Patterns of food allergic responses Quickonset symptoms

These often follow the ingestion of a single food, such as egg, peanut or sesame. Within minutes the sufferer may notice tingling of the tongue, and there may be the rapid development of skin rash, urticaria or wheezing. One localized variant, the oral allergy syndrome, is often seen in older pollen-sensitized individuals and is characterized by lip tingling and mouth swelling after ingestion of certain fruits and vegetables.24 More serious reactions, however, can occur at any age, and antigens such as peanut, tree nuts, fish and shellfish can cause exquisite sensitization from early childhood. Swelling of the mucous membranes of the mouth and upper airway (angioneurotic edema) can develop extremely quickly, and the airway may become compromised. In cases where appropriate therapy is not available, life-saving tracheostomy has even been performed in the presence of gross laryngeal edema. Anaphylactic shock may also occur, with dramatic systemic hypotension accompanying the airway obstruction. A grading system for anaphylaxis has been suggested by Sampson,25 with a severity score based on the worst symptom present (Table 22.3).

Specific therapy for mild cases of immediate hypersensitivity would include antihistamines such as chlorpheniramine, together with inhaled bronchodilators as appropriate. It is notable that some patients can have a biphasic response, with a relatively modest initial reaction followed several hours later by a more profound and potentially life-threatening response, and therefore care should be taken in the assessment to ensure that adequate instructions and therapy are adminis tered before allowing the patient home. There have indeed been several cases of anaphylactic death in patients discharged home after initial resuscitation, up to 6 h after food ingestion, and it is therefore prudent to maintain observation for several hours if there are any clear risk factors, such as active asthma or a history of a severe reaction.25,26 The presence of wheezing on examination should suggest caution; a bronchodilator should certainly be prescribed, and in many cases a few days' course of oral prednisolone.

More severe reactions should be assessed very rapidly, and any evidence of airway obstruction or systemic hypotension warrants the immediate use of intramuscular epinephrine (adrenaline) (Table 22.3). Use of a preloaded syringe pen, such as a pediatric or adult EpiPen®, prior to transfer to hospital, may be life-saving, and avoids potential

Table 22.3 A grading for anaphylactic reactions, proposed by Sampson.25 The severity score should be based on the most severe symptom in any domain. Symptoms in bold are absolute indications for the use of epinephrine (adrenaline)

Grade Skin

Gastrointestinal tract




1 Localized itching, flushing, urticaria, angioedema

oral itching or tingling, mild lip swelling

2 Generalized itching, flushing, urticaria, angioedema

any of the above, nausea and/or single vomiting episode

nasal congestion and/or sneezing

change in activity level

3 Any of the above

any of the above plus repetitive vomiting

rhinorrhea, marked congestion, sensation of throat itching or tightness

tachycardia (increase > 15 beats/min)

change in activity level plus anxiety

4 Any of the above

any of the above plus diarrhea

any of the above, hoarseness, 'barky' cough, difficulty swallowing, dyspnea, wheezing, cyanosis

any of the above, dysrhythmia and/or mild hypotension

'light headedness,' feeling of 'impending doom'

5 Any of the above

any of the above, loss of bowel control

any of the above, respiratory arrest

severe bradycardia and/or hypotension or cardiac arrest

loss of consciousness

dosage errors at such a time of extreme stress. Any child thought to be at risk of an anaphylactic reaction to food should be prescribed such injection devices (at least two or three should be prescribed, so that all those caring for the child are equipped), and parents and carers should be trained in their use. Any severe immediate reaction to foods necessitates urgent transfer to an appropriate medical setting, such as an Accident and Emergency Department. Other treatments that may be needed include oxygen, intravenous hydrocortisone, chlorpheniramine and inhaled P-adrenergic bron-chodilator therapy.25 Supportive treatment for hypotension or cardiac dysrrhythmia may be required, and in the most severe cases the patient may need to be transferred to an intensive therapy unit.

The true incidence of anaphylactic death due to food allergy is unknown. A recent UK report suggested a low incidence of 0.006 deaths per 100 000 children per year,27 but this is thought to be a significant underestimate, as many cases were unlikely to be identified from the study of death certificates and clinical reporting alone.25

In the follow-up of a patient who has had an immediate hypersensitive response to food antigens, a decision needs to be taken about the level of prophylaxis required, and whether or not to prescribe an epinephrine pen. Clearly the severity of the first response will inform this decision, and it is probably better to err on the side of caution if foods such as peanuts are implicated, because of their propensity for triggering particularly severe episodes. If there is doubt about the food involved, both skin prick tests and specific IgE radioaller-gosorbent test (RAST) may be very helpful. However, these should be postponed for several weeks after an episode of anaphylaxis, as they may be artifactually negative in the immediate aftermath of a severe reaction.

