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Gastrointestinal Manifestations of Allergy in Children
GASTROINTESTINAL MANIFESTATIONS OF ALLERGY IN CmLDREN JOSEPH H. FRIES, M.D.
I t is strange that a clinical entity so specifically named as "gastrointestinal allergy" should be so often confused. Properly analyzed, gastrointestinal allergy must be an allergic response and must occur in the gastrointestinal tract. It is a consequence of union of antigen with the specific reagin (antibody) residing in the tissues of the alimentary tract. It not only can be a specifically localized tissue response, but may be part of a more widespread reaction with other shock organs participating. In contrast, it should be obvious that "food allergy" implies the simple and specific concept of allergy to foods. Such hypersensitiveness is capable of provoking symptoms in any tissue of the body, including the gastrointestinal tract. Both terms are frequently interchanged. Today the term "gastrointestinal allergy" unfortunately is loosely used to cover obscure digestive disorders which actually are organic or psychic, or, conversely, complaints due to food sensitivity, wherein the gastrointestinal tract is not even the shock or reactive organ. INCIDENCE
The incidence of gastrointestinal allergy does not lend itself to statistical determination. Inasmuch as the diagnosis is being used with increasing frequency as a label, especially in obscure, vague and indefinite disturbances of the digestive tract, accurate diagnoses of gastrointestinal allergy are few in number. Mild episodes are difficult to substantiate. Those which are immediate, severe and consistently and repeatedly provoked are easier to recognize. The incidence of gastrointestinal allergy is not static, inasmuch as it decreases with increase in age. Early literature on allergy mentions
995
996
GASTROINl'ESTINAL MANIFESTATIONS OF ALLERGY IN CHILDHOOD
the transition of infantile eczema to asthma, and of "abdominal migraine" to a cephalic type. 1 The spontaneous shift of reactivity, with increase of age, from the gastrointestinal tract (as from the skin) to other organs would result in a larger incidence of this malady in infants, in contrast with the older child or adult. Certain physiologic and anatomic changes occur in the skin which make it less vulnerable in later years, and by analogy it may be reasoned that comparable alterations occur in the gastrointestinal tract. Sensitivity to food, which is the most common cause of allergic reactions in the digestive tract, is also more frequently encountered in infancy and gradually and spontaneously decreases with maturity. For these reasons no definitive statistics of incidence are available. MECHANISM
The mechanism by which the allergen is brought into contact with the sensitized cells, thereby provoking gastrointestinal symptoms, may be that of direct or indirect exposure. The allergic reaction resulting from direct contact of the causative substance, usually a food, with the mucous membrane lining of the digestive tract is usually immediate. This is probably the phenomenon which produces the sudden swelling and blistering of the buccal mucosa, or the nausea and vomiting which may ensue immediately after ingestion. A further demonstration of reaction resulting from direct mucosal contact was the experimental production of colonic spasm promptly on the rectal instillation of an allergen in a barium enema in specifically sensitive subjects. The spasm which was demonstrable roentgenographically was not seen with a plain barium enema. 6 ,7 Secondly, production of gastrointestinal disturbances may involve the absorption of the antigen into the blood stream and its return via the circulatory system to the specifically reactive portion of the digestive tract. 21 This would account for allergic reactions in the lower bowel (e.g., rectal tenesmus) immediately after ingestion. Remarkably illustrative are the allergic reactions which have been induced experimentally in the exposed digestive tracts of passively sensitized rhesus monkeys and of human beings. 22 , 23 The clinical reaction, whether immediate or delayed, consists in mucosal edema, hyperemia and concomitant hyperactivity of; the secretory and mucous glands, with secondary muscle spasm. ETIOLOGY
Gastrointestinal reactions are most commonly caused by foods. In order of decreasing frequency of incrimination, they are milk, egg,
JOSEPH H. FRIES
997
chocolate, fish, nuts and orange, in addition to almost any other food. Drugs such as acetylsalicylic acid, sulfonamides, antibiotics and vitamins are occasional offenders. Parenterally injected substances such as pollen extracts and antibiotics may cause systemic allergic reactions in which the digestive tract participates; on rare occasions the digestive tract may be the only shock organ. Still more infrequent are gastrointestinal reactions to inhalants (osmyls), and these do not constitute a problem in the average pediatric practice. SYMPTOMATOLOGY
There is no symptom or pattern of symptoms which is specifically characteristic for allergy per se. Moreover, a single symptom (allergic abdominal pain, for example) may vary in its intensity, reaction time, duration, constancy, and association with coexisting symptoms. It helps to group these varied clinical manifestations according to the portion of the gastrointestinal tract involved, as follows: Buccal and pharyngeal Gastric Intestinal Miscellaneous (e.g., constitutional reactions' in which the gastrointestinal tract participates, mucous colitis,l1 rectal bleeding17 )
Visible changes of the digestive tract are readily recognized, such as angioedema of the buccal mucous membrane, palate, pharynx and tongue. Changes of the stomach and intestines are not normally visible. However, one must appreciate that these changes can and do occur in these less observable organs,14 Symptoms of urticaria or angioedema of the skin or mucous membranes concomitant with alimentary disturbances imply that similar changes may be occurring in these less obvious parts of the gastrointestinal tract. Groups of symptoms may form patterns not commonly characteristic of disorders on a hypersensitive basis. Some of these syndromes, heretofore considered organic and functional, are now recognized as being provoked on occasion by an allergic reaction, among them recurrent vomiting, pylorospasm, the celiac syndrome and colitis. Protective Mechanisms
The body utilizes several mechanisms to protect itself from encounters with substances noxious to the host. With reference to ingestants, these "protective" mechanisms vary from rejection to rapid expulsion of the substance from the bowel. For example, there is frequently a pronounced dislike for a specific allergenic ingestant when the untoward response is in the gastrointestinal tract. In infants a previous
998
GASTROINTESTINAL MANIFESTATIONS OF ALLERGY IN CHILDHOOD
