Summary and future directions W. A l l a n W a l k e r , MD From the Harvard Medical School, Combined Program in Pediatric Gastroenterology and Nutrition, Children's Hospital and Massachusetts General Hospital, Boston
This conference brought together international experts in immunology and gastroenterology to discuss our current understanding of food intolerance and allergy in children. What we know about the pathogenesis, diagnosis, and management of food intolerances was clarified, and the major shortcomings of our knowledge and important areas for future research were identified. In the past, the advance of knowledge in this important clinical area has been hindered by a lack of agreement over terminology, inadequate study designs, and the small numbers and poor characterization of allergic symptoms reported in clinical studies. Important insights emerged from this conference that will help fill the gaps in our knowledge and provide approaches to the clinical management of adverse food reactions. DEFINITIONS
AND DISTINCTIONS
For interpretation of research, agreement about appropriate definitions is important. The public and many health professionals often use the term "food allergy" for any adverse food reaction. The accepted definition o f a food allergy, however, is a food intolerance that has an immunologic basis. Although IgE-mediated allergic reactions are best characterized and easiest to diagnosel we must also recognize the importance of other possible immune mechanisms. The term "food intolerance" applies to any reproducible adverse reaction to a food that is not psychologically based. Making a distinction between antigenicity and allergenicity is also important. Antigenicity was defined as the ability of a substance to combine specifically with a preformed antibody from a previously sensitized organism. Cow milk, for example, has numerous protein fractions that can cause an immune response. All infants ingesting cow milk have an immune response to cow milk proteins, as measured by serum IgG antibodies, indicating the antigenicity of these proteins. Allergenicity,, however, is deter-
Reprint requests: W. Allan Walker, MD, Children's Hospital, 300 Longwood Ave., Boston, MA 02215. 9/0/42375
$4
mined by an abnormal immune reaction resulting in adverse clinical symptoms. Although in vitro tests can rank the antigenicity of proteins found in cow milk, this ranking seems to have little association with allergenicity. Because of this lack of association, only controlled clinical testing can confirm the allergenicity of any food substance. PATHOGENESIS
OF FOOD ALLERGY
Much remains to be understood about the pathogenesis of food allergies in early childhood. The Figure illustrates some factors that may influence the development of allergic reactions. Tolerance, defined as the absence of an adverse immunologic effect after exposure to a specific food antigen, is one important bu~(poorly understood aspect of this process. In animal studies, tolerance depends on factors within the animal diet such a s its immunologic status and on factors associated with the feeding, such as the nature and amount of antigen. The evidence for the development of tolerance in human beings i s incomplete and requires further study. The pathogenesis of food-sensitive enteropathies is not as well understood as that Of immediate IgE-mediated allergic reactions, and the immunologic basis for these reactions is not as well documented. Cell~mediated immune mechanisms have been suggested, but evidence is only indirect. These food-sensitiye enteropathie s have variable effects on the small intestinal mucosa; they occur principally during the first 6 months Of life and are generally limited to early childhood. Predisposing factors may be malnutrition, infection, and genetic predisposition. Several conference participants also noted the recent worldwide decrease in the prevalence of severe cow milk-sensitive enteropathies. This decrease appears to be related to changes in infant feeding practice's, particularly to the increased use of adapted formulas. Two questions remain: Are these reactions due to the immaturity of protective immune substances, or to the immaturity of the enterocyte or other intestinal factors such as proteolytic activity? Are they due to the way that antigens cross the epithelial barrier? To answer these questions, we need a better understanding of the mucosal immune system and its development during infancy.
Volume 121 Number 5, Part 2
Summary and future directions
S5
INFLUENCE OF DIETARY PROTEIN ON IMMUNE RESPONSE DIETARY PROTEIN PROTEIN SOURCE
-QUALITY
DIETARY TREATMENT 9DIFFERENT PROTEIN 9HYDROLYZED PROTEIN LONG CHAIN \ POLYUNSATURATED FA'I-rY ACIDS
9 GUTFACTORS ,PROCESSING ,PERMEABILITY
AGE ?? J
l
?
