This issue was sponsored by Pharmaplan Tel: +27 11 652 0950 www.pharmaplan.co.za

 

Contents A. Case study B. More information C. Editors' comments D. References E. CEU questions

Index

A. Case study
A four-month-old baby girl was seen by her paediatrician after presenting with bloody stools. On examination, she seemed to have abdominal discomfort and was restless. Medical history revealed that she had grown well since birth until about three months of age; after which time her weight gain had started decreasing, and her growth curve started to plateau. She was exclusively breastfed from birth until three months, after which time a number of infant formulas had been trialled. Her mother reported that her daughter suffered from colic-like symptoms, excessive flatulence, severe abdominal cramping and discomfort and excessive positing – symptoms were present since birth but had been exacerbated from three months of age. Since three months, her stools had become harder than usual, and she seemed to have pain when stooling. After blood had appeared in her stools, the clinic sister suggested that the mother see a medical doctor.

THOUGHT PROCESS:
Possible reasons for the various symptoms could include:
a. Excessive positing may be gastro-oesophageal reflux which, if moderate to severe, may result in poor weight gain and oesophagitis, causing pain on swallowing, and contributing to irritability and colic-like symptoms
b. A mechanical problem of the gastrointestinal tract
c. Inadequate nutrition contributing to insufficient caloric intake, leading to poor weight gain
d. Dietary changes leading to constipation, and pain in stooling
e. Incorrect fluid intake may contribute to harder stools
f. An allergic reaction to a food protein, resulting in bloody stools, gastrointestinal disturbance and constipation
g. Metabolic disorder leading to malabsorption of nutrients, and thus poor weight gain
h. Sub-clinical urinary tract infection

What investigations should be done at this stage?
a. In order to establish whether she has clinically significant reflux, a 24-hour pH study could be done. A trial of a proton pump inhibitor could be considered in order to inhibit acid production, and this would help to minimise pain and treat any oesophagitis.
b. A barium study would help to establish structural and motility abnormalities of the upper gastrointestinal tract. A scope could also be taken of the oesophagus, upper gastrointestinal tract and colon, as well as a biopsy to confirm any abnormal pathology.
c, d & e. A detailed diet history should be taken to understand what her average nutritional and fluid intake is and to establish any dietary changes since birth. A full blood count and haemoglobin should be done to test for presence of anaemia.
f. Allergy tests (Phadiatop, serum-specific IgE evaluation and skin-prick tests), although her symptoms seem to be more indicative of non-IgE-/cell-mediated reactions. A trial elimination diet of the most likely problem allergens currently consumed in her diet followed by a controlled food challenge is advisable for a more accurate diagnosis. An atopy patch test could be considered, especially considering the strong likelihood of a non-IgE-mediated reaction to cow’s milk.
g. Because of the lack of diarrhoea and severe vomiting, and the fact that she grew adequately until three months, lactose intolerance (in breast milk) is unlikely. At this point a metabolic disorder is unlikely, and should be considered only once the other options have been ruled out as negative.
h. Urinary tract assessment

DISCUSSION
a. The mother refused to allow her daughter to be admitted to hospital to perform the pH-study. The paediatrician decided on a trial of proton pump inhibitor. Within five days, her oral intake of both fluids and solid foods had improved substantially suggesting oesophagitis due to gastro-oesophageal reflux.
b. A barium swallow showed normal upper gastrointestinal tract function with acceptable gastric outlet. Mild reflux was noted, although a modified swallow using thicker porridge demonstrated more significant gastro-oesophageal reflux. A scope of the upper GIT showed oesophageal eosinophilia (= 15 intraepithelial eosinophils per 1 High Powered Field). The remaining GIT was normal.
c, d, e. A thorough diet history revealed the girl had been exclusively breast-fed since birth. Her mother had not eliminated any food from her diet apart from peanuts, to which she was allergic. At three months, her mother had tried to wean her onto an infant formula and had tried a number of cow’s-milk-based, soya-based and partially-hydrolysed formulas. Symptoms (reflux and abdominal discomfort) had been aggravated, and after trying the soya formula, blood appeared in the stools. The constipation at three months may have been due to the increased iron introduced through the fortified infant formulas. Her overall fluid intake had also decreased due to the reflux and subsequent oesophagitis, further contributing to hard stools. Her blood count and haemoglobin were normal. Solids (maize cereal) had been given at three months to try to minimise reflux, but the little girl gagged and vomited even more than with the liquids, so the mother had stopped immediately.
f. Total IgE was high. All food-specific IgE tests were negative except for peanuts, and skin-prick tests were all negative. Peanuts were not tested by means of skin-prick testing following the serum-specific IgE test results. She also tested positive to cats. An atopy patch test was done, revealing a mildly positive reaction to both cow’s milk and soya. The blood tests and skin-prick test results ruled out an IgE-mediated reaction to cow’s milk and soya, but the comprehensive diet and medical history indicated a strong association with cow’s milk and soya protein. The atopy patch test was mildly positive, pointing to a possible non-IgE-mediated/cell-mediated reaction to cow’s milk and soya proteins. In light of the findings, the allergist decided that a controlled food challenge was unnecessary initially, and a trial food elimination of soya and dairy should first be considered. If symptoms persisted despite food restriction, an oral food challenge could then be considered.
g. A urinary analysis was done which came back negative for any pathogens, ruling out an infection.

