SESSION I' BASIC CONCEPTS OF FOOD ALLERGY AND FOOD INTOLERANCE

Definitions and diagnosis of food intolerance and food allergy: Consensus and controversy

A n n e Ferguson, FRCP, FRCPath

From the Gastrointestinal Unit, Department of Medicine (Western General Hospital), University of Edinburgh, Edinburgh, Scotland

This article describes the terms used for the various syndromes and diseases as- sociated with reactions to foods; it outlines the principal types of food intoler- ance encountered in children, with particular emphasis on those caused by im- mune-mediated reactions of immediate hypersensitivity. Terms defined include food intolerance or food sensitivity; food allergy or food hypersensitivity; psy- chological ly based food reactions (food aversions); and psychosocial and neurologic dysfunction. The spectrum of food sensitivity is considerable, and diagnosis is generally based on the monitoring of effects of exclusion diets and provocation tests, after appropriate objective measures are first selected. In children, manifestations of IgE-mediated food allergy (often in association with other immune mechanisms) include self-limiting and immediate reactions (e.g., urticaria, wheeze) and chronic diseases (food-sensitive enteropathies, eczema). Controversial and unresolved issues exist with some other conditions, including eosinophilic gastroenteritis, occult gastrointestinal bleeding, protein- losing enteropathy, and attention deficit disorder with hyperactivity. New meth- ods for clinical investigation of gastrointestinal tract function and intestinal immune reactions are required to assess the relevance of foods in these con- ditions. (J PEDIATR 1992;121:$7"$11)

B A C K G R O U N D

The increased public awareness of the relevance of diet to health has enhanced the idea that "allergy" to foods, food additives, beverages, and even water causes a wide range of distressing physical and psychologic problems and chronic, disabling diseases. It is true that there are many different mechanisms by which an individual may develop an adverse clinical reaction to a food and that psychologically based reactions to foods are common. Unfortunately, despite many claims for effective in vitro diagnostic tests, the pre- cise diagnosis of diseases and reactions of food intolerance generally relies on clinical methods. For excellent, compre- hensive, and up-to-date coverage of specific diseases, the reader is referred to a 1991 book edited by Metcalf et al.,

Reprint requests: Anne Ferguson, FRCP, FRCPath, Department of Medicine, Western General Hospital, Edinburgh, Scotland EH4 2XU, United Kingdom. 9/0/42042

Food Allergy: Adverse Reactions to Foods and Food Ad- ditives. 1

This article describes the terms used for the various syn- dromes and diseases associated with reactions to foods; it also outlines the types of food intolerance encountered in

CMP Cow milk protein ]

children, with particular emphasis on those caused by im- mune-mediated reactions of immediate hypersensitivity.

S C O P E A N D D E F I N I T I O N S

Adverse reactions to ingested food cause a wide variety of symptoms, syndromes, and diseases for which the general descriptive terms "sensitivity" and "intolerance" are use- ful.2, 3 These terms do not imply specific mechanisms for their pathogenesis and can be applied to a reaction with an unknown mechanism as well as to a clearly defined meta- bolic, pharmacologic, or immunopathologic process. The

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S 8 Ferguson The Journal of Pediatrics November 1992

provoking agent may be a single food or ingredient, although sometimes many different foods are involved, par- ticularly in IgE-mediated food allergy.

Recommended definitions. Food intolerance or food sen- sitivity is a reproducible, unpleasant (i.e., adverse) reaction, not psychologically based, to a specific food or food ingre- dient. It occurs even when the affected person cannot iden- tify the type of food that has been eaten. Mechanisms responsible include enzyme deficiency (e.g., lactase defi- ciency), pharmacologic effects (e.g., those caused by caf- feine), nonimmunologic histamine-releasing effects (e.g., those caused by certain shellfish), and direct irritation (e.g., by gastric acid in esophagitis, colonic flatus in carbohydrate intolerance).

Food allergy or food hypersensitivity is a form of food intolerance in which there are both a reproducible food in- tolerance and evidence of an abnormal immunologic reac- tion to the food (mediated by antibody or T lymphocytes or both). Unfortunately, many people believe that the word "allergy" implies any type of adverse reaction, and many health professionals use the terms "food sensitivity" and "food allergy" interchangeably. Furthermore, those practi- tioners most familiar with the concept of IgE-mediated hy- persensitivity (such as otolaryngologists and thoracic phy- sicians) frequently fail to take into account the importance of immune mechanisms resulting from other forms of reac- tion, such as delayed,type hypersensitivity or immune com- plex reactions. The term "pseudo food allergy" is usually used for reactions involving histamine or mast cell degran- ulation as a mechanism in which the primary stimulus is nonimmunologic (i.e., not IgE antibody).

