Max's House

ADVERSE REACTIONS TO FOOD

W. GRANT GUILFORD
Diplomate, ACVIM,  Small Animal Medicine

Adverse reactions to food are frequently observed in dogs and cats. They are composed of a variety of subclassifications (Table 1). Most adverse reactions to food result from ingestion of the inciting agent, followed by interaction of the agent with a cellular or noncellular' biologic amplification system that leads to inflammation and the generation of clinical signs. The amplification system varies considerably mith the inciting agent but may include mast cells, phagoeytes, the autonomic nervous system, the antigen-specific immune system, the arachidonic acid cascade, the complement cascade, and the kinin system. At times, sufficient toxic material is present in food to produce clinical signs without need for amplification.

CLINICAL SIGNS AND DIAGNOSIS OF ADVERSE REACTIONS TO FOOD

Adverse reactions to food (food sensitivities) are suspected when an association is noted between the ingestion of a certain foodstuff and the appearance of a particular clinical sign or group of signs. The clinical signs are usually dermatologic or gastrointestinal (Table 2). Diagnosis is confirmed by resolution of clinical signs after the elimination of the suspected food, followed by recrudescence of the signs when the patient is subsequently challenged with the incriminated foodstuff. A protocol for an elimination-challenge trial is presented in Table 3. The success of elimination-challenge trials depends on good client cooperation. Patients undergoing food challenges must be closely, observed. Short periods of avoidance of the food to which an animal is sensitive may markedly exacerbate adverse signs when the food is reintroduced ("unmasking"). To reiterate, elimination-challenge trials confirm or rule out food sensitivities. Definitive differentiation of food allergy or intolerance necessitates immunologic investigations. The latter are often omitted because the management of most patients will not be altered whether the clinical signs result from food allergy or from food intolerance.


Table 1
. Major Subclassifications of Adverse Reactions to Food*


Adverse reaction (sensitivity) to food--
general terms applied to a clinically abnormal response attributed to an ingested food or food additive.

Food allergy (hypersensitivity)-
an adverse reaction to food with a proven immunologic basis.

Food intolerance-
a general term describing an adverse reaction to food that does not have an immunologic basis.

Food idiosyncrasy-
a quantitatively abnormal response to a food or food additive that resembles a hypersensitivity response but does not involve immune mechanisms.

Pharmacologic reactions to food-
an adverse reaction to food as a result of a naturally derived or added chemical that produces a druglike or pharmacologic effect in the host.

Metabolic reactions to food-
an adverse reaction to food due to an effect of a substance upon the metabolism of the host, or as a result of defective metabolism of a nutrient by the host.

Food poisoning-an adverse reaction to food caused by the direct action of a toxin.

*The terms and definitions are those recommended by the American Academy of Allergy and Immunology.

FOOD ALLERGY

The term food allergy has been overused in the veterinary literature, obscuring the true incidence of the condition. The cause of food allergy is unknown. Most evidence points to a failure of the immunologic mechanisms that mediate oral tolerance or to a breakdown of the mucosal permeability barrier. In cases of a breakdown of the mucosal permeability barrier, food allergies may be precipitated by viral or chronic inflammatory disorders of the bowel. The pathogenesis of the disorder can involve type 1, 111, or IV hypersensitivity.

Chemistry of Food Antigens

Food allergens are almost exclusively proteins.  There is little evidence that food additives act as allergens. Additives are, however, thought to be an important cause of food intolerances. Foods suggested to be prevalent causes of food allergy in dogs and cats include milk, beef, soy, tuna, wheat, eggs, chicken, and corn.  On most occasions, the protein to which an animal is allergic will be the one that is present in greatest quantity in its usual diet.  Cross-reactivity is particularly common with seafoods and legumes.

Clinical Features

The history usually reveals adverse reactions that are uniform in clinical manifestation and that consistently occur on exposure to a food. On rare occasions a suspected food may fail to consistently lead to & expected clinical signs. One reason for such inconsistency is an altered method of preparation of the food. The clinical signs are nonseasonal (in contrast to many inhalation allergies) and often occur suddenly after months of consuming the diet containing the inciting foodstuff (in contrast to most food intolerances). A wide age range of dogs and cats can be affected, including animals less than 1 year of age.

