From Joseph Levy. A Guide to Children's Digestive and Nutritional Health. 2001. With permission.
FOOD ALLERGYConsidering the complexities of the interaction between ingested foods and the intestinal lining, it is not surprising that reactions to foreign proteins and other chemicals are commonplace. The remarkable fact is the effectiveness of antigen processing and the development of tolerance in the majority of children by the time they are 1 year of age.
Knowledge of food families and composition of frequently used commercial foodstuffs is very helpful in the detective work often needed to unravel the obscure histories presented by the concerned and baffled parent.
MECHANISMS OF FOOD ALLERGY
Not all adverse reactions to foods are allergic in origin, and the term should be used more precisely to describe reactions mediated through immune mechanisms. Some of the identified mechanisms include:
The IgE-mediated reactions can be of extreme severity, producing anaphylactic shock after exposure to minute amounts of the offending antigen. Direct exposure to the GI tract lining is usually needed to trigger the reaction, but cases have been described in which inhalation of food being prepared or cooked can result in the same severe reaction. This type of reaction is mediated through mast cells in the intestinal lining, and both histamine and prostaglandins have been implicated in the allergic cascade. It is less clear that immune complexes (Arthus type II reaction) participate in allergies to food, but IgG does have the potential to form complexes in vitro when reacting with certain antigens.
Cell-mediated delayed hypersensitivity (Type IV) can be expressed via intra-epithelial lymphocytes. In some patients with cow’s milk protein allergy, it has been found that a subpopulation of the circulating lymphocytes is specifically inducible to release leukocyte migration inhibition factor. This is suggestive of a T cell-mediated mechanisms homing on the intestinal cell and causing cell damage. The lining of the intestinal tract becomes progressively more effective in blocking out foreign proteins. Absorption of large food proteins is more pronounced in infants and children, one reason why reactions to foods are more prevalent in the younger years. Absorption is also enhanced by damage to the lining, as occurs with severe gastroenteritis or during sensitization to one particular antigen. In pancreatic insufficiency, processing of proteins is impaired and more exposure to foreign antigens takes place. Once the damage has occurred, multiple allergies can develop from absorption of “innocent bystander” antigens and from a more "leaky" gut.
Keeping toxins and foreign antigens away is a complex process that involves immunologic and nonimmunologic components. The intestinal mucus produced throughout the GI tract, breakdown of proteins by stomach acid, and engulfment of absorbed antigens by specialized cell contribute to keeping the outside world away from the “self”.Immune protection is afforded locally by other special cells, the GALT or gut-associated lymphoid tissue. The secretory IgA system is of particular importance in decreasing the invasiveness of bacteria. In conditions of selective IgA deficiency or generalized immune deficiency, chronic digestive problems are common and are often responsible for much of the patient's suffering.
Antigens in Food
Every food imaginable has been implicated in cases of abnormal reactions after ingestion. Whether the underlying mechanism is an allergic one or not cannot be determined in most cases, but from a practical standpoint, once the suspicion is raised that something in the diet is responsible for the patient’s symptoms, the challenge is to narrow the range of possible allergens, establish a casual relationship, and prove it by a process of elimination and careful rechallenge. Milk proteins are powerful allergens and probably the most common trigger of childhood food allergies. When milk curdles, two major protein fractions are generated: the soluble whey and the precipitated casein. Caseins constitute about 80% of cow’s milk protein compared to only 60% in human milk. Whey proteins are considered to be the most immunogenic, particularly the ones contained in the lactalbumin fraction: beta-lactoglobulin, alpha-lactalbumin, and serum albumin. In addition to those protein synthesized in the mammary gland of the cow, sensitization can occur to bovine serum proteins passively excreted in the milk. Similarly, human milk can contain foreign proteins circulating in the mother, and these are able to induce allergy even in the exclusively breast-fed infant.Interestingly, in view of the recent popularity of goat’s milk, cross-reactivity with cow’s milk proteins is frequent since they share antigenic similarities. Clinically, positive challenges to goat’s milk have been reported in children with documented cow’s milk allergy. Cow’s milk has been shown to contain other substances potentially allergenic such as antibiotics, bacteria and pesticides. When milk is heated, some of its proteins are denatured, thus becoming less allergenic. Whey proteins are among the heat labile fractions, and some patients will tolerate milk that has been boiled. Caseins are stable at 100C. Digestion of caseins with trypsin markedly reduces their antigenicity, and casein hydrolysates are commonly used in proprietary hypoallergenic formulas such as Nutramigen and Pregestimil (Mead-Johnson).
Other proteins commonly implicated in food allergy include ovalbumin (eggs), fish and shellfish, nuts, including chocolate (cocoa), yeast, and fruits from the rose (strawberries and other berries), citrus, and plum families. Soy has been used as a hypoallergenic protein source, but as many as 30% of patients with cow’s protein allergy have also shown reactions to soy, and it appears to be an important cause of food allergy in children since it is so frequently prescribed as a substitute of choice when formula intolerance is suspected. The better tolerance of soy-based formulas after gastroenteritis is more likely to be related to being lactose-free rather than to having a different protein source.
