INTRODUCTION
Public health recommendations and medical guidelines emphasize the importance of a healthy lifestyle, which is associated with a longer life expectancy, free from serious chronic diseases [1, 2]. The main factors that define an optimal lifestyle include a healthy diet, physical activity, not smoking, limited television viewing, reduced alcohol consumption and a correct body mass index (BMI) [3]. The term healthy diet and lifestyle may be ambiguous, but it is generally thought to be beneficial in every aspect of life. From the perspective of personalized medicine, we should be able to distinguish what is useful and beneficial for each individual and what may be harmful or allergic.
Studies have shown that women are less likely than men to adhere to healthy lifestyle principles, especially when it comes to physical activity, due to many conditions [4].
A healthy lifestyle can reduce the incidence of diabetes, hypertension and hypercholesterolaemia, and reduce the incidence of coronary heart disease and ischaemic and haemorrhagic stroke in women [5–8].
Regular physical activity, recommended as part of a healthy lifestyle, contributes to bone health and is recommended to prevent the development of osteoporosis [9]. A healthy postpartum lifestyle in young women is necessary for optimal maternal health and return to pre-pregnancy weight [10].
However, regular physical activity and a balanced diet rich in vegetables, fruit, cereals and nuts, which are considered indispensable components of a healthy lifestyle, can also have adverse health effects. The combination of these factors can lead to the development of food-induced exercise-induced anaphylaxis [11]. Anaphylaxis is the most severe IgE-mediated systemic hypersensitivity reaction. It requires immediate intervention as it can be fatal if left untreated. Classic symptoms of anaphylaxis include flushing, pruritus, urticaria, shortness of breath, nausea, vomiting, diarrhoea, hypotension, oxygen desaturation and cardiovascular collapse. From the data available in the literature, it appears that the dominant symptoms of anaphylaxis are related to skin and mucous membrane (> 90%), followed by respiratory or cardiovascular symptoms (> 50%). Sometimes, anaphylaxis occurs without skin and mucosal symptoms, making an accurate diagnosis difficult.
Prompt use of intramuscular adrenaline as the first-line treatment is recommended, with adrenaline auto-injectors available to patients [12–14].
Anaphylaxis has a significant impact on the quality of life not only of the individual but also of their family members. Women experience higher levels of anxiety and fear about the consequences of anaphylaxis than men [15].
AIM
The aim of the study was to evaluate the demographic and clinical characteristics of patients suffering from anaphylaxis and the efficacy of the component resolved diagnosis in the search for causative food allergens in combination with exercise.
MATERIAL AND METHODS
PROCEDURE
A single-centre, prospective, observational study was conducted in adults. Participants were recruited from the Outpatient Clinic and the Clinic of Internal Diseases, Allergology and Clinical Immunology of the Medical University of Silesia in Katowice. The only inclusion criterion was at least one episode of anaphylaxis with inconclusive results from a detailed medical history, skin prick tests with inhalant allergens (birch, alder, hazel, grass, rye, Artemisia, ragweed, Plantago, nettle, Cladosporium herbarum, Alternaria alternata, Aspergillus fumigatus, Dermatophagoides pteronyssinus, Dermatophagoides farinae, cat allergens, dog allergens and food allergens (milk, egg yolk, egg white, hazelnut, peanut, walnut, wheat flour, rye flour, barley flour, tomato) (Allergopharma, Reinbeck, Germany) and extended diagnosis of other internal diseases that mimic anaphylaxis (mastocytosis, carcinoid, pheochromocytoma, epilepsy, cardiac arrhythmia).
All patients underwent component-resolved diagnosis (CRD) using an ALEX2 Test (MacroArray Diagnostics, Vienna, Austria). It is performed as a multiplex assay, analysing 295 allergens (117 extracts and 176 molecules) in a single blood sample. This method enables the differentiation of primary sensitisation, co-sensitisation and cross-sensitisation phenomena and may be useful for stratifying the clinical risk of anaphylaxis.
Allergen extracts and molecular components of allergens are coupled to nanoparticles forming the so-called solid phase. Allergen-coated nanoparticles are applied to the substrate layer to form an orderly arrangement of microdots, each containing nanoparticles coated with a different allergen. In the first, specific stage of the test, IgE from the tested serum sample binds specifically to allergens immobilized on nanoparticles. In the next stage, the indicator stage, a colour reaction is induced, the intensity of which is proportional to the amount of IgE antibodies immobilised on the nanoparticles of each dot. ALEX2 test results are reported in kilounits of allergen-specific IgE per litre (kU/l) and categorized into five specific IgE classes in the 0.3–50 kU/l range (quantitative): negative or uncertain (< 0.3 kU/l), low (0.3 to < 1 kU/l), moderate (1 to < 5 kU/l), high (5 to < 15 kU/l), and very high (≥ 15 kU/l). The ALEX2 test’s range of total IgE was 1–2500 kU/l (semiquantitative).
