Prevention of food allergy in infants and children

An understanding of the immunologic basis of atopy helps one to devise strategies for allergy prevention. A duality of T-helper cells (i.e., Th1 and Th2) exists in rodents and probably also in humans. 69 Th1-like cells are linked to a lymphokine profile that stimulates cell-mediated immunity while suppressing IgE antibody formation, whereas Th2-type cells are linked with IgE antibody formation, the appearance of mast cells and eosinophils, and atopic diatheses. A hypothesis of IgE immunoregulation suggests that the magnitude of the IgE reponse to antigen-specific immune responses to persistent allergens depends upon the relative balance between antigen-specific Th1 and Th2 cells represented in relevant T-memory populations. 36 Repeated allergen exposure by immunologically naive rat pups from low IgE responder strains usually results in transient and low-level IgE antibody responses. Low IgE responders are typically Th1-dominant, whereas high IgE responders are Th2-phenotype dominant. This form of genetically determined immunologic tolerance induction and Th profiles are markedly influenced by a range of environmental factors, including chemical air pollutants and also infection. Exposure to infections and microbial adjuvants simultaneously with allergen or large doses of antigen suppresses the Th2 response in high responder rat pups. In contrast, a switch towards a Th2 response occurs in low responder pups with simultaneous exposure to allergen and air pollutants (e.g., tobacco smoke). Cytokine regulation of IgE synthesis in humans is consistent with this animal model. The human immune system appears to begin responding to ubiquitous food and inhalant allergens in the early perinatal period. High-atopic risk infants (infants from allergic families or with elevated cord blood IgE levels) have less capacity to produce interferon gamma (IFN-γ), and thereby a less efficient induction of Th1-type responses. 80 Furthermore, infants developing allergic disease by 18 months of life have elevated levels of interleukin (IL)-4, the major cytokine from Th2-type cells. 2 In addition, epidemiologic studies indicate that certain recurrent infections (varicella and tuberculosis) in infancy protect against sensitization to inhalant allergens by switching the Th balance to Th1-type cells. The kinetics of humoral antibody responses to food and inhalant antigens/allergens in infants and young children support the previous animal model. IgG antibodies to ubiquitous environmental antigens appear very early in life and remain detectable in serum from the majority of both atopic and normals throughout life. In contrast, the humoral IgE antibody response to environmental allergens is markedly different. Serum IgE levels to foods are commonly detected in atopic and nonatopic infants during the first year of life, although the magnitude of the response is higher and of longer duration in the atopic. 30 In most children, however, these initial IgE responses to foods are terminated spontaneously by 2 to 4 years of age, leaving intact IgG responses to the same food antigens that persist into adulthood. Immunologic intervention that switches high-risk newborns to a Th1 from a Th2 bias may be a fruitful avenue for allergy prevention (Fig. 1). This issue is discussed later. Clinical Aspects of Allergy Prevention Food allergy occurs in about 4% to 6% of children, is increasing in prevalence over the past decade, and represents a major burden to our young. The natural history of food allergy documents that allergies to cow's milk (CM), egg, and soy frequently remit, whereas allergies to peanut, nuts, and fish typically persist into adulthood, although exceptions exist. Food allergen avoidance subsequent to sensitization and manifestation of symptoms appears to hasten tolerance; however, the immunologic mechanism responsible for tolerance to one food group and not another is poorly understood. Identification and characterization of allergens and determination of B- and T-cell epitopes has provided an opportunity to better define these mechanisms. Identifying and developing effective strategies to prevent food allergy and other atopic diseases represents a high priority for medicine at this time because of the unbridled increase in their prevalence and morbidity. Immunologic engineering holds the greatest promise for allergy prevention in the not-too distant future, but environmental strategies that promote food and aero-allergen avoidance provide an avenue for prevention at the present time. Such efforts rely actively on reducing the allergenic load and exposure of atopic-prone infants and children to allergens. Systematically, allergy prevention may be directed at three potential stages: (1) primary prevention that inhibits IgE and other immunologic sensitization, (2) secondary prevention that abrogates disease expression subsequent to immunologic sensitization, and (3) tertiary prevention that suppresses symptoms after and despite disease expression (Fig. 2). 86 Strategies to promote allergen avoidance have met with great difficulty at all of these stages because of limitations in knowledge, societal compliance, and resources. Whereas primary prevention of allergy is optimal, secondary prevention may be a necessary adjunct to the former or serve as a fall-back option to families disinterested in allergy prevention until real markers or indicators of atopic risk are identified in their offspring. Tertiary prevention, the realm most familiar to practicing allergists and pediatricians, is generally instituted after manifestations of allergy are recognized, often, long after clinical disease has been expressed and suffering experienced (see Fig. 2). These stages must be integrated into any program that attempts to prevent the consequences of atopic disease. The success of allergy prevention strategies must be judged by the degree to which they satisfy specific criteria, including the ability to (1) predict the high-risk infant and child, (2) demonstrate effectiveness of the intervention strategy, (3) utilize acceptable interventions, (4) minimize adverse effects, and (5) generate cost-effective outcomes. To date, no allergen avoidance intervention study has met all of these prerequisites. A critical period exists early postnatally and possibly prenatally in which the genetically programmed atopic-prone infant may be at an increased risk to become sensitized to exposed or encountered allergens. As such, prompt perinatal identification of such at-risk neonates is important to institute preventive efforts early. Many genetic linkage markers and immunologic factors or markers (e.g., elevated cord blood and infancy IgE levels, egg-specific IgE, lower IFN-γ or IL-4 ratio) have been determined to be significantly associated with the subsequent development of allergic disease. Presently, none of these markers possess greater predictive value than atopic family history for the practical screening of at-risk neonates for allergy prevention. 3 The extent to which atopic risk factors are amenable to preventive modulation depends upon the factor. Factors such as atopic heredity, male gender, and nonwhite ethnicity cannot be modulated, whereas factors such as birth month, low socioeconomic status, and urban residence require great effort to modulate. Other risk factors conducive to and fruitful for modulation include (1) low atopic health consciousness; (2) early introduction of allergenic foods during infancy; (3) high household dust-mite, cockroach, and dander levels; and (4) environmental pollution and environmental tobacco exposure (ETS). A strategy that identifies high-risk newborns and infants and directs preventive measures at all three stages of allergy prevention is depicted in Figure 2.