 

Table 2. Proven or Suspected Clinical Signs or Disorders Associated with Food Sensitivity

Dermatologic
    
Excessive grooming
     Eosinophilic dermatitis
     Hyperesthesia
     Miliary dermatitis
     Otitis externa
     Papules and erythema
     Pododermatitis
     Pruritus (head and neck; face, feet, ears; generalized)
     Seborrhea
     Urticaria or angioedema

Gastrointestinal
     Abdominal pain
     Colitis
     Diarrhea
     Vomiting
     Eosinophilic gastroenteritis
     Gluten-sensitive enteropathy
     Oral and pharyngeal pruritus

Respiratory
     Asthma?
     Bronchitis?
     Nonseptic pneumonitis?
     Rhinitis?

Miscellaneous
     Anal pruritus?
     Anaphylaxis
     Glomerulonephritis?
     Hyperactivity?
     Malaise?
     Polyarthritis?
     Vasculitis?
? Reported in humans but as yet not in dogs and cats.

Table 3. Suggested Protocol for Elimination Challenge Trials for the
Diagnosis of Adverse
Reactions to Food*

Elimination trial
1.   Place the patient on a controlled diet of a single protein source and a single
      carbohydrate source until signs resolve,e.g., lamb and boiled white rice, or cottage
      cheese and rice,or tofu and rice.

2.  
After 2 symptom-free weeks, add to the controlled diet a small quantity of the
      incriminated food (100 gm) or food additive for the first 3 days of the week
      (or for less time if clinical signs occur rapidly). The dose of the food additiveused
      is the calculated average daily dietary intake of the additive.

3.   Observe for clinical signs during the 3-day challenge period and the 4 days thereafter
      during which the patient is returned to the controlled diet without the incriminated agent.

4.   If no evidence of clinical abnormality occurs, repeat the procedure using another food
      or additive every week, until a dietary component is identified that appears to cause
      clinical  signs.

5.   If a prolonged trial becomes necessary, supplement the diet with appropriate quantities
      of vitamins and minerals.

      Challenge trial
6.   After a suspected food or food additive has been identified, immediately remove it from
      the diet, and observe for evidence of resolution of signs.

7.   Wait a minimum of 1-2 weeks from the last ingestion of the suspected agent and until
      the patient is symptom free, and then, under close observation, challenge the patient
      with the suspected food or additive to ensure that similar signs are manifested on the
      second exposure.

*Modified with permission from Strombeck, D. R., and Guilford WG.: Small Animal Gastroenterology, 2nd ed.    Davis, CA: Stonegate Pub lishing, 1990, p. 344.


Food allergy may potentially result in any of the clinical signs of food sensitivity listed in Table 2,   but dermatologic and gastrointestinal manifestations appear to predominate. Gastrointestinal signs need not be present to attribute a dermatologic abnormality to a food allergy.

Diagnosis of Food Allergy

The diagnosis of food allergy requires that an adverse reaction to a food first be confirmed by elimination-challenge trials (Table 3). Second, the adverse reaction to the food must be proved to have an immune-mediated basis. Tests used for this purpose include skin tests, radioallergosorbent test, enzymelinked immunosorbent assay, assays of cellmediated immune reactions and mast-cell degranulation, endoscopic intragastric challenge tests, and gastrointestinal biopsy. All of these procedures have significant limitations.

Intradermal skin testing detects antigen-specific IgE in the skin. Food allergies with symptoms restricted to the gastrointestinal tract or those predominantly caused by non-IgE-mediated processes are rarely diagnosed by skin tests. The specificity of skin testing for foods has also been questioned, with some studies yielding a high incidence of falsepositive results. These observations suggest that skin testing cannot be relied on to confirm food allergy or to predict which foods the patient should avoid, particularly if the predominant manifestation of the allergy is gastrointestinal.

The concentration of antigen-specific IgE in the serum can be measured by radioallergosorbent test or enzyme-linked immunosorbent assay. In humans and dogs, poor correlations between these tests and oral challenge, skin, and intragastric tests have usually been observed. This poor correlation is to be expected because an elevated serum level of antigen-specific IgE indicates only that the patient has the potential to manifest a reaginic response to the food antigen. A multitude of other factors determines whether the elevated level of IgE actually will produce clinical signs. Radioallergosorbent test and enzyme-linked immunosorbent assay should be regarded as screening tests for only one form of food allergy-that mediated by IgE released in sufficient quantities to enter the systemic circulation in measurable amounts. Tests to measure canine and feline reaginic antibody levels are commercially available (Bio-Medical Services, Austin, TX).

Endoscopic intragastric testing can be used to evaluate the acute response of the gastrointestinal mucosa to food antigens. Extracts of foods (0.5 ml; 1000 PNU; Greer Labs, Lenoir, N.C.) are dripped onto an area of gastric mucosa and the mucosal response is observed. In food-sensitive dogs, welts develop within minutes at the site of antigen application. The diagnostic accuracy of this technique is as yet unknown.