The follow-up analysis was conducted after one year of following the dietary and behavioural recommendations. Recommendations were made on the basis of medical history and the results of component-resolved diagnostic tests. At the follow-up visit, patients were asked about recurrence of anaphylaxis and the need to use an adrenaline autoinjector (AAI).
STATISTICAL ANALYSIS
Descriptive statistics (frequencies, means, SDs) were calculated for the whole sample and for the subgroups with exercise-induced food anaphylaxis (FDEIA) and for food anaphylaxis without exercise (FAWE) subgroups. The one-tailed Student’s t-test was used to compare two groups and the z-test for frequencies. All analyses were performed with a software package (Statistica 13.3 StatSoft, Poland). Statistical significance was set at p < 0.05.
RESULTS
Twenty-eight adults (22 females and 6 males) with a mean age of 39 ±14.6 years were recruited into the study. Twelve (43%) survived more than one episode of anaphylaxis. The mean number of anaphylactic reactions in the entire study group was 1.93 per patient. The maximum number of anaphylactic reactions observed was 5 and involved only 1 (4%) patient. All patients experienced a drop in blood pressure, loss of consciousness, dyspnoea and skin symptoms (urticaria and/or angioedema). In addition, 12 (43%) patients presented with gastrointestinal symptoms. Eleven (39%) patients suffered from other allergic diseases (asthma: n = 4, 14%, seasonal allergic rhinitis: n = 6; 21%, perennial allergic rhinitis: n = 4, 14% and atopic dermatitis: n = 2, 7%). In 14 patients we found specific IgE to highly allergenic components, namely storage proteins (n = 1; 4%); lipid transfer proteins (LTP) (n = 7, 25%), PR-10 (n = 10; 36%), tropomyosins (n = 2; 8%) and ovalbumin (n = 1; 4%). Specific IgE to more than one protein family were found in 6 (21%) patients. A FDEIA (food-dependent exercise-induced anaphylaxis) subgroup of 4 patients was identified from the total group studied: 3 (11%) women and 1 (4%) man who tolerated all foods at rest and developed anaphylaxis after eating the offending food (wheat: Tri a 14 – LTP – 3 patients, hazelnuts: Cor a 8, Cor a 14 – 1 patient) with exercise as a cofactor. In the FDEIA subgroup, three patients had a concomitant allergic disorder – 2 patients (n = 2, 5%) seasonal allergic rhinitis, 1 patient (n = 1, 25%) seasonal allergic rhinitis, asthma and atopic dermatitis. Detailed data of the FDEIA group are shown in Table 1. A FAWE (food anaphylaxis without exercise) subgroup consisted of 24 patients with anaphylaxis in the absence of exercise. In the FDEIA subgroup, the mean number of anaphylactic episodes was 2.75 ±0.96, in the subgroup without anaphylaxis it was 1.66 ±1.09, p = 0.0359 (one-tailed Student’s t-test).
Table 1
Characteristics of patients from food-dependent exercise-induced anaphylaxis (FDEIA) subgroup
Comparison between the frequency of positive results (≥ 0.3 kU/l) of IgE to food components in the FDEIA and FAWE subgroups (Z-test for frequencies) is shown in Table 2. The statistically significant difference between the frequencies of positive concentrations of specific IgE (≥ 0.3 kU/l) between the FDEIA and FAWE subgroups was observed only for LTP and PR-10 proteins. After 1 year of full compliance with dietary and behavioural recommendations, none of our patients had a repeated anaphylaxis and none used an adrenaline autoinjector.