The girl was diagnosed as with eosinophilic oesophagitis, with moderate gastro-oesophageal reflux and allergic colitis. The mother was advised to eliminate cow’s milk and soya protein. By the time her daughter was four months old, she had stopped breastfeeding, so did not need to have these foods eliminated from her diet. The doctor referred the mother to a clinical dietician, who assisted in ensuring adequate nutrition was provided for growth while implementing a strict dairy- and soya-free diet. She was placed onto an extensively hydrolysed casein infant formula. Solid foods would only be introduced from six months, and due to the daughter’s allergic diagnosis, the dietician advised the mother to avoid peanuts and tree nuts as well as the other major allergens until at least one year of age. Guidelines for appropriate introduction of solid foods were discussed. The family had no pets; but her grandmother had a cat, and the mother was advised to limit contact with it.

Within two weeks the little girl had improved dramatically. She was advised to see an occupational and speech therapist, to ensure she had no tactile defensiveness or oral sensitivities which could inhibit ingestion of various textures over time.

B. More information
A food allergy is defined as an adverse response to one or a number of food proteins with an immune aetiology.¹ Symptoms may involve several organs and systems, whether cutaneous, gastrointestinal, respiratory or systemic; and reactions may be acute and possibly life-threatening as well as chronic debilitating diseases.^1,2 The diverse clinical manifestations of food allergy result in part from different immune mechanisms, target organ responses and characteristics of triggering proteins. For greater ease of understanding, the immune mechanisms may be divided into three general types:
• immunoglobulin E (IgE) antibody-dependent diseases (IgE-mediated reactions);
• cell-mediated disorders, without detectable IgE antibodies (non-IgE-mediated reactions);
• disorders with mixed IgE and non-IgE mechanisms.^1,3

Food hypersensitivity reactions will result in reactions which are either immediate or delayed, occurring within hours to days following ingestion of a trigger food. The severity and immediacy of IgE-mediated food reactions such as anaphylaxis and urticaria/angio-oedema, as well as generally being easier to diagnose, has resulted in an under-appreciation of the significance of the non-IgE-mediated mechanisms. These types of reactions may be responsible for up to 30% of delayed immune-mediated reactions to food.⁴

In the past, because of phenotypic similarities between food-induced and idiopathic gastrointestinal (GI) disorders, and a lack of reliable diagnostic markers, food allergy was not always recognised.⁵ Although diagnostic tests may still be unreliable, the more recent acknowledgement, identification and better understanding of the different mechanisms involved in true food hypersensitivity reactions has resulted in a number of clinical manifestations (usually delayed in onset, affecting the GI tract), previously overlooked, now being identified as having an allergic cause. Many of these conditions may be transient and resolve spontaneously, but their early recognition and appropriate dietary management may prevent unnecessary drug therapy or adverse nutritional outcomes.⁵ This review is the first part of two documents that will discuss unusual presentations of food hypersensitivity, and attempt to highlight conditions in which the role of food allergy may not always be considered.

1. Eosinophilic oesophagitis (EE)
1.1 General information, symptoms and diagnosis
Often misclassified as gastro-oesophageal reflux (GOR), EE is now acknowledged as a distinct clinicopathologic disease, occurring in both adults and children, of either sex (currently there appears to be more of a male predominance) and of any age or race, and involves a localised eosinophilic inflammation of the oesophageal mucosa, often with eosinophil micro-abscesses.^6,7,8,9

The exact aetiology is unknown, but EE is believed to be a mixed IgE- and non-IgE-mediated allergic response to food antigens, with non-IgE cell-mediated responses predominating.^6,7,8 It is interesting to note that the majority of patients with EE (50-80%) are atopic, and present with coexisting allergic conditions such as atopic dermatitis, allergic rhinitis, and/or asthma; as well as presence of allergic antigen sensitisation based on skin-prick tests or measuring plasma-antigen-specific IgE.^6,8,9 Up to 50% of patients have one or more parents with an allergic history.^6,10 Food antigens shown to aggravate symptoms following a strict elemental elimination diet and controlled food challenges include milk, soya, tree nuts, peanuts, wheat, egg, corn, beef, rye, oats, potatoes, chicken, fish and shellfish.^6,7,10 Aeroallergens, such as pollens, moulds, cat, dog, ragweed, roach, and dust mite allergens, may also play a role in the development of the condition.^6,7,10

The presenting symptoms resemble those of gastro-oesophageal reflux disease (GORD) and include vomiting, regurgitation, chronic nausea, heartburn, chest pain, feeding intolerance and weight loss (in younger children), dysphagia (in older children and adults), odynophagia, and food impaction (in older children and adults).^6,8,9,10,11 It is important to distinguish between the two conditions, as they may coexist. Oesophageal eosinophilia may also be associated with other diseases, namely: GORD, Crohn’s disease and inflammatory bowel disease, collagen vascular disease, infectious oesophagitis (herpes, Candida), parasitic infections, food allergy, drug-associated oesophagitis, hypereosinophilic syndrome, eosinophilic gastroenteritis and Churg-Strauss syndrome.^6,8,9,11

