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1. A 9 year old boy presents to the physician's office complaining of new onset of dysphagia to solids. When he eats small bites he has no symptoms. Dysphagia occurs intermittently and is usually followed by vomiting. Tbere is no past medical history of illnesses, with the exception of having suffered from eczema as an infant. No history of ahdominal pain or gastroesophageal reflux. A hemogram showed normal white blood cell count but the differential shows 24% eosinophils. The most pJ:Obable diagnosis is:

A. Type one hypersensitivity reaction B. Psychogenic vomiting C. Eosinophilic anaphylaxis D. Intestinal obstruction E. Eosinophilil: esophagitis

2. Type One hypersensitivity reactions are characterized by;

A. Slow onset of symptoms B. Chronic diarrhea C. Constipation D. Excessive gas production E. Rapid or immediate onset of symptoms

3. An example of food intolerance is:

A. Eosinophilic Gastroenteropathy B. Type 3 mediated reaction C. Anaphylactic reaction D. Peptic ulcer disease E. Phenylketonuria

4. For Type 1 hypcrsensiti vi ty reactions wi t11 respiratory invol vement, you r fi r~l Iioe of treatment should be:

A. Prednisone 2mg/kg/dose orally B. Start an IV and hydrate at 1.5 times maintenance C. Observe for few minutes

5. The most common food allergies seen in young children involve:

1\.. Peanuts B. Soy C. Eggs D. Cow's milk: protein Lunch 1

E. All of the above

G. A 2 month old breastfed infant patient is being seen by you for a history of si gn.ific3nt rectal bleeding and hematocrit drop. You have restricted the mother's diet from cow's m.ilk protein, but there is no resolution of symptoms. Colonoscopy shows patchy erythematous lesions, edema, and fliability. Biopsies showed eosinophilia as deep as the muscularis mucosa. Your next step in management is:

A. Stmi soy protein containing milk B. Continue exclusive breast feeding and ask for a dietary diary [rom the mother to confinn absolute absence of cow's milk protein in her diet. C. Stru.i a trial of goat's Ir'ilk D. Start extensively hydrolyzed formula

7. True or False

A. The vast majority of food allergies disappear with time B. Elimimltion of gluten in a patient diagnosed with celiac disease wi II lead to resolution of symptoms an.d eradication of the condition. C. Infants with true cow's milk protein allergy respond uniformly well to extensively hydrolyzed fonnulas. D. There is conclusive evidence that manipulation or mother's diet during pregnancy or while breastfeeding will prevent the development of allergies in high risk infants E. The AA P guidelines for prevt:nlion of food allergies in high risk infants only mentioned to avoid peanuts and lree nuts during lactation period.

8. The gold standard for diagnosis of food re.lated allergies is:

A. Skin lesting B. Patch testing C. Stool testing for cosinophils, blood and n1l\CllS D. Double blind placebo challenge E. RAST testing Lunch 1

ALLERGIC GASTROENTEROPATHY CASE

RY is a 13-9/12 yr. old white male admitted for small bowel biopsy for further work up of failure to thrive (<3% for both ht. and wt.)

His pediatrician’s w/u included: nl. thyroid fxn tests., nl. L-dopa growth hormone study, nl. LFT’s. T protein 3.2 albumin 2.1 51Cr labeled albumin in 4-day stool collection is 17% (nl. is <1%). Imp: excessive GI protein loss. No hx. of loose stools, diarrhea, or constipation. UGI with SBFT – normal except for small sliding hiatal hernia. PMH + for cow’s milk protein as an infant and asthma.

Nutritional Assessment: ht. <5%, wt. <5% Hgb 14 nl. MAC 18 cm, 3-5% Hct 42.2 nl. TSF 12.5 mm, 50-75% BUN 5 nl. MAMC 14.1, <5% PT + PTT – nl. Lymphocytes, WBC 11.4, 25% lymph -- nl. Fe 74 (nl. 42-135) Albumin 2.4 Low TIBC 210 (nl. 280-400) nl. for ↓ prot Ascorbic acid, 2.5 (nl 0.2-2), nl. Carotene 96 (nl. 50-300) nl. % satn. 35% (nl 26-43) Folate 4.7 (nl 2.3-15.2) nl. gastrin – nl. Zinc 78 (55-150) nl.