experience or two with a burning taste in the mouth or other unpleasant sensation implants a memorable impression resulting in subsequent refusal of the food. If the food is accepted into the mouth, the child may reject it by spitting it out after the food has made contact with the buccal mucosa. In our experimental studies of ingestion of allergens 6 • 7 there was sometimes difficulty in getting children to swallow the antigen even when disguised in a barium meal. Nausea is most frequent in severe immediate types of gastrointestinal allergy to foods. 8 Vomiting is also common in severe sensitivity and represents a method of getting rid of the food substance before it is passed on to the intestine.8 Pylorospasm, by meting out small portions either through a narrowed obstructed pylorus or through prolonged, intermittent closures, slows down the rate of delivery of the antigen to the mucosal surfaces of the intestine. 3 Esophagospasm and cardiospasm are observable, although rare, "protests" to the passage of an antigen into areas of greater absorption. Diarrhea is a common method by which the host disposes of the antigen as rapidly as possible, thereby minimizing absorption. One can deduce that the forcing or disguising by parents of a specifically disliked or rejected food, especially one not essential to nutrition, is unwise and probably contrary to nature's intention in a known allergic child. Furthermore, it can be questioned whether a food which is producing physiologic disturbances in the gastrointestinal tract is adequately utilized nutritionally. Abdominal Pain
The classification of allergic abdominal pain made by the author5 in 1936 is still serviceable, utilizing three arbitrary divisions, depending on severity: 1. Severe abdominal pain, simulating an acute surgical condition of the abdomen in which differentiation from appendicitis, gallbladder disease, and so forth, is challenging 2. Abdominal pain of subacute recurrent nature 3. Abdominal pain as a subsidiary symptom (appearing during acute attacks of asthma or, more often, during severe outbreaks of urticaria or angioneurotic edema). Recurrent Vomiting
Vomiting (recurrent, cyclic or periodic) is a symptom-complex due to a variety of causes, including food hypersensitiveness. Studies by the
JOSEPH H. FRIES
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writer4 on selected allergic children noted that the purposeful ingestion of an offending food initiated attacks of vomiting, sometimes prolonged or recurrent. The avoidance of this food resulted in comparative freedom from attacks. Clinical sensitivity to a specific food correlated with positive cutaneous tests and passive transfer tests. There are many variables which make the establishment of proof in suspected cases difficult. There. are "anergic" periods and changes in the threshhold of tolerance depending on precipitating factors of stress, infection, and the like. Furthermore, there is the possibility of cumulative effects from the ingestion of the same allergen or a combination of different allergens. Pylorospasm
Visualization of allergic manifestations in the gastrointestinal tract by fluoroscopy and roentgenogram has made it apparent that the pylorus plays a large role in the allergic symptomatology of the stomach, a variety of disturbances of the pylorus being observed. Roentgen changes and associated gastrointestinal symptoms are reproducible experimentally by intentional feeding of barium meals containing the allergen.3 Such experiments point out that in the clinical interpretation of abnormalities in the pylorus the possibility of allergic involvement must be considered. In the opinion of some authors, constantly recurrent spasm of the pylorus may result in muscular hypertrophy, which may in some instances lead to pyloric stenosis.12 NUTRITION
Nutritional impairment in children with chronic, recurrent gastrointestinal reactions-as with other gastrointestinal disorders-is to be expected. Clinically, one sees, in severe instances, skin lesions which are highly suggestive of vitamin A deficiencies and evidences of other vitamin deprivations. Growth is sometimes stunted, and there may be impairment of musculature. The refusal of various foods frequently encountered results in a poor, finical eater, the child subconsciously associating nausea and other unpleasant reactions with intake of food. Severe restrictions in diet of essential foods such as milk, eggs, legumes, readily embarked upon by ent~usiastic physicians, cause havoc if followed too long or compensated for inadequately. Incomplete utilization of nutrients and vitamins resulting from disturbed motor function of the digestive tract certainly must exist. In addition, local angioedema may be induced which may affect the permeability of the gut for the ready passage of
1000
GASTROINTESTINAL MANIFESTATIONS OF ALLERGY IN CHILDHOOD
nutrients. In support of this, in studies as yet incomplete, I have ob· served interference with the absorption of vitamin A as indicated by an abnormally flat absorption curve in a few children with severe gastrointestinal allergy. DIAGNOSIS
The capriciousness of gastrointestinal allergy makes it necessary that all possible organic and psychic factors be thoroughly explored. It is worthy of repetition that allergy accounts for only a small percentage of digestive disorders in children. History
A careful history is of primary importance. It is in this field that a leisurely and detailed questioning of the parents (and, when possible, the patient) can be most informative. Cognizance should be taken of any possible association which may have been made between ingestants and symptoms, of food dislikes, and of common allergenic foods being eaten in large amounts. A familial or personal background for allergy, or association of other allergic manifestations in other shock tissues, gives confirmation that the gastrointestinal symptoms may be on an allergic basis. Cutaneous Tests
The frequent failure of cutaneous tests to correlate positively with proved clinical digestive symptoms of food hypersensitiveness points to the limitation of this diagnostic procedure. Occasionally, however, cutaneous reactions of the immediate wheal type do indicate the offending antigen. These range from markedly positive to negative reactions, both by direct and passive transfer methods. It is noteworthy that those patients demonstrating immediate, pronounced gastrointestinal disturbances are the ones who most frequently give marked positive dermal reactions (Table 32). Positive cutaneous reactions sometimes are obtainable with higher concentrations of the testing extracts, although not with the routine testing strengths. Sensitization may possibly exist specifically to the digested products of foods-to the proteose or other split derivatives of proteins, and not to the natural food. 2 • 19 In such cases routine cutaneous tests are negative. The absence of reactions in some subjects possibly may be due to the existence of other forms of food intolerance which are not based on a reaginic mechanism.
