Food allergy in gastroenterologic diseases： Review of literature

INTRODUCTION Food allergy is recognized as a common worldwide prob- lem, and, like other atopic disorders, its incidence seems to increase. Moreover, food-related allergic disorders are the leading cause of anaphylactic reactions treated in the emer- genc…     

Food allergy: a challenge for the clinician

Adverse reactions to food resulting in gastrointestinal symptoms and due to immunologic reactions (allergy) are discussed: their pathogenesis, the prevalence of food allergens and the clinical digestive expressions of food allergy in children and adults are reviewed. In IgE-mediated food allergy, the usefulness of the biological available tests is considered, mainly CAP tests, for proceeding to the diagnosis and the monitoring of the allergic disease. Finally, the best actual diagnostic tools in food allergy are considered (clinical history, skin tests, biological tests and food oral challenges), with their limitations and indications.     

Gastrointestinal food hypersensitivity: Symptoms, diagnosis and provocation tests.

As many as 25% of the general population in Western countries believe that they suffer from adverse reactions to food. However, the actual prevalence of food allergy is much lower. Food-induced allergic reactions cause a variety of symptoms including cutaneous, gastrointestinal and respiratory tract. Food allergy might be caused by IgE-mediated, mixed (IgE and/or non-IgE) or non-IgE-mediated (cellular) mechanisms. The clinical diagnosis is based on a careful history, laboratory findings (total and specific IgE), skin prick test, elimination diet and food challenges. New intestinal provocation tests have also been applied to pick up the allergic response of the duodenal mucosa by endosonography and external ultrasound. The management of food allergy continues to be a strict avoidance of the offending food item.     

HRQoL questionnaire evaluation in lactose intolerant patients with adverse reactions to foods

The occurrence of patients with gastrointestinal symptoms attributed either to food allergy or intolerance has significantly increased. Nevertheless, an accurate and detailed case history, a systematic evaluation and the outcomes of specific allergy tests to identify the offending foods, including “in vivo” and “in vitro” allergy tests, are often negative for food allergy and may indicate a lactose intolerance, which is a recurrent condition affecting about 50% of adults. The aims of our study were the following: (1) What is the real incidence of the food hypersensitivity and the primary lactose intolerance in patients with gastrointestinal symptoms, initially referred to allergy or food intolerance? (2) Does lactose intolerance affect the quality of life and compliance to the therapy program? We investigated 262 consecutive patients, 72 men and 190 women. An accurate and detailed history and clinical examination were completed to investigate the offending foods. The evaluation in each patient included: allergy tests, lactose H₂ breath test (LHBT) and the HRQoL questionnaire. Five years after the diagnosis of lactose intolerance, a questionnaire on the persistence of gastrointestinal symptoms after lactose ingestion and the diet compliance was distributed. Our results demonstrate an high prevalence of lactose intolerance, more frequent in women; in these patients, bloating and diarrhea are the most reported symptoms. We observe only a significant positive correlation between adverse drug reaction (ADR) and LHBT+ patients, but not an augmented prevalence of food allergy and a negative impact on the HRQoL questionnaire of lactose intolerance.     

Food allergy diagnosis

The diagnosis of food allergies (FA) relies upon the sequential use of different means and tools, according to a decision tree. Ten clinical characteristics point to a potential FA. A diary for food consumption during a week surveys all labellings, in order to detect masked food allergens. The second step is based on skin prick tests to natural foods, and epicutaneous tests to a few proteins (casein, gluten...). Biological tests using multi detection tests of specific IgEs to numerous allergens are not advised owing to the frequency of clinically not relevant in vitro cross-reactivity. Single determination of specific IgEs, have a 95% predictive positive value of high levels in cases of allergy to milk, egg, fish and peanut, and can spare oral challenges. The primary use of biological tests is not currently advised but may be of interest in litigious cases. Standardized oral challenges are the golden standard. Eviction regimens are an alternative used for cow's milk allergy in infancy, or for suspected digestive allergies in adults.     