Small bowel biopsy by Crosby capsule – normal

2nd Admission for special chromium labeled albumin study when pt. was 14 years old. Prior to that admission an esophagoscopy was done to see if esophagitis could explain the protein loss. Mild esophagitis was seen. Antacids relieved the child’s epigastric discomfort.

The child was placed NPO with an NG tube in the stomach to collect secretions from stomach and stool.

When NPO: a) 0.17% of injected Chromium-51 tagged albumin found in stool b) 0.08% found in NG drainage

After restarting a normal diet: excreted 51Cr labeled albumin = 10.9% (↑↑) (nl. <1%) c/w allergic protein-losing enteropathy.

Additional history Family history ++ for allergy. Dad had hx. as child of severe food allergies. Mom has history of asthma. The pt has history of: 1) asthma; 2) eczema; 3) food allergies.

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Patient’s birth and feeding hx: 7 lb @ birth. Started on Similac + changed to soy secondary to colic. Many foods caused diarrhea and colic. Age 2-3 had onset of asthma. Age 3-1/2-4 had allergy w/u by scratch tests: + for up to 21 foods including wheat, shellfish, chocolate. All the offending foods were removed from the list and gradually reintroduced one at a time. He was currently able to tolerate all foods except milk, eggs, wheat products, some fruits.

Dx’d with Iron Deficiency Anemia age 8-10 yr. (no primary dx. made). Tx with Fe x 2-3 mos. Dx’d again 3 months before 1st admission and treated – leading to a “normal” Hgb + Hct + MCV for the 1st admit.

In light of Aubrey Katz et al: Gastric mucosal biopsy in eosinophilic (allergic) gastroenteropathy. Gastroenterology 73:705-709, 1977 -- they described 6 pts. all with clinical dx of allergic gastroenteropathy. • all had albumin <2.9 • all had peripheral eosinophilia • all had Hct <30 • all had reduced immunoglobulin levels • systemic allergy present in 5/6 • serum IgE ↑ in all • Eos ↑ in intestinal bx in 5/6 • But ↑ in gastric bx’s in 6/6

Our pt. - IgA 46 (82-462) IgG 280 (750-2000) IgM 194 (63-250) IgE = 1600 units ↑↑ (nl <100) T.prot 4.2 albumin 2.7 WBC 7.8 with 12% eosinophils Fe 13 (60-135) % satn 5 (26-43) TIBC 279 (250-350) Hgb 11.7 Hct 36 MCV 76

Majority of RBC’s slightly microcytic

Working Dx: Allergic Gastroenteropathy

Tx: 1) Restrict dietary allergens (no dairy, no eggs, no wheat) 2) Vivonex 3 packets/day 3) Cromolyn Na 300 mg Qid from Fisons Corporation (IRB approved, obtained IND# from FDA)

4) Fe sulfate

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IgE RAST Food panel, Age 19 yr. Age 16 2190 Class PRU Age 16 975 whole milk 4 >17.5 Age 17 2000 casein 3 16.45 Age 18 1820 egg white 4 >17.5 Age 19 3793 codfish 1 .69 Age 19 2443 rye 4 >17.5 barley 4 >17.5 Age 19 T.prot 5.7 oat 4 >17.5 Alb 3.7 rice 3 16.61 Hgb. 14.2 corn 4 >17.5 Hct. 41.9 peanut 4 >17.5 MCV 75 soy 3 13.10

When Cromolyn dose was decreased to 300 mg tid, albumin fell from 3.3 to 2.9. Hct went from 41.6 to 35.9. Dose was increased back to Q.i.d.

Age 19-9/12: Fecal alpha-1- antitryipsin = 10 mg/gm stool ↑↑ (abnl is >3.4 mg/gm) At age 20: now a sophomore @ Arizona State University. Still on Cromolyn sodium 300 mg Qid; Vivonex 1 package bid; Diet: avoid wheat, eggs, dairy Ht = 20% wt = 8% IgE – 3559 u/mL. T. prot. 5.2, alb 3.4, Hgb 14.4, Hct 43.7, mcv 80, WBC 9.6 with 14% eos.

Age 23: UGI with SBFT Thickening of small bowel folds EGD with bx’s for dysphagia 1) Acute esophageal ulcer; no increased eos. 2) Normal jejunal bx. 3) No antral bx.