JOSEPH H. FRIES TABLE
32. Skin Reactions Resulting from I ntracutaneOU8 Testing with Gastrointestinal Allergy ALLERGEN
of
NITROGEN
DEGREE OF
AGE OF
CONTENT IN
REACTION
PATIENT
1001
30 Children
IN YEARS
MG. PER CC., OR DILUTION
Egg
0.0001
Egg
0.0001
Egg
0.0001
Egg
0.0001
Egg
0.01
Egg
0.01
Egg
0.01
Egg
0.01
Egg
0.01
Egg
0.01
Egg
++++ (x)* ++++ (x) ++++ (x) +++ (x)
3 6 6
6
12
0.01
+++ +++ ++ ++ + + +
Egg
0.01
0
12
Egg
0.01
0
6
Egg
0.01
0
5
Egg
0.01
0
11
Egg
0.01
0
9
Codfish
0.00001
6
Codfish
0.00001
++++ (x) ++++ (x) +++ ++++ (x)
Herring
0.0001
Walnut
0.005
Almond
0.05
Almond
0.05
+++ +
8
7 5
7 8 12
10
13 6 11
14
* (x) indicates patients who had marked clinical disturbances following ingestion of the alIergenic food. The technique used consisted in the intracutaneous injection of about 0.02 cc. of the testing extract. Reactions were classified according to the size of the wheal.
1002 TABLE
GASTROINTESTINAL MANIFESTATIONS OF ALLERGY IN CHILDHOOD
32 (Continued) ALLERGEN
NITROGEN
DEGREE OF
AGE OF
CONTENT IN
REACTION
PATIENT
MG. PER CC.,
IN YEARS
OR DILUTION
Oats
1:10
++ +++ ++++ (x) +++ +
Milk
1:10
0
5
Milk
1: 10
0
7
Milk
1:10
0
9
Wheat
0.05
Wheat
0.05
Cabbage
1:5
Sweet corn
1:5
4
8
7
12 10
Roentgen Findings
Intentional feeding of an identified allergenic substance for the purpose of inducing roentgenographic changes and the use of a contrasting meal of plain barium were reported first by Serio ls and later Rowe. 16 These reports were followed by the writer's studies on children,6. 7 which have since been corroborated by other workers. 13. 20 In my studies, gastric retention, hypermotility and gastric atony have been visualized in children (Fig. 33). Alterations in the roentgenographic pattern of the small intestine were infrequent. However, some instances of segmentation and hypermotility were observed. Regional constriction or dilatation of the large bowel also occurred occasionally. Furthermore, I have demonstrated marked spasticity of the transverse and descending colons by means of barium enemas containing antigen. Although the alterations found in the allergic gut are not pathognomonic, their presence should suggest the possibility of allergic gastrointestinal disturbances, particularly when other confirmatory findings are present.
Food Diary
For lack of accuracy of the skin test and of all other finite tests, reliance must be placed on a detailed food diary and on controll<:;d ingestion trials of suspect foods. The food diary must record daily intake
JOSEPH H. FRIES
1003
of all possible ingestants, including vitamins, medications and betweenmeal "snacks," in the quantity ingested and indicating time relationships. This should be paralleled by a record of symptoms in their proper time relationship. Trial Ingestion
With the clues provided by the history and by the food diary, ingestion of the suspected foods should be tried under controlled circumstances. Only one food may be tested at a time. This test should be
Fig. 33. Roentgenograms of a 6 year old boy who had asthma. Ingestion of nuts on many occasions caused vomiting and abdominal pain. Skin tests (intracutaneous) to almond, walnut and Brazil nut were positive. The roentgenograms shown here were 6 hour studies. A, Control with plain barium sulfate shows slight retention within the stomach. B, A comparative study with lh teaspoonful of nut added to the plain barium, without the patient's knowledge, shows gastric retention of more than two thirds of the meal. There is also marked spasm (closure) of the pylorus.
made on an empty stomach, preferably in the morning, and when the child is symptom-free. A small amount of the test food is given, and after fifteen to thirty minutes an increased quantity of the food is fed until symptoms are provoked or until the amount ingested considerably exceeds the quantity customarily eaten. When disturbances are delayed and occur beyond the testing period, the trial must be repeated for confirmation.
