Allergic responses to many food proteins have been described. The most common in childhood are to cows' milk, soy, eggs and fish, with peanut allergy rapidly becoming more common.1,3,4,24 However, intolerance to fruits, vegetable, meats, chocolate, nuts, shellfish and cereals has been described. In adult life there is a different spectrum, with allergy to nuts, fruits and fish relatively more common than in childhood. However, as the dietary exposures of UK children broaden, the range of reported allergens also increases: thus sesame, kiwi fruit, mango, avocado and other allergies have increased in frequency. Such sensitization may depend as much on a combination of genetics, infectious challenges and timing and dose of exposure as on innate antigenicity of individual foodstuffs.
There are no consistent associations between any particular food and specific syndromes, although some foods are more likely than others to induce enteropathy, such as cow's milk and soy, and others usually induce immediate hypersensitivity, such as peanut. The incidence of gastrointestinal food allergy is greatest in early life and appears to decrease with age. However, analogy with celiac disease, in which late-onset enteropathy is more likely to be clinically subtle, suggests that the increase in colonic salvage that occurs with age may mask true food-sensitive enteropathy. Although enteropathy can cause significant failure to thrive, complex multiple allergies may also occur in the presence of normal growth.5
Cow's milk allergy may commonly present either as an immediate response, including anaphylaxis, or with delayed responses within the gut or skin. CMSE was frequently diagnosed in the past because of failure to thrive following an episode of gastroenteritis,97 and the consequent lactose intolerance often inappropriately managed with reduced-lactose formulas without cow's milk antigen exclusion (still common practice in some developing world countries). Modern adapted formulas are now much less sensitizing, and the mucosal lesions less severe. While positive skin prick tests and milk-specific IgE may be seen in some children with enteropathy, they are much more frequent in children who have immediate reactions to milk. Cow's milk colitis is most common in breast-fed babies, whose mothers are consuming milk in their diet, and usually presents with low-grade rectal bleeding. For reasons unknown, it is unusual for one infant to develop both cow's milk enteropathy and colitis. Milk-
induced dysmotility is discussed above. Egg
By contrast to cow's milk, egg allergy usually presents either as an acute hypersensitive response or with delayed respiratory or cutaneous reactions, with worsening of asthma or eczema. While vomiting may occur soon after ingestion, or diarrhea ensue after a few hours, there is little evidence that egg can induce small-intestinal enteropathy.1 Skin prick tests, patch tests and specific IgE to egg are more often positive than for other antigens,86 and may be predictive of time taken to outgrow egg allergy. About half of under-2-year-old children who develop egg allergy will tolerate it during 3 years of follow-up, with the size of skin prick reaction and specific IgE potentially predictive of those children who are unlikely to outgrow allergy.79,98
Soy-based formulas have for some years been used in infants with cow's milk allergy, although more commonly by general pediatricians than pediatric gastroenterologists. However, recommendation of soy milk use by the American Academy of Pediatrics Committee on Nutrition99 may increase the use of soy in comparison to hydrolysates. Soy-based formulas are as antigenic as cow's milk formulas,100 and the reported reactions span the range from anaphylaxis to enteropathy, eczema and respiratory symptoms.1 A 30kD protein in soy may induce cross-reactivity to cow's milk caseins,101 potentially explaining the high incidence of soy intolerance in cow's milk-allergic children. An important consideration is that anti-genicity of soy-derived products is strongly influenced by methods of preparation, and thus children may react to some soy-based products and not others.102 Unlike in antigens such as peanut and egg, skin prick testing is frequently not a good predictor of subsequent clinical reactions to soy.79 Patch testing may provide more clinically relevant information, particularly in a child with eczema.85
Acute allergic reactions to wheat are very uncommon, although wheat anaphylaxis has been described,103 and an ra-gliadin has been characterized as the likely sensitizing antigen in children with immediate reactions.104 By contrast to the relative rarity of immediate reactions, delayed hypersensitive reactions are common and clinically important. Celiac disease is particularly important, and affects at least 1% of European and North American populations.105 Celiac disease is discussed in Chapter 27 in depth. However, it is important to recognize that a low IgA predisposes to both celiac disease and food allergies. It is thus advisable that serological testing for celiac disease should be performed in all food-allergic patients at some stage during their diagnostic evaluation.