Table 2
Comparison between frequency of positive results (≥ 0.3 kU/l) of IgE against food components in the subgroups with food-dependent exercise-induced anaphylaxis (FDEIA) and with food anaphylaxis without exercise (FAWE) (Z-test for frequencies)
DISCUSSION
Physical activity and good eating habits form the basis of our health. The majority of lifestyle diseases are caused by inappropriate food intake, poor food quality, inappropriate dietary patterns and lack of physical activity. Regular physical activity at all ages reduces the prevalence of many diseases and even mortality [16], and also has social and psychological benefits. Another important condition for a healthy lifestyle is diet. It is well known that foods of plant origin, including nuts and cereals, are rich in protein and have a beneficial effect on the blood lipid profile and inhibit atherosclerotic processes [17]. Fish and seafood are considered ‘healthy foods’ because of their high content of essential fatty acids [18]. It is obvious that the above reasons are the best motivation for individuals of all ages and genders to follow healthy lifestyle rules, but some types of food can cause allergic reactions. The last few decades have brought us many well-documented cases of food allergy. Molecular-based allergy diagnostics has ushered in a new era of accurate allergy diagnosis and has given us a better understanding of the nature of cross-reactivity and the true significance of panallergens. We have also gained knowledge about the possible role of co-factors in food allergy and its most severe form, i.e. anaphylaxis. Food-exercise interactions leading to anaphylaxis are a growing health problem.
Anaphylaxis is the most severe generalised, rapid-onset, potentially life-threatening hypersensitivity reaction. All patients included in our study had survived at least one episode of anaphylaxis of unknown origin. The vast majority of our group were women (78.6%; n = 22). The sex and gender differences observed in our study are confirmed by other authors [19, 20]. Interestingly, women suffer from hay fever at the same rate as men [21]. The female predominance in the food allergy group suggests that there are interactions between chromosomes, environment, microbiome and sex hormones playing a pivotal role in the different clinical and symptomatic manifestations of the same pathology. Female sex hormones, especially oestrogen and progesterone, are thought to increase Th17 cell expression of IL-23R and IL-17A production, a role that is more subtle than simply increasing airway inflammatory processes [22]. Oestrogens increase the expression of histamine receptors of type 2 and 3 and promote the type 2 response, affecting the function of mast cells, dendritic cells and type 2 innate lymphoid cells. The consequence of these responses is a shift to a Th2 response and intense production of inflammatory cytokines such as IL-4, IL-5 and IL-13. Experimental studies in a murine model showed increased levels of serum estradiol, oestrogen receptor, and decreased levels of PPAR-γ in female mice, which caused disturbances in mucosal integrity and intestinal permeability in ovalbumin-sensitised female mice [23]. This study showed that female mice were more susceptible to more severe systemic food allergy reactions than male mice.
Food allergy is reported as an increasing public health problem, so in any case of anaphylaxis, after excluding other non-allergic diseases with similar clinical manifestations, insect venom allergy and drug allergy, the wide field of search for food allergy opens up. The available diagnostic tools are still far from perfection. Prior to enrolment in the study, all patients studied underwent skin prick testing with food and inhalant allergens and the levels of allergen-specific IgE to food and inhalant allergens were analysed. This initial diagnosis was not sufficient to determine the cause of anaphylaxis. Therefore, we decided to extend the diagnostic procedures and use component-resolved diagnostics in the study group. Specific IgE to more than one protein family was found in 6 patients (n = 6, 21%).
FDEIA is a rare reaction (estimated prevalence 0.02%) [24] characterised by the onset of anaphylaxis during or shortly after exercise. The history of patients from the FDEIA subgroup (n = 4; 11%), who had statistically significantly more episodes of anaphylaxis (p = 0.0359), clearly shows that food allergy with the involvement of cofactors (exercise, drugs, alcohol consumption, phase of the menstrual cycle, infection) is much more difficult to diagnose and the search for the offending factor is often time-consuming. The exact mechanism of FDEIA is still poorly understood, but one of the main hypotheses is increased gastrointestinal permeability and increased allergen absorption [25]. Increased plasma osmolality and/or activation of intestinal tissue transglutaminase (tTG) are also likely to be involved [26]. Patients often do not adequately recognise the signs and symptoms of anaphylaxis, and the fact that they can tolerate all types of food makes them even less alert.
From a practical point of view, it is often impossible for patients to recall the detailed circumstances of the anaphylaxis episode. The most common food allergens responsible for exercise-induced food allergy are seafood and wheat, tree nuts, peanuts, but there are clear regional variations [27]. It should be noted that the food allergens of plant origin responsible for the most severe reactions (lipid transfer proteins, storage proteins) are heat resistant and the integrity of their protein structure remains intact after cooking, boiling, freezing, frying and digestion. This information is essential for correct dietary advice. In our study all patients in the FDEIA subgroup tolerated all offending food allergens well at rest, but developed anaphylaxis after ingestion of the offending food (wheat Tri a 14 LTP – 3 patients, hazelnuts – Cor a 8, Cor a 14 – 1 patient) with exercise as a cofactor. Interestingly, in the group with exercise-induced food anaphylaxis (FDEIA), the mean number of anaphylaxis episodes was 2.75 ±0.957, which is statistically significantly more frequent (vs. 1. 66 ±1.09, p = 0.0359) than in the group without exercise involved in the development of anaphylaxis (FAWE).