Late-onset symptoms

Slow-onset symptoms may be more insidious and their true allergic nature may not be recognized (Table 22.4). These may include failure to thrive or chronic diarrhea due to enteropathy or colitis, eczema, rhinitis, or rectal bleeding.1,24 As these are likely to be mediated by T cells in a delayed hypersensitive reaction, they may not be so clearly linked to food ingestion. Children may, however, manifest both delayed and immediate-onset symptoms. Analysis of IgG subclasses and peripheral lymphocyte subsets may identify the child at increased risk of delayed food allergic reactions.14 Certain specific presentations can be recognized, as discussed below.

Food protein-induced enterocolitis

This disorder is most common in young infants below the age of 3 months, and usually presents with blood streaking of stools in the absence of marked weight loss or systemic upset. Anemia is

Table 22.4 Clinical manifestations in food allergic responses

  1. Quick onset
  2. Late onset
  3. Less clear responses
  4. Secondary general effects wheezing, urticaria, angioedema, rashes, vomiting, gastroesophageal reflux, anaphylaxis diarrhea, abdominal pain, allergic rhinitis, atopic eczema, food-sensitive enteropathy or colitis, rectal bleeding, constipation, protein-losing enteropathy irritable bowel syndrome, chronic fatigue, attention-deficit with hyperactivity, autistic symptoms eosinophilia, iron deficiency anemia, hypoproteinemia

For group 3 conditions, there are anecdotal reports of clinical improvement with dietary exclusions. However, there are as yet few properly validated studies, and it is likely that only a proportion of such patients will benefit. While many maintain an open-minded approach, it is important to ensure that any such diet is nutritionally adequate (joint management with dietitians is ideal), and that clinical responses to exclusion and challenge are sufficiently striking to justify continuing exclusion diets.

unusual, but an elevated platelet count (>450x109/l) is characteristic. Cow's milk or soy proteins are the most common causative antigens, and it is common for such symptoms to occur in exclusively breast-fed infants, triggered by milk protein in the mother's diet.28 It is important to recognize that negative skin prick tests do not exclude this diagnosis, and indeed most cases are negative.24 If colonoscopy is performed, the colitic changes are usually milder than with classic inflammatory bowel disease, and the macroscopic findings are dominated by loss of vascular pattern, prominent lymphoid follicles with a rim of perifol licular erythema (red halo sign) and an easily traumatized mucosa. Histological changes include mononuclear cell infiltration, mucosal eosinophilia with evidence of degranulation and the presence of lymphoid follicles in the majority of colonic biopsies. If the ileum is visualized, lymphoid hyperplasia is usually seen. Recent data suggest a concordance between the endoscopic finding of ileocolonic lymphoid hyperplasia and food allergies (Figure 22.1), not restricted to those infants with allergic enterocolitis alone,29 which may be associated with an increase in mucosal y§ T-cell infiltration.30 See also Chapter 30.

Cow Milk Protein Allergy Mucosa

Figure 22.1 Lymphoid hyperplasia is an important endoscopic feature in food allergies.29 This ileocolonoscopy was performed in a 2-year-old girl with multiple food allergies, and demonstrated ileal lymphonodular hyperplasia (a), with prominent reactive germinal centers on histology (b), together with multiple colonic lymphoid follicles (c - a typical follicle is arrowed). Histology of each biopsy in her colonic series demonstrated a lymphoid follicle (d).

Figure 22.1 Lymphoid hyperplasia is an important endoscopic feature in food allergies.29 This ileocolonoscopy was performed in a 2-year-old girl with multiple food allergies, and demonstrated ileal lymphonodular hyperplasia (a), with prominent reactive germinal centers on histology (b), together with multiple colonic lymphoid follicles (c - a typical follicle is arrowed). Histology of each biopsy in her colonic series demonstrated a lymphoid follicle (d).

Some infants manifest a form of food protein-induced enterocolitis that is more severe than the classic variant, and is less often induced by cow's milk.24 The histological response is more severe, with evidence of frank colitis including crypt abscesses, and the response to food challenge may include shock.