Oral Food Challenges in Children: Review and Future Perspectives

Food allergy is a lifelong condition with no known treatment or cure. Allergy tests such as skin tests and blood tests are not always accurate when positive and are not necessarily diagnostic of a food allergy. A food allergy takes into consideration both the history of exposure and the testing. The food challenge is considered the diagnostic gold standard for food allergy. However, recent evidence suggests that not enough challenges are being performed. Several techniques exist with which clinicians can challenge patients. Providers who perform challenges should be familiar with assessing signs and symptoms of a potential reaction and must be prepared to treat anaphylaxis. The magnitude of the serum and skin tests may be of assistance in stratifying a patient’s risk of passing a challenge, and newer diagnostic tests may help better stratify such risk of based on particular epitope recognition.     

Food allergy

Food allergy encompasses a range of disorders that result from adverse immune responses to dietary antigens. This group of conditions includes acute, potentially fatal reactions, and a host of chronic diseases that mainly affect the skin and gastrointestinal tract. Tools for diagnosis and management have not changed much in the past two decades, and include the clinical history, physical examination, tests for specific IgE antibody to suspected foods, elimination diets, oral food challenges, and provision of medications such as epinephrine for emergency treatment. However, much research in the past few years has enhanced our understanding of the clinical, epidemiological, and immunological aspects of these disorders. In this review I will discuss these advances and incorporate them into an improved diagnostic and management scheme. Additionally, emergent diagnostic, treatment, and prevention strategies are reviewed.     

"Atopy patch tests" in the diagnosis of delayed food hypersensitivity

The prevalence of atopic diseases is increasing worldwide. Food allergies are the earliest manifestation of atopy. Atopic eczema affects about 18% of infants in the first 2 years of life and the main cause is allergy to multiple foods. A strong association has been shown between atopic eczema and IgE mediated allergy to milk, egg or peanut, but more than two-thirds of patients intolerant to food proteins have no evidence of IgE sensitization to the relevant food protein. Recently, patch testing with proteins has been found to be helpful in diagnosing food allergy in cases where skin prick tests and estimation of specific antibodies have failed. The methodology of atopy patch test (APT) is unstandardized, and contradictory results have been reported. In contrast to the more standardized APT methodology with aeroallergens, the sensitivities and specificities of food allergens can easily be estimated with food challenge tests. With multiallergic children adding of APTs to the skin prick tests and specific antibody estimation tests give more information for planning a wide enough elimination diet to get the skin and gastrointestinal tract symptomless in order to perform the challenge test which remains the only reliable test for food allergy. Standardization of the APT materials and reading procedure will add to the reliability of this new test method.     

The diagnosis and management of egg allergy

Egg allergy is a common food hypersensitivity in children. Atopic dermatitis represents the main clinical manifestation in infancy. On first exposure, many of these infants present with urticaria, angioedema, or anaphylaxis. The role of egg allergy in gastrointestinal conditions is less well understood. The “gold standard” for the diagnosis of egg allergy is the double-blind, placebo-controlled food challenge. Diagnostic cut-off levels have been defined for food-specific serum immunoglobulin E antibody level and skin prick test wheal diameter that predict an adverse challenge outcome. This has significantly reduced the need for formal food challenges. Atopy patch testing, in conjunction with immunoglobulin E-based tests, may further improve the accuracy of predicting a positive challenge. The treatment of egg allergy consists of dietary elimination, or a maternal elimination diet in breast-fed infants. Approximately two thirds of infants with egg allergy will become tolerant by 7 years of age.     