In our opinion, this discrepancy is due to the fact that it is very difficult to prove the involvement of possible cofactors. There is a risk that some patients in this group have been diagnosed with idiopathic anaphylaxis. There are data showing that even negative diagnostic provocation tests do not exclude the diagnosis [28, 29]. Furthermore, there is still no standardised protocol for provocation testing in suspected food allergy involving cofactors. It was surprising to us that the majority of our FDEIA group were allergic to LTP (lipid transfer proteins), as Tri a 19 ω-5 gliadin is described as the most potent allergen in the FDEIA reaction in Europe. This model of allergy is more characteristic of the Mediterranean area [30]. This may be explained by the high exposure of the population of our region to Artemisia vulgaris (Art v3, which belongs to the LTP family) [31]. Our study clearly shows (Table 2) that the statistically significant difference between the frequencies of positive concentrations of specific IgE (≥ 0.3 kU/l) between the FDEIA and FAWE groups was observed only in relation to LTP and PR-10 proteins. We were not surprised to find that there was no statistically significant difference between these two groups in the case of storage proteins, which, due to their molecular structure, are responsible for the most severe food allergy reactions, regardless of the contribution of cofactors.
One of our patients in the FDEIA group had elevated specific IgE to Cor a 8 and Cor a 14 and regularly ate grains and bread before exercise, but developed two anaphylactic reactions after eating chocolate nougat cream just before running. The first episode was not considered to be nut-induced anaphylaxis as she ate this cream very often but had never eaten it shortly before exercise. A clear sex distribution with a strong predominance of women in the whole group studied was also explained in the FDEIA subgroup, suggesting that hormones (all our patients were hormonally active, premenopausal) play a role not only in the mechanisms of food allergy, but also in more complicated cases with exercise as a cofactor. Interestingly, there are data suggesting that there is no gender difference in the incidence of food anaphylaxis deaths, which affect both sexes equally [32].
The mean age of our group was 39 ±14.6 years. The mean age of the exercise-induced food anaphylaxis group was 27.8 years and was lower than that of the group without exercise as a cofactor. This difference was not statistically significant, but it suggests that young adults are more exposed to severe reactions, and this group is characterised by the highest rate of food allergy deaths [32]. Little is known about this observation and it is currently unexplained.
The weakness of our study was the small number of participants, but this is due to the still low incidence of food anaphylaxis and less frequent FDEIA. Unfortunately, we were not able to analyse the contribution of other cofactors in detail as the patients enrolled in the study mostly remembered the episode, but had difficulties with detailed data on the drugs taken or the menstrual cycle phase. None of the patients had an infection during the development of anaphylaxis. Our study clearly shows that female sex is a predisposing factor not only for food anaphylaxis but also for exercise-induced food anaphylaxis as the vast majority of our two study groups were female.
CONCLUSIONS
Component-resolved diagnosis is an effective tool in reducing the rate of idiopathic anaphylactic reactions, allowing the precise identification of allergens responsible for food allergy in cases of multifactorial origin, as well as extending and optimising diagnostic possibilities. Early and correct diagnosis prevents recurrent anaphylaxis. The search for critical foods is crucial as the mainstay of treatment for food allergy and its specific form, FDEIA, is avoidance of the offending food for at least 2 hours before exercise [33]. A healthy lifestyle can be dangerous for some people, especially women, and any allergic reaction should be taken seriously and appropriate diagnostic procedures undertaken as soon as possible. We have concluded that LTP is the most offending protein in patients with exercise as a cofactor of anaphylaxis in our region. Women are much more at risk, so the combination of so-called healthy food and exercise can be life-threatening. FDEIA patients have a higher risk of recurrent anaphylaxis. Maintaining an appropriate time interval between eating the offending food and exercising may protect FDEIA patients from anaphylaxis.
We are fully aware of the fact that the statistical analysis is only informative. Due to the small sample size, it is difficult to draw any binding general conclusions. Nevertheless, our 1-year follow-up demonstrated the importance of dietary and behavioural education for patients, especially women, to promote healthy lifestyles and prevent future recurrence of anaphylaxis.
