The recognition of constipation as a possible non-Immunoglobulin E (IgE) mediated allergic condition is challenging because functional constipation (unrelated to food allergies) is a common health problem with a reported worldwide prevalence rate of up to 32.2% in children. However, many studies in children report challenge proven cow’s milk allergy and constipation as a primary symptom, have found that between 28-78% of children improve on a cow’s milk elimination diet. Due to the paucity of data and a focus on IgE mediated allergy, not all food allergy guidelines list constipation as a symptom of food allergy. Yet, it is included in all cow’s milk allergy guidelines available in English language. The Exploring Non- IgE Mediated Allergy(ENIGMA) Task Force (TF) of the European Academy for Allergy and Clinical Immunology (EAACI) considers in this paper constipation in the context of failure of standard treatment and discuss the role of food allergens as culprit in constipation in children. This position paper has used the Delphi approach in reaching consensus on both diagnosis and management, as currently published data is insufficient to support a systematic review.

Background: This study aims to investigate whether immune dysregulation and gut microbiome alteration are exacerbated in atopic dermatitis (AD) with food allergy (ADFA) and potential treatment strategies. Methods: Total 159 children with AD (tAD) were divided into two groups: AD without-food allergy (ADNFA) and with food allergy (ADFA); 100 children without AD were included as control. Eosinophil counts and total serum IgE levels were measured by routine methods, serum food-specific IgE levels by quantitative fluorescence immunoassay, and serum cytokine levels by multi-microsphere flow immunofluorescence. The intestinal microbiota was evaluated in fecal specimens using metagenomic sequencing. A novel ADFA mouse model was generated to evaluate whether probiotic candidates identified from human fecal samples contributed to the improvement in ADFA pathology. Results: The levels of eosinophils, IgE, IL-2, TNF-α, IL-4, IL-5, IL-6, IL-10, IL-17, IL-12P70 and IFN-α were elevated in tAD compared to normal controls. Compared with ADNFA, the levels of eosinophils, IgE and IL-5 were persistently increased, while IFN-γ was decreased, the species of Lactococcus lactis (L. lactis) was reduced in ADFA. Compared with AD, the ADFA model had more severe skin lesions on the back and significantly higher serum OVA-specific IgE, IL-4 and IL-5. Following oral administration of L. lactis ( L. lactis 1.1936+1.3992), skin lesions in ADFA mice was significantly improved. The levels of OVA-specific IgE, IL-4 and IL-5 decreased in a dose-dependent manner. Conclusions: Food allergy aggravates immune dysregulation and gut microbiome dysbiosis in children with AD. L. lactis could be a candidate probiotic for the treatment of ADFA.

Gastro-oesophageal reflux (GOR) and food allergy (FA) are common conditions, especially during the first 12 months of life. When GOR leads to troublesome symptoms, that affect daily functioning of the infant and family, it is referred to GOR disease (GORD). The role of food allergens as a cause of GORD remains controversial. This European Academy of Allergy and Clinical Immunology (EAACI) position paper aims to review the evidence for FA-associated GORD in young children and translate this into clinical practice that guides healthcare professionals through the diagnosis of suspected FA-associated GORD and the medical and dietary management. The Task Force (TF) on non-IgE mediated allergy consists of EAACI experts in paediatric gastroenterology, allergy, dietetics and psychology from Europe, United Kingdom, United States, Turkey and Brazil. Six clinical questions were formulated, amended and approved by the TF to guide this publication. A systematic literature search using PubMed, Cochrane and EMBASE databases (until June 2021) using a predefined inclusion criteria based on the 6 questions was used. The TF also gained access to the database from the European Society of Paediatric Gastroenterology and Hepatology working group, who published guidelines on GORD and ensured that all publications used within that position paper were included. For each of the 6 questions, practice points were formulated, followed by a modified Delphi method consisting of anonymous web-based voting that was repated with modified practice points where required, until at least 80% consensus for each practice point was achieved. This TF position paper shares the process, the discussion and consensus on all practice points on FA-associated GORD.

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 There is substantial interest in allergen-specific immunotherapy in food allergy. We systematically reviewed its efficacy and safety. Methods We searched six bibliographic databases from 1946 to 30 April 2021 for randomised controlled trials about immunotherapy alone or with biologicals in IgE-mediated food allergy confirmed by oral food challenge. We pooled the data using random-effects meta-analysis. Results We included 36 trials with 2,126 participants, mainly children. Oral immunotherapy increased tolerance whilst on therapy for peanut (RR 9.9, 95% CI 4.5. to 21.4, high certainty); cow’s milk (RR 5.7, 1.9 to 16.7, moderate certainty) and hen’s egg allergy (RR 8.9, 4.4 to 18, moderate certainty). The number needed to treat to increase tolerance to a single dose of 300mg or 1000mg peanut protein was 2. In peanut allergy, oral immunotherapy did not increase adverse reactions (RR 1.1, 1.0 to 1.2, low certainty) or severe reactions (RR 1,6, 0.7 to 3.5, low certainty). It may increase adverse reactions in cow’s milk (RR 3.9, 2.1 to 7.5, low certainty) and hen’s egg allergy (RR 7.0, 2.4 to 19.8, moderate certainty), but reactions tended to be mild and gastrointestinal. Epicutaneous immunotherapy increased tolerance whilst on therapy for peanut (RR 2.6, 1.8 to 3.8, moderate certainty). Results were unclear for other allergies and administration routes. Conclusions Oral immunotherapy improves tolerance whilst on therapy and is probably safe in peanut, cow’s milk and hen’s egg allergy. However, our review found little about whether this improves quality of life, is sustained or cost-effective.