Psychologically based food reactions (food aversions) comprise both psychologic avoidance, in which the subject avoids food for psychologic reasons, and psychologic intol- erance, which is an unpleasant bodily reaction caused by emotions associated with the food, rather than by the food itself, and which does not occur when the food is given in an unrecognizable form.

Psychosocial and neurologic dysfunction. Rarely, evi- dence of food-brain interactions is present in patients with psychologic or neurologic diseases, such as attention deficit disorder with hyperactivity, epilepsy, or migraine. How- ever, careful clinical studies have revealed that such asso- ciations may be the result of suggestion or adverse condi- tioning, rather than the result of a pharmacologic mecha- nism; in any event, foods are not a component of these disorders in most patients.

D I A G N O S T I C A P P R O A C H E S

Elimination diet and challenge. Even the most experi- enced clinician may have difficulty elucidating the exact re-

lationship between dietary constituents and the clinical phenomena observed in an individual patient or a specific disease. It has therefore become established practice to use, as diagnostic criteria, the objectively monitored effects of exclusion diets and provocation tests. Some ingenuity may be required to define the objective measures, which may in- clude, for example, serial recordings of forced expiratory volume or of nasal airflow, mapping of the extent and severity of skin rashes, daily aphthous ulcer counts, mea- surements of fecal characteristics, intestinal permeability tests, and morphometry of mucosal biopsy specimens.

The spectrum of food sensitivity is considerable and en- compasses virtually all medical specialties. For example, in children with atopic eczema, appropriate elimination and challenge protocols have shown that approximately 60% respond positively to specific food challenges with dermal, gastrointestinal, and respiratory reactions. Many different foodstuffs may be implicated, and the mechanism of food intolerance is allergic, involving IgE and mast cells. Celiac disease is currently defined by a different approach: the his- tologic effects on the small bowel of a gluten-free diet fol- lowed by a gluten challenge. The intestinal damage is prob- ably induced by activated T cells. On the other hand, the common condition of lactose intolerance is highly dose de- pendent and is due to deficiency of an intestinal brush-bor- der enzyme, lactase.

Problems with placebo responses. Experience with elim- ination diets and challenge protocols reveals that patients' perceptions and physicians' diagnoses of food intolerance are not invariably accurate. In patients with clear and con- vincing histories of adverse reactions, fewer than half can usually be confirmed as intolerant by means of objective testing. Furthermore, double-blind protocols reveal a high rate of symptomatic responses to placebo in some groups of adults; this placebo effect is rare in children. The diagnosis for those individuals who respond to open but not to blind challenge is a matter of great controversy. One school of thought is that m~ny such patients have masked psychiat- ric disease that should be recognized and appropriately treated .4

I M M E D I A T E H Y P E R S E N S I T I V I T Y R E A C T I O N S : R E L E V A N T T H E O R E T I C A L A S P E C T S

An antigen is a substance capable of inducing an immune response when introduced into the tissues of an animal. At the molecular level, reactions of immediate hypersensitivity result from cross-linking of the Fab regions of two IgE molecules on the surface of a mast cell, by divalent antigen. To evaluate the way that such reactions might arise in a human infant, one must consider the induction phase,

Volume 121 Definitions and diagnosis of food intolerance and food allergy $ 9 Number 5, Part 2

whereby lgE antibodies to harmless dietary antigens are produced, as well as factors that influence the expression of the hypersensitivity reaction after reexposure to antigen. 5

Active immunization. Normally, there should be oral tol- erance (i.e., specific suppression) rather than induction of IgE antibody when antigen is fed. Circumstances in which IgE is induced relate more to the patient's atopy than to the nature or molecular form of antigen or to the amount or se- lectivity of gut permeability. Typically, extremely small doses of antigen prime the individual and sustain IgE responses. For example, the annual dose of pollen allergen encountered by an adult is 1 #g.

Detection and measurement of IgE antibody. If a suitable antigen preparation is available, IgE (reaginic) antibody is detected by skin-prick tests or, in serum, by the radioaller- gosorbent technique. However, the absence of detectable antibody in an apparently sensitized person may merely mean that the reagent being used is subtly different from the molecule that triggers mast cells in vivo. Furthermore, many atopic patients have IgE antibodies, often in high ti- ter, to substances that they fully tolerate.