1004
GASTROINTESTINAL MANIFESTATIONS OF ALLERGY IN CHILDHOOD
Laboratory Investigations
Determination of the eosinophil content of the blood is of questionable value because it varies widely from day to day. The leukopenic index9 has proved equally unreliable in my experience. Rectal smears for eosinophils I have tried sporadically with questionable success and feel that further observation should be made before evaluating the favorable conclusions of others.15 One must bear in mind that destructive processes in the colonic area, or parasitic infestations, are also capable of producing eosinophils in the mucus obtained from the rectum. 24 TREATMENT
Elimination of food or chemical offenders is, of course, ideal therapy. In some instances, however, trial diets and cutaneous tests still fail to identify clearly all the incitants. In this circumstance the child can be placed on an empirically determined hypo allergenic diet, not ignoring the necessary inclusion of substitute foods to meet vitamin and nutritional requirements. This diet makes liberal use of foods processed by heat or dehydration, which lower their allergenicity (evaporated milk, dehydrated banana), and of foods of known low allergenicity even when these may be somewhat unusual in a child's diet (beet tops, Swiss chard, soy beans). When symptoms are controlled by such a diet, foods may be added gradually, paying particular attention to the detection of any which may cause untoward reactions. Hyposensitization by injection of an extract of the offending food is not only hazardous, but has never proved effective; nor has oral desensitization been successful in my experience. The antihistaminic drugs have been of doubtful value. I have had no experience with the use of corticosteroids for this type of allergic reaction, but presume that they might be effective for a severe episode when other agents have failed. Since most allergic gastrointestinal symptoms decrease with increasing age, the duration of the necessity for limitation ·of foods and of supportive medication should be relatively short. Whether it will ever be possible completely to prevent development of allergic reactions in the gastrointestinal tract is questionable, on the basis of the knowledge of immunology we have to date. It would seem, however, that active sensitization of the digestive tract in children of known allergic inheritance might be minimized by the avoidance in early years of the more common, potent antigenic ingestants. A longterm study in this direction has been reported by Glaser and Johnstone. 10
JOSEPH H. FRIES
1005
REFERENCES
1. Bray, G. W.: Recent Advances in Allergy. 2d ed. Philadelphia, P. Blakiston's Son & Co., 1934, p. 370. 2. Cooke, R. A.: Protein Derivatives as Factors in Allergy. Ann. Int. Med., 16:71, 1942. 3. Fries, J. H.: Roentgen Studies of Allergic Children with Disturbances of the Pylorus Resulting from Food Sensitivity. J. Allergy, 23:39, 1952. 4. Fries, J. H., and Jennings, K. G.: Recurrent Vomiting in Children. J. Pediat., 17:458, 1940. 5. Fries, J. H., and Merrill, G. A.: Allergic Abdominal Pain in Children. Am. J. Dis. Child., 52:1107, 1936. 6. Fries, J. H., and Mogil, M.: Roentgen Observations on Children with Gastro· intestinal Allergy to Foods. J. Allergy, 14:310, 1943. 7. Fries, J. H., and Zizmor, J.: Roentgen Studies of Children with Alimentary Disturbances Due to Food Allergy. Am. J. Dis. Child., 54:1239, 1937. 8. Fries, J. H,. and Zizmor, J.: Gastrointestinal Allergy in Children. J. Pediat., 16: 69, 1940. 9. Gay, L. P.: Gastro-intestinal Allergy. IV. The Leukopenic Index as a Method of Specific Diagnosis of Allergy Causing Peptic Ulcer. J.A.M.A., 106:969, 1936. 10. Glaser, J., and Johnstone, D. E.: Prophylaxis of Allergic Disease in the Newborn. J.A.M.A., 153:620, 1953. 11. Hollander, E.: Mucous Colitis Due to Food Allergy. Am. J. M. Sc., 174:495, 1927. 12. Horowitz, A., Alvarez, \\T. C., and Ascanio, H.: The Normal Thickness of the Pyloric Muscle and the Influence on It of Ulcer, Gastroenterostomy and Carcinoma. Ann. Surg., 89:521, 1929. 13. Lepore, M. J., Collins, L. C., and Sherman, W. B.: Small Intestine Roentgen Studies in Food Allergy. J. Allergy, 22:146, 1951. 14. Pollard, H. M., and Stuart, G. J.: Experimental Reproduction of Gastric Allergy in Human Beings with Controlled Observations on the Mucosa. J. Allergy, 13:467, 1942. 15. Rosenblum, A. H., and Rosenblum, P.: Gastrointestinal Allergy in Infancy. Pediatrics, 9:311, 1952. 16. Rowe, A. H.: Roentgen Studies of Patients with Gastrointestinal Food Allergy. J.A.M.A., 100:394, 1933. 17. Rubin, M. 1.: Allergic Intestinal Bleeding in the Newborn: Clinical Syndrome. Am. J. M. Sc., 200:385, 1940. 18. Serio, F.: La sintolmatologia radiologica della anafilassi gastro-intestinale. Riforma med., 48:1742, 1932. 19. Stull, A. H., and Hampton, S. F.: The Study of Antigenicity of Proteoses. J. Immunol., 41:l43, 1941. 20. Tallant, E. J., O'Neill, H. A., Urbach, F., and Price, A. H.: Gastro-intestinal Food Hypersensitivity: Roentgen Demonstration. Am. J. Digest. Dis., 16:l40, 1949. 21. Walzer, M.: Studies in Absorption of Undigested Protein in Human Beings. J. Immunol., 14:143, 1927. 22. Walzer, M.: Allergy of the Abdominal Organs. J. Lab. & Clin. Med., 26:1867, 1941. 23. Walzer, M., Gray, I., Strauss, H. W., and Livingston, S.: Studies in Experimental Hypersensitiveness in the Rhesus Monkey. IV. The Allergic Reaction in Passively Locally Sensitized Abdominal Organs. J. Immunol., 34:91. 1938. 24. Withers, O. R.: Gastrointestinal Allergy. Ann. Allergy, 11:637, 1953. 52 Eighth Avenue Rrooklyn 17, N.Y.
