Allergy tests for the diagnosis of culprit allergens in eosinophilic esophagitis: A systematic review. To the Editor,Eosinophilic esophagitis (EoE) is a chronic inflammatory disease with esophageal dysfunction and marked eosinophil-predominant infiltration of the esophagus and a clinicopathologic diagnosis (1,2). Dietary interventions have confirmed the etiological role of food allergens and their combination with topical glucocorticoids is the standard treatment of EoE (1). Three different dietary approaches are usually practiced; an elemental formula diet, “empiric” food eliminations diets (e.g. the 6-FED) and diets based on multimodality allergy testing(1). Skin prick tests (SPT), serum specific (s)IgE, atopy patch tests (APT), but also serum specific (s)IgG4 have been used as allergy diagnostic tools for such diets(1).Elimination diets can serve as the first step to identify the culprit antigens in EoE; after symptoms’ remission foods can be sequentially reintroduced and food triggers can be defined clinicopathologically (1,2). In the present systematic review, the outcomes of a food-reintroduction diagnostic approach served as comparator to the results of allergy tests serving as diagnostic tools of the EoE food triggers. Our aim was to review the literature on the diagnostic value of allergy tests used in everyday practice.The detailed methods of the present systematic review are reported in the published protocol (3). The evidence search and selection process are presented in Figure 1. Fourteen studies fulfilling the quality assessment criteria were included in the review; their characteristics are summarized in Table 1 (references in the supplement). The Risk-of-Bias ratings are shown in Table S1. The studies were assessing complete data of 453 EoE patients. Biopsies were used for re-evaluation in all studies, and as the main criterion of EoE remission in most of the studies.The positive predictive value (PPV) of allergy tests is reported in Table S2. It is deduced by the percentage of allergy tests that have correctly predicted the culprit allergen out of the total number of allergy tests resulting positive. The percentage of patients who responded to treatment was calculated by dividing the number of patients who presented EoE remission after food elimination diets based on positive allergy tests, out of the total number of patients following such diets. Reviewed studies have offered either, or both, of these data.Studies have followed a protocol with a single allergy test, or with the combination of two (SPT+sIgE, SPT+APT), or three. Most single-allergy-test studies have reported PPVs lower than 50%. PPV was better for combined tests; PPV of SPT+APT combination was 67.1%, with 65-88.3% of patients presenting symptom amelioration after following a relevant elimination diet. A study combining SPT+APT+sIgE reported symptoms’ improvement in 67% of the patients.The effectiveness of amino-acid-based elemental diet is approximately 90%, while 6-FED shows a 72.1% effectiveness (4) . The empiric elimination of cow’s milk or dairies is a slightly less-effective strategy. According to our review’s outcomes, allergy-test-driven elimination diets have a maximum efficacy of 66-88.3%, so following them is not superior to empirical diets. The decision to follow any of these options, or alternatively a 4-FED or 2-FED, is individualized according to what best fits to patient’s lifestyle.Esophageal prick testing (EPT) performed with food extracts directly on the esophageal lining is a new diagnostic method offering the advantage to examine the local esophageal response to dietary triggers, that might be completely different to IgE-detection with the usual allergy tests (5). Ex vivo food antigen stimulation method, using stimulation of esophageal biopsies with food extracts is another promising alternative (6).Concluding, although the use of food specific IgE-detection and the performance of APT do not seem useful for selecting which food should be eliminated, it is a fact that personalized elimination of different foods in each patient is highly advised.

Background: Guidelines for management of patients with allergic conditions are available, but the added value of nurses, allied health care professionals (AHPs) and general practitioners (GPs), in the management of allergic disease has not been fully clarified. The European Academy of Allergy and Clinical Immunology (EAACI) appointed a task force to explore this issue. Aim: To investigate the added value of nurses, AHPs and GPs in management of allergic diseases, in an integrated model of care. Methods: A search was made of peer-reviewed literature published between 2010 and December 2020 (Cochrane Library, PubMed, and CINAHL) on the involvement of the various specific health care providers (HCPs) in the management of allergic diseases. Results: Facilitative models of care for patients with allergies can be achieved if HCP collaborate in the diagnosis and management. Working in multidisciplinary teams (MDT) can increase patients’ understanding of the disease, adherence to treatment, self-care capabilities, and ultimately improve quality of life. The MDT competencies and procedures can be improved and enhanced in a climate of mutual respect and shared values, and with inclusion of patients in the planning of care. Patient-centered communication among HCPs and emphasis on the added value of each profession can create an effective integrated model of care for patients with allergic diseases. Conclusion: Nurses, AHPs, and GPs, both individually and in collaboration, can contribute to the improvement of the management of patients with allergic disease. The interaction between the HCPs and the patients themselves can ensure maximum support for people with allergies.