Localization of the IgE-sensitized mast cells. Mast cells in tissues may acquire IgE from serum or from plasma cells in the immediate vicinity, or they may have been sensitized as they migrate before lodging in the tissues. Organ distri- bution of mast cells is an aspect little considered by aller- gists, but it is probably the main reason that some individ- uals have a primarily dermal reaction to antigen challenge, others react in the nose or the gut, and others have systemic anaphylaxis.

Antigen challenge. A hypersensitivity reaction requires reexposure to antigen. The very small quantity needed for degranutation of IgE-sensitized mast cells normally reaches the tissues via the bloodstream, after entry into the body through the mucous membrane of the mouth, stomach, or proximal portion of the intestine. Theoretically, antigen could also reach the gut lamina propria through the over- lying surface epithelium.

Mediators of hypersensitivity. In the case of immediate hypersensitivity, the visible, histopathologic, and functional effects are entirely due to mast cell mediators. Some are preformed and released from the cell at the time of antigen exposure; others require synthesis and thus are secreted more slowly.

Detection and measurement of reactions. Mast cell medi- ators such as histamine may be secreted after antigen chal- lenge and can be assayed in a biopsy specimen or in blood. A reduction in mast cell count in histologic sections taken after challenge is indirect evidence that degranulation has occurred.

"Cascade" of additional inflammatory and immunologic

responses to other antigens. As a result of secretion of inflammatory mediators, the capillaries and epithelium of the affected tissue become more permeable to plasma, lym- phocytes, polymorphonuclear and other cells, and, in the gut, enteric antigens. Thus, soon after the antigen-specific hypersensitivity response starts, a variety of other hyper- sensitivity and inflammatory reactions may develop. These effects may be much greater than those directly related to the original antigen challenge. In other words, the local re- action of immediate hypersensitivity facilitates the expres- sion of local IgE responses to other antigens, as well as to immune complex and delayed-type hypersensitivity reac- tions.

Prevalence of atopy. In view of the importance of family history as a risk factor for the development of food allergy in childhood, data on prevalence of the atopic state are of great importance. In a study that we carried out in Edinburgh several years ago, 6 36 of 103 healthy volunteers aged 17 to 70 years were atopic (defined as the presence of a positive skin-prick reaction to at least one inhalant anti- gen, with appropriate negative and positive responses to sa- line and histamine control solutions). Sixteen subjects had three positive skin test results. The prevalence was highly age related: up to age 30 years, 60% of subjects were atopic, but in those older than 30 years, only 24% were atopic. Similar frequencies were found in groups of patients with inflammatory bowel disease. 6

M U L T I P L E M E C H A N I S M S IN A N I N D I V I D U A L P A T I E N T W I T H F O O D S E N S I T I V I T Y

Even when there is proof that food sensitivity may cause a symptom or disease, more than one immunologic, phar- macologic, or other pathophysiologic mechanism may be at work, relating to one or more constituents of the diet. Of- ten, physiologic changes and pathologic processes coexist.

Several well-recognized diseases are associated with ex- posure to wheat, such as celiac disease and "baker's asth- ma." On the other hand, when a person starts to ingest a high-fiber diet, there may be profound, though physiologic, effects on several aspects of gut function in the absence of disease. An introspective individual may, however, become concerned about these effects unless forewarned. These ef- fects include the following:

�9 Rapid gastric emptying �9 Rapid mouth-anus transit time �9 High stool weight �9 Softer stool �9 Increased frequency of defecation �9 Increased quantity and altered nature of flatus. Migraine is an excellent example of the interweaving of

S 1 0 Ferguson The Journal of Pediatrics November 1992

Table. Protocol for the diagnosis and management of food sensitivity

1. Full clinical assessment and relevant general investigations

2. Personal and family features of atopy, allergy, immune status

3. Elimination diet (until well) 4. Open food reintroduction 5. Objective measurements of disease activity 6. Maintenance diet 7. Double-blind challenges 8. Final maintenance diet (with nutrient supplements if

necessary)

many factors in triggering an attack. Such factors include genetic predisposition or an unusually strong family history of migraine, social and life-style factors (e.g., smoking, use of contraceptive pills, fatigue, stress, menstrual cycle), use of certain drugs (e.g., monoamine oxidase inhibitors), activity of hormones, and diet (e.g., cheese, chocolate, alco- hol, citrus fruit).