T T
INFECTION
?
?
I
'
~"
TOLERANCE
GENETICS
DRUG TREATMENT 9CROMOLYN SODIUM 9B ADRENERGIC BLOCKERS 9 ANTI HISTAMINE 9EPINEPHRINE 9OTHERS
~I
ALLERGIC MANIFESTATIONS RAPID REACTION SLOW REACTION
Ig E MEDIATED RESPONSE (Permanent: Fish, Peanut)
~E
'
ENTERIC RESPONSE (Transient:Cow Milk, Soy)
Figure. Interaction of factors mediating influence of dietary protein on immune response. Arrows with question marks indicate a suggested effect requiring verification by additional studies.
T Y P E S OF FOOD A L L E R G I E S IN I N F A N T S Although cow milk allergy is the most common food allergy in infancy, other proteins such as soy are used in infant feeding and can also cause food intolerance. Like cow milk proteins, all soy proteins are potentially antigenic, but allergic reactions to soy seem to occur less frequently than those to cow milk. A review of the literature indicated that most studies reporting soy allergy in children with cow milk allergy have failed to confirm these cases with a challenge test, and anaphylactic reactions to soy are rare. The feeding habits of a specific country can dictate the types of food sensitivity. An example discussed in this conference was fish, which is ingested at an early age in some European countries. Studies with fish indicated that there are both general fish allergens and species-specific allergens. Therefore children reacting to one species of fish might or might not show cross-reactivity to other fish species. DIAGNOSTIC PROCEDURES The diagnosis of a food intolerance is based first on a careful medical history. Skin tests or radioallergosorbent
tests are not acceptable as the only way to diagnose food allergies, except in cases of severe anaphylaxis after the ingestion of a specific food. Standardized skin prick tests are sensitive and fairly specific for IgE-mediated allergies, but positive reactions occur in children without clinical symptoms. A negative test result has a predictive accuracy of 95%, whereas a positive test result is predictive of clinical symptoms only 50% of the time. Radioallergosorbent tests are slightly less sensitive than skin prick tests. Therefore these tests are useful ways to screen patients with suspected IgE-mediated allergies; however, positive reactions must be confirmed by the "gold standard" for diagnosis, the doubleblind, placebo-controlled food challenge. Foods unlikely to provoke allergic reactions may be screened by open or single-blind challenges. FEEDING WITH SUBSTITUTE
FORMULAS
Everyone agrees that allergies must be treated by eliminating the offending protein, but there is less agreement over what is to be fed in its place. Soy formulas may be the best choice for children with IgE-mediated symptoms
S6
Walker
The Journal of Pediatrics November 1992
caused by cow milk, but all formulas must first be tested in the individual child by in vitro and in vivo methods. A negative skin test result indicates that the child is not likely to react to the formula, but a positive skin test result must be confirmed by double-blind, placebo-controlled food challenges in a supervised setting. When the highly sensitized child is treated, formulas based on amino acids have been shown to be completely nonallergenic. Extensively hydrolyzed formulas also have been successfully fed to children with allergies for many years, and the experts generally agreed that they are the treatment of choice for food-sensitive enteropathies. In a study reported in this conference, no adverse reactions to extensively hydrolyzed casein formulas were found in children with cow milk allergies. In contrast, the role of partially hydrolyzed formulas has not been defined. These formulas are less allergenic than cow milk formulas but are probably not appropriate for children with allergies. DEVELOPMENT FORMULAS
OF HYPOALLERGENIC
More effective hypoallergenic formulas are needed, and the development and testing of these formulas were discussed in this conference. A proposed definition of a hypoallergenic formula for cow milk-allergic children is that it does not provoke any allergic signs or symptoms in at least 90% of infants with documented cow milk protein allergy when tested in double-blind, placebo-controlled food challenge trials. Before these formulas undergo clinical testing for allergenicity, nonclinical testing can characterize their molecular and physical properties to assess antigenicity. PREVENTION The conference also addressed the issue of prevention. To institute preventive measures for infants at risk of the development of allergies, we must first identify those at risk. The experts agreed that a family history of allergy is still the strongest predictor of the development of allergies. Cord blood lgE has been used to predict risk of allergy in research studies, but it is not as reliable as the family history and cannot be used as the only test.