In diagnosing EE, the previously-mentioned conditions should be excluded and oesophageal endoscopic biopsies performed to help establish a correct diagnosis. EE is defined as a primary clinicopathologic disorder of the oesophagus, characterised by oesophageal and/or upper gastrointestinal (GI) tract symptoms, in association with oesophageal mucosal biopsy specimens containing = 15 intraepithelial eosinophils per 1 HPF (high-powered field – 400x) in 1 or more biopsy specimens; and absence of pathologic GORD, as evidenced by a normal pH-monitoring study of the distal oesophagus, or lack of response to acid suppression by means of high-dose PPI medication (up to 2mg/kg/day). Due to the patchy nature of the disease, multiple biopsies obtained from the mid and distal oesophagus are preferred. It is also suggested that the remaining GI tract be normal to rule out other diseases.^6,7,8,11

In terms of allergy markers, serum peripheral eosinophilia or elevated IgE levels are considered unreliable, responding to both environmental and ingested or inhaled allergens, and are usually not present in the majority of patients.^6,8 Serum RAST testing for food-specific IgE antibodies has little use in EE. A combination of skin-prick testing (SPT) and atopy patch testing (APT) may be effective in identifying IgE- and non-IgE-based causative food allergens respectively.^6,8 In EE, SPT has been shown to identify positive reactions to milk, egg and soy most frequently, while the most common foods identified by APT are corn, soy and wheat.⁶

1.2 Treatment and management
Patients with EE should be evaluated and monitored by a well-informed allergist. Dietary therapy has been reported to be effective in managing the condition, with the fact that most patients improve on allergen-free diets (particularly paediatric patients) providing supportive evidence that an antigen may be eliciting the disease.^6,8,11 As yet there is no definitive evidence confirming that EE is a food allergy, but removal of food antigens has been clearly demonstrated to treat both clinical symptoms and the underlying histopathology (does not normalise completely) successfully in over 95% of patients with EE.^6,8,9

Elimination of causative foods can either be done as specific food elimination, based on allergy testing and clinical history; or the most likely causative foods (e.g. milk, soy, wheat, egg, fish, shellfish and nuts) can be removed regardless of history.^6,8 Foods considered to be the most commonly antigenic for EE include milk, soya, corn, wheat, peanuts, beef and rye.^6,7,10 Despite strict elimination, some patients remain symptomatic and continue to demonstrate abnormal oesophageal histology. In these cases, a strict elemental diet utilising an amino-acid-based formula is necessary.⁶ This approach may be difficult for patients (and parents), particularly as nasogastric tube feeding may be necessary, but the benefits far outweigh the risks of other treatments. When deciding on the use of a specific dietary therapy, the patient’s lifestyle and family resources need to be considered. Consultation with a registered dietician is strongly encouraged to ensure proper calories, vitamins, and micronutrients are maintained.⁸ Once the oesophagus has healed, foods are reintroduced systematically. Clinical symptoms may be erratic, so endoscopy should be performed to determine improvement in oesophageal histology.⁶

The use of dietary therapy in adults requires further study. Instituting long-term dietary changes is challenging in adults, given the poor tolerability of significantly restricted diets. Unless the patient remains refractory to medical and endoscopic therapy, the emphasis in treating adult patients with EE tends to be on anti-inflammatory medications and endoscopic approaches (dilations).^8,12

Once the culprit food(s) has been eliminated, it may take approximately 1-3 weeks for symptoms to improve. In patients with EE, onset of symptoms may be delayed by several days to weeks following the reintroduction of eliminated foods. A systematic approach may be required to accurately identify responsible food antigens: eliminate foods for 6-8 weeks; perform a repeat endoscopy; introduce new foods every seven days; repeat biopsies based on clinical symptoms or after 5-8 new foods are introduced.⁶

Patients may experience secondary acid reflux and should be prescribed a proton pump inhibitor.^6,8 Oesophageal endoscopic dilation may have a role in alleviating severe oesophageal strictures; however, its results tend to be temporary, may result in perforation, and the problem often recurs.⁶ While systemic steroids have been shown to work rapidly to improve both symptoms and oesophageal histology effectively, symptoms recur once their use is discontinued. They cannot be used chronically, they do not cure the disease and they often have serious side effects with prolonged use (bone, growth and mood abnormalities).^6,8,9

Topical steroids, sprayed into the pharynx and swallowed, have been found to be as effective as systemic steroids but with fewer side-effects, although they are associated with oesophageal candidiasis, dry mouth, epitaxis and recurrence of symptoms once their use is discontinued.^6,8,9

Long-term management of this condition should attempt to provide relief of symptoms together with histologic healing. Currently, both topical corticosteroids and dietary restriction have been shown to be successful in managing EE over time.^6,8 It is not yet known whether children outgrow the condition, or progress to long-term sequelae such as fibrosis and strictures.⁷

2. Eosinophilic gastroenteritis (EG)
2.1 General information, symptoms and diagnosis
This condition refers to eosinophilic inflammation to one or more areas of the GI tract, particularly the stomach and small intestine, with the presence of GI symptoms in the absence of parasitic infection.^6,7,13 It affects patients of all ethnicities and ages, although typically presents in the third through fifth decades and has a more equal gender distribution than EE. ^6,7,13

It can be characterised into three categories (Klein classification), depending on the extent of the eosinophilic infiltration and the different layers of the bowel wall affected: mucosal, muscular and serosal.^6,7,13
• Mucosal – most common presentation (present with non-specific abdominal complaints and signs of malabsorption – growth failure, weight loss, diarrhoea, hypoalbuminemia)
• Submucosal/Muscular – typically present with obstructive symptoms (gastric outlet or intestinal)
• Serosal – rarest form (usually affects all layers of bowel and may cause eosinophilic ascites)