Adult food allergy

Adult food allergy is estimated at approximately 3.2% worldwide. The persistence of childhood food allergy is unusual, peanut allergies excepted. Once established in adults, food allergy is rarely cured. Factors favoring the acquisition of allergy could be sensitization to pollens, occupational sensitization by inhalation, drugs (such as tacrolimus), and sudden dietary changes. Severe anaphylaxis and oral allergy syndrome are frequent. The fatality risk is estimated at 1% in severe anaphylaxis. Risk factors for severe anaphylaxis are agents causing increased intestinal permeability, such as alcohol and aspirin. β-blockers, angiotensin-converting enzyme (ACE) inhibitors, and exercise are other factors. Gastrointestinal food allergy remains, to a large extent, undiagnosed in adults. Food allergens are mainly fruit and vegetable, related to pollen sensitizations, or to latex allergy. Wheat flour allergy is increasing. The diagnosis relies on prick skin tests, detection of specific IgEs, and standardized oral challenges. Strict avoidance diets are necessary. Specific immunotherapy to pollens may be efficient for cross-reactive food allergies.     

Diagnosis of gluten related disorders: Celiac disease,wheat allergy and non-celiac gluten sensitivity

Cereal crops and cereal consumption have had a vital role in Mankind's history. In the recent years gluten ingestion has been linked with a range of clinical disorders. Gluten-related disorders have gradually emerged as an epidemiologically relevant phenomenon with an estimated global prevalence around 5%. Celiac disease, wheat allergy and non-celiac gluten sensitivity represent different gluten-related disorders. Similar clinical manifestations can be observed in these disorders, yet there are peculiar pathogenetic pathways involved in their development. Celiac disease and wheat allergy have been extensively studied, while non-celiac gluten sensitivity is a relatively novel clinical entity, believed to be closely related to other gastrointestinal functional syndromes. The diagnosis of celiac disease and wheat allergy is based on a combination of findings from the patient's clinical history and specific tests, including serology and duodenal biopsies in case of celiac disease, or laboratory and functional assays for wheat allergy. On the other hand, non-celiac gluten sensitivity is still mainly a diagnosis of exclusion, in the absence of clear-cut diagnostic criteria. A multimodal pragmatic approach combining findings from the clinical history, symptoms, serological and histological tests is required in order to reach an accurate diagnosis. A thorough knowledge of the differences and overlap in clinical presentation among gluten-related disorders, and between them and other gastrointestinal disorders, will help clinicians in the process of differential diagnosis.     

Test de provocation par voie orale aux aliments chez l'enfant. Quand,pour qui et comment ? Interprétation

Oral food challenges (OFC) have to be carefully interpreted. OFC prove the food allergy or persistent food allergy. OFC prove also the absence or the cure of food allergy. Objective and subjective signs are distinguished. Cutaneous and gastrointestinal symptoms are more frequent than respiratory or systemic symptoms. Delayed reactions, isolated or associated, have to be taken into account. In some cases, the OFC cannot be interpreted. Negative double-blind placebo-controlled food challenge must be confirmed by an open manner.     

Gastrointestinal Food Allergy in Infants

Food allergies are classified into three types, “IgE-mediated,” “combined IgE- and cell-mediated” and “cell-mediated/non-IgE-mediated,” depending on the involvement of IgE in their pathogenesis. Patients who develop predominantly cutaneous and/or respiratory symptoms belong to the IgE-mediated food allergy type. On the other hand, patients with gastrointestinal food allergy (GI allergy) usually develop gastrointestinal symptoms several hours after ingestion of offending foods; they belong to the cell-mediated/non-IgE-mediated or combined IgE- and cell-mediated food allergy types. GI allergies are also classified into a number of different clinical entities: food protein-induced enterocolitis syndrome (FPIES), food protein-induced proctocolitis (FPIP), food protein-induced enteropathy (Enteropathy) and eosinophilic gastrointestinal disorders (EGID). In the case of IgE-mediated food allergy, the diagnostic approaches and pathogenic mechanisms are well characterized. In contrast, the diagnostic approaches and pathogenic mechanisms of GI allergy remain mostly unclear.In this review, we summarized each type of GI allergy in regard to its historical background and updated clinical features, offending foods, etiology, diagnosis, examinations, treatment and pathogenesis. There are still many problems, especially in regard to the diagnostic approaches for GI allergy, that are closely associated with the definition of each disease. In addition, there are a number of unresolved issues regarding the pathogenic mechanisms of GI allergy that need further study and elucidation. Therefore, we discussed some of the diagnostic and research issues for GI allergy that need further investigation.     

