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SHORT COMMUNICATION

Evolution of laboratory parameters in patients with lipid transfer protein syndrome after 3 years of immunotherapy

Alejandra González Péreza, Ana Isabel Escudero Pastora, Rosa Alba Sola Martínezb, Antonio Carbonell Martíneza*

aAllergology Section, General Hospital, Reina Sofía University, Murcia, Spain

bDepartamento de Bioquimica y Biología Molecular B e Inmunologia, Universidad de Murcia

Abstract

Lipid transfer protein (LTP) syndrome is an increasingly prevailing disease, especially in the young population, with severely affected quality of life. Since 2013, a specific treatment, called sublingual immunotherapy (SLIT), with peach extract (SLIT-peach®) has been used, but with no long-term effectiveness studies. The main objective of the present study was to assess the long-term effectiveness of SLIT-peach® and to relate the clinical evolution of patients. This was an ambispective study conducted for 3 years. A total of 25 patients with LTP syndrome were selected and treated with SLIT-peach®. They underwent a provocation test in the first year with reintroduced foods that had produced symptoms in the past. Analytical determination of specific immunoglobulin E (IgE) and immunoglobulin G4 (IgG4) to peach (Pru p 3) was performed at the beginning of treatment, at the first year of initiation, and at the end of treatment. These data were compared with the control group comprising 14 patients with LTP syndrome without treatment. A statistically significant decrease in specific IgE to Pru p 3 at the end of the treatment and an increase in specific IgG4 to Pru p 3 1 year after treatment initiation were observed in the active group in relation to tolerance to foods with LTPs. These results indicate that food tolerance begins after the first year and is maintained after the end of 3 years of treatment. In conclusion, treatment with SLIT-peach® for 3 years is effective for patients with LTP syndrome, preventing the evolution of the disease, allowing patients to restart a diet with plant foods, and improving their quality of life.

Key words: allergic reaction, anaphylaxis, food tolerance, immune tolerance, immunotherapy, lipid transfer proteins, LTP syndrome, Pru p 3

*Corresponding author: Antonio Carbonell Martínez, Hospital General, Universitario Reina Sofía Murcia, c/Intendente Jorge Palacios nº 1, 30003 Murcia, Spain. Email address: [email protected]

Received 2 November 2022; Accepted 16 January 2023; Available online 1 May 2023

DOI: 10.15586/aei.v51i3.790

Copyright: Pérez, AG et al.
License: This open access article is licensed under Creative Commons Attribution 4.0 International (CC BY 4.0). http://creativecommons.org/licenses/by/4.0/

Introduction

Lipid transfer protein syndrome is an increasingly prevailing disease that primarily affects the young population, resulting in diminished quality of life because of high rate of anaphylactic reactions.

Lipid transfer proteins are part of the super family of proteins called prolamines. Owing to their function, LTPs are considered as proteins related to pathogenesis (PR-14 proteins). They were originally called LTPs for their ability to transfer phospholipids and other groups of fatty acids through cell membranes. LTPs are a highly conserved group of small proteins with a very stable structure, which provides them great resistance to extreme temperatures and pH changes and, therefore, great allergenicity. They are capable of crossing gastrointestinal (GI) immune system, allowing sensitization and inducing specific immunoglobulin E (IgE).1 This structural stability provides LTPs resistance against digestive enzymatic processes, but on a second exposure to allergen leads to severe food allergy symptoms.

In recent decades, progress has been made in the identification and characterization of hundreds of allergenic components present in various foods of animal and plant origin.2 LTPs, although present in plant foods, such as nuts, legumes, vegetables, cereals, and even pollens, are important allergens of fruits of the genus Prunus, belonging to the rose family Rosaceae, such as peach (Pru p 3), apple (Mal d 3), apricot (Pruar 3), cherry (Pru av 3), and plum (Pru d 3), among others. Presently, 177 LTPs and isoforms are described in Allergome (http://allergome.org).

Despite the fact that LTPs are present in all plant foods, some patients develop clinical reactivity to one food or a food group, while others expand their clinical recognition profile to a wide variety of taxonomically different foods because of the high cross-reactivity of these allergens, calling this condition “LTP syndrome.”3 This characteristic significantly affects patients’ quality of life.

The treatment of choice for LTP syndrome is to avoid symptom-causing foods as well as management of acute and long-term reactions. Since 2013, a sublingual immunotherapy (SLIT) with peach extract quantified in Pru p 3, “SLIT-peach®” (50-μg Pru p 3/mL) (ALK-Abelló A/S, Horsholm, Denmark), has been utilized. To date, a few studies have been published on its efficacy and safety but with no promising results.4

The objective of the present study was to evaluate the evolution of parameters in vitro in patients with anaphylaxis because of LTP syndrome after treated with SLIT-peach®. Further, the study compared the results with the control group that had not received specific immunotherapy.

Material and Methods

Study population

Twenty-five patients, aged more than 18 years, were included in the active group. All these patients were diagnosed with anaphylaxis because of LTP syndrome, and were treated with SLIT-peach® for 3 years. These patients presented adequate symptom control and were no longer excluding LTP-containing foods from their diet.4 The control group included 14 patients with the same clinical characteristics but had not started SLIT-peach® treatment because of personal reasons, but the patients were excluding the foods to which they were allergic. All foods that induced symptoms and were related to LTP and those causing species–species allergies (not LTP) were excluded. However, intake of foods related to LTP was slowly increased in patients receiving active treatment.