Clinical Aspects of Food Allergy
The most common manifestations of milk allergy are diarrhea, vomiting, and abdominal pains. A third of the patients will have allergic congestion of the nose (rhinitis) and eczema. Less than 15% will present with anaphylaxis. Half of the patients will have more than one symptom. If the intestinal damage is severe enough, fat and protein malabsorption can also occur. Occult or frank GI bleeding, and iron deficiency anemia can develop over a period of weeks or months, resulting in poor weight gain and malnutrition.
Symptoms can occur immediately following ingestion of the offending antigen, or slowly over a period of days. These two different patterns make the interpretation of food challenges difficult at times, since exposure has to be continued for at 48-72 hours, if not more, in order to determine a cause and effect relationship.
Other respiratory symptoms include asthma, chronic cough, and signs of bronchial or small airway congestion. The association of pulmonary infiltrates from recurrent pneumonia, spitting of blood, and wheezing has been described in a few cases with the so-called milk-induced syndrome with pulmonary disease (Heiner’s). In addition, those patients exhibit iron deficiency anemia, eosinophilia and failure to thrive. Milk-induced hemosiderosis, recurrent pneumonia, spitting of blood (hemoptysis), and anemia are also found in some children, and this diagnosis is strongly suggested by the presence of iron-filled white cells in the sputum or gastric washings. Skin manifestations can occur in 50%-75% of infants with cow’s milk allergy. Eczema or atopic dermatitis are most commonly encountered, urticaria (hives) less frequently so. Local reactions in the lips and oral mucosa, irritation around the rectum, and other rashes occurring after food ingestion have been observed.More controversial and difficult to prove are behavioral and psychological reactions interpreted by some as allergic manifestations in the brian. The allergic tension fatigue syndrome, as it has been called, includes such nonspecific symptoms as inability to concentrate, restlessness, depression, learning difficulties, headaches, tiredness, muscle aches, growing pains, and respiratory congestion. Iron deficiency anemia can also be present. Interestingly, a similarly constellation of psychiatric and physiologic features is present in the untreated child with wheat sensitive intestinal damage, and the response to a gluten-free diet can be as dramatic as that seen in the allergic tension fatigue syndrome when a successful elimination diet is instituted.
Infectious gastroenteritis can initially mimic all the symptoms of food intolerance. The acute onset, presence of fever, similar cases in the community, and clinical course will usually help in the diagnosis. Infection with parasites, on the other hand, can present over many weeks and months. Abdominal distention, diarrhea, fat malabsorption, poor appetite, and worsening of symptoms in relation to meals can be subtle, and stool examinations can be helpful. Carbohydrate intolerance (lactose, sucrose, or even glucose malabsorption) should be considered in every case of food and formula intolerance. Symptoms associated with rapid intestinal transit, watery diarrhea, and fermentation of malabsorbed sugars are often clinically indistinguishable from immunologically mediated food. Celiac disease, a specific intolerance to gliadin, a component of gluten found in wheat, rye, and other cereals, can present with gastrointestinal symptoms suggestive of food allergy. Abdominal distention and loose bowel movements can be prominent. Some patients will have only one or two stools a day, but their description and analysis confirms fat malabsorption. Failure to thrive, muscle wasting, and iron and folic acid deficiencies can be part of the full-blown celiac syndrome or develop secondary to intestinal damage secondary other protein allergies. Occult blood loss detectable by the guaiac (Hemoccult) test can result from invisible or obvious inflammation of the large intestine (colitis) triggered by cow’s milk allergy.The differential diagnosis of colitis in a young child includes, in addition to the chronic ulcerative form, infections with bacteria such as Salmonella, Campylobacter, Shigella, or Yersinia. Involvement of the colon by rotavirus can also occur. The presence of pulmonary symptoms suggestive of hypersensitivity, wheezing, recurrent bronchitis or cough, and gastrointestinal complaints worsened by food ingestion should always prompt a consideration of cystic fibrosis. At times, pulmonary symptoms can be minimal, and diarrhea or fatty diarrhea can be more obvious.
Nonspecific Diarrhea of Childhood
Probably one of the most common causes of loose stools in children under age 4 years who otherwise are well and thriving is the interesting syndrome of chronic nonspecific diarrhea of childhood, sometimes also called “Toddler’s diarrhea”. It is usually a diagnosis of exclusion, but the clinical picture is characteristic. Diarrhea usually appears around the first birthday and clears gradually by age 3-4 years. Stools tend to have some mucus, are large, and run out of the diaper. Visible vegetable fibers are commonly reported (not an abnormal finding, considering that fiber is, by definition, indigestible). Four to six movements a day are commonplace. Major considerations in the differential diagnosis include:
In most of these children, simple manipulation of the diet and reduction of total fluid intake (especially of high carbohydrate drinks and fruit juices) are helpful. A low-fat diet is also a common finding among this group of children, either because of the parent’s beliefs that such a diet is more healthful, or because their physicians have instituted restricted intakes for prolonged periods of time. Often, a return to a more normal diet and restriction of fluids can result in a dramatic and welcomed change in the stool pattern.