There is increasing recognition that wheat products may play a disproportionate role in inducing intestinal dysmotility, such as gastroesophageal reflux and constipation. There are also reports that wheat and cow's milk may induce behavioral effects, possibly because of their natural content of morphine-like exorphins such as P-casomorphine and gliadomorphine.106,107 While this may also contribute to constipation, such a response would technically be an intolerance rather than a true allergy. However, further work is clearly needed in what is a poorly understood but potentially important area.
Peanut allergy is concerning, because of its rising incidence and its propensity to induce severe anaphylaxis.3,4,24,25 It is particularly important in childhood allergy as a cause of fatal anaphylactic reaction.108 Even trace amounts of peanut can cause death in those severely sensitized. The surge in peanut hypersensitivity may relate to novel patterns of exposure, and there is recent evidence to suggest that percutaneous sensitization may be more important than simple ingestion.108 Analysis of the Avon Longitudinal Study of Parents and Children identified that prenatal sensitization was extremely uncommon, but that peanut allergy was associated with intake of soy milk, rash over joints or a crusted oozing rash, and in particular use of skin creams for eczema that contained peanut oil.109 In this study, cases were initially identified on the basis of a questionnaire, and then subsequently the diagnosis was confirmed by doubleblind placebo-controlled food challenge. From a studied cohort of just under 14 000 children, 49 were identified with a history of peanut allergy and the diagnosis confirmed in 23 of 36 children tested.
T-cell responses appear important in determining sensitization to peanut, and indeed there has been one report of peanut anaphylaxis transferred to the recipient of a liver transplant.110 Intriguingly, chimerism was noted in the skin, but not the blood, of the recipient, which implies that lymphocyte homing had occurred. The T-cell response of peanut-allergic, but not tolerant, children is skewed towards Th2 cytokines,94 suggesting that there is no innate property of peanuts that is responsible for allergic sensitization. However, the severity of peanut reactions does argue for some additional factor beyond simple Th2 skewing, and it is thus notable that the peanut-derived lectin peanut agglutinin is used by pathol-ogists to identify germinal centers in lymphoid follicles. In a rodent model of food allergic sensiti-zation, peanut agglutinin was notable amongst dietary antigens for its ability to induce high IgE responses.111 Whether the presence of peanut agglutinin affects the level of response to the recognized sensitizing epitopes for humans is currently unknown. Similar evidence from this model that a wheat lectin, wheat germ agglutinin, has a modulating effect on ovalbumin res-ponses,112 suggests that the presence of lectins within foods may contribute to immune sensitiza-tion events.
In the UK, it is recommended that children from an atopic background should not be given peanut products until after the age of 6.3,4 However, as most children may be sensitized early in life by non-classical routes,109 this may not be as effective as was initially hoped. There is evidence that many children may outgrow peanut allergy, and that skin prick testing may identify those with a good chance of a successful peanut challenge (see above). For those with established allergy and a history of anaphylaxis, monoclonal anti-IgE therapy is a promising option.113 This is discussed in more depth in the section on basic mechanisms later in the chapter.
Many infants develop gastrointestinal and other symptoms related to a wide variety of foods. The condition of multiple food allergy5 provides great challenges for the family, the child and the allergist. Reactions may be immediate or delayed, and do not differ significantly from those described above for individual foods. Affected children often have a family history of atopy, may have increased eosinophils in the peripheral blood, with elevated serum IgE and positive specific IgE, and skin tests to specific foods.8,14,24,51 Many cases appear to sensitize through maternally ingested antigens during exclusive breast feeding, with the small amounts of dietary proteins either sufficient to sensitize or insufficient to tolerize. A specific defect in oral tolerance for low-dose antigen has been postulated as a cause of this phenomenon,114 supported by recent data of a defective generation of Th3 cells within the mucosa of affected chil-dren.34 Affected children may show residual intolerance of hydrolysates.5,14,52
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