Milk allergy is implicated in various chronic diseases. Three different situations pertain in these patients:

1. All cases of the disease are caused by milk allergy (e.g., cow milk-sensitive enteropathy). However, other sin- gle foods, such as soya, may produce an identical condition.

2. Several substances--milk, other foods, and other al- lergens, particularly inhalants--are implicated in the patho- genesis of the disease (e.g., atopic eczema).

3. Allergy, including food allergy, is only one of several possible causes of a symptom or disease (e.g., diarrhea, wheeze).

I M M E D I A T E H Y P E R S E N S I T I V I T Y R E A C T I O N S A N D F O O D I N T O L E R A N C E I N C H I L D R E N

There is a wide range of manifestations of food allergy of the IgE type. In many cases, other immune mechanisms are also involved.

Self-limiting and immediate reactions. In an atopic child, who may have IgE antibodies to many inhalant and dietary antigens, wheeze, rhinorrhea, urticaria, angioedema, diar- rhea, vomiting, or even systemic anaphylaxis may develop within minutes of exposure to a provoking substance.

Chronic diseases associated with food allergy Food-sensitive enteropathy. Small intestinal mucosal

damage with malabsorption is best doct~mented for intoler- ance to cow milk protein but can also occur with intolerance to soy, chicken, rice, fish, and egg. The classic case of the malabsorption syndrome with CMP intolerance consists of diarrhea and failure to thrive in an infant; vomiting is also a feature, and some patients have atopic eczema and recur-

rent respiratory infections. Gastrointestinal investigations show malabsorption, and jejunal biopsy reveals abnormal- ities of the jejunal mucosa, ranging from moderate villus atrophy to pathologic findings indistinguishable from those of celiac disease. Treatment with a cow milk-free diet (e.g., banked human milk, elemental diet) induces rapid remis- sion. Once clinical recovery is complete, the diagnosis may be confirmed by an in-hospital milk provocation test. Most of these Children will be clinically tolerant of cow milk by the age of 1 year, although the proximal jejunal mucosa of- ten shows persistent but minor abnormalities.

Lactose intolerance overlaps with the syndrome of CMP- sensitive enteropathy. When there is extensive villus atro- phy, loss of disaccharidase-containing mature enterocytes leads to a relative reduction in the disaccharidase activity of the small-bowel mucosa; there may be reversible lactose intolerance induced by the intestinal damage caused by CMP intolerance. The most important practical aspect is that lactose intolerance should not be accepted as a primary explanation of malabsorption or failure to thrive. Lactose intolerance can accompany a number of other more serious enteropathies. When a milk challenge is to be given, it is of- ten advisable first to carry out a lactose challenge in the symptom-free infant whose diet includes no milk. If this produces no clinically adverse effect, a subsequent reaction to a challenge with whole cow milk can be attributed to the protein constituents rather than to the lactose.

Gastrointestinal bleeding. Blood loss associated with the use of formula diets instead of human milk has been proposed as an explanation for iron deficiency anemia in infants. No immunologic evidence supports the theory that this phenomenon has an immune basis.

Eosinophilic gastroenteritis. Eosinophilic gastroenteritis encompasses inflammatory lesions, discrete or diffuse; the disease may affect any part of the gut. The relationship to foods probably varies from one case to another, and the presence or absence of atopy as an independent variable should be considered. Treatment with corticosteroids may be preferable to the empiric use of elimination diets. Proper studies of mucosal mast cells sometimes show that these are abnormally abundant.

Attention deficit disorder with hyperactivity. In the few well-documented cases in which food sensitivity has been established, the mechanism is likely to be pharmacologic.

Foods colitis. Food-sensitive colitis is character- ized by bloody diarrhea but differs from ulcerative colitis in many clinical and pathologic features. Many years ago, rectal bleeding was described as a feature of cow milk al- lergy in infants. The fact that this symptom might be due to colitis emerged when studies of the age distribution of children with colitis were performed and an excess number of infants emerged, producing a bimodal distribution; this

Volume 121 Definitions and diagnosis of food intolerance and food allergy S 1 1 Number 5, Part 2

finding suggested that colitis might have different causes in infancy and at other ages. From careful clinical descrip- tions, the specific entity of allergic infantile colitis was rec- ognized and formally documented.