I t is strange that a clinical entity so specifically named as "gastrointestinal allergy" should be so often confused. Properly analyzed, gastrointestinal allergy must be an allergic response and must occur in the gastrointestinal tract. It is a consequence of union of antigen with the specific reagin (antibody) residing in the tissues of the alimentary tract. It not only can be a specifically localized tissue response, but may be part of a more widespread reaction with other shock organs participating. In contrast, it should be obvious that "food allergy" implies the simple and specific concept of allergy to foods. Such hypersensitiveness is capable of provoking symptoms in any tissue of the body, including the gastrointestinal tract. Both terms are frequently interchanged. Today the term "gastrointestinal allergy" unfortunately is loosely used to cover obscure digestive disorders which actually are organic or psychic, or, conversely, complaints due to food sensitivity, wherein the gastrointestinal tract is not even the shock or reactive organ. INCIDENCE
The incidence of gastrointestinal allergy does not lend itself to statistical determination. Inasmuch as the diagnosis is being used with increasing frequency as a label, especially in obscure, vague and indefinite disturbances of the digestive tract, accurate diagnoses of gastrointestinal allergy are few in number. Mild episodes are difficult to substantiate. Those which are immediate, severe and consistently and repeatedly provoked are easier to recognize. The incidence of gastrointestinal allergy is not static, inasmuch as it decreases with increase in age. Early literature on allergy mentions
995
996
GASTROINl'ESTINAL MANIFESTATIONS OF ALLERGY IN CHILDHOOD
the transition of infantile eczema to asthma, and of "abdominal migraine" to a cephalic type. 1 The spontaneous shift of reactivity, with increase of age, from the gastrointestinal tract (as from the skin) to other organs would result in a larger incidence of this malady in infants, in contrast with the older child or adult. Certain physiologic and anatomic changes occur in the skin which make it less vulnerable in later years, and by analogy it may be reasoned that comparable alterations occur in the gastrointestinal tract. Sensitivity to food, which is the most common cause of allergic reactions in the digestive tract, is also more frequently encountered in infancy and gradually and spontaneously decreases with maturity. For these reasons no definitive statistics of incidence are available. MECHANISM
The mechanism by which the allergen is brought into contact with the sensitized cells, thereby provoking gastrointestinal symptoms, may be that of direct or indirect exposure. The allergic reaction resulting from direct contact of the causative substance, usually a food, with the mucous membrane lining of the digestive tract is usually immediate. This is probably the phenomenon which produces the sudden swelling and blistering of the buccal mucosa, or the nausea and vomiting which may ensue immediately after ingestion. A further demonstration of reaction resulting from direct mucosal contact was the experimental production of colonic spasm promptly on the rectal instillation of an allergen in a barium enema in specifically sensitive subjects. The spasm which was demonstrable roentgenographically was not seen with a plain barium enema. 6 ,7 Secondly, production of gastrointestinal disturbances may involve the absorption of the antigen into the blood stream and its return via the circulatory system to the specifically reactive portion of the digestive tract. 21 This would account for allergic reactions in the lower bowel (e.g., rectal tenesmus) immediately after ingestion. Remarkably illustrative are the allergic reactions which have been induced experimentally in the exposed digestive tracts of passively sensitized rhesus monkeys and of human beings. 22 , 23 The clinical reaction, whether immediate or delayed, consists in mucosal edema, hyperemia and concomitant hyperactivity of; the secretory and mucous glands, with secondary muscle spasm. ETIOLOGY
Gastrointestinal reactions are most commonly caused by foods. In order of decreasing frequency of incrimination, they are milk, egg,
JOSEPH H. FRIES
997
chocolate, fish, nuts and orange, in addition to almost any other food. Drugs such as acetylsalicylic acid, sulfonamides, antibiotics and vitamins are occasional offenders. Parenterally injected substances such as pollen extracts and antibiotics may cause systemic allergic reactions in which the digestive tract participates; on rare occasions the digestive tract may be the only shock organ. Still more infrequent are gastrointestinal reactions to inhalants (osmyls), and these do not constitute a problem in the average pediatric practice. SYMPTOMATOLOGY
There is no symptom or pattern of symptoms which is specifically characteristic for allergy per se. Moreover, a single symptom (allergic abdominal pain, for example) may vary in its intensity, reaction time, duration, constancy, and association with coexisting symptoms. It helps to group these varied clinical manifestations according to the portion of the gastrointestinal tract involved, as follows: Buccal and pharyngeal Gastric Intestinal Miscellaneous (e.g., constitutional reactions' in which the gastrointestinal tract participates, mucous colitis,l1 rectal bleeding17 )
Visible changes of the digestive tract are readily recognized, such as angioedema of the buccal mucous membrane, palate, pharynx and tongue. Changes of the stomach and intestines are not normally visible. However, one must appreciate that these changes can and do occur in these less observable organs,14 Symptoms of urticaria or angioedema of the skin or mucous membranes concomitant with alimentary disturbances imply that similar changes may be occurring in these less obvious parts of the gastrointestinal tract. Groups of symptoms may form patterns not commonly characteristic of disorders on a hypersensitive basis. Some of these syndromes, heretofore considered organic and functional, are now recognized as being provoked on occasion by an allergic reaction, among them recurrent vomiting, pylorospasm, the celiac syndrome and colitis. Protective Mechanisms
The body utilizes several mechanisms to protect itself from encounters with substances noxious to the host. With reference to ingestants, these "protective" mechanisms vary from rejection to rapid expulsion of the substance from the bowel. For example, there is frequently a pronounced dislike for a specific allergenic ingestant when the untoward response is in the gastrointestinal tract. In infants a previous
998
GASTROINTESTINAL MANIFESTATIONS OF ALLERGY IN CHILDHOOD