Age 43: EGD with bx’s 1) milk stricture at mid esophagus 2) narrowed antrum bx’s - ↑↑ eos @ both sites c/w eosinophilic esophagitis eosinophic gastroenteritis Plan: 20 mg prednisone/day → dysphagia resolved

Admitted 12/5/07 for a “flare” EGD: 1) feline esophagus 2) infiltrating submucosal process of the antrum 3) partial gastric outlet obstruction

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Tx with Flovent swallows and 40 mg prednisone

The pt’s brother has eosinophilic esophagitis – dx’d in his 30’s; tx with balloon dilatations. No hx of PLE. The pt. has twin son + daughter age 8 yr. Daughter has eosinophilic esophagitis and gastritis; son with many food intolerances.

W/u for his Eosinophilic Disorder by Hematology: 1. FISH for a CHIC 2 deletion → - 2. Serum Interleukin 5 3. Serum tryptase – nl. 4. Eosinophilic cationic protein – slightly elevated 5. PCR for T-cell receptor gene rearrangement → -

Age 44: off steroids; Hct 40.3, wt 64 kg; no dysphagia small bowel series: dilated jejunum; radiolucent filling defects of several mm in mid jejunum (? Eosinophilic infiltrates). He is on Gastrocrom 200 mg bid Tolerex, 2 packets/day, Flovent 1 puff/day swallowed.

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ALLERGIC COLITIS CASE

18 month old vegetarian Indian male referred as a 2nd opinion for “bloody stools since early infancy despite allergy and G-I F/u.”

The patient was born full term. Delivered @ 41 wks. Family history positive for father with a history of asthma and seasonal allergies. The child was breast fed for the first 15 months.

At 4 months of age the child presented with rectal bleeding (small specks of bright red blood on and off). Mom continued to breast feed and discontinued cow’s milk protein, soy, wheat, egg, nuts, tomato, citrus from her diet and the bleeding continued. The baby was diagnosed with otitis and treated with antibiotics, which led to diarrheal stools and more specks of blood. Previous trials of Nutramigen & Alimentum – no help. The child reportedly did actually worse on Nutramigen.

Workup then included: negative infectious w/u including c.difficile; stool occult blood +; moderate WBC’s; Hgb 11.8, Hct 34.2 nl. differential, nl.eos.

Follow up CBC @ 7 mo.: WBC 10.1 with 8% eos, 22% neutrophils, 60% lymphs, Hgb 11.0, Hct 32.6.

At the private G-I office, Lactobacillus GG (Culturelle) prescribed for mom and baby. Repeat c.diff toxin was negative.

At 9 months of age the Pediatric Allergist did RAST and skin tests: 1) skin tests 2 + for oat, egg, wheat, peas 2) RAST IgE + for oat, wheat; negative for milk, soy

The patient developed severe atopic dermatitis after the 6-month visit to G-I.

At 15 months the child had a colonoscopy by the private G-I. The bleeding had decreased and the child was prescribed Carnation Good Start. After 10 days the child passed a fairly large amount of blood. CBC, PT, PTT were all normal.

Colonoscopy findings: erythematous rectal vault with prominent lymphoid hyperplasia. There was significant lymphoid hyperplasia up to the splenic flexure. Good Start was discontinued.

Biopsies reviewed @ Stanford: Marked increase in the number of eosinophils present in the lamina propria. As many as 43 eosinophils in a high power field. The number of eosinophils consistently exceeds 25 per high power field (40X) field. The underlying architecture is well preserved. Occasional lymphoid aggregates are present. The terminal ileum shows normal morphology. There is less inflammation in the distal rectum (~11 eos/HPF). Lunch 1

The findings are compatible with allergic colitis.

Prior to our first visit, a chemistry panel was nl. CRP < 3 (nl < 5); WBC 9.4, Hgb 12.2, Hct 34.6, MCV 77, pH 472K; 31 neut., 40 lymph, 23 mono 6% Eos; occult blood positive X 2.

The child at 18 mos. was vegetarian, now on Neocate providing 39 kcal/kg/day and 1.2 g/kg/d protein plus limited vegetarian diet restricting wheat, oat, and dairy; tried egg but had blood in the stool.

We further restricted the diet to get at the source of the bleeding, leading to increased bleeding. Bleeding improved on Neocate alone.

Further, the child’s bleeding decreased when the family ran out of Lactobacillus GG (Culturelle), so I D/C’d the probiotic. Looking up the product, it “contains casein and whey” – perhaps that is the problem here.

We were able to get resolution of the bleeding with Elecare and gradual advancement of the diet.