The exact aetiology of EG remains unknown, although it appears to occur due to both IgE- and non-IgE-mediated sensitivity. Up to 50-70% of patients have a past or family history of atopy and an increased likelihood of presenting with other allergic disorders, such as atopic disease, food allergies, asthma, eczema and seasonal allergies.^6,7,13 Allergic history tends to be more common in children with this condition.⁷ Regarding the non IgE-mediated immune dysfunction, there appears to be an interplay between lymphocyte-produced cytokines (IL-5 significantly increased) and eosinophils.⁶

Symptoms generally include colicky abdominal pain, bloating, dysphagia, vomiting, and diarrhoea, in combination with the presence of eosinophils in the GI tract; and in more severe cases, GI bleeding, iron-deficiency anaemia, poor weight gain, hypoalbuminemia and protein-losing enteropathy. In infants, the condition may resemble hypertrophic pyloric stenosis, with progressive projectile vomiting, dehydration, electrolyte abnormalities and thickening gastric outlet. Infants presenting with this clinical picture but with the addition of atopic symptoms, such as eczema and reactive airway disease, an elevated eosinophil count or a strong family history of atopic disease, should be evaluated for EG before surgical intervention is considered. Children with allergic EG typically demonstrate intestinal loss of blood and protein, thought to be because of increased intestinal permeability due to eosinophilic inflammation.^6,13

There are no strict diagnostic criteria or standards for EG. Approximately 75% of patients will have elevated blood eosinophil levels and/or an elevated IgE level (especially if there is mucosal involvement).^6,13 Eosinophils in the GI tract must be documented before EG can definitely be considered.^6,13 The absolute eosinophil count averages 2000 cells/uL in patients with mucosal disease; 1000 cells/uL when there is muscular involvement; and as high as 8000 cells/uL in serosal disease.⁷ Multiple biopsies of the upper GI tract through oesophagogastroduodenoscopy and the lower tract through colonoscopy are the most useful tests, due to the patchy disease distribution and the fact that mucosal EG may affect any portion of the GI tract, ranging from the gastric antrum (a lacy mucosal pattern, commonly known as areae gastricae, uniquely seen in EG), proximal small intestine, oesophagus to the gastric corpus and even the colon (usually seen in infants under six months), in order of frequency of involvement.⁶ Various tests should be considered in the diagnostic workup, including allergic investigations similar to those done for EE, stool ova and parasite testing (three separate stool samples), serum EBV PCR, giardia antigen, helicobacter pylori testing, rheumatologic testing in the appropriate clinical context, measures of absorptive activity and possible small bowel damage (D-xylose absorption test, lactose hydrogen breath testing).^6,13

Certain conditions which also present with eosinophil infiltration do need to be ruled out in the differential diagnosis – parasitic infection, inflammatory bowel disease, cytomegalovirus, neoplasm, chronic granulomatous disease, collagen vascular disease, inflammatory fibroid polyps, solid organ transplantation and hypereosinophilic syndrome.^6,7,13

2.2 Treatment and management
Due to the complexity of the condition and its treatment, these patients should be managed in consultation with a number of specialists, including an allergist, gastroenterologist, infectious disease specialist, rheumatologist and dietician.⁶

Management of potential food allergy will follow the same approach as for EE. The type of dietary therapy (elimination or elemental diet) will depend on the patient’s age, the particular EG presentation and the expected compliance. A food diary is useful to determine the extent of food elimination. The empiric removal of the eight major food allergens (milk, soy, wheat, egg, peanuts, tree nuts, fish and seafood) is considered a practical option in all patients with primary EG who do not have obvious food allergies on allergy testing. Unlike in treating EE, use of strict elemental diets is not uniformly successful in EG.^6,7,13 Elemental diets tend to be considered for patients with multiple food allergies, and will produce improvement of symptoms and histology in 4-9 weeks, although their duration should ideally be limited to 6-8 weeks. These diets have poor palatability and may be impractical due to high cost and extreme restriction. Patients who respond positively may have a new food introduced every 5-7 days with vigilant follow-up.¹³

Corticosteroids are usually considered when restricted diets fail. They produce both symptomatic and histologic improvement within a few days to weeks, regardless of the type of EG, although patients with serosal involvement will often seem to respond quicker and better to steroids.^6,13 However, usually remission is not likely to be achieved; once weaned from the medication, symptoms usually return. A slow taper over several weeks is suggested, and should patients relapse, a maintenance regimen may be necessary.⁷ In addition, long-term steroid treatment results in a number of undesirable side effects, which has led to the use of substitutes to act as steroid-sparing agents (e.g. Budesonide) while still allowing for control of symptoms. Orally administered cromolyn sodium and some oral anti-inflammatory medications may show promise in treating EG in the future.^6,7,13 Biologic therapies such as Anti-interleukin 5 and Anti-IgE therapy have also been shown to be effective in treating EG; however, the evidence is currently limited.¹³

The condition appears to have a chronic, relapsing course, so long term management should aim to identify and restrict potential food allergens in a step-wise approach, and combine therapies to ensure the best chance of success with the smallest likelihood of side effects. Corticosteroids remain a reliable treatment if other options have failed. Attempts should be made to limit the overall dose or number of treatment courses. Serial endoscopy and biopsies are advisable to monitor disease progression.^6,13