experience or two with a burning taste in the mouth or other unpleasant sensation implants a memorable impression resulting in subsequent refusal of the food. If the food is accepted into the mouth, the child may reject it by spitting it out after the food has made contact with the buccal mucosa. In our experimental studies of ingestion of allergens 6 • 7 there was sometimes difficulty in getting children to swallow the antigen even when disguised in a barium meal. Nausea is most frequent in severe immediate types of gastrointestinal allergy to foods. 8 Vomiting is also common in severe sensitivity and represents a method of getting rid of the food substance before it is passed on to the intestine.8 Pylorospasm, by meting out small portions either through a narrowed obstructed pylorus or through prolonged, intermittent closures, slows down the rate of delivery of the antigen to the mucosal surfaces of the intestine. 3 Esophagospasm and cardiospasm are observable, although rare, "protests" to the passage of an antigen into areas of greater absorption. Diarrhea is a common method by which the host disposes of the antigen as rapidly as possible, thereby minimizing absorption. One can deduce that the forcing or disguising by parents of a specifically disliked or rejected food, especially one not essential to nutrition, is unwise and probably contrary to nature's intention in a known allergic child. Furthermore, it can be questioned whether a food which is producing physiologic disturbances in the gastrointestinal tract is adequately utilized nutritionally. Abdominal Pain
The classification of allergic abdominal pain made by the author5 in 1936 is still serviceable, utilizing three arbitrary divisions, depending on severity: 1. Severe abdominal pain, simulating an acute surgical condition of the abdomen in which differentiation from appendicitis, gallbladder disease, and so forth, is challenging 2. Abdominal pain of subacute recurrent nature 3. Abdominal pain as a subsidiary symptom (appearing during acute attacks of asthma or, more often, during severe outbreaks of urticaria or angioneurotic edema). Recurrent Vomiting
Vomiting (recurrent, cyclic or periodic) is a symptom-complex due to a variety of causes, including food hypersensitiveness. Studies by the
JOSEPH H. FRIES
999
writer4 on selected allergic children noted that the purposeful ingestion of an offending food initiated attacks of vomiting, sometimes prolonged or recurrent. The avoidance of this food resulted in comparative freedom from attacks. Clinical sensitivity to a specific food correlated with positive cutaneous tests and passive transfer tests. There are many variables which make the establishment of proof in suspected cases difficult. There. are "anergic" periods and changes in the threshhold of tolerance depending on precipitating factors of stress, infection, and the like. Furthermore, there is the possibility of cumulative effects from the ingestion of the same allergen or a combination of different allergens. Pylorospasm
Visualization of allergic manifestations in the gastrointestinal tract by fluoroscopy and roentgenogram has made it apparent that the pylorus plays a large role in the allergic symptomatology of the stomach, a variety of disturbances of the pylorus being observed. Roentgen changes and associated gastrointestinal symptoms are reproducible experimentally by intentional feeding of barium meals containing the allergen.3 Such experiments point out that in the clinical interpretation of abnormalities in the pylorus the possibility of allergic involvement must be considered. In the opinion of some authors, constantly recurrent spasm of the pylorus may result in muscular hypertrophy, which may in some instances lead to pyloric stenosis.12 NUTRITION
Nutritional impairment in children with chronic, recurrent gastrointestinal reactions-as with other gastrointestinal disorders-is to be expected. Clinically, one sees, in severe instances, skin lesions which are highly suggestive of vitamin A deficiencies and evidences of other vitamin deprivations. Growth is sometimes stunted, and there may be impairment of musculature. The refusal of various foods frequently encountered results in a poor, finical eater, the child subconsciously associating nausea and other unpleasant reactions with intake of food. Severe restrictions in diet of essential foods such as milk, eggs, legumes, readily embarked upon by ent~usiastic physicians, cause havoc if followed too long or compensated for inadequately. Incomplete utilization of nutrients and vitamins resulting from disturbed motor function of the digestive tract certainly must exist. In addition, local angioedema may be induced which may affect the permeability of the gut for the ready passage of
1000
GASTROINTESTINAL MANIFESTATIONS OF ALLERGY IN CHILDHOOD
nutrients. In support of this, in studies as yet incomplete, I have ob· served interference with the absorption of vitamin A as indicated by an abnormally flat absorption curve in a few children with severe gastrointestinal allergy. DIAGNOSIS
The capriciousness of gastrointestinal allergy makes it necessary that all possible organic and psychic factors be thoroughly explored. It is worthy of repetition that allergy accounts for only a small percentage of digestive disorders in children. History
A careful history is of primary importance. It is in this field that a leisurely and detailed questioning of the parents (and, when possible, the patient) can be most informative. Cognizance should be taken of any possible association which may have been made between ingestants and symptoms, of food dislikes, and of common allergenic foods being eaten in large amounts. A familial or personal background for allergy, or association of other allergic manifestations in other shock tissues, gives confirmation that the gastrointestinal symptoms may be on an allergic basis. Cutaneous Tests
The frequent failure of cutaneous tests to correlate positively with proved clinical digestive symptoms of food hypersensitiveness points to the limitation of this diagnostic procedure. Occasionally, however, cutaneous reactions of the immediate wheal type do indicate the offending antigen. These range from markedly positive to negative reactions, both by direct and passive transfer methods. It is noteworthy that those patients demonstrating immediate, pronounced gastrointestinal disturbances are the ones who most frequently give marked positive dermal reactions (Table 32). Positive cutaneous reactions sometimes are obtainable with higher concentrations of the testing extracts, although not with the routine testing strengths. Sensitization may possibly exist specifically to the digested products of foods-to the proteose or other split derivatives of proteins, and not to the natural food. 2 • 19 In such cases routine cutaneous tests are negative. The absence of reactions in some subjects possibly may be due to the existence of other forms of food intolerance which are not based on a reaginic mechanism.