Double blind, placebo controlled food reactions do not correlate to IgE allergy in the diagnosis of staple food related gastrointestinal symptoms.

BACKGROUND: The mechanisms for adverse reactions to foods in the gastrointestinal tract are poorly understood. There is conflicting evidence in the literature on the role for IgE mediated allergy in gastrointestinal reactions to staple foods. AIM: The aim was therefore to study the role of IgE mediated allergy in a group of patients with a history of gastrointestinal symptoms related to staple foods (cows' milk, hens' egg, wheat and rye flour) verified in double blind placebo controlled challenges (DBPCFC). PATIENTS: Fifteen patients with DBPCFC, identified by screening of 96 consecutive patients referred to our allergy clinic for investigation of suspected gastrointestinal symptoms due to staple foods. METHODS: The screening included diaries as well as elimination diets and open and blinded food challenges. The frequency of atopy were compared between the double blind positive and double blind negative patients. RESULTS: The positive DBPCFC in the 15 patients included eight patients with milk intolerance, four with wheat flour, two with egg, and one with rye flour. There was no indications of an allergic pathogenesis in all 15 patients with positive DBPCFC, as the skin prick test and radioallergosorbent test were negative for the relevant allergens. The frequency of atopy was four of 21 (19%) in the double blind negative group and three of 15 (20%) in the double blind positive group. CONCLUSION: In adult patients with staple food induced gastrointestinal symptoms, objectively verified by DBPCFC, there were no indications of IgE mediated allergy to the relevant foods suggesting other mechanisms in adults than in children. Future studies may include measures of local events in the shock organs in relation to food intake, for instance utilising inflammatory markers in jejunal fluids.     

Symptoms of food allergy

Adverse reactions to foods can be due to many causes, but only those involving an immunological mechanism can be defined as food allergic disease. An increasing number of gastrointestinal and other diseases are being shown to involve food intolerances. Immediate reactions with symptoms within hours of eating a particular food are most readily shown to be due to food allergy and are often associated with the presence of food-specific IgE as shown by skin prick tests and RASTs. When reactions are delayed for 24 to 48 hours or more, underlying food intolerance is harder to recognize and much less often shown to be due to allergy. At present, diagnosis and management depends on dietary manipulation, showing that symptoms improve on food avoidance and are reproduced by food challenge (preferably double-blind). Further understanding of the mechanisms involved in food allergy, in Crohn's disease and irritable bowel syndrome may allow the development of simple tests to identify the foods concerned and perhaps, in the case of allergic disease, cure by the induction of tolerance.     

Food allergy and the respiratory tract

Previous studies have confirmed that IgE-mediated, food allergy-induced respiratory tract symptoms occur, typically accompanied by cutaneous or gastrointestinal symptoms. The possibility that respiratory tract symptoms are food allergy induced should be considered in patients who have a current or past history of one or more of the following: atopic dermatitis, wheezing (or experiencing anaphylactic symptoms) after ingesting a particular food or foods, and confirmed food allergy. Moreover, the work-up of food allergy in asthma should be considered in patients in whom asthma is poorly controlled despite persistent use of appropriate asthma medications. A definitive diagnosis of food allergy should be based on clinical history, appropriate laboratory testing, and, when indicated, well-controlled oral food challenges. Treatment is based on establishing a safe elimination diet and an emergency plan for managing reactions caused by accidental ingestion.     

