Skip to main content

High prevalence of sensitization to non-specific lipid transfer protein in adult patients with primary eosinophilic gastrointestinal disorders in Italy: a single center series

Dear editor

Primary eosinophilic gastrointestinal disorders (EGID) are globally increasing in prevalence, having a high disease burden. An increased awareness of these entities has allowed -at least for some of them- an earlier diagnosis. Besides, pathogenesis-driven therapies will probably be available shortly [1, 2].

Type 2 inflammation and allergy have shown to be central to the pathogenesis of eosinophilic esophagitis (EoE) [3], as reflected by the beneficial effect of topical steroids and allergen-free diets, although the understanding of the mechanistic development of this disorder is still elusive. Inhaled and ingested allergens of various sources and allergens administered for immunotherapy, via both the sublingual and oral routes, are recognized as important triggers, acting through cellular-mediated and IgE-mediated mechanisms. The main foods deemed to be relevant in the pathogenesis are cow milk, wheat, egg, soy/legumes, seafood, and nuts. Among allergen classes, PR-10 has been found to be implicated in adults with EoE [4]. Non-specific lipid transfer protein (nsLTP) among food allergens has been given much attention due to the fact that the main studies on EoE have been carried out in the US where the sensitization to this allergen is not as relevant as in the Mediterranean area. Moreover, the pathogenesis of EGID not affecting the esophagus and the role of allergic sensitization is even unclearer [1], although an allergic component has been postulated.

On these bases, in the present study we retrospectively evaluated all consecutive cases of adult-onset primary EGID referred to our allergy outpatient clinic in Northern Italy, from 2020 to 2021, for assessing the sensitization profile to food and other allergens. The diagnosis of primary EGID was made according to internationally-recognized criteria, including tissue eosinophil infiltration reaching the predefined cut-off level for each segment of the gastrointestinal tract, after the exclusion of secondary or systemic causes, such as drug reactions, helminthic infections, and hypereosinophilic syndrome [2].

After a careful history taking, including ongoing therapies for EGID, patients underwent a comprehensive screening of allergic comorbidities (i.e., atopic dermatitis, allergic rhinitis, asthma, and allergies to inhalants, food, drugs and Hymenoptera venom). Skin prick tests for inhalants and food allergens (Lofarma, Italy, and ALK, Denmark) were carried out and total and specific IgE to respiratory and food allergens were determined through ImmunoCAP (Thermofischer, Sweden). Data were analyzed by descriptive statistics and results reported as median and interquartile range or mean and standard deviation. Categorical variables were reported as proportions. The study was approved by the local ethics committee (IRCCS San Matteo Hospital) and all patients provided written informed consent.

In our series of 14 adult patients (median age 41 years, IQR 25–48, M:F ratio 6:1; Table 1), food allergy was the second most frequent allergic comorbidity after allergic rhinitis, while sensitization to nsLTP was the most frequent (50%), followed by PR-10 (21.3%) and profilin (14.2%). Of note, most patients sensitized to peach displayed clinical symptoms after eating the peel of this fruit, ranging from contact dermatitis and oral allergic syndrome to anaphylaxis, and thus avoided eating peaches (Table 2). Besides, most patients reacted to other processed nsLTP containing foods, thus supporting the main clinical significance of the sensitization to this allergen as compared to thermolabile allergens, such as PR-10 and profilin. Additionally, sensitization to nsLTP was also present in patients with non-EoE EGID and associated with symptoms when eating a peach.

Table 1 Main demographic, clinical, and laboratory characteristics of the 14 included patients
Table 2 Sensitization and reactivity to food-containing non-specific lipid transfer protein (LTP) and other food in the seven patients sensitized to Pru p3

To the best of our knowledge, this is the first study describing the sensitization to nsLTP in primary EGID adult patients. In our Italian cohort, the sensitization to nsLTP seems to be particularly relevant, and much greater than the rate of sensitization to this class of allergens in patients evaluated in allergology clinics in the Mediterranean area according to previous studies, which is estimated at about 9–12.3%, depending on the assay of detection [5]. Notably, a previous study from Spain has evaluated the sensitization to nsLTPs in EoE with specific IgE detection, by a combination of “singleplex” and “multiplex” assay or microarray, the latter to detect nPru p3, and estimated it a 20.9% [6]. The higher prevalence of sensitization to the peach nsLTP found in EoE patients in our study, as compared to that detected in the aforementioned one, may be related to the different assay used. More precisely, in our study a quantitative singleplex assay was used to detect rPru p3, whereas a semiquantitative microarray method was adopted to detect nPru p3 [6].

Fruits (mainly in the peel) and vegetables are the main source of nsLTP, and particularly peach with Pru p3, which is considered the primary sensitizer to this class of allergens in the Mediterranean area, though they are not usually part of the list of the commonly implicated allergens [7] and are not included in the “standard” food elimination diets for EoE treatment [3].

This study suggests that local epidemiology could influence the sensitization profile in primary EGID patients and this in turn could portend therapeutical implications as far as allergen avoidance strategies are concerned, at least in EoE. Indeed, the only allergen sources containing nsLTP which are at present considered in food elimination diets for EoE, such as the 6-food elimination diet (6-FED), are nuts and wheat. However, their avoidance may be of reduced or uncertain clinical benefit in EGID patients sensitized to Pru p3, because the quantity of nsLTP in nuts (such as nut and hazelnut) is lower compared to peach [8], and the degree of cross-reactivity of the LTP of wheat, Tri a14, with Pru p3 is much lower [8, 9].