JOSEPH H. FRIES TABLE
32. Skin Reactions Resulting from I ntracutaneOU8 Testing with Gastrointestinal Allergy ALLERGEN
of
NITROGEN
DEGREE OF
AGE OF
CONTENT IN
REACTION
PATIENT
1001
30 Children
IN YEARS
MG. PER CC., OR DILUTION
Egg
0.0001
Egg
0.0001
Egg
0.0001
Egg
0.0001
Egg
0.01
Egg
0.01
Egg
0.01
Egg
0.01
Egg
0.01
Egg
0.01
Egg
++++ (x)* ++++ (x) ++++ (x) +++ (x)
3 6 6
6
12
0.01
+++ +++ ++ ++ + + +
Egg
0.01
0
12
Egg
0.01
0
6
Egg
0.01
0
5
Egg
0.01
0
11
Egg
0.01
0
9
Codfish
0.00001
6
Codfish
0.00001
++++ (x) ++++ (x) +++ ++++ (x)
Herring
0.0001
Walnut
0.005
Almond
0.05
Almond
0.05
+++ +
8
7 5
7 8 12
10
13 6 11
14
* (x) indicates patients who had marked clinical disturbances following ingestion of the alIergenic food. The technique used consisted in the intracutaneous injection of about 0.02 cc. of the testing extract. Reactions were classified according to the size of the wheal.
1002 TABLE
GASTROINTESTINAL MANIFESTATIONS OF ALLERGY IN CHILDHOOD
32 (Continued) ALLERGEN
NITROGEN
DEGREE OF
AGE OF
CONTENT IN
REACTION
PATIENT
MG. PER CC.,
IN YEARS
OR DILUTION
Oats
1:10
++ +++ ++++ (x) +++ +
Milk
1:10
0
5
Milk
1: 10
0
7
Milk
1:10
0
9
Wheat
0.05
Wheat
0.05
Cabbage
1:5
Sweet corn
1:5
4
8
7
12 10
Roentgen Findings
Intentional feeding of an identified allergenic substance for the purpose of inducing roentgenographic changes and the use of a contrasting meal of plain barium were reported first by Serio ls and later Rowe. 16 These reports were followed by the writer's studies on children,6. 7 which have since been corroborated by other workers. 13. 20 In my studies, gastric retention, hypermotility and gastric atony have been visualized in children (Fig. 33). Alterations in the roentgenographic pattern of the small intestine were infrequent. However, some instances of segmentation and hypermotility were observed. Regional constriction or dilatation of the large bowel also occurred occasionally. Furthermore, I have demonstrated marked spasticity of the transverse and descending colons by means of barium enemas containing antigen. Although the alterations found in the allergic gut are not pathognomonic, their presence should suggest the possibility of allergic gastrointestinal disturbances, particularly when other confirmatory findings are present.
Food Diary
For lack of accuracy of the skin test and of all other finite tests, reliance must be placed on a detailed food diary and on controll<:;d ingestion trials of suspect foods. The food diary must record daily intake
JOSEPH H. FRIES
1003
of all possible ingestants, including vitamins, medications and betweenmeal "snacks," in the quantity ingested and indicating time relationships. This should be paralleled by a record of symptoms in their proper time relationship. Trial Ingestion
With the clues provided by the history and by the food diary, ingestion of the suspected foods should be tried under controlled circumstances. Only one food may be tested at a time. This test should be
Fig. 33. Roentgenograms of a 6 year old boy who had asthma. Ingestion of nuts on many occasions caused vomiting and abdominal pain. Skin tests (intracutaneous) to almond, walnut and Brazil nut were positive. The roentgenograms shown here were 6 hour studies. A, Control with plain barium sulfate shows slight retention within the stomach. B, A comparative study with lh teaspoonful of nut added to the plain barium, without the patient's knowledge, shows gastric retention of more than two thirds of the meal. There is also marked spasm (closure) of the pylorus.
made on an empty stomach, preferably in the morning, and when the child is symptom-free. A small amount of the test food is given, and after fifteen to thirty minutes an increased quantity of the food is fed until symptoms are provoked or until the amount ingested considerably exceeds the quantity customarily eaten. When disturbances are delayed and occur beyond the testing period, the trial must be repeated for confirmation.