Prior to that, when the child was in India for 50 days in 2005 (2nd year of life): 1) had only minimal diarrhea and blood in stool only a handful of times 2) eczema totally resolved while there 3) able to eat almost a normal diet

Currently, age 4 yr., ht. 75%, wt 85%, BMI/wt/ht 85% not receiving any cow’s milk protein. Did recently have an allergic rxn. to egg. On 31 kcal/kg Elecare. Allergist is considering a soy protein trial to wean off Elecare (pt has never had skin test or RAST positive for soy). No rectal bleeding now. Lunch 1

CASE OF SOY PROTEIN ALLERGY

Birth Hx. 6 lb. 3 oz. product of an uncomplicated term first pregnancy to a 28-yr. old Filipino mom. Uncomplicated labor & delivery.

Neonatal period extreme hypotonia, stigmata of Down’s syndrome (brachycephaly, slanted eyes with prominent epicanthal folds, low set ears with ↓ cartilage).

Karyotype → Trisomy 21

Feeding History was begun on Prosobee (the old preparation that still contained sucrose); was a poor feeder with poor suck & drooling; @ 4 wks – 6 lb. 14 oz. 2 d. later developed frequent loose stools → improved after ∆ to rice H20 and glucose → returned on reintroduction of soy: loose stools ↑ to Q.30-60 min. mom noted duskiness, sunken fontanelle, ↓ activity; @ pediatrician’s office had a cyanotic spell; ambulance to El Camino where Ringer’s Lactate + IV HC03 given after obtaining weight of 5 lb. 10 oz. (pt. was felt to be 15% dehydrated). After fluids → pH 7.40, nl lytes. → transferred to Stanford where WBC was 39,100 with 17% poly 56% bands 5% metas.

1st SUMC Admission 8/28 – 10/5/80.

G-I had ↑ stooling on ½ str. Isomil. Later tolerated full strength Pregestimil; discharged on Pregestimil

Seen in outpatient clinic @ CHAS 10/9/80 – doing well on Pregestimil.

Seen by pvt. Pediatrician 11/17/80 – given DPT, OPV #1 and changed to Soyalac

nd 2 SUMC Admission 11/19 – 11/24-80. H20y diarrhea and vomiting developed after formula change → severe dehydration, 15% dehydration noted in our E-R. TX: NPO, rehydration I.V.; gradually: Pedialyte → ¼ str. Pregestimil ½ → ¾ → Full strength Pregestimil without difficulty

12/4/80 Well baby √ @ 4 mos. – doing well on Pregestimil; wt. 4.4 kg 1/15/81 Well baby √ @ 5 ½ mos – doing well on Pregestimil; wt. 5.4 kg Making good progress in developmental milestones. DPT, OPV #2 2/26/81 family wished to switch from Pregestimil to Isomil 3/7/81 Family ∆’d formula to Isomil

rd 3 Admit 3/8 – 3/14/81 after formula change: 2 hrs. later pt. developed profuse H20y stool x 24 hrs, unimproved on Pedialyte. @ our ER: mottled, lethargic, hypernatremic dehydration, acidosis, 10-15% dehydrated. Full sepsis w/u – D/C on Pregestimil

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4th Admit 3/31 – 4/6/81 SUCROSE tolerance test → normal rise of glucose: a) baseline 65 mg, b) 30 min 112 mg% (2 gm/kg in 10% solu.) - no abnormal rise in breath H2, no stools after challenge

ISOMIL challenge – 1st 5 cc, then 100 cc → ½ hr. later → emesis, 1 hr → 3 hr p → diarrhea

Stool pH stool guaiac neutrophil count Pre-challenge 7.5 - 2,079 Post-challenge 5.0 + 6 hrs. 8,040 20 hrs. 22,610

5/1/81 Outpatient F/U @ 9 months of age Tolerating Pregestimil well – no vomiting Developing well, 1 formed stool/day/wt. 7.6 kg (5%), ht @ 3% Plan: ↑ diet to include cooked + strained rice, apple juice, bananas

REFERENCES

Powell GK: Milk and soy-induced enterocolitis of infancy. J Pediatr 93(4):533, 1978.