Food protein enteropathy

The most common and best described mucosal manifestation of food allergy is food-sensitive enteropathy, in which there is an immunologically mediated abnormality of the small intestinal mucosa, which may include excess lymphocyte infiltration, epithelial abnormality or architectural disturbance. This may often impair absorption and less commonly causes a frank malabsorption syndrome. This continues while the food remains in the diet and remits on an exclusion diet. This is best described for cow's milk, and cow's milksensitive enteropathy (CMSE) has been recognized for over two decades.32 Enteropathy can also occur in response to other antigens, notably soy. The lesion is less severe than celiac disease, but is characterized by similar findings of crypt elongation and villus shortening, giving a reduction of overall crypt/villus ratio. There is usually an increase of mononuclear cell density within the mucosal lamina propria, often including prominent eosinophils, and the intraepithelial lymphocyte density is often increased (Figures 22.2 and 22.3). The lesion is not associated directly with systemic IgE responses, and skin prick tests are often negative. Analysis of mucosal lymphocytes confirms excess T-cell activation, with either a Th1 dominated or mixed Th1/Th2 response.31,33,34 The consequences of this mucosal T-cell activation include reduction in brush-border disaccharidase expression, leading to impaired carbohydrate absorption, and a secondary reduction in pancreatic enzyme release,35 both contributing to malabsorption. There is evidence that some children do not grow out of CMSE in early childhood, and an abnormal mucosa may be seen in later child-


In cases of diagnostic uncertainty, it may be necessary to confirm the return of mucosal abnormality by food challenge. This was a more common practice in the past, when the very existence of food-sensitive enteropathies other than celiac disease was uncertain. Improvements in infant formulas have led to a change in the mucosal appearances of CMSE, so that celiac-like villous atrophy is now very rare in the developed world. Morphometry of recent cases of CMSE confirms a less severe lesion than archival biopsies from the 1980s.14 This causes some histopathological difficulty, as there is no international consensus in the reporting of subtle lesions such as villous blunting or mild mucosal eosinophilia.

Eczema/atopic dermatitis

There seems little doubt that food-allergic responses may contribute to the clinical presentation of eczema in infancy, but considerable uncertainty about whether adults have anything to gain from exclusion diets.37 There is evidence that children with eczema have elevated food-specific IgE in serum, and that food challenges of eczematous children induce increases in circulating eosinophil and mast cell products.38 There is evidence of enhanced intestinal permeability in infants with eczema, potentially contributing to sensitization through bypass of enterocyte antigen-handling mechanisms.39 The response within the skin is dominated by Th2 cytokines, and characterized by influx of both T lymphocytes, which express skin-homing markers such as the cutaneous lymphocyte antigen (CLA), and eosinophils.37,40 The mechanisms by which skin-homing markers become expressed on gut sensitized cells remains uncertain, as expression of the gut-homing marker P7 integrin is likely to have been required for initial homing to the intestine.1 There remains the intriguing possibility that bacterial products, particularly superantigens from staphylococci and streptococci, may specifically up-regulate CLA expression in an interleukin (IL)-12-dependent fashion, and thus promote skin homing of lymphocytes sensitized to dietary antigens.41 Staphylococcus aureus may be an important specific complicating factor, as 24 and 28kD proteins within the toxins may directly induce an IgE-medi-ated response and thus contribute to allergic immunopathology.42,43 Deficiency in innate immune responses, in particular production of P-defensins, may contribute to the propensity for superinfection with toxin-producing staphylococci in children with allergic eczema.44 Therefore, an important consideration in the infant or young child with eczema is whether both the diet and the

Allergy Infants Enterocolitis Allergic ProctocolitisFood Induced Enteropathy

Figure 22.2 The relatively subtle appearances of food-sensitive enteropathy. Duodenal biopsy of the same patient as shown in Figure 22.1, showing minimal evidence of duodenal blunting, but with a patchy increase in mononuclear cell infiltration within the lamina propria (a). High-power views (b, c) show infiltration of eosinophils within the lamina propria and epithelium, together with a moderate increase in mononuclear cells.

bacteriological status of the child have been optimized.