Gastrointestinal biopsy is rarely helpful in the confirmation of food allergy because many of the acute-phase changes, such as edema, are transient, and there are no pathognomonic histologic features that differentiate food hypersensitivity from other causes of chronic intestinal inflammation. Eosinophilic infiltration is compatible with, but not diagnostic of, food allergy.

Treatment of Food Allergy

Treatment of food allergy depends on elimination of the allergen from the diet for a minimum of 6 months, whereafter oral tolerance to the foodstuff is sometimes regained. Because most true food allergies are caused by dietary proteins, successful control of the clinical signs of animals with allergies to specific foods can often be achieved by changing to a high-quality commercial brand of pet food that does not contain the protein to which the patient is allergic. This will rarely be successful, however, in animals with food intolerance rather than food allergy (see later). Similarly, in patients predisposed to acquiring multiple allergies, such as atopic animals or those with chronic gastrointestinal inflammatory disorders, different commercial foods are likely to offer only transient benefit. To reduce the likelihood of clinical relapses caused by acquired hypersensitivities, predisposed animals should be placed on a "hypoallergenic" diet or, alternatively, on a rotation diet.

So-called hypoallergenic or oligoantigenic diets vary greatly in their hypoallergenicity. The least allergenic of the hypoallergenic diets available for use in dogs and cats are elemental diets. Enteral diets composed of protein hydrolysates are less antigenic than intact proteins. Homemade diets composed of single protein and carbohydrate sources may also be considered less antigenic than commercial diets containing a variety of different protein sources. Commercial hypoallergenic pet foods are the most convenient but least effective of the hypoallergenic diets because most contain intact proteins from a number of different sources and a variety of food additives.

Elemental diets such as Vivonex (Norwich Eaton, Norwich, NY) are useful for short-term use in dogs with multiple allergies. Most dogs will readily drink Vivonex. Its major drawback is expense. Enteral diets containing protein hydrolysates (e. g., Criticare HN, Mead Johnson) or purified proteins (e.g., Pulmocare, Ross Labs) are potential alternatives to Vivonex. These products need supplemental calcium and phosphorus and, for use in cats, additional protein (15 to 30 gm of casein powder per can) and taurine (250 mg per can).

Homemade hypoallergenic diets are beneficial for animals with allergies to one or more proteins or intolerances to food additives. They should be composed of a single, high-quality protein source, a gluten-free carbohydrate source such as rice (nice also contains some protein), and a vitamin and mineral- supplement (avoid those labeled "palatable" or "chewable"). The use of a single protein source lowers the antigenicity of the diet. The protein should be provided in minimal quantity (approximately 2 gm/kg and 3.5 gm/kg for adult dogs and cats, respectively, unless concomitant protein-losing enteropathy is suspected). Most animal proteins are suitable for inclusion in hypoallergenic diets. The choice of protein should be based on the results of the patient's elimination-challenge trial and on practical constraints such as cost. Contrary to popular belief, there is nothing inherently "hypoallergenic" about lamb. Dogs and cats can readily acquire allergies to sheep meats if such meats form a regular part of their diet. It is important to note that because both homemade and commercial hypoallergenic diets contain intact proteins, it is not uncommon for animals with gastrointestinal inflammatory disorders to rapidly acquire sensitivities to the proteins in these diets.

Rotation diets can be used to delay or prevent the acquisition of new dietary allergies in predisposed patients. The protein sources in the diet are changed every few days on a rotating basis. It is thought that the brief period of oral exposure to each protein is insufficient to incite a clinically significant hypersensitivity response. Moreover, if acquired allergies do develop, they are easily diagnosed. The optimal duration of ingestion of each protein and the minimum interval between reingestion have not been determined.

Anti-inflammatory drug therapy can be used if the food allergen(s) cannot be eliminated from the diet. Diphenhydramine (2.0 to 4.0 mg/kg PO) or prednisone (0.5 mg/kg PO) administered before meals may temper signs of the allergy. Hyposensitization therapy has no proven benefit in food hypersensitivity. Symptomatic therapy with antiseborrheic shampoos, antibiotics, and moisturizing rinses, or with fluids and electrolytes, and motility modifiers may assist in control of dermatologic and gastrointestinal signs, respectively.