3. Eosinophilic proctocolitis (EP)
3.1 General information, symptoms and diagnosis
EP is now recognised as one of the most common causes of infant rectal bleeding.⁶ It is also known as milk-protein proctocolitis, is defined as an abnormal number of eosinophils confined to the colon, and is thought to be a non-IgE-mediated reaction. The condition usually presents within the first 60 days of infancy and then much later, in adolescence or early adulthood.⁶

The GI tract plays a key role in the development of oral tolerance to foods. This usually effective barrier may not be mature for the first few months of life, leading to an increased risk of ingested antigens being presented intact to the immune system, stimulating an inappropriate immune response. The antigens most frequently implicated in EP are cow’s milk and soy proteins. These are major components of an infant’s diet, usually introduced through commercially-available infant formulas. Interestingly, up to 50% of EP cases occur in breastfed infants, with infants manifesting allergy to proteins transferred from the maternal diet via the breast milk.⁶

Clinical symptoms include diarrhoea, rectal bleeding and increased mucous production, irritability and straining with stools (may be confused with anal fissures), despite a generally well-looking infant, and are generally seen in infants less than two months of age.⁶ Continuous exposure to the problem protein may aggravate bleeding leading to anaemia, and in rare cases, poor weight gain. Atopic symptoms such as eczema and reactive airway disease are associated with the condition.

In clinical practice endoscopy is usually not performed, and the diagnosis is established when infants present with rectal bleeding that resolves on a protein hydrolysate formula. Initial assessment should be directed at the overall health of the child, as a toxic, ill-looking infant is not consistent with EP, and usually indicates another cause of rectal bleeding. Stool samples and assays should be taken to rule out Salmonella and Shigella, Clostridium difficile, and to test for white blood cells and eosinophils specifically, although this test has questionable sensitivity. Depending on the clinical situation, and particularly in older children, it may be necessary to rule out other conditions which may cause the accumulation of eosinophils in the colon – pin and hookworm infections, inflammatory bowel disease, drug reactions, vasculitis. A complete blood count is useful, as these infants almost always present with normal to borderline low haemoglobin, and may have elevated serum eosinophils.⁶

3.2 Treatment and management
In a well-appearing infant with a history consistent with EP, it is acceptable to make an empiric formula change to a protein hydrolysate formula. Symptoms will usually begin to resolve as soon as the problem food has been eliminated, with continued improvement evident over time. Should symptoms persist beyond 4-6 weeks, other antigens as well as other potential causes for rectal bleeding should be considered. In breastfed infants, restriction of dairy and soya from the maternal diet is advised, and usually results in improvement. Dietetic expertise should be sought to ensure the mother obtains adequate protein and calcium from other sources.⁶

EP in infancy is generally benign, and will resolve once the milk-protein trigger is removed. Usually gross blood loss in stools will disappear within 72 hours, but occult blood loss may still occur occasionally. The prognosis is excellent, and most patients will be able to tolerate the introduction of the responsible milk protein by 1-3 years of age. An open challenge performed in a doctor’s office setting is advised at one year of age. Should a reaction occur, the infant should be rechallenged at 15 months of age and then referred to an allergist. Older onset EP, unfortunately, is chronic and relapsing.⁶

4. Constipation
4.1 General information, symptoms and diagnosis
Chronic constipation is characterised by the infrequent passage of hard, lumpy stools for more than 8 weeks, in association with faecal incontinence, withholding behaviour or painful defecation. About 97% of constipation in young children is functional. Constipation in young children is generally believed to result from a fear of painful defecation and stool withholding behaviour which may lead to overflow incontinence, although organic motility disorders (slow-transit constipation, obstructed defecation) may also cause treatment-resistant childhood constipation.^5,14,15,16 More recently, in a number of studies, CMA has been suggested as a cause of resistant constipation in infants and children. Withdrawal of cow’s milk and dairy products for a one-month period, followed by cow’s milk challenge, demonstrated improvement or resolution and then relapse of symptoms on challenge in up to 78% of cases. Tolerance to cow’s milk was achieved in 89% of cases after 12 months of elimination.^{5,17,18,19,20}

The pathophysiological mechanisms of cow’s-milk-protein-induced constipation remain elusive. Breast-feeding for less than four months and a high intake of cow’s milk (> 200 ml per day) have been associated with anal fissures and chronic constipation. Also, allergy to cow’s milk and other food proteins may induce constipation in association with an eosinophilic proctitis.^5,20,21 Lymphonodular hyperplasia in the colon and terminal ileum may be a helpful marker of cow’s-milk-protein-induced constipation. Colon and ilial biopsies of constipated patients have been found to have significantly higher eosinophil numbers, and a greater density of certain T lymphocytes. Serum-specific IgE values to whole cow’s-milk protein and beta-lactoglobulins may be significantly higher in constipated patients – these values are helpful, although not definitive for diagnosis.¹⁷ Although evidence of an association between cow’s milk allergy and constipation remains inconclusive, current thinking suggests that eosinophilic proctitis should be considered in the differential diagnosis of infantile constipation, and rectal biopsies should be obtained in infants with refractory symptoms. Also, cow’s-milk allergy should be evaluated in patients suffering from chronic functional constipation which remains non-responsive to laxative therapy.^5,17

