Improving the safety of oral immunotherapy for food allergy

Food allergy is a major public health problem in children, impacting upon the affected individual, their families and others charged with their care, for example educational establishments, and the food industry. In contrast to most other paediatric diseases, there is no established cure: current management is based upon dietary avoidance and the provision of rescue medication in the event of accidental reactions, which are common. This strategy has significant limitations and impacts adversely on health‐related quality of life. In the last decade, research into disease‐modifying treatments for food allergy has emerged, predominantly for peanut, egg and cow's milk. Most studies have used the oral route (oral immunotherapy, OIT), in which increasing amounts of allergen are given over weeks–months. OIT has proven effective to induce immune modulation and ‘desensitization’ – that is, an increase in the amount of food allergen that can be consumed, so long as regular (typically daily) doses are continued. However, its ability to induce permanent tolerance once ongoing exposure has stopped seems limited. Additionally, the short‐ and long‐term safety of OIT is often poorly reported, raising concerns about its implementation in routine practice. Most patients experience allergic reactions and, although generally mild, severe reactions have occurred. Long‐term adherence is unclear, which rises concerns given the low rates of long‐term tolerance induction. Current research focuses on improving current limitations, especially safety. Strategies include alternative routes (sublingual, epicutaneous), modified hypoallergenic products and adjuvants (anti‐IgE, pre‐/probiotics). Biomarkers of safe/successful OIT are also under investigation.     

Oral desensitization in children with immunoglobulin E-mediated cow's milk allergy – follow-up at 4 yr and 8 months

Until now, the basic treatment for food allergy has been to avoid the offending item. This approach is difficult in the case of common foods and in the case where there is a risk of severe reaction after consuming the offending food, even inadvertently. This is the follow‐up of a previous study aimed at desensitizing 21 children with immunoglobulin E (IgE)‐mediated cow’s milk (CM) allergy. This protocol was totally or partially successful in 85% of cases, but failed in the remaining 15%. Our aims were to study the long‐term effectiveness and safety of oral CM desensitization, and the prognostic value of Skin Prick Test (SPT) and specific serum CM IgE. The 21 children were called back (one dropped out). The allergic history and other information on CM intake over the last 4–5 yr were recorded. Children underwent SPT, and end‐point SPT, with casein and α‐lactoalbumin. Specific CM IgE was also measured. At follow‐up, 14/20 children totally (n = 13, 65%) or partially (n = 1, 5%) tolerated CM. None of the recalled children reported use of emergency care. SPT positivity to casein and/or α‐lactoalbumin decreased significantly (p < 0.01), and all the negative SPT referred to the tolerant children. Cutaneous sensitivity to both casein and α‐lactoalbumin (end‐point SPT) significantly decreased after the 6‐month desensitization period of the previous study (p < 0.001), but did not decrease significantly at follow‐up. A significant reduction of serum‐specific CM IgE was also observed (p < 0.05). Clinical tolerance induced by oral CM desensitization persists in time. Negativization of SPT and reduction of specific CM IgE could be considered prognostic indicators of CM tolerance. Oral CM desensitization seems to be a promising method to treat CM food allergy. This protocol is time‐consuming but offers the advantage that it can be performed at home. This methodology must only be used by trained staff.     

New visions for food allergy: An iPAC summary and future trends

The spectrum of food allergy consists of a variety of different clinical pictures including immunoglobulin (Ig)E, and non-IgE food allergy as well as mixed, IgE and non-IgE disorders. In addition, eosinophilic diseases of the gastrointestinal (GI) tract with occasional IgE-type sensitization are increasingly recognized. As a consequence, the clinical picture of food allergy is pleomorphic and can range from chronic GI symptoms to severe anaphylaxis. The diagnosis of food allergy is mostly hampered by the lack of reliable in vitro tests for non-IgE-mediated diseases, and in most cases relies on a reoccurrence of symptoms upon re-exposure to the antigen; in general during a standardized food challenge. Currently, there is no safe and efficient treatment for food allergy and the treatment relies on avoidance diets. Priorities for research have been identified by iPAC (international Pediatric Allergy and Asthma Consortium) and outlined in this review. They include studies to better identify the pathogenesis of food allergy, including genetic aspects; studies to develop diagnostic and follow-up tests; studies for standardization of food challenges; as well as studies addressing a safe and efficient treatment of food allergy.     