FOOD INTOLERANCES

Nonimmunologic adverse reactions to foods are collectively termed food intolerances. The majority of food sensitivities in humans are thought to be food intolerances. A similar situation may exist in dogs and cats, partly explaining the frequent failure of skin and radioallergosorbent tests to correctly identify animals suffering from food sensitivity and the poor efficacy of antihistamines and corticosteroids in its treatment. Food intolerances result in the same range of clinical signs as food allergy, but the signs may occur on the first exposure to the food, and for some categories of intolerance, large quantities of food may have to be ingested before signs develop.

Food Idiosyncrasy

A wide variety of food additives have been noted to produce adverse reactions to food in susceptible people and may also affect dogs and cats in an idiosyncratic manner. These reactions closely mimic food allergies, but with the exception of certain contact urticarias, most appear to be mediated by nonimmunologic mechanisms such as direct initiation of the arachidonic acid cascade. Identification of offending additives requires the use of eliminationchallenge diets. No in vitro tests are available. A partial list of incriminated food additives commonly included in pet foods is given in Table 4. Treatment is by avoidance of the additive.

 

Table 4. Partial List of Potentially AdverseAdditives Commonly Added to Pet Foods and Treats

Additive

Clinical Signs in Humans or Animals

Artificial colorings
Butylhydroxyanisole (BHA)
Carrageenan
Metabisulfite
Monosodium glutamate
Propylene glycol
Sodium nitrite
Sulfur dioxide
Sorbic acid
Spices
Vegetable gums
Asthmatic attacks,* urticaria*
Urticaria*
Colitis+ urticaria*
Asthmatic attacks,* hypotension*
Headache,* chest pain*
Heinz body anernias++
Urticaria,* diarrhea*++ Methemoglobinemia*
Asthmatic attacks,* hypotension*
Urticaria,* angioneurotic edema*
Urticaria*
Urticaria*

*Reported in humans +Reported in laboratory animals *Reported in cats++

Pharmacologic Reactions to Food

A variety of foods contain vasoactive amines and other pharmacologically active substances capable of inducing a wide range of signs. Histamine is a vasoactive amine present in high amounts in yeast and poorly preserved tuna and mackerel. In humans, ingestion of spoiled tuna can lead to diarrhea, nausea, urticaria, or bronchospasm. Histamine potentially could cause similar adverse reactions in cats. Psychoactive agents and stimulants are contained in some foods. Theobromine, for instance, is the major toxicant in chocolate.

Metabolic Adverse Reactions to Food

Lactase deficiency is a common metabolic defect in dogs and cats that results in diarrhea, bloating, and abdominal discomfort following ingestion of moderate amounts of lactose. Collectively, inborn errors of metabolism are important causes of metabolic adverse reactions to food in humans and also occur in animals, for example, urea cycle enzyme deficiencies (see this volume, p. 18). Treatment involves minimizing the intake of the poorly tolerated food.

Food Toxicity

Food poisoning is a frequent cause of gastrointestinal disease in small animals. Poisoning can result from foodstuffs that are inadequately prepared, spoiled, or contaminated by microorganisms or their toxins. Many foods contain natural toxicants. For example, ingestion of onions by dogs can cause Heinz body anemia probably caused by N-propyl disulfide; all onions, raw or cooked will cause Heinz body anemia in cats; undercooked red kidney beans contain lectins that can cause intense epithelial inflammation, diarrhea, and abdominal pain; excessive quantities of preserved meats containing nitrates and nitrites can lead to methemoglobinemia and diarrhea; high levels of oxalates and anthraquinone glycosides contained in spinach and beets can lead to a corrosive gastroenteritis; and large quantities of spices can cause abdominal discomfort.

Gluten-Sensitive Enteropathy

Gluten-sensitive enteropathy has been described in Irish setter dogs and is characterized by poor weight gain, mild chronic intermittent diarrhea, partial villus atrophy, and brush-border enzyme defects that are particularly severe in the proximal small intestine. The cause of the gluten sensitivity is unknown. The disease may affect dogs other than Irish setters, perhaps accounting for some cases incorrectly labeled as idiopathic lymphocyticplasmacytic enteritis. Diagnosis is made by intestinal biopsy and elimination-challenge trials with glutencontaining cereals. Treatment is by elimination of wheat, barley, rye, buckwheat, and oats from the diet. Gluten-free diets such as d/d (Hill's Pet Products) are available. Avoidance of gluten-containing diets during rearing may prevent the disease.

Reference

American Academy of Allergy and Immunology Committee on Adverse Reactions to Foods. National Institute of Allergy and Infectious Diseases: Adverse Reactions to Foods. NIH Publ. No. 84-2442.,

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