Due to their thermal and proteolytic resistance [5], nsLTPs may play a role as undenatured allergens in primary EGID, particularly with reference to esophagus, stomach, and proximal small bowel, as attested by experimental models of gastric and pancreatic digestion [5]. Their pathogenic role in other portions of the intestinal tract, and hence in eosinophilic colitis, is at present uncertain and needs further investigation. To conclude, peach avoidance should be considered according to the clinical history, in a subset of patients with primary EGID, especially in the Mediterranean area, and possibly combined to other allergen-free diets, according to the clinical characteristics of the patient.

Availability of data and materials

All data pertaining the study have been presented in the manuscript. Additional data can be asked to the corresponding author.

Abbreviations

EoE:

Eosinophilic esophagitis

EGID:

Eosinophilic gastrointestinal disorder

nsLTP:

Non-specific lipid transfer protein

References

  1. Peterson K, Safroneeva E, Schoepfer A. Emerging therapies for eosinophilic gastrointestinal Diseases. J Allergy Clin Immunol Pract. 2021;9:3276–81.

    Article  Google Scholar 

  2. Rossi CM, Lenti MV, Merli S, et al. Primary eosinophilic gastrointestinal disorders and allergy: clinical and therapeutic implications. Clin Transl Allergy. 2022. https://doi.org/10.1002/clt2.12146.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Gonsalves NP, Aceves SS. Diagnosis and treatment of eosinophilic esophagitis. J Allergy Clin Immunol. 2020;145:1–7.

    Article  CAS  Google Scholar 

  4. Van Rhijn BD, van Ree R, Versteeg SA, Vlieg-Boerstra BJ, Sprikkelman AB, Terreehorst I, et al. Birch pollen sensitization with cross-reactivity to food allergens predominates in adults with eosinophilic esophagitis. Allergy. 2013;68:1475–81.

    Article  Google Scholar 

  5. Skypala IJ, Asero R, Barber D, Cecchi L, Diaz Perales A, Hoffmann-Sommergruber K, et al. European academy of allergy; clinical immunology (EAACI) task force: non-specific lipid transfer protein allergy across europe allergen structure and function, cross-reactivity, sensitization, and epidemiology. non-specific lipid-transfer proteins. Clin Transl Allergy. 2021. https://doi.org/10.1002/clt2.12010.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Armentia A, Martín-Armentia S, Martín-Armentia B, Santos-Fernández J, Álvarez R, Madrigal B, Fernández-González D, Gayoso S, Gayoso MJ. Is eosinophilic esophagitis an equivalent of pollen allergic asthma? Analysis of biopsies and therapy guided by component resolved diagnosis. Allergol Immunopathol. 2018;46:181–9.

    Article  CAS  Google Scholar 

  7. Cianferoni A, Shuker M, Brown-Whitehorn T, Hunter H, Venter C, Spergel JM. Food avoidance strategies in eosinophilic oesophagitis. Clin Exp Allergy. 2019;49:269–84.

    Article  Google Scholar 

  8. Pastorello EA, Farioli L, Pravettoni V, Robino AM, Scibilia J, Fortunato D, et al. Lipid transfer protein and vicilin are important walnut allergens in patients not allergic to pollen. J Allergy Clin Immunol. 2004;114:908–14.

    Article  CAS  Google Scholar 

  9. Palacín A, Gómez-Casado C, Rivas LA, Aguirre J, Tordesillas L, Bartra J, et al. Graph based study of allergen cross-reactivity of plant lipid transfer proteins (LTPs) using microarray in a multicenter study. PLoS ONE. 2012;7: e50799.

    Article  Google Scholar 

  10. Pastorello EA, Toscano A, Scibilia G, Stafylaraki C, Rossi CM, Borgonovo L, et al. Clinical features of wheat allergy are significantly different between tri a 14 sensitized patients and tri a 19 sensitized ones. Int Arch Allergy Immunol. 2021;20:1–9.

    Google Scholar 

Download references

Acknowledgements

We thank University of Pavia for supporting our work.

Funding

University of Pavia, PRIN 2017, prof. A Di Sabatino. The funding source had not role in the design, execution, analysis and interpretation of the data.

Author information

Authors and Affiliations

Authors

Contributions

CMR: study concept and design; CMR, GA, SM, AM: clinical management of patients; CMR, MVL, AA, ADS: analysis and interpretation of data, and manuscript preparation. ADS: critical revision for important intellectual contents, supervision. All Authors provided approval of the final submitted version. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Antonio Di Sabatino.

Ethics declarations

Ethics approval and consent to participate

The study was approved by the local ethics committee.

Consent for publication

Informed consent from all patients was obtained.

Competing interests

None to disclose.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Rossi, C.M., Lenti, M.V., Achilli, G. et al. High prevalence of sensitization to non-specific lipid transfer protein in adult patients with primary eosinophilic gastrointestinal disorders in Italy: a single center series. Clin Mol Allergy 20, 8 (2022). https://doi.org/10.1186/s12948-022-00174-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12948-022-00174-z

Keywords

  • Diet
  • Eosinophilic esophagitis
  • Food allergy
  • Non-specific lipid transfer protein
  • Peach