Typically, an infant with food-sensitive colitis is seen be- fore the age of 1 year with loose stools containing mucus and blood. An elimination diet, with clinical monitoring and rectal biopsies, results in a pattern of improvement similar to that seen clinically and with jejunal biopsy in cow milk- sensitive malabsorption syndrome. The pathologic changes in the rectum differ from those of classic ulcerative colitis in that there is preservation of the architecture of the mu- cosal crypts with no crypt abscess formation and no deple- tion of goblet cell mucus. Additionally, substantial numbers of eosinophils and plasma cells are seen in the infiltrate of the lamina propria. These infants respond well to the elim- ination of cow milk from their d ie t - -or from the mother's diet if they are still being breast fed. Severe clinical colitis may be induced by a milk challenge; it is recommended that the rectal abnormalities, together with clinical and patho- logic improvement on an elimination diet, be used to diag- nose food-sensitive colitis. As in food-sensitive enteropathy, most children can tolerate cow milk by the age of 2 years.

Atopic eczema. The incidence of atopic eczema is rising in Britain, and foods are among the many environmental factors that make this distressing skin disease worse. The strongest evidence of a role for food in the pathogenesis of atopic eczema comes from studies in which children with atopic eczema have responded well to exclusion diets in double-blind, controlled, crossover trials. Although eczema can occur in exclusively breast-fed infants, this may be due to the transfer of absorbed food antigens from the mother's diet to her milk. Food intolerance and enhanced immune responsiveness to foods are also features of atopic eczema in adults. The antigens concerned are usually fish, shellfish, eggs, andnuts; milk sensitivity does not seem to be impor- tant.

Controversial and unresolved issues Protein-losing enteropathy. When not accompanied by

other signs of gastrointestinal disease, protein-losing enter- opathy has in the past been attributed to food allergy. In animal experiments, considerable increase in gut perme- ability to marker proteins occurs in association with ana- phylaxis. However, in clinical practice, a patch of lym- phangiectasia or jejunal Crohn's disease should be consid- ered in the differential diagnosis.

In protein losing enteropathy and also in suspected gas- trointestinal bleeding, the recently described technique of whole-gut lavage, with assay of plasma-derived proteins in the lavage fluid, 7 provides a safe, new method for objective

appraisal of the effects of the elimination diet and challenge. Hemoglobin loss can also be quantified by using this approach.

A P P R O A C H E S TO D I E T A R Y T R E A T M E N T O F F O O D S E N S I T I V I T Y

There are two patterns of food sensitivity. The symptoms and clinical features may conform to well-recognized phe- nomena or to a disease associated with a specific food. The medical diagnosis and the foods concerned will be suspected from the history and confirmed by a small number of tests. Examples include asthma, rhinitis, and eosinophilia associ- ated with salicylate intolerance; flatus and diarrhea induced by sorbitol in diabetic foods; an increase in milk consump- tion, unmasking a previously asymptomatic lactose intoler- ance; and celiac disease in an anemic child with failure to thrive and a family history of allergy.

In other patients, food intolerance will be included in a wider differential diagnosis. When symptoms are mild, simple symptomatic treatment such as antihistamines for nasal stuffiness, antidiarrheal drugs, and analgesic agents for headache may be more appropriate initially than diag- nostic and therapeutic diets, which tend to be time- consuming and difficult (see the Table). If food intolerance is to be pursued, a baseline elimination diet is given for some weeks; if symptoms and signs disappear, relevant foods are identified during a planned perioffof reintroduc- tion and confirmed by placebo-contr61"[ed challenges, if feasible, before a nutritionally sound maintenance diet is prescribed.

REFERENCES

1. Metcalf D, Simon R, Sampson HA, eds. Food allergy: adverse reactions to foods and food additives. Cambridge, Massachu- setts: Blackwell, 1991.

2. Royal College of Physicians and the British Nutrition Foun- dation [joint report]. Food intolerance and food aversion. J R Coll Physicians Lond 1984;18:83-123.

3. American Academy of Allergy and Immunology and National Institute of Allergy and Infectious Diseases. Adverse reactions to foods. (NIH publication No. 84-2442, July 1984.) Bethesda, Maryland: National Institute of Health, 1984.

4. Ferguson A. Food sensitivity or self-deception? N Engl J Med 1990;323:476-8.

5. Ferguson A. Models of immunologically driven small intesti- nal damage. In: Marsh MN, ed. Immunopathology of the small intestine. New York: John Wiley & Sons, 1987:225-52.

6. Troncone R, Merrett TG, Ferguson A. Prevalence of atopy is unrelated to presence of inflammatory bowel disease. Clin Al- lergy 1988;18:111-77

7. O'Mahony S, Barton JR, Crichton S, Ferguson A. Appraisal of gut lavage in the study of intestinal humoral immunity. Gut 1990;31:1341-4.