A recent large study of skin prick reactivity to dietary antigen in infants with eczema identified positive skin prick tests for cow's milk, egg or peanut in 22% of 6-month-old infants with eczema, compared to only 5% without eczema.45

At 1 year the incidences were 36% and 11%, respectively, giving a calculated attributable risk of 65%. This supports data by Kjellman and Hattevig46 that the development of infantile, but not later-onset eczema, is associated with IgE antibodies to food antigens. Whether the IgE antibodies are directly causative, or alternatively a marker of dietary sensitization in infants

Normal Lymphocytes ChildrenLamina Propria Lymphocytes

Figure 22.3 There may be an increase of intraepithelial lymphocytes in food-allergic children. This child with cow's milksensitive enteropathy showed normal villous architecture, but increase in CD8 intraepithelial lymphocytes (a). The CD4 cell population lies essentially within the lamina propria (b). Photomicrographs courtesy of Dr Franco Torrente.

predisposed to high IgE levels, remains uncertain. However, there is clear evidence that manipulation of the diet of the eczematous child may be beneficial. A double-blind study by Atherton et al in 197847 found that two-thirds of 2-8-year-old children with atopic eczema were improved by exclusion diets. Subsequent studies have broadly confirmed this finding, although in most cases the response was not so striking, except in younger infants.37 The dominant inducing antigens of food allergy-induced childhood eczema are eggs, milk, soy, and peanut in young infants, with the addition of wheat, tree nuts and fish in older infants. Most children tend to outgrow allergies to eggs, milk, wheat and soy, but tend to have persistent reactions to peanuts, tree nuts, shellfish and fish. The use of skin patch testing has suggested that multiple sensitizations are common in affected infants below 2 years, and thus exclusion of single antigens may not give satisfactory clinical responses.48

In addition to antigen exclusion, the use of pro-biotic treatment has been reported to improve the symptoms of chronic eczema in food-allergic infants.49 Whether this is because of a direct effect on epithelial integrity, or competitive reduction of toxin-producing staphylococci is as yet unknown. Probiotics are considered in further depth later in this chapter, as well as in Chapter 32. For the affected infant who is exclusively breast fed, maternal dietary exclusions can improve the eczema, but potentially at the cost of maternal nutritional inadequacy if multiple exclusions are required.50 In addition, some infants may not respond completely to extensively hydrolyzed formulas, due to response to the residual milk antigens, and these may show improvement only with an amino acid formula.51,52

Allergic dysmotility

The concept that food allergies might trigger intestinal dysmotility in pediatric patients is relatively new, but there is mounting evidence that dietary antigens (most commonly cow's milk, soy or wheat) can induce gastroesophageal reflux or constipation.8,53-55 Gastrointestinal investigation of children with delayed food allergic responses frequently uncovers a history of infant colic, gastroesophageal reflux and chronic abdominal pain.5,14,24,51,52 Conversely, amongst infants presenting with colic, there is a significant incidence of underlying cow's milk allergy.56,57 There may additionally be evidence of small-intestinal enteropathy or allergic colitis. However, it is not uncommon for food allergy to be overlooked because 'the investigations are negative'.

In infancy, food allergy-induced gastroesophageal reflux is often accompanied by a complex presentation, including low-grade enteropathy with secondary carbohydrate malabsorption, colic, irritability, eczema and prolonged viral infections.5,8,14 The infants may fail to thrive, and show food-aversive behavior, or weight gain may be accept-able.5,14 In many cases, reactions to hydrolysate formulas occur, and a therapeutic trial of an amino acid formula should be considered.5,52,58,59 Dermatographia may be a useful clinical pointer in an apparently colicky infant, as is a family history of allergies. A distinct pattern on 24-h pH testing has been reported to be associated with antigen-induced gastroesophageal reflux, in which there is gradual reduction in esophageal pH following a feed.53 The frequent finding on esophageal biopsy is mucosal eosinophilia, which may be related to expression of the chemokine eotaxin in milk-induced gastroesophageal reflux.55