The results of a study using a hydrolyzed formula as a supplement to breast-feeding or by itself during early infancy for the prevention of allergies in high-risk children were presented, Allergic eczema was shown to be decreased by early feeding of hydrolysate at 2 and 4 years of age but not during the first year. These results contrast with those in another prospective, controlled study that showed a benefit of dietary intervention only during the first year of life. There is also some evidence that such factors as breastfeeding, the avoidance of antigen exposure during pregnancy and lactation, and the delay and staged introduction of solid foods can decrease the incidence of allergy in highrisk populations. RECOMMENDATIONS Finally, the following recommendations can be made for future research: 1. We need more basic research to understand better the pathophysiology of food-sensitive enteropathies so that we can better diagnose, prevent, and manage these conditions. 2. The allergenicity of any formula used for the treatment of allergies must be confirmed in clinical studies using double-blind, placebo-controlled food challenges in children with confirmed allergies. In addition, future studies must address the efficacy of formulas for various subclasses of food intolerance. 3. The infant formula industry and academic institutions need to work together (a) to develop better methods of identifying the components of hydrolyzed formulas that are still antigenic and (b) to develop more palatable formulas that have a greater proportion of small peptides. 4. Further studies, especially in human infants, are needed to understand the mechanisms of oral tolerance. 5. We need a better understanding of the factors that p affect allergy expression so that we can institute effective preventive measures. The use of special formulas and other dietary modifications for allergy prevention must be studied further before general recommendations can be made to parents of children at risk of allergies.
This conference brought together international experts in immunology and gastroenterology to discuss our current understanding of food intolerance and allergy in children. What we know about the pathogenesis, diagnosis, and management of food intolerances was clarified, and the major shortcomings of our knowledge and important areas for future research were identified. In the past, the advance of knowledge in this important clinical area has been hindered by a lack of agreement over terminology, inadequate study designs, and the small numbers and poor characterization of allergic symptoms reported in clinical studies. Important insights emerged from this conference that will help fill the gaps in our knowledge and provide approaches to the clinical management of adverse food reactions. DEFINITIONS
AND DISTINCTIONS
For interpretation of research, agreement about appropriate definitions is important. The public and many health professionals often use the term "food allergy" for any adverse food reaction. The accepted definition o f a food allergy, however, is a food intolerance that has an immunologic basis. Although IgE-mediated allergic reactions are best characterized and easiest to diagnosel we must also recognize the importance of other possible immune mechanisms. The term "food intolerance" applies to any reproducible adverse reaction to a food that is not psychologically based. Making a distinction between antigenicity and allergenicity is also important. Antigenicity was defined as the ability of a substance to combine specifically with a preformed antibody from a previously sensitized organism. Cow milk, for example, has numerous protein fractions that can cause an immune response. All infants ingesting cow milk have an immune response to cow milk proteins, as measured by serum IgG antibodies, indicating the antigenicity of these proteins. Allergenicity,, however, is deter-
Reprint requests: W. Allan Walker, MD, Children's Hospital, 300 Longwood Ave., Boston, MA 02215. 9/0/42375
$4
mined by an abnormal immune reaction resulting in adverse clinical symptoms. Although in vitro tests can rank the antigenicity of proteins found in cow milk, this ranking seems to have little association with allergenicity. Because of this lack of association, only controlled clinical testing can confirm the allergenicity of any food substance. PATHOGENESIS
OF FOOD ALLERGY