4.2 Treatment and management
Treatment strategies for constipation generally include dietary changes (fibre and fluid intake), non-accusatory toilet training, and use of laxatives or polyethylene-based colonic lavage solutions.^5,15,16

A 4-6 week trial of a hypoallergenic formula may be justified if all other treatment has failed. Once an association with cow’s milk has been established, patients should be placed on a cow’s-milk-free diet with extensively hydrolysed formula, if formula-fed (amino-acid-based formula indicated if no response due to residual allergenicity of extensively hydrolysed formula), or if breast-fed, mothers should avoid all dairy, closely supervised by an experienced dietician.⁵

5. Gastro-oesophageal reflux (GOR)
5.1 General information, symptoms and diagnosis
GOR is the involuntary, passive flow of gastric contents into the oesophagus. In children and adults, reflux episodes occur predominantly during transient lower-oesophageal sphincter relaxation. In infants and young children, severe reflux may be difficult to distinguish from vomiting. It is also important to be aware that more than 50% of healthy infants will regurgitate milk after feeds in the first months after birth, and symptoms will resolve or improve significantly by the age of one year.^5,22,23,24 Reflux is considered pathological when associated with failure to thrive, respiratory complications (aspiration pneumonia, persistent wheeze, stridor, apnoeic episodes), or peptic mucosal injury (oesophigitis, peptic strictures, Barrett’s metaplasia, adenocarcinoma).^5,22

Increasing evidence suggests a possible causal link between GOR with oesophagitis in infancy and the development of food hypersensitivity, particularly to cow’s milk and soy proteins. A group of infants with GOR disease and histologic oesophagitis, have been shown to respond favourably to either extensively hydrolysed formula or amino acid-based formula.^5,25,26 Also, a large percentage of children with GORD have been found to have cow’s-milk allergies (CMA) on open or double-blind challenge.²⁷

The mechanisms by which food allergens induce GOR and oesophagitis are poorly understood. It appears plausible that release of pro-inflammatory mediators from activated T cells and eosinophils may stimulate the enteric nervous system, either directly or via the release of motility-active gastrointestinal hormones, but further research is necessary to characterise the upper GI motility in infants with food-protein-induced GOR.^5,24

Due to the suspected cell-mediated nature of GORD-associated food allergy, diagnosis may prove difficult. IgE-based testing, including skin-prick testing and measurement of food-specific IgE antibody, is usually not helpful; and although the atopy patch test may potentially identify infants with gastrointestinal manifestations of CMA, it has a low sensitivity, and may miss a significant proportion of infants with delayed-onset food allergy. Formal food challenges, adapted to identify delayed reactions, are required in order to make an accurate diagnosis. Endoscopic biopsies from the upper and lower gastrointestinal tract may provide useful information, e.g. presence of tissue eosinophilia in the oesophagus, or small-intestinal villous damage in infants with malabsorptive symptoms.^{5,28,29,30,31}

5.2 Treatment and management
In formula-fed infants with clinically significant GORD a 4-6-week trial of a hypoallergenic formula may be justified, particularly if conventional treatment has failed. Anti-reflux medications may provide relief if oesophagitis is present, but are not always effective. Failure to respond to an extensively hydrolysed formula may be due to its residual allergenicity, warranting use of an amino-acid-based formula (may occur in about 10% of infants). In breast-fed infants, maternal hypoallergenic elimination diets may be effective. Supervision by an experienced dietician is advised to minimise nutritional risk to both mother and infant.^5,32

6. Colic
6.1 General information, symptoms and diagnosis
Unexplained irritability, fussing or crying that persists for more than three hours per day, on more than three days per week and for at least three weeks have been described as infantile ‘colic’, and can affect up to 20% of generally well infants, in the first few months of life, usually improving by age 3-4 months.⁵ Less than 5% of distressed infants appear to have a medical explanation for their crying. Interactive factors and infant behaviour patterning significantly influence the clinical course of colic. Although the exact aetiology of infantile colic remains unknown, it is likely to be multifactorial. GOR and oesophagitis are commonly found in infants with colic; but current research suggests a direct causal relationship between acid reflux (GOR) and infantile colic is unlikely, with the duration of crying and fussing per day not correlating to the severity of GOR, and treatment with anti-reflux medications not providing clinical improvement.⁵ Evidence is now linking persistent crying in some young infants to food allergy, particularly CMA.^5,33,34

Colic is not usually associated with elevated serum IgE or food-specific IgE levels, making a non-IgE-mediated reaction likely. Several clinical trials have demonstrated a significant treatment benefit from extensively hydrolysed formula, amino-acid-based formula or maternal elimination diets in reducing persistent crying in infants with colic, following elimination of cow’s milk protein from the infant’s or breastfeeding mother’s diet.^{5,35,36,37,38}

6.2 Treatment and management
In infants with prolonged symptoms of colic, a 4-6 week trial of cow’s milk elimination from the infant’s diet (with the infant on an extensively hydrolysed or amino-acid-based formula) – or, in the case of breast-fed infants, from the mother’s diet – under dietetic supervision, may be effective in reducing and improving symptoms. This should then be followed by a formal food challenge in order to confirm the diagnosis (consideration should be given to delayed onset of symptoms).⁵ In infants with colic and co-existing GOR symptoms, anti-reflux medications are not usually effective.