Food Allergy in childhood: phenotypes,prevention and treatment

The prevalence of food allergy in childhood increased in the last decades, especially in Westernized countries where this phenomenon has been indicated as a second wave of the allergic epidemic. In parallel, scientific interest also increased with the effort to explain the reasons of this sudden rise and to identify potential protective and risk factors. A great attention has been focused on early exposures to allergenic foods, as well as on other nutritional factors or supplements that may influence the immune system in a positive direction. Both interventions on maternal diet before birth or during breastfeeding and then directly on infant nutrition have been investigated. Furthermore, the natural history of food allergy also seems to be changing over time; IgE‐mediated cow's milk allergy and egg allergy seem to be more frequently a persistent rather than a transient disease in childhood, as described in the last years. Food avoidance and the emergency drugs in case of an adverse event, such as epinephrine self‐injector, are currently the first‐line treatment in patients with food allergies, with a resulting impairment in the quality of life and social behaviour. During the last decade, oral immunotherapy emerged as an optional treatment with remarkable results, offering a novel perspective in the treatment for and management of food allergy.     

Sesame food allergy and sensitization in children: the natural history and long-term follow-up

Sesame food allergy (SFA) in children is an increasingly recognized one in many countries. Our objective was to describe the course and natural history of SFA. Seventy-four patients sensitized to sesame were evaluated using clinical records, questionnaires, skin prick tests (SPT), in vitro specific immunoglobulin (sIg) E, and oral challenges (OC) and categorized into three groups: group A: patients who experienced allergic reaction after ingestion of sesame-containing food (n = 45); group B: patients evaluated for atopic dermatitis and found to be sesame SPT-positive (n = 11); group C: patients with sensitization to sesame allergen (n = 18). Group A patients were followed for an average of 6.7 yr. Analysis of our results revealed that 76% of patients in group A developed the allergy by the age of 2. The median age at onset of allergy in these patients was 1 yr. Immediate reaction to a minimal amount of sesame was characteristic. Skin was the most common site of involvement, followed by respiratory and gastrointestinal systems. Tolerance developed in only 20% of the patients. High sIgE (>0.15 IU) was demonstrated only in 75% of those in which it was examined. Sixteen patients performed oral sesame food challenge which was found positive in 88%. No correlation was found between the size of SPT and the level of in vitro sesame IgE antibodies, the outcome of OC results, and the development of tolerance to sesame. In conclusion, SFA tends to appear early in life, but unlike cow's milk and egg allergy, persists in 80% of the cases. Typical reactions combined with positive sesame SPT are reliable for diagnosis.     

The predictive value of skin prick testing for challenge-proven food allergy: a systematic review

Immunoglobulin E-mediated (IgE) food allergy affects 6-8% of children, and the prevalence is believed to be increasing. The gold standard of food allergy diagnosis is oral food challenges (OFCs); however, they are resource-consuming and potentially dangerous. Skin prick tests (SPTs) are able to detect the presence of allergen-specific IgE antibodies (sensitization), but they have low specificity for clinically significant food allergy. To reduce the need for OFCs, it has been suggested that children forgo an OFC if their SPT wheal size exceeds a cutoff that has a high predictability for food allergy. Although data for these studies are almost always gathered from high-risk populations, the 95% positive predictive values (PPVs) vary substantially between studies. SPT thresholds with a high probability of food allergy generated from these studies may not be generalizable to other populations, because of highly selective samples and variability in participant's age, test allergens, and food challenge protocol. Standardization of SPT devices and allergens, OFC protocols including standardized cessation criteria, and population-based samples would all help to improve generalizability of PPVs of SPTs.     