Lunch 1 Invited Review

Gastrointestinal Manifestations of Food Allergies in Pediatric Patients

Manuel Garcia-Careaga, MD; and John A. Kerner, Jr, MD Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Lucile Packard Children’s Hospital, Stanford University Medical Center, Stanford, California

ABSTRACT: Foods that account for 90% of allergic re- Definitions actions in children are cow’s milk protein, eggs, peanut, soy, tree nuts, fish, and wheat. Food allergy can manifest as Food allergies are, by definition, the result of a urticaria/angioedema, anaphylaxis, atopic dermatitis, respi- pathologic immune reaction to a food protein. In ratory symptoms, or a gastrointestinal (GI) disorder. GI contrast, an adverse food reaction is the occurrence allergic manifestations can be classified as immunoglobulin of an ill effect as a result of the intake of food, which E (IgE) mediated (immediate GI hypersensitivity and oral could be the result of an immunologic- or a nonim- allergy syndrome); “mixed” GI allergy syndromes (involving munologic-related response (Table 1). some IgE components and some non-IgE or T-cell-mediated Food intolerances of nonimmunologic etiology components) include eosinophilic esophagitis and eosino- could be secondary to an enzyme deficiency such as philic gastroenteritis. Non-IgE-mediated or T-cell-mediated disaccharidase deficiency, galactosemia, hereditary allergic GI disorders include dietary protein enteropathy, protein-induced enterocolitis, and proctitis. All these condi- fructose intolerance, favism, pancreatic insuffi- tions share a common denominator: the response of the ciency, and phenylketonuria. The most common immune system to a specific protein leading to pathologic adverse food reaction as a result of an enzyme inflammatory changes in the GI tract. This immunological deficiency is lactose intolerance, which affects response can elicit symptoms such as diarrhea, vomiting, approximately 6% of the US population but as much dysphagia, constipation, or GI blood loss, symptoms consis- as 90% of some ethnic groups.1 Adverse food reac- tent with a GI disorder. The detection of food allergies can be tions could also be secondary to a pharmacologic accomplished by the use of radioallergosorbent (RAST) test- effect like those seen with food dyes; preservatives; ing and skin prick tests in helping to assess the IgE- bacterial, fungal, and seafood toxins; pesticides; mediated disorders. Patch tests may help evaluate delayed metabisulfites; monosodium glutamate; caffeine; hypersensitivity reactions. Treatment of GI allergic disor- ders ranges from strict dietary elimination of offending and heavy metals. Food poisoning is another com- food(s), use of protein hydrolysates, and use of L-amino mon cause of an adverse reaction to food, with the acid–based formula when protein hydrolysates fail. Treat- most common offending organisms being bacteria ment with topical (for eosinophilic esophagitis) or systemic like Staphylococcus, Salmonella, Campylobacter, steroids is used if all dietary measures are unsuccessful. E. coli, and Shigella. Other less common food poi- Maternal breast feeding or the use from birth of hydrolysate soning etiologies include parasites like Giardia lam- formulas (extensive or partial hydrolysates) may be effica- blia and viral hepatitides. cious in the prevention of atopic disease in “high-risk” families (with at least 1 parent or sibling with a history of atopic disease). Overview of Gastrointestinal (GI) Food Allergies It has been estimated that about 25% of the US population believe they have experienced a food allergy, although the actual incidence suggests a rate closer to 2%–8% in young infants and approxi- mately 2% in the adult population. Marklund et al2 assessed health-related quality of life among 1488 adolescents with emphasis on food hypersensitivi- ties. They found that 64% of the respondents reported an allergic-type process to defined sub- Correspondence: John Alan Kerner, Jr, MD, Professor of Pediat- rics, Director of Nutrition, Stanford University Medical Center, stances and 51% reported allergic disease like 750 Welch Road, Suite 116, Palo Alto, CA 94304. Electronic mail asthma, eczema, and rhinoconjunctivitis. A total of may be sent to [email protected]. 19% reported food hypersensitivity (these were self- reported and not necessarily medically confirmed). 0884-5336/05/2005-0526$03.00/0 Nutrition in Clinical Practice 20:526–535, October 2005 The authors’ questionnaires suggest that food aller- Copyright © 2005 American Society for Parenteral and Enteral Nutrition gies in the adolescent group may have a more 526 October 2005 GASTROINTESTINAL MANIFESTATIONS OF FOOD ALLERGIES Lunch 1 527