Dietary treatment of the irritable bowel syndrome

Opinion statement Most patients with functional gastrointestinal disorders report that food ingestion appears to exacerbate their symptoms and consequently conclude that they have some form of gastrointestinal food allergy or intolerance. Dietary management of functional gastrointestinal conditions is an attractive therapeutic option for the patient and physician alike because it is safe and economical and empowers the patient to help themselves. However, in practice, dietary manipulation frequently yields rather disappointing results. Exclusion diets can be helpful, but are labor intensive and occasionally can be very restrictive. Laboratory testing for immunoglobulin E food antibodies usually is not helpful, except in a small subgroup of patients with diarrhea, predominant irritable bowel syndrome (IBS), and atopy. There is some preliminary evidence to suggest that elimination diets based on immunoglobulin G food antibody testing may possibly have therapeutic potential in IBS, but this requires confirmation.     

Troubles des conduites alimentaires et allergies alimentaires

Many eating disorders are observed in food allergy practice. It is common to see patients avoiding many foods because they have been poorly informed of cross-reactions that are not clinically relevant. For children, parental anxiety may multiply irrational avoidance. The diagnosis of Münchausen syndrome by proxy should be envisaged, although it is rare. Abnormal eating behavior in children can be related to a Pavlovian reaction of disgust, to anxiety or depression, a perturbed relationship with the mother or simply due to an aversion to new foods. In adults, food avoidance is linked to poor interpretation of positive laboratory tests indicating cross-reactions that are clinically irrelevant. Irritable bowel syndrome results in food avoidance even where food allergy is poorly documented. Fibromyalgia also leads to unnecessary avoidance diets. True neurosis (obsession and anxiety neurosis) may occur. Patients taking alternative medicines or belonging to certain sects often follow aberrant avoidance diets. All patients should undergo a nutritional evaluation. Psychologists, psychiatrists and dieticians should also be involved in treatment. Allergists should not limit themselves to simply eliminating food allergy to a given food allergy, but should make patients aware that problems arise from “not” eating different foods. Accurate tests, detailed information and careful monitoring of proposed changes in diet should result in more rational eating habits. Established neurosis will not improve, since patients are in denial about these disorders, psychiatrists know little about them.     

Food allergies and food intolerances

Adverse reactions to foods, aside from those considered toxic, are caused by a particular individual intolerance towards commonly tolerated foods. Intolerance derived from an immunological mechanism is referred to as Food Allergy, the non-immunological form is called Food Intolerance. IgE-mediated food allergy is the most common and dangerous type of adverse food reaction. It is initiated by an impairment of normal Oral Tolerance to food in predisposed individuals (atopic). Food allergy produces respiratory, gastrointestinal, cutaneous and cardiovascular symptoms but often generalized, life-threatening symptoms manifest at a rapid rate-anaphylactic shock. Diagnosis is made using medical history and cutaneous and serological tests but to obtain final confirmation a Double Blind Controlled Food Challenge must be performed. Food intolerances are principally caused by enzymatic defects in the digestive system, as is the case with lactose intolerance, but may also result from pharmacological effects of vasoactive amines present in foods (e.g. Histamine). Prevention and treatment are based on the avoidance of the culprit food.     

Genetics of food allergy

Allergic reactions to foods are an important medical problem throughout the industrialized world. The occurrence of food allergy appears to be strongly in.uenced by genetics, but the basis of the genetic predisposition to food allergy has not been differentiated from that for atopy in general. In addition, genetic susceptibility alone does not explain the prevalence of food allergy satisfactorily, leaving ample room to consider the importance of environmental in.uences (external, maternal, and gastrointestinal environment) and interactions between the host and the environment. Several features of food allergy are highlighted in this review: 1) patients with severe food allergies are overwhelmingly atopic, but food allergy occurs only in approximately 10% of patients with other atopic diseases; 2) most patients are clinically reactive to a single food, and although a substantial minority have multiple food allergies, the variety of bonefide food allergies in a given individual is limited; 3) foods contain multiple proteins whereas only a small subset are allergenic; 4) there is likely an important contribution of the environment, becoming manifest in genetically susceptible individuals.