Much remains to be understood about the pathogenesis of food allergies in early childhood. The Figure illustrates some factors that may influence the development of allergic reactions. Tolerance, defined as the absence of an adverse immunologic effect after exposure to a specific food antigen, is one important bu~(poorly understood aspect of this process. In animal studies, tolerance depends on factors within the animal diet such a s its immunologic status and on factors associated with the feeding, such as the nature and amount of antigen. The evidence for the development of tolerance in human beings i s incomplete and requires further study. The pathogenesis of food-sensitive enteropathies is not as well understood as that Of immediate IgE-mediated allergic reactions, and the immunologic basis for these reactions is not as well documented. Cell~mediated immune mechanisms have been suggested, but evidence is only indirect. These food-sensitiye enteropathie s have variable effects on the small intestinal mucosa; they occur principally during the first 6 months Of life and are generally limited to early childhood. Predisposing factors may be malnutrition, infection, and genetic predisposition. Several conference participants also noted the recent worldwide decrease in the prevalence of severe cow milk-sensitive enteropathies. This decrease appears to be related to changes in infant feeding practice's, particularly to the increased use of adapted formulas. Two questions remain: Are these reactions due to the immaturity of protective immune substances, or to the immaturity of the enterocyte or other intestinal factors such as proteolytic activity? Are they due to the way that antigens cross the epithelial barrier? To answer these questions, we need a better understanding of the mucosal immune system and its development during infancy.
Volume 121 Number 5, Part 2
Summary and future directions
S5
INFLUENCE OF DIETARY PROTEIN ON IMMUNE RESPONSE DIETARY PROTEIN PROTEIN SOURCE
-QUALITY
DIETARY TREATMENT 9DIFFERENT PROTEIN 9HYDROLYZED PROTEIN LONG CHAIN \ POLYUNSATURATED FA'I-rY ACIDS
9 GUTFACTORS ,PROCESSING ,PERMEABILITY
AGE ?? J
l
?
T T
INFECTION
?
?
I
'
~"
TOLERANCE
GENETICS
DRUG TREATMENT 9CROMOLYN SODIUM 9B ADRENERGIC BLOCKERS 9 ANTI HISTAMINE 9EPINEPHRINE 9OTHERS
~I
ALLERGIC MANIFESTATIONS RAPID REACTION SLOW REACTION
Ig E MEDIATED RESPONSE (Permanent: Fish, Peanut)
~E
'
ENTERIC RESPONSE (Transient:Cow Milk, Soy)
Figure. Interaction of factors mediating influence of dietary protein on immune response. Arrows with question marks indicate a suggested effect requiring verification by additional studies.
T Y P E S OF FOOD A L L E R G I E S IN I N F A N T S Although cow milk allergy is the most common food allergy in infancy, other proteins such as soy are used in infant feeding and can also cause food intolerance. Like cow milk proteins, all soy proteins are potentially antigenic, but allergic reactions to soy seem to occur less frequently than those to cow milk. A review of the literature indicated that most studies reporting soy allergy in children with cow milk allergy have failed to confirm these cases with a challenge test, and anaphylactic reactions to soy are rare. The feeding habits of a specific country can dictate the types of food sensitivity. An example discussed in this conference was fish, which is ingested at an early age in some European countries. Studies with fish indicated that there are both general fish allergens and species-specific allergens. Therefore children reacting to one species of fish might or might not show cross-reactivity to other fish species. DIAGNOSTIC PROCEDURES The diagnosis of a food intolerance is based first on a careful medical history. Skin tests or radioallergosorbent
tests are not acceptable as the only way to diagnose food allergies, except in cases of severe anaphylaxis after the ingestion of a specific food. Standardized skin prick tests are sensitive and fairly specific for IgE-mediated allergies, but positive reactions occur in children without clinical symptoms. A negative test result has a predictive accuracy of 95%, whereas a positive test result is predictive of clinical symptoms only 50% of the time. Radioallergosorbent tests are slightly less sensitive than skin prick tests. Therefore these tests are useful ways to screen patients with suspected IgE-mediated allergies; however, positive reactions must be confirmed by the "gold standard" for diagnosis, the doubleblind, placebo-controlled food challenge. Foods unlikely to provoke allergic reactions may be screened by open or single-blind challenges. FEEDING WITH SUBSTITUTE