Speculations on the connection of α-Gal allergy to Coronary Artery Disease.Pitsios Constantinos1,2, Dimitriou Anastasia2, Vassilopoulou Emilia3.1. Medical School, University of Cyprus, Nicosia, Cyprus2. Allergy Private Practice Network, Athens, Greece3. International Hellenic University, Department of Nutritional Sciences and Dietetics, Thessaloniki, GreeceAuthors have no conflict of interest to declareCorresponding author :Constantinos PitsiosMedical School, University of CyprusPanepistimiou 1, 2109 AglantziaNicosia, CyprusTel; +30 6974348638Email; [email protected]:Authors have no conflict of interestPitsios C, was the main author and clinical supervisor.Dimitriou A; [email protected] , was the clinician of the cases reported and reviewed the paper.Vassilopoulou E; [email protected] , has contributed as author to the diet suggestions and as reviewer.Text word count; 866To the Editor,In 2009, we reported a case-report of generalized allergic reaction during the performance of allergy tests to red meat products [1]. It was the case of a 59-year-old male, with a 10-year-long anamnesis of several anaphylactic episodes (urticaria-angioedema and asthma attacks) 2 hours after the consumption of mammalian meats. He was tolerating dairies and avian meat. His medical history was including seborrheic dermatitis, gastric ulcer, coronary artery disease (CAD) and symptoms of exercise-induced bronchospasm [1]. Since all reactions were reported to happen after the ingestion of well-cooked meat we concluded that the culprit allergen was heat-stabile, without being able to specify it.Two more cases of allergy to red meat, males, 68-year-old (yo) and 52yo respectively, were referred to us last year, both confirmed with skin prick tests. The 68yo patient reported tolerating small quantities of cold cuts. They both had anamnesis of CAD. At that time, CAD had been recently described as comorbidity to mammalian meat allergy and α-Gal allergen was inculpated [2]. Patients’ sensitization to α-Gal was later confirmed with specific IgE test (sIgE) against this allergen. We tried to contact the first case of meat allergy in order to prescribe the same test, but unfortunately we were informed that he had passed away due to myocardial infarction.In the 2010s, tick bites were recognized as the main “sensitizer” to α-Gal, causing cross-allergic reactions to mammalian meat [3]. Our patients are located in the rural area of the island of Euboea, Greece, engaged in outdoor activities and tick bites seem the most reasonable explanation of their sensitization. Three genera of IxodidaeFamily are the main ticks parasitizing humans in Greece;Rhipicephalus , Ixodes and Hyalomma [4]. Although not all tick bites cause IgE-sensitization to α-Gal, the above mentioned do [3, 5].Alpha-Gal has been recognized as the culprit allergen for severe and fatal anaphylaxis to the mAb cetuximab, while case-reports have been published also for drugs like heparin, vaccines and anti-venom [3]. Although parenteral administration can cause immediate allergy, food allergy due to α-Gal is commonly expressed with a delay in symptom onset and is dose-unrelated, features also noticed in our cases [6]. The pathophysiological mechanism differs when α-Gal is administeredvia the parenteral route than intake via the gastrointestinal system. α-Gal parenteral administration (i.g injection of cetuximab) triggers an acute IgE-mediated reaction, while a delayed allergy is observed when it enters through the digestive system.The pathophysiological background of the ‘digestive’ delay has been elucidated by an in vitro study, analyzing the transport of α-Gal through the intestinal epithelium [7]. It was found that only the lipid-bound α-Gal is able to cross the intestinal epithelium, while protein-bound α-Gal was not detected in the basolateral media of enterocytes [7]. Alpha-Gal contained in glycolipids is digested, absorbed and enters the blood stream by the thoracic duct after hours, explaining the late-onset of allergic symptoms [3, 7]. Furthermore in α-Gal allergic patients, dairies may cause delayed onset of gastrointestinal symptoms over 2 hours [8].There is a strong epidemiological connection between CAD and “α-Gal syndrome”, a term used to describe different clinical allergies due to this allergen [9]. This relationship has been confirmed by a study using intravascular ultrasound imaging in subjects undergoing cardiac catheterization [2]. A mechanistic model has been proposed to clarify this connection, describing the delivery of α-Gal epitopes -connected to lipid particles- to mast cells within atherosclerotic plaques [9].Due to the intraindividual tolerability to the culprit allergen, patients with α-Gal allergy exclude or reduce mammalian meat from their diet, but often consume tolerable quantities of products containing α-Gal. This can induce local mast cell degranulation leading to chronic mast cell activation and pro-inflammatory events contributing to the chronic inflammatory procedures of CAD pathogenesis [9]. Our objection is that if mast cells play a pivotal role to this inflammation, red meat ingestion would cause a massive mast cell degranulation in atherosclerotic plaques so angina would be a common symptom of the delayed-type allergic reactions to red meat, resembling to Kounis Syndrome.The hypothesis that small tolerable quantities cause the ongoing coronary inflammation via local mast cell degranulation is an emerging concern for us. Based on the knowledge that participation of chylomicrons and inflammation are common parameters of CAD and α-Gal sensitization, their exact immunological connection remains to be clarified. Can α-Gal molecules generate the inflammation, as plaque’s component, maybe through a process of immune-complexes? Are they inducing transdifferentiation of vascular smooth muscle cells to macrophages or local proliferation of monocytes and formation of foam cells?Immunological pathophysiology of CAD is still unclear, while on the other hand epidemiological data seem definite and alarming. In order to avoid worsening of CAD by accumulation of lipoproteins containing α-Gal, we recommend the strict avoidance of all α-gal containing food, regardless the tolerance-level of each patient. Thus, dairies, gelatin and mammalian meat products should be avoided.Should a patient with CAD be tested for α-Gal? Screening in vivoand in vitro tests have been established as prevention in the field of Cardiology. The impact of α-Gal should further be investigated and compared between areas with high prevalence of sensitization due to tick bites and tick bites free. Metabolomic profiling of such patients will clarify the future of α-Gal allergy.