Even in the older child, milk responses may be a cause of continuing symptoms, including chronic abdominal pain, with endoscopic findings of lymphonodular hyperplasia.60 There is some evidence that delayed allergic responses to milk in infancy are not always outgrown, and thus the diagnosis should be considered in the older child with an atopic history who presents with chronic abdominal pain.36 There is also evidence that constipation can be triggered by delayed allergic responses to cow's milk protein in older children.54 Once again, mucosal eosinophil infiltration was characteristic. Studies using anorectal mano-metry suggested that this pattern of constipation was caused by antigen-induced spasm of the anal spincter muscles, rather than a more widespread colonic dysmotility.61 The use of radio-opaque markers may confirm the pattern of normal colonic transit with impaction within the rectum. Clinically the children often demonstrate avoidance posturing, leaning forward during defecation in an attempt to stop the large rectal hard mass from bearing down, while passing the softer stool from above. Clinical examination may be difficult, and even a sizeable acquired megarectum may be difficult to palpate. In cases of clinical doubt, a plain abdominal X-ray may be helpful (Figure 22.4). One characteristic pattern is of fecal impaction within the rectum, together with abundant gas within the small intestine, related to malabsorption of carbohydrates plus constipation-associated small-bowel bacterial overgrowth.

Ige Mediated Responses
Figure 22.4 Plain abdominal X-ray of a child with non-IgE-mediated food allergies, demonstrating acquired megarectum with fecal impaction. Conventional constipation therapy was ineffective, and a cow's milk- and wheat-free diet were required.

Eosinophilic esophagitis and eosinophilic enteropathy

Eosinophilic esophagitis and eosinophilic enterocolitis are emerging clinical entities, which overlap with non-IgE-mediated food allergy, but which may also occur without recognizable food responses.62 While an apparently increasing cause of infant gastroesophageal reflux disease, eosinophilic esophagitis is also increasingly seen in older children, who often present with abdominal pain, dysphagia or vomiting, sometimes with associated loose stools.63,64 In some cases, eosinophil recruitment is confined to the serosa, and may be missed on mucosal biopsies. In many cases, symptoms of esophagitis are severe and prolonged.

At endoscopy, the esophagus shows a distinctive finding of linear furrows or transverse rings, and the mucosa appears granular.64 The mucosa is traumatized unusually easily.65 Histological diagnosis is based on the detection of five or more eosinophils per high-powered field. Recent reports of endoscopic ultrasound examination show increased thickness of the esophageal wall.66 The results of 24-h pH testing are variable, and novel techniques such as luminal impedance testing suggest that much non-acid reflux may occur.67 Skin prick testing is often negative, but a combination of skin prick and skin patch testing may be helpful in identifying cases of food-induced eosinophilic esophagitis.68

Later in the chapter, the potential mechanisms of eosinophil recruitment within the mucosa will be addressed. The eosinophil chemokine eotaxin is clearly important in this process, and indeed this chemokine was up-regulated within the basal esophageal epithelium in infants with milk-induced reflux, in comparison to those with simple mechanical gastroesophageal reflux.55

Management of eosinophilic esophagitis

Particularly in younger infants, it is important to perform adequate dietary exclusions. In a significant minority of affected infants, symptoms are not adequately relieved using hydrolysate formulas, and an amino acid-based formula may be required.58 Effective acid reduction therapy with ranitidine or omeprazole, together with a pro-kinetic such as domperidone, are frequently used in conjunction.67 An important clinical finding is the rapid symptomatic worsening during viral illnesses, which is unresponsive to dietary exclusion. This often requires a temporary increase in antacid therapy.

For the older child, dietary exclusions are often less helpful, but a therapeutic trial of a 'few foods' diet may determine whether this is an avenue worth exploring. Topical corticosteroids such as inhaled fluticasone have proved effective in cases where diet has proved ineffective.69 More recent evidence suggests that leukotriene antagonists such as montelukast may be helpful in corticos-teroid-resistant eosinophilic esophagitis.70

Respiratory symptoms

Respiratory allergies, particularly asthma, are increasingly common in young children. It is also well recognized that the immediate hypersensitive response to a food allergen includes respiratory symptoms such as wheeze (Table 22.4). What has been less clear is whether delayed responses to food antigens may include worsening of respiratory status in asthma, or can be implicated in upper airway disorders such as rhinitis.71 Food-induced wheezing appears most common in young infants.5,17 The estimated prevalence of food-induced wheezing is under 6% of the total population of children with asthma, but it occurs much more frequently in children with cow's milk allergy (29%) or atopic dermatitis (17-27%71). Whether antigen-induced gastroesophageal reflux can contribute to respiratory symptoms is an important consideration, and there is potentially important recent evidence suggesting that effective treatment of gastroesophageal reflux may significantly diminish the requirements for bronchodila-tor therapy in an unselected population of childhood asthmatics.72 However, it is not clear how many children had straightforward mechanical gastroesophageal reflux and how many may have had an underlying allergic dysmotility.

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