All patients provided written informed consent to participate in the study. The study was approved by the Clinical Research Ethics Committee of the Hospital General Universitario Reina Sofía (Murcia, Spain).

Analytical parameters

All patients in the study were tested for Pru p 3-specific immunoglobulin E (IgE) and immunoglobulin G4 (IgG4) at the beginning and end of the study. Patients in the active group had these values analyzed after first year of the treatment, prior to performing the oral provocation test.

Controlled exposure test

All patients in the active group underwent a single-blind oral challenge test after 1 year of the treatment with SLIT-peach® to assess the effectiveness of immunotherapy.

Statistical analysis

Statistical analysis was carried out in R programming language (version 4.0.5). The normality of continuous variables was evaluated using the Shapiro–Wilks test. In case of independent samples, the comparison between groups of continuous variables was performed using the Student’s t-test (normal data distribution) or the Mann–Whitney U test (non-normal data distribution). In case of dependent samples, the comparison between groups of continuous variables was carried out using the paired t-test (normal data distribution) or the Wilcoxon Signed Rank test (non-normal data distribution). For all statistical analyses, P < 0.05 was considered as statistically significant. The ggplot2 graphics package was used for elaboration of graphs (boxes and whisker graphs) worked in this study.

Results

The active group comprised nine males and 16 females, with an age range of 20–61 years and a mean age of 36.9 years. The control group comprised four males and 10 females with an age range of 18–65 years and a mean age of 38.7 years.

Analysis of analytical parameters after 3 years of treatment revealed a statistically significant decrease in IgE specific to Pru p 3 in the treatment group, compared to the control group (Figure 1). In addition, a statistically significant increase in IgG4 specific to Pru p 3 was observed in both groups (Figure 2). However, comparison of differences between both groups revealed a greater increase in IgG4 specific to Pru p 3, although not statistically significant, in the active group. Moreover, analysis of the data after the first year revealed that increase in IgG4 specific to Pru p 3 started after the first year of the treatment and was maintained until the end of the treatment (Figure 2).

Figure 1 IgE pru p3 levels in patients (A) with and (B) without treatment at indicated periods, and changes in IgE pru p3 in patients (C) with and without treatment. Individual patients are represented by data points. Boxes represent interquartile range (Q1, Q3), and horizontal lines inside the boxes are the medians. P-values were calculated using paired t-test, Wilcoxon Signed Rank test, Student’s t-test, or the Mann–Whitney U test.

Figure 2 IgG4 pru p 3 levels in patients (A, B, and C) with treatment, and (D) without treatment at indicated periods. (E) Changes in IgG4 pru p3 in patients with and without treatment. Individual patients are represented by data points. Boxes represent interquartile range (Q1, Q3), and horizontal lines inside the boxes are the medians. P-values were calculated using the paired t-test, Wilcoxon Signed Rank test, Student’s t-test, or the Mann–Whitney U test.

Discussion

The main objective of this study was to analyze the long-term effectiveness of SLIT peach® treatment that LTP syndrome patients had received for 3 years. For this, an exhaustive follow-up of patients was carried out by determining analytical parameters.

The results obtained after the analysis of these parameters were consistent with the results of previous studies.4 Increase in specific IgG4–IgE ratio to Pru p 3 was observed after 3 years of treatment.

Patients in the active group underwent an oral challenge test after the first year of treatment. Prior to performing the provocation test, the patients were asked to again determine both IgE specific and IgG4 specific to Pru p 3, observing that significant increase in IgG4 occurred after the first year of treatment. However, decrease in IgE specific to Pru p 3 values was not statistically significant up to 3 years.

It is important to consider these data when scheduling a provocation test in patients, because this test can present a real risk if the treatment has not been effective enough up to that point. Hence, in order to assess appropriate moment to perform provocation test, an increase in IgG4 specific to Pru p 3, which acts as a protective factor, must be taken into account.5

All patients in the active group tolerated the controlled exposure test without any adverse effect. This demonstrated that increase in IgG4 acquired a protective role against allergic reactions, and period of 1 year after start of the treatment was proposed as an ideal time for carrying out a provocation test. This was a safe and competent test to provide tranquility and comfort to patients regarding their treatment, and they were able to restart a diet of plant foods that had previously caused allergic symptoms. The test also established tolerance to food after finishing the treatment for LTP syndrome, demonstrating the long-term effectiveness of SLIT-peach®.

Conclusion

Treatment with SLIT-peach® for 3 years is effective for LTP syndrome patients, preventing evolution of the disease and improving their quality of life. Protective IgG4 increased after the first year of treatment, thus allowing to perform a provocation test, with the subsequent introduction of plant foods.

REFERENCES

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2. Chapman M. Allergen nomenclature. In: Lockey RF BS, editors. Allergens and allergen immunotherapy. Marcel Dekker Inc. New York, NY; 1999. pp. 73–83.

3. Asero R, Mistrello G, Roncarolo D, Amato S, Caldironi G, Barocci F, et al. Immunological cross-reactivity between lipid transfer proteins from botanically unrelated plant-derived foods: A clinical study. Allergy. 2002 Oct;57(10):900–6. 10.1034/j.1398-9995.2002.t01-1-23541.x

4. González Pérez A, Carbonell Martínez A, Escudero Pastor AI, Navarro Garrido C, Miralles López JC. Pru p 3 oral immunotherapy efficacy, induced immunological changes and quality of life improvement in patients with LTP syndrome. Clin Transl Allergy. 2020 Jun 8;10(1): 10.1186/s13601-020-00325-y

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