The diagnosis of food allergy is made on the basis of the clinical history and the response to a carefully designed elimination diet. Overdiagnosis is common, and this results in unfair limitations to the patients diet. Ascribing a host of complaints to food allergy does not always result in their resolution. The bewilderment and frustration of parents trying to understand what they are doing wrong with their child’s feedings is usually avoidable if the problem is approached with an open attitude from the beginning.The younger the child, the easier it is to sort out a possible connection between ingested food and symptoms. The history should focus on the specific components of the intake, their amounts, frequency, and associated responses. A thorough knowledge of the composition of infant formulas and baby foods is necessary to properly evaluate a suspicion of allergy. A common mistake is to change formulas without realizing that all that has been changed is the name of the manufacturer!
Associated features to be elicited in the evaluation are other pulmonary, skin, or immunological manifestations of hypersensitive skin. A family history, if reliable, is also useful. More often, evidence of milk and other allergies in other family members (close and distant) is totally based on hearsay and is more confusing than helpful.
Asking the parents to keep a food diary can be revealing and gives them an opportunity to be objective, concentrating on the reporting rather than on the interpretation of symptoms. At times, a clear correlation will be evident from the diary, and a lack of correlation will also be important information. Diaries should be kept for a full week or 10 days since, in certain instances, ingestion of the responsible food is not frequent enough to allow detection.
Laboratory investigations can offer support to a tentative diagnosis of allergic mediated symptoms, but negative results do not rule out food allergy. Peripheral eosinophilia (absolute eosinophil count greater than 400/cu mm) is suggestive of allergy, but not necessarily of food allergy. In fact, increase in the neutrophil count is seen more commonly during challenge in milk-allergic children. Eosinophilic debris can be detected in the stool, the so-called Charcot-Leyden crystals, or in gastric mucus and other secretions of children who are food allergic. Serum immunoglobulins can show a diffuse or specific pattern of abnormality. Selective IgA deficiency is commonly associated with gastrointestinal symptoms, including allergy. Elevation of the IgE fraction is suggestive of a hypersensitivity-mediated mechanism. Parasitic infestation and pulmonary allergies can elevate the serum IgE.
More sophisticated tests of food allergy have been developed in recent years; none is fail-proof and a negative test does not rule out clinical disease. The radioallergosorbent (RAST) technique allows identification of IgE antibodies against specific antigens located in specially treated paper discs. The test is expensive and requires a reliable laboratory. It is precise and reproducible, but antigens need to be standardized. The RAST technique is useful for screening highly allergic patients in whom previous reaction have been worrisome or life threatening. In patients with extensive atopic dermatitis where skin scratch or prick tests are not feasible or recommended, the RAST test offers a valuable alternative. New antibodies to IgG-mediated allergic reactions will expand the usefulness of this test. Other in vitro tests for food allergy, such as precipitation and agglutination tests or identification of antibodies in the stool (coproantibodies), have not gained widespread use because of their lack of specificity and sensitivity and the problems associated with the processing of fresh stool needed for some of the tests.
Elimination of the suspected protein is instituted when there is enough in the history to raise a reasonable doubt for the connection to symptoms. Based on the history, and review of food diaries, the diet is modified either singly or by elimination of several high-risk food groups. It is most important to be familiar with the many ways in which milk, egg, or wheat products are hidden in commonly used foodstuffs. Processed meats (unless they are kosher) will usually contain milk as fillers. The same applies to prepared soups, cereals and pasta, baked goods, pudding, and of course, ice cream. Chocolate contains milk and egg proteins and is one item to avoid in any highly sensitive patient. Other highly allergenic products include corn, nuts and legumes (including soy), fish, and cola.
The elimination diet should be continued for at least 3 weeks before deciding whether it has been useful or not. After symptoms have improved or subsided, reintroduction of new foods is made slowly, one at a time every week or two. If the patient is confirmed milk allergic, no challenge should be made for at least 6 months. Based on the initial presentation and severity of the intolerance, this period should be extended to a year or two. As the child grows, tolerance develops for many foreign proteins, and only a minority of milk-allergic children will remain so after the toddler years. On the other hand, other proteins might develop allergies later in life.
As mentioned before, many proteins are sensitive to heat, and cooking will make them less allergenic. It is good practice to avoid the ingestion of uncooked food such as eggs, beef or fish in highly allergic individuals.
If one concludes at the end of the investigation that wheat-related symptoms are highly probable and if the patient has the signs of malabsorption syndrome, arrangements should be made for consultation with a gastroenterologist. An intestinal biopsy is necessary to rule out celiac disease. More harm is done by empirically placing a patient on a longstanding gluten-free diet than by documenting damage of the lining of the intestine prior to the institution of such a restrictive diet. Celiac disease is a lifelong diagnosis that should not be made on the basis of the clinical response alone, since the implications of not following a strict gluten-free diet for life can be detrimental. There are reports of increased intestinal cancers in untreated celiac patients, and it is also known that gluten intolerance can be well established with total or subtotal damage to the intestine with few clinical signs or symptoms. Unfortunately, there are no shortcuts when it comes to the firm diagnosis and adequate management of celiac disease.