Table 1 digested, absorbed into the systemic circulation, Food intolerance processed, and then presented to a competent immune system.1 Adverse reaction to food: any untoward reaction I. Food allergy/hypersensitivity (immunologic response) II. Food intolerance (nonimmunologic) a. Enzyme Deficiency (eg, disaccharidase deficiency, The GI Barrier galactosemia, hereditary fructose intolerance) The GI tract is a very specialized organ, rich in b. Toxins (shellfish, staphylococcus, mushrooms) lymphoid tissue containing macrophages, immuno- c. Pharmacologic (metabisulfites in wine and salad: globulins, mast cells, intraepithelial lymphocytes, bronchospasm; wine, MSG: headache; caffeine: arrhythmia) and helper and suppressor T-cells at the subepithe- lial level (gut-associated lymphoid tissue, or GALT). MSG, monosodium glutamate. This well-organized system of cells and their prod- ucts acts as the mucosal barrier, guarding the body 7 far-reaching consequence than just the organic com- against intrusive antigens. ponent; they may also affect psychosocial health. There are also nonspecific factors that aid in Factors that have been associated with an increased protecting the GI tract from antigenic intrusions, risk for developing food allergy–associated GI dis- which starts at the moment of food intake. The ease are age Ͻ3 years, acute reaction close to eating digestion and breakdown of proteins starts in the a particular food, atopic dermatitis, bronchial oral cavity, continues in the stomach with the help of asthma, and family history of atopy.3 Atopy is the hydrochloride acid and pepsin, and in the small tendency to develop immediate-type (IgE) hypersen- bowel in the presence of pancreatic proteases. In sitivity reactions: atopic eczema, food allergy, addition to the enzymatic breakdown of protein, asthma, allergic rhinitis. There is a genetic predis- other nonspecific barriers help in reducing the anti- position to synthesize IgE antibodies (inappropri- genic stimulation of the intestinal mucosa, and ately) against environmental antigens. these include the inherent GI motility, GI secretions Various manifestations of allergic disease many (water, electrolytes, mucus, and defensins), the epi- times do present in a characteristic sequence (eg, thelial barrier, the microvillous membrane, and, at atopic dermatitis 3 allergic rhinitis 3 asthma). the level of the enterocyte, the lysosomes.7 This sequence has been referred to as the “atopic or 4 The intestinal mucosa is the gatekeeper, prevent- allergic march.” ing the penetration of macromolecules that could be A meta-analysis carried out in 1999 of all avail- potentially harmful (Figure 1). The intestinal sur- able studies on the age of onset of the “allergic face is directly exposed to an environment rich in march” found that during the first year of life in antigenic load and unique in the sense that its main atopic children, there was the onset of atopic derma- role is that of suppression rather than active titis in 79.8%, cow’s milk allergy (CMA) in 72.7%, 8 egg allergy in 71%, and fish allergy in 51.3%. Of immune response. those developing bronchial asthma, 41.8% mani- fested it in the first year of life, 49.3% in the second year, and by the eighth year, 92.5% of atopic chil- Immunologic Reactions dren. Allergic rhinitis started in 35% of the infants Given the exposure to antigenic material, it is in the first year of life and in 59% by 5 years of age. also in the intestinal mucosa, where allergic reac- These data indicate that allergy develops early in tions could be initiated. Two types of immunoaller- life in those predisposed, and any early intervention genic reactions have been described in the develop- and strategies for prevention could have a signifi- 5 ment of GI allergies: the IgE-mediated reaction, and cant impact. the T-cell-mediated reaction, also known as non– Few foods account for 90% of the reactions seen in IgE-mediated. children. The most commonly seen food allergens in The IgE-mediated reaction is also known as an children are cow’s milk protein (2% of children), eggs immediate onset allergic reaction (type I). In a type (1.3% of children), peanut (0.5% of children), soy, I reaction, the IgE antibodies bind to the mast cells tree nuts, fish, and wheat.1 In older pediatric patients, the list expands to include berries and in the GI tract, skin, and lungs, causing a release of 6 mediators when they are exposed to determinate chocolate. Most common food allergens in adults 9 are peanuts, tree nuts, fish, and shellfish. antigens. Circulating IgE also binds and activates Patients who develop a GI food allergy could basophils, eosinophils, and macrophages. The pro- present with urticaria, angioedema, anaphylaxis, cess involves the sensitization to the offending anti- atopic dermatitis, diarrhea, GI bleeding, abdominal gen; when that antigen is reintroduced into the diet, pain, or respiratory symptoms. it activates the immune system, with the food anti- The development of a food allergy requires an gen binding to the cell surface of the IgE molecule immunological reaction directed to a food antigen. In triggering the release of histamine, prostaglandins, order for this to occur, it is necessary that the food be leukotrienes, and cytokines. 528 GARCIA-CAREAGA AND KERNER Vol.Lunch 20, No.1 5