FORMULAS
Everyone agrees that allergies must be treated by eliminating the offending protein, but there is less agreement over what is to be fed in its place. Soy formulas may be the best choice for children with IgE-mediated symptoms
S6
Walker
The Journal of Pediatrics November 1992
caused by cow milk, but all formulas must first be tested in the individual child by in vitro and in vivo methods. A negative skin test result indicates that the child is not likely to react to the formula, but a positive skin test result must be confirmed by double-blind, placebo-controlled food challenges in a supervised setting. When the highly sensitized child is treated, formulas based on amino acids have been shown to be completely nonallergenic. Extensively hydrolyzed formulas also have been successfully fed to children with allergies for many years, and the experts generally agreed that they are the treatment of choice for food-sensitive enteropathies. In a study reported in this conference, no adverse reactions to extensively hydrolyzed casein formulas were found in children with cow milk allergies. In contrast, the role of partially hydrolyzed formulas has not been defined. These formulas are less allergenic than cow milk formulas but are probably not appropriate for children with allergies. DEVELOPMENT FORMULAS
OF HYPOALLERGENIC
More effective hypoallergenic formulas are needed, and the development and testing of these formulas were discussed in this conference. A proposed definition of a hypoallergenic formula for cow milk-allergic children is that it does not provoke any allergic signs or symptoms in at least 90% of infants with documented cow milk protein allergy when tested in double-blind, placebo-controlled food challenge trials. Before these formulas undergo clinical testing for allergenicity, nonclinical testing can characterize their molecular and physical properties to assess antigenicity. PREVENTION The conference also addressed the issue of prevention. To institute preventive measures for infants at risk of the development of allergies, we must first identify those at risk. The experts agreed that a family history of allergy is still the strongest predictor of the development of allergies. Cord blood lgE has been used to predict risk of allergy in research studies, but it is not as reliable as the family history and cannot be used as the only test.
The results of a study using a hydrolyzed formula as a supplement to breast-feeding or by itself during early infancy for the prevention of allergies in high-risk children were presented, Allergic eczema was shown to be decreased by early feeding of hydrolysate at 2 and 4 years of age but not during the first year. These results contrast with those in another prospective, controlled study that showed a benefit of dietary intervention only during the first year of life. There is also some evidence that such factors as breastfeeding, the avoidance of antigen exposure during pregnancy and lactation, and the delay and staged introduction of solid foods can decrease the incidence of allergy in highrisk populations. RECOMMENDATIONS Finally, the following recommendations can be made for future research: 1. We need more basic research to understand better the pathophysiology of food-sensitive enteropathies so that we can better diagnose, prevent, and manage these conditions. 2. The allergenicity of any formula used for the treatment of allergies must be confirmed in clinical studies using double-blind, placebo-controlled food challenges in children with confirmed allergies. In addition, future studies must address the efficacy of formulas for various subclasses of food intolerance. 3. The infant formula industry and academic institutions need to work together (a) to develop better methods of identifying the components of hydrolyzed formulas that are still antigenic and (b) to develop more palatable formulas that have a greater proportion of small peptides. 4. Further studies, especially in human infants, are needed to understand the mechanisms of oral tolerance. 5. We need a better understanding of the factors that p affect allergy expression so that we can institute effective preventive measures. The use of special formulas and other dietary modifications for allergy prevention must be studied further before general recommendations can be made to parents of children at risk of allergies.