Colic and its management have been discussed in detail in a previous educational review. For more comprehensive information on the condition, please click here.

PLEASE NOTE: A follow-up, PART 2, of Unusual Food Allergy Symptoms will be released shortly.

C. Comments by our editors

Prof Janice M. Joneja Ph. D., RDN This month’s topic powerfully illustrates the enormous challenge posed by an increasing number of food-related adverse reactions, especially with regard to diagnosis and accurate identification of the foods involved in their aetiology. Thirty years ago, we had scarcely heard of food allergy; knowledge of food intolerances was more or less limited to lactose intolerance; and most of the reaction mechanisms responsible for adverse reactions to foods were barely understood. Food sensitivity management was largely confined to the area of “alternative medicine”. In the past 20 years there has been a vast increase in our knowledge of the science behind the physiological mechanisms responsible for the symptoms of food sensitivities, and hence greater acknowledgement of their importance in clinical practice. However, we are a long way from understanding the processes leading from ingestion of the food to the development of symptoms. Consequently, we have no accurate tests for identification of the specific foods involved. Skin tests and blood tests for allergen-specific IgE have a notoriously low level of accuracy. At best they correlate with challenge of the offending food about 50% of the time. There is no other medical test that would be ordered in any clinical diagnostic capacity with an accuracy rate that low! But we have no other lab tests with any greater accuracy to guide us in determining the most effective diet for the ever-expanding array of food-related food sensitivities with which we are presented. Thus, after the putative diagnosis of a food-related condition has been determined, based on clinical signs, symptoms, and history, we are left with elimination and challenge to identify the specific foods involved. This is one of the greatest challenges in dietary practice. Much greater emphasis on this procedure must be given in the education of the dietitians, as well as a call for increased funding for research in this extremely important field of practice. Dr. Harris Steinman M.B.Ch.B As suggested by this overview, one needs to have a high index of suspicion when assessing children with GIT problems for underlying immune-mediated mechanisms, and consequent relevant food-directed interventions. Importantly, one should be aware of the sensitivity and specificity of allergy tests realising that they are unhelpful in many of these conditions, and therefore a negative result does not exclude an underlying food allergy cause.

