 19.3%, followed by hazelnut storage protein Cor a 9, at 2.8%. For other storage proteins, prevalence was less than 2%. Notably, "the majority of the participants sensitized to hazelnut did not report any symptoms to hazelnut and were sensitized only to Cor a 1, a molecule that is closely related to birch pollen and hence is predicted to induce mild (OAS) to no symptoms," the researchers wrote.

Tree nut allergy at age 24 years was associated with current eczema and current asthma severity. The odds of reporting tree nut allergy at 24 years increased with an increase in polysensitivity to both the tree nut extract and tree nut storage protein allergen molecules, the researchers note. "The increase was steeper for the storage protein allergen molecules Cor a 9, Cor a 14, Jug r 1 and Ana o 3 than for the larger group of tree nut extracts, implying the higher specificity of the allergen molecules compared to the extracts," they write.

Individuals with egg allergy, eczema, or asthma as preschoolers were significantly more likely to experience tree nut symptoms and tree nut storage protein sensitization at age 24, with adjusted odds ratios of 8.50 (egg allergy), 2.53 (eczema), and 5.59 (asthma). In addition, the individuals sensitized to any of the tree nut storage proteins (Cor a 9, Cor a 14, Jug r 1, or Ana o 3) demonstrated more extensive allergic disease than those sensitized to tree nut extract only. Among those sensitized to tree nut storage proteins, prevalence of eczema and severe asthma at age 24 years was significantly higher. In addition, these individuals were more likely to have used an adrenaline autoinjector in the past 12 months, and levels of exhaled nitric oxide were elevated.

The study findings were limited by several factors, including the inability to verify tree nut symptoms with food challenges and the lack of data on symptoms related to specific tree nuts, such as cashews in comparison with walnuts, the researchers note. However, the results were strengthened by the high-quality, longitudinal data and a low dropout rate, they say.

The results indicate that most individuals with extract-based tree nut sensitization but not tree nut allergy are sensitized to birch pollen only, the researchers say. "The study also confirms that sIgE-ab to tree nut storage proteins are the best markers for specific tree nut allergy symptoms and storage protein sensitized individuals also showed several signs of more extensive allergic disease as compared to tree nut extract sensitized individuals," they conclude.

Testing for Allergen Molecules May Prove More Reliable

"This study increases the understanding of tree nut allergy in a general population, followed from infancy up to adulthood," said Bager in an interview with Medscape Medical News. "There is a reported increase in prevalence of tree nut allergy in the past decades, which makes it more important to really understand how common it is, who has a higher risk of developing it, and how this allergy is clinically manifested," she explained.

"We were surprised that the majority of the tree nut–sensitized individuals in our cohort did not report any symptoms at all," said Bager. "We had expected most of the sensitized individuals to at least report mild oral allergy syndrome symptoms related to cross-reactions to birch pollen," she noted.

"Since our study reveals that most extract‐based tree nut–sensitized individuals do not have tree nut allergy, our conclusion is that extract-based IgE-testing for tree nuts without a specific clinical suspicion should not be performed," Bager said. "Also, we confirmed that testing for specific allergen molecules is a more reliable method to find clinically relevant allergy, rather than extract-based IgE-testing," she added.

"Despite its clinical relevance, tree nut allergy is an understudied area," Bager said. "More studies on the development of tree nut allergy over time are needed, especially those that also include oral food challenges with tree nuts," she emphasized.

"We do not know enough about the prevalence of specific tree nut allergies," said Ruchi Gupta, MD, of Northwestern University, Chicago, Illinois, in an interview with Medscape. Gupta was not involved in the Swedish study. "This is an important study to help us better understand many important details about tree nut allergies," she said.

Gupta said he was not surprised but was "intrigued" by the study findings because of their potential to aid in clinical management and understanding of tree nut allergies.

"This study is important to understand that testing is not great for tree nut allergy, as most extract-based tree nut–sensitized individuals do not have tree nut allergy," she explained. "This could lead to many false positives and many people avoiding tree nuts who can actually eat them. More reliable is the sIgE-ab (specific IgE-antibodies) to tree nut storage proteins. This is important when testing for tree nut allergies," she noted.

Much more research is needed on this topic, Gupta emphasized. "We need to understand tree nut allergies in different parts of the world as well as improve our diagnostics, prevention, and treatments for them," she said.

The study was supported by the European Research Council, the Swedish Research Council, the Swedish Heart Lung Foundation, Region Stockholm, the Konsul Th C Bergh's Foundation, the Swedish Society of Medicine, Karolinska Institutet grants, the Hesselman Foundation, Swedish Grand lodge of Freemasonry Foundation Barnahuset, the Swedish Asthma and Allergy Association's Research Foundation, Kerstin Hejdenberg's arresting's scholarship, the Pediatric Research Foundation at Astrid Lindgren Children's Hospital, the Samariten Foundation for Paediatric Research, the Sven Jerring Foundation, the Swedish Association for Allergology, the Magnus Bergwall Foundation, the Swedish Cancer and Allergy Foundation, and the King Gustaf V 80th Birthday Foundation. The researchers have disclosed no relevant financial relationships. Gupta is the author of a recently published book on food allergies, Food Without Fear.

Clin Exp Allergy. Published online August 6, 2021. Full text

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