1004
GASTROINTESTINAL MANIFESTATIONS OF ALLERGY IN CHILDHOOD
Laboratory Investigations
Determination of the eosinophil content of the blood is of questionable value because it varies widely from day to day. The leukopenic index9 has proved equally unreliable in my experience. Rectal smears for eosinophils I have tried sporadically with questionable success and feel that further observation should be made before evaluating the favorable conclusions of others.15 One must bear in mind that destructive processes in the colonic area, or parasitic infestations, are also capable of producing eosinophils in the mucus obtained from the rectum. 24 TREATMENT
Elimination of food or chemical offenders is, of course, ideal therapy. In some instances, however, trial diets and cutaneous tests still fail to identify clearly all the incitants. In this circumstance the child can be placed on an empirically determined hypo allergenic diet, not ignoring the necessary inclusion of substitute foods to meet vitamin and nutritional requirements. This diet makes liberal use of foods processed by heat or dehydration, which lower their allergenicity (evaporated milk, dehydrated banana), and of foods of known low allergenicity even when these may be somewhat unusual in a child's diet (beet tops, Swiss chard, soy beans). When symptoms are controlled by such a diet, foods may be added gradually, paying particular attention to the detection of any which may cause untoward reactions. Hyposensitization by injection of an extract of the offending food is not only hazardous, but has never proved effective; nor has oral desensitization been successful in my experience. The antihistaminic drugs have been of doubtful value. I have had no experience with the use of corticosteroids for this type of allergic reaction, but presume that they might be effective for a severe episode when other agents have failed. Since most allergic gastrointestinal symptoms decrease with increasing age, the duration of the necessity for limitation ·of foods and of supportive medication should be relatively short. Whether it will ever be possible completely to prevent development of allergic reactions in the gastrointestinal tract is questionable, on the basis of the knowledge of immunology we have to date. It would seem, however, that active sensitization of the digestive tract in children of known allergic inheritance might be minimized by the avoidance in early years of the more common, potent antigenic ingestants. A longterm study in this direction has been reported by Glaser and Johnstone. 10
JOSEPH H. FRIES
1005
REFERENCES
1. Bray, G. W.: Recent Advances in Allergy. 2d ed. Philadelphia, P. Blakiston's Son & Co., 1934, p. 370. 2. Cooke, R. A.: Protein Derivatives as Factors in Allergy. Ann. Int. Med., 16:71, 1942. 3. Fries, J. H.: Roentgen Studies of Allergic Children with Disturbances of the Pylorus Resulting from Food Sensitivity. J. Allergy, 23:39, 1952. 4. Fries, J. H., and Jennings, K. G.: Recurrent Vomiting in Children. J. Pediat., 17:458, 1940. 5. Fries, J. H., and Merrill, G. A.: Allergic Abdominal Pain in Children. Am. J. Dis. Child., 52:1107, 1936. 6. Fries, J. H., and Mogil, M.: Roentgen Observations on Children with Gastro· intestinal Allergy to Foods. J. Allergy, 14:310, 1943. 7. Fries, J. H., and Zizmor, J.: Roentgen Studies of Children with Alimentary Disturbances Due to Food Allergy. Am. J. Dis. Child., 54:1239, 1937. 8. Fries, J. H,. and Zizmor, J.: Gastrointestinal Allergy in Children. J. Pediat., 16: 69, 1940. 9. Gay, L. P.: Gastro-intestinal Allergy. IV. The Leukopenic Index as a Method of Specific Diagnosis of Allergy Causing Peptic Ulcer. J.A.M.A., 106:969, 1936. 10. Glaser, J., and Johnstone, D. E.: Prophylaxis of Allergic Disease in the Newborn. J.A.M.A., 153:620, 1953. 11. Hollander, E.: Mucous Colitis Due to Food Allergy. Am. J. M. Sc., 174:495, 1927. 12. Horowitz, A., Alvarez, \\T. C., and Ascanio, H.: The Normal Thickness of the Pyloric Muscle and the Influence on It of Ulcer, Gastroenterostomy and Carcinoma. Ann. Surg., 89:521, 1929. 13. Lepore, M. J., Collins, L. C., and Sherman, W. B.: Small Intestine Roentgen Studies in Food Allergy. J. Allergy, 22:146, 1951. 14. Pollard, H. M., and Stuart, G. J.: Experimental Reproduction of Gastric Allergy in Human Beings with Controlled Observations on the Mucosa. J. Allergy, 13:467, 1942. 15. Rosenblum, A. H., and Rosenblum, P.: Gastrointestinal Allergy in Infancy. Pediatrics, 9:311, 1952. 16. Rowe, A. H.: Roentgen Studies of Patients with Gastrointestinal Food Allergy. J.A.M.A., 100:394, 1933. 17. Rubin, M. 1.: Allergic Intestinal Bleeding in the Newborn: Clinical Syndrome. Am. J. M. Sc., 200:385, 1940. 18. Serio, F.: La sintolmatologia radiologica della anafilassi gastro-intestinale. Riforma med., 48:1742, 1932. 19. Stull, A. H., and Hampton, S. F.: The Study of Antigenicity of Proteoses. J. Immunol., 41:l43, 1941. 20. Tallant, E. J., O'Neill, H. A., Urbach, F., and Price, A. H.: Gastro-intestinal Food Hypersensitivity: Roentgen Demonstration. Am. J. Digest. Dis., 16:l40, 1949. 21. Walzer, M.: Studies in Absorption of Undigested Protein in Human Beings. J. Immunol., 14:143, 1927. 22. Walzer, M.: Allergy of the Abdominal Organs. J. Lab. & Clin. Med., 26:1867, 1941. 23. Walzer, M., Gray, I., Strauss, H. W., and Livingston, S.: Studies in Experimental Hypersensitiveness in the Rhesus Monkey. IV. The Allergic Reaction in Passively Locally Sensitized Abdominal Organs. J. Immunol., 34:91. 1938. 24. Withers, O. R.: Gastrointestinal Allergy. Ann. Allergy, 11:637, 1953. 52 Eighth Avenue Rrooklyn 17, N.Y.