Allergen immunotherapy for IgE‐mediated food allergy: There is a measure in everything to a proper proportion of therapy

IgE‐mediated food allergy (FA) is a potentially life‐threatening condition with a negative impact on quality of life and an increasing prevalence in westernized countries in the recent two decades. A strict avoidance of the triggering food(s) represents the current standard approach. However, an elimination diet may be difficult and frustrating, in particular for common foods, (eg, milk, egg, and peanut). Food allergy immunotherapy (FA‐AIT) may provide an active treatment that enables to increase the amount of food that the patient can intake without reaction during treatment (ie, desensitization), and reduces the risk of potential life‐threatening allergic reaction in the event of accidental ingestion. However, several gaps need still to be filled. A memorable Latin orator stated: “Est modus in rebus” (Horace, Sermones I, 1, 106‐07). This sentence remembers that there is a measure in everything to a proper proportion of therapy. The common sense of measure should find application in each stage of treatment. A personalized approaching should consider the specific willing and features of each patient. Efforts are devoted to improve the efficacy, the safety but also the quality of life of patients suffering from FA. In the near future, it will be important to clarify immunologic pathways of FA‐AIT, and to identify reliable biomarkers in order to recognize the most suitable candidates to FA‐AIT and algorithms for treatments tailored on well‐characterized subpopulations of patients.     

The predictive value of specific immunoglobulin E levels for the first diagnosis of cow''s milk allergy. A critical analysis of pediatric literature

Investigators have tried to identify a level of seric specific immunoglobulin E (IgE) that had a sufficient predictive value to diagnose a food allergy without having will resort to the food challenge. To search in literature, all the studies that have estimated the possibility to identify a level of seric specific cow milk IgE with a positive predictive value (PPV) of 95% for the first diagnosis of cow's milk allergy (CMA) in pediatric age. We have identified six studies, nearly all studies suffer from relevant methodological bias. Proposed cut-off are all different. The studied pediatric populations were highly selected. Also neglecting the methodological bias of the studies and the great difference of value between the proposed cut-off, it always remains to consider that the pre-test probability of having a CMA between the children enrolled in the six studies included in this review is particularly high. The likelihood ratio helps to transfer the results of a study on a diagnostic test just to our population, and it is more realistic rather than to entrust itself to the PPV or the negative predictive value, that are much influenced from the prevalence of the disease in the studied population.     

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??Objective To investigate the efficacy and safety of enteral nutritional powder ??AA-PA?? an amino acid-based formula?? therapy in treatment of the infants with food protein allergy.Methods The prospective?? blind?? controlled?? multi-center trial was performed.Two hundred and forty-eight infants with cow’s milk allergy or food protein allergy??with exclusion of positive diagnostic serum-specific IgE values to soy protein were randomized either to be treated with an amino acid-based formula ??n = 124?? or soy protein-based formula ??n = 124?? for 12 weeks. The weight?? height?? allergic clinical manifestations?? adverse events and adverse reactions were estimated in pre-treatment and 4th ??8th and12th week during treatment respectively. The serum total protein and albumin were measured in pre-treatment and 12th week during treatment respectively.Results The feeding of enteral nutritional powder satisfied the need of growth and improved significant clinical manifestations for food protein allergy in two groups. In amino acid-based formula group there was a significantly increase in the weight??compared with the soy protein-based formula group??the different value between week 4 and base weight??0.65kg ± 0.45 kg vs 0.61 kg ± 0.47 kg?? P = 0.6720?? between week 8 and base weight??1.22 kg ± 0.73 kg vs 1.02 kg ± 0.65 kg?? P = 0.0368?? between week 12 and base weight??1.74 kg ± 0.91 kg vs 1.39 kg ± 0.87 kg?? P = 0.0022. The height?? clinical manifestations?? serum total protein and albumin during observation were similar in both groups. The adverse event rate was 44.35% in amino acid-based formula group and 45.16% in soy protein-based formula group?? observed almost in respiratory and digestive system. No statistical significance was noticed in all safety parameters in amino acid-based formula group compared with soy protein-based formula group.Conclusion The amino acid-based formula proves to be an effective substitute formula for the infants with cow’s milk allergy or food protein allergy?? and it is superior to soy protein-based formula in weight gain and safety and is well tolerated.