AbstractNonspecific lipid transfer proteins (NsLTP) of plants are the major frequent cause of food allergens, especially in the Mediterranean region. A large number of foods are allergenically defined and the list is still growing. Exercise-induced anaphylaxis is a potentially fatal clinical outcome in which anaphylaxis is triggered by mild to heavy exercise. When food is identified as a co-factor, the condition is referred as food-dependent exercise-induced anaphylaxis (FDEIA).We describe the case of women who developed three separate episodes of urticaria and anaphylaxis during exercise after consuming an apple, with evidence that nonspecific lipid transfer proteins may have been responsible for these reactions. Lipid transfer protein allergy should be considered when anaphylaxis is inconsistent, such as in patients who can tolerate fruit on resting.INTRODUCTIONNonspecific lipid transfer proteins (NsLTP) of plants are the major frequent cause of food allergens, especially in the Mediterranean region. In European populations, apples, peaches, and kiwis are most commonly allergic fruits. Carrots, tomatoes, and celery are the most common causes of allergy to vegetables. A large number of foods are allergenically defined and the list is still growing. NsLTP are small, basic proteins found in plants and some fungi and that panallergens have mainly been considered clinically relevant in patients, who are often considered to have lipid transfer protein syndrome mainly due to the peach LTP (Pru p 3), apple LTP (Mal d 3) and hazelnut LTP (Cor a 8). Four disulfide bonds in the protein play a protective role against destruction by heat and in the gastrointestinal tract and provide endurance.Exercise-induced anaphylaxis is a potentially fatal clinical outcome in which anaphylaxis is triggered by mild to heavy exercise. When food is identified as a co-factor, the diagnose is referred as food-dependent exercise-induced anaphylaxis (FDEIA). The pathogenic mechanism of FDEIA is still unknown. One interesting theory suggests that changes in mucosal permeability induced by cofactors such as NSAIDs, alcohol intake exercise or a combination of both can enhance allergen absorption, through the mucous membranes, resulting in a more exposure of mast cells to allergens7. Other mechanisms proposed to explain this syndrome are increased skeletal muscle and splanchnic blood flow and increased gastrin-induced mediator release in the postprandial phase.We describe the case of women who developed three separate episodes of urticaria and anaphylaxis during exercise after consuming an apple, with evidence that nonspecific lipid transfer proteins may have been responsible for these reactions. There are few published case reports in Pubmed describing exercise-induced allergic reactions to apple.CASE REPORTA 40-year-old female presented to the Emergency Department with generalized urticaria, headfirst, sweating, facial angioedema of the lips and tongue. She had no significant past medical history (except depression) or allergies and was taking only Venlafaxine as a regular medication for 6 years. Her serum total IgE was normal (67.1 kU/L). However, she would have started a new job at this time, which was certainly exciting. She presented to the Emergency Department a second time after developing head tingling with dizziness, swelling of the face and sweating during jogging in the forest. Also, this phase was exciting. The previous evening, the patient drank beer and ate goulash with beef. The next morning she had an apple. Her symptoms developed approximately 120 minutes after consuming apple during exercise. She presented to the Emergency Department a third time after developing generalized urticaria with slight Quincke’s edema. After a long sleep, the patient had gotten up, had drunk coffee and eat breakfast. After that, she went running and developed the allergic reaction. She eats apples almost every day.Skin prick testing revealed sensitization to all components of Apple (Green and Red). She was also sensitized to Walnut, Celery, Anice, Kiwi and Chamomile, but did not have symptoms of allergic rhinitis or oral allergy syndrome (Table 1.). The patient has eaten an apple in a resting-state before the prick test and tolerated well. The patient went on to have specific IgE testing to individual allergens molecules using Immunocap (Immuno Solid-phase Allergen Chip, Phadia, Uppsala, Sweden). This revealed low to moderate sensitization to nonspecific LTPs from Apple (rMal d 3), peach (Pru p 3), peanut (Ara h 9), hazelnut (Cor a 8) and wheat (Tria a 14) (Table 2.). Other nonspecific LTPs including wheat (Tri a 14) and olive (Ole e 7) were tested, with negative results. She was not sensitized to any of the storage proteins, PR-10 proteins or profilins included allergens.A diagnosis of allergy to apple and Lipid Transfer Protein Sensitization was made. Given the skin prick tests and specific IgE results, cross-reactive, nonspecific LTPs were considered to be the likely allergens.The patient was advised to avoiding the consumption of fruits of the Rosacea family.The thermal treatment of food is not an adequate preventive measure due to the high stability of the allergens. We also recommend watching the consumption of food in connection with physical exertion and alcohol consumption, as well as taking NSAID. She was prescribed an adrenaline auto-injector, oral cetirizine, and prednisolone and provided with an anaphylaxis action plan.DISCUSSIONFDEIA is a rare disorder in which urticaria or anaphylaxis occurs after physical activity. The symptoms may include nausea, pruritus, hives, flushing, wheezing, and gastrointestinal symptoms including diarrhea and abdominal cramping. The symptoms may vary from mild to severe life-threatening anaphylactic reaction if the physical activity continues, including facial angioedema, laryngeal edema, hypotension, and, ultimately, cardiovascular collapse. Quitting of physical activity usually causes immediate improvement of symptoms. Co-factors such as foods, alcohol intake, temperature, drugs (eg, nonsteroidal anti-inflammatory drugs or aspirin), humidity, seasonal changes, lack of sleep, familial background, and phase of the menstrual cycle are important in the precipitation of attacks.In our case, Apple-dependent exercise-induced anaphylaxis was demonstrated. This patient had an IgE-mediated sensitization to apple, peach, peanut, hazelnut and wheat NsLTPs; however, there is no clinical relevance and allergic reactions except apple. The patient eats apples almost every day, and has eaten an apple in a resting-state before the prick test and tolerated well without any symptoms. The Apple-dependent, NsLTP-mediated, immediate-hypersensitivity-type reaction would be subthreshold on resting-status, but, because of the influence of exercise on mast-cell releasability, it becomes clinically overt. We think in our case as cofactors (exercise and alcohol) played an important role in the development of urticaria and anaphylaxis. However, environmental factors such as cold temperature and other nonimmunologic factors may have contributed to mediator release. Published Study in 2012 by Pascal et al., found that there was no correlation between LTP-specific IgE levels and the severity of allergic reaction. In their research, the main suspected foods reported by LTP allergic patients were peach, lettuce, walnut, hazelnut, peanut and green bean. In 40% of patients, cofactors were necessary to induce symptoms. Some cases in the Literature developed in the following period a allergic symptoms only by an intake of foods containing heated apple without exercise. ConclusionThe described patient suffers from a life-threatening food allergy. Apple allergy, which is very rare in Europe, was confirmed by specific IgE and prick testing. The patient was advised to avoiding the consumption of fruits of the Rosacea family and watching the consumption of food in connection with physical exertion and alcohol consumption. The prognosis and long-term follow-up of FDEIA has not been well described. However, our knowledge of LTP sensitization is slowly increasing and sublingual immunotherapy is currently available in some countries, such as Spain with the aim to increase the provocation threshold of severely allergic patients.