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D. References
1. Sicherer SH, Sampson HA. Food allergy: recent advances in pathology and treatment. Annu. Rev Med. 2009; 60: 261-277
2. Patriarca G, Schiavino D, Pecora V, Lombardo C, et al. Food allergy and food intolerance: diagnosis and treatment. Intern Emerg Med 2009; 4: 11-24
3. Sicherer SH, Sampson HA. Food Allergy (Chapter 9). J Allergy Clin Immunol 2006; 117: S470-475
4. Levin ME, Steinman H. Mimics of food allergy. Current Allergy and Clinical Immunology 2009 (in press)
5. Heine RG. Gastroesophageal reflux disease, colic and constipation in infants with food allergy. Curr Opin Allergy Clin Immunol. 2006 Jun; 6(3): 220-5
6. Metcalfe DD, Sampson HA, Simon RA. Food Allergy. Adverse reactions to foods and food additives. Chapter 15. Eosinophilic , gastroenteritis and colitis. Fourth edition. Blackwell Publishing: Massachusetts 2008, p182-190
7. Gonsalves N. Food allergies and eosinophilic gastrointestinal illness. Gastroenterol Clin N Am 2007; 36: 75–91
8. Furuta GT, Liacouras CA, Collins MH, Gupta SK, et al. Eosinophilic esophagitis in children and adults: A systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology 2007; 133: 1342-1363
9. Putnam PE. Eosinophilic esophagitis in children: Clinical manifestations. Gastroenterol Clin N Am 2008; 37: 369-381
10. Vighi G, Marcucci F, Sensi L, Di Cara G, Frati F. Allergy and the gastrointestinal system. Clin Exp Immunol 2008; 153(1):3-6
11. Liacouras CA. Eosinophilic esophagitis. Gastroenterol Clin N Am 2008; 37: 989-998
12. Prasad GA, Talley NJ. Eosinophilic esophagitis in adults. Gastroenterol Clin N Am 2008; 37: 349-368
13. Khan S. Orenstein SR. Eosinophilic gastroenteritis. Gastroenterol Clin N Am 2008; 37: 349-368
14. Benninga M, Candy DC, Catto-Smith AG, et al. The Paris Consensus on Childhood Constipation Terminology (PACCT) Group. J Pediatr Gastroenterol Nutr 2005; 40:273–275
15. Loening-Baucke V. Prevalence, symptoms and outcome of constipation in infants and toddlers. J Pediatr 2005; 146:359–363
16. Di Lorenzo C, Benninga MA. Pathophysiology of pediatric fecal incontinence. Gastroenterology 2004; 126:S33–S40
17. El-Hodhod MA, Younis NT, Zaitoun YA, Daoud SD. Cow's milk allergy related pediatric constipation: Appropriate time of milk tolerance. Pediatr Allergy Immunol 2009 Jun 25
18. Eigenmann PA, Zamora SA, Belli DC. Cow’s milk and chronic constipation in children. N Engl J Med 1999; 340:891
19. Daher S, Tahan S, Sole D, et al. Cow’s milk protein intolerance and chronic constipation in children. Pediatr Allergy Immunol 2001; 12:339–342
20. Andran F, Day S, Mete E. Cow’s milk consumption in constipation and anal fissure in infants and young children. J Paediatr Child Health 2003; 39: 329–33
21. Carroccio A, Scalici C, Maresi E, et al. Chronic constipation and food intolerance: a model of proctitis causing constipation. Scand J Gastroenterol 2005; 40:33–42
22. Orenstein SR, Izadnia F, Khan S. Gastroesophageal reflux disease in children. Gastroenterol Clin North Am 1999; 28:947–969
23. Omari TI, Barnett CP, Benninga MA, et al. Mechanisms of gastro-oesophageal reflux in preterm and term infants with reflux disease. Gut 2002; 51:475–479
24. Ravelli AM, Tobanelli P, Volpi S, Ugazio AG. Vomiting and gastric motility in infants with cow’s milk allergy. J Pediatr Gastroenterol Nutr 2001; 32:59–64
25. Salvatore S, Vandenplas Y. Gastroesophageal reflux and cow milk allergy: is there a link? Pediatrics 2002; 110:972–984
26. Hill DJ, Heine RG, Cameron DJ, et al. Role of food protein intolerance in infants with persistent distress attributed to reflux esophagitis. J Pediatr 2000; 136: 641–647
27. Nielsen RG, Bindslev-Jensen C, Kruse-Andersen S, Husby S. Severe gastroesophageal reflux disease and cow milk hypersensitivity in infants and children: disease association and evaluation of a new challenge procedure. J Pediatr Gastroenterol Nutr 2004; 39:383–391
28. Hill DJ, Heine RG, Hosking CS. The diagnostic value of skin prick testing in children with food allergy. Pediatr Allergy Immunol 2004; 15:435–441
29. de Boissieu D, Waguet JC, Dupont C. The atopy patch tests for detection of cow’s milk allergy with digestive symptoms. J Pediatr 2003; 142:203–205
30. Niggemann B, Beyer K. Diagnostic pitfalls in food allergy in children. Allergy 2005; 60:104–107
31. Niggemann B, Rolinck-Werninghaus C, Mehl A, et al. Controlled oral food challenges in children – when indicated, when superfluous? Allergy 2005; 60:865–870
32. Mofidi S. Nutritional management of pediatric food hypersensitivity. Pediatrics 2003; 111:1645–1653
33. Søndergaard C, Olsen J, Friis-Hasche E, et al. Psychosocial distress during pregnancy and the risk of infantile colic: a follow-up study. Acta Paediatr 2003; 92:811–816
34. Hill DJ, Hosking CS. Infantile colic and food hypersensitivity. J Pediatr Gastroenterol Nutr 2000; 30 (Suppl.):S67–S76
35. Heine RG. Pathophysiology, diagnosis and treatment of food protein-induced gastrointestinal diseases. Curr Opin Allergy Clin Immunol 2004; 4:221–229
36. Heine RG, Elsayed S, Hosking CS, Hill DJ. Cow’s milk allergy in infancy. Curr Opin Allergy Clin Immunol 2002; 2:217–225
37. Lucassen PL, Assendelft WJ, Gubbels JW, et al. Effectiveness of treatments for infantile colic: systematic review. Br Med J 1998; 316:1563–1569
38. Hill DJ, Roy N, Heine RG, et al. Effect of a low-allergen maternal diet on colic among breastfed infants: a randomized, controlled trial. Pediatrics 2005; 116:e709–e715

E. CPD Questions (For South African dietitians only. Australian dietitians: where you have relevant learning goals, CEU hours related to this resource can be included in your APD log.)

PLEASE ANSWER ALL THE QUESTIONS
(There is only one correct answer per question.)
1. True or false: Eosinophilic oesophagitis is believed to be due to a predominantly IgE-mediated response.
a. True
b. False

2. True or false: Eosinophilic oesophagitis and gastroesophageal reflux disease may coexist.
a. True
b. False

3. True or false: The following tests are considered reliable in testing for eosinophilic oesophagitis: serum peripheral eosinophilia, elevated IgE levels, serum RAST testing for food-specific IgE antibodies.
a. True
b. False

4. True or false: Strict elemental diets are uniformly successful in treating both eosinophilic oesophagitis and eosinophilic gastroenteritis.
a. True
b. False

5. True or false: Corticosteroids remain a reliable treatment of eosinophilic gastroenteritis if other options have failed, but overall dose or number of treatment courses should be limited.
a. True
b. False

6. True or false: The antigens most frequently implicated in eosinophilic proctocolitis are cow’s milk and wheat.
a. True
b. False

7. True or false: Cow’s-milk allergy is considered a cause of resistant constipation in infants and children.
a. True
b. False

8. True or false: Serum-specific IgE values to whole cow’s-milk protein and beta-lactoglobulins may be significantly higher in constipated patients, and are helpful, but not definitive, for diagnosis of cow’s milk allergy in these patients.
a. True
b. False

9. True or false: In formula-fed infants with clinically significant GORD, failure to respond to an extensively hydrolysed formula may be due to its residual allergenicity, warranting use of an amino-acid-based formula.
a. True
b. False

10. True or false: Fewer than 25% of distressed ‘colic’ infants appear to have a medical explanation for their crying.
a. True
b. False

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Unusual Food Allergy Symptoms PART 1
CPD Reference number: DT/A01/2009/00088

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This issue was sponsored by Pharmaplan Tel: +27 11 652 0950 www.pharmaplan.co.za