IgE-Mediated GI Disorders Immediate Hypersensitivity Disorders The primarily IgE-mediated reaction, immediate GI hypersensitivity reaction, could present at any time of life, although the usual age of onset is seen from infancy to childhood. As the word implies, it could occur within minutes of the ingestion of the food protein or could present within a few hours. Most commonly implicated proteins are milk, soy, egg, peanut, shellfish, and cereal. The rapid onset of presentation is the diagnostic clue for a type I hypersensitivity reaction. The patient can develop nausea, vomiting, diarrhea, colic, or just plain abdominal pain. Vomiting may be intermittent. In those patients with longstanding exposure who have Figure 1. Components of mucosal barrier of gastrointesti- acquired partial desensitization to the food antigen, nal tract. Reprinted from Gastroenterology. Sanderson IR, the vomiting may be followed by anorexia, poor Walker WA. Uptake and transport of macromolecules by weight gain, abdominal pain, and colic.1 the intestine: possible role in clinical disorders (an Type I hypersensitivity reactions, as they become update). Pages 622–639, © 1993, with permission from systemic, can affect the lungs and the skin, producing The American Gastroenterological Association. reactive airways, rhinoconjunctivitis or generalized acute urticaria, skin flushing, or angioedema. These patients may develop life-threatening bronchospasm Type III reactions involve the formation of auto- and anaphylactic shock. The treatment for this condi- immune complexes with IgG antibodies and activa- tion is the strict avoidance of the offending protein. tion of the complement cascade. The appearance of The patient may need to have epinephrine adminis- symptoms is not immediate and may occur 1–20 tered to avert life-threatening complications. The nat- hours after the exposure. ural history of this condition is that around 80% of A type IV reaction, also known as delayed-onset cases resolve over several years, except for those with allergic reaction, is caused by T-cell lymphocyte peanut and shellfish allergy. activation; hence, a T-cell-mediated hypersensitiv- ity. As a result of this sensitization, interleukins 4 Oral Allergy Syndrome and 5 are produced, causing an inflammatory Another manifestation of IgE hypersensitivity reac- response. Patients exhibiting a delayed hypersen- tion is the oral allergy syndrome, also known as sitivity reaction have shown an imbalance in the pollen-food allergy syndrome. This reaction is mostly ␥ 10 production of interleukin 4 and -interferon. limited to the oral cavity, and it rarely manifests A type II reaction has been reported only rarely in systemic symptoms. It is usually characterized by food allergy. Conditions associated with this type of itching, burning, erythema, or tingling of the lips, immunologic response (antibody mediated) are auto- tongue, palate or oropharynx. The most common immune hemolytic anemia and Goodpasture’s syn- implicated proteins are those of fresh fruit and vege- drome. tables. These plant proteins can cross-react with air- Another type of immune response is that of toler- borne allergens, like birch, ragweed, and mugwort ance. Tolerance to an antigen is the result of the pollens. Patients with birch allergy may react to the absence of a reaction between the immune system ingestion of raw apples, pears, celery, hazelnuts, kiwi, and the circulating antigen. Most people acquire potatoes, and carrots. Allergy to ragweed may cross- tolerance to food antigens. react when exposed to fresh melon and bananas. In essence, the GI allergy syndromes could be Patients allergic to grass pollen may cross-react when 11 primarily IgE mediated (reaginic), mixed IgE/non- ingesting raw tomatoes. The reaction is caused by a reaginic, and nonreaginic/non–IgE-mediated. The heat-labile antigen that is rendered inactive when IgE-mediated food hypersensitivity causes an imme- cooked. The treatment consists of avoidance of the diate GI reaction, leading to nausea, abdominal fruit and with the cooking of the vegetables. This pain, and emesis. condition can persist into adulthood. Food allergies can cause multiple or isolated symptoms, with the most common being diarrhea, Mixed-IgE/Nonreaginic Allergy Syndromes vomiting, and abdominal pain. Unfortunately, a myriad of other pathologic conditions can elicit the Eosinophilic Gastroenteritis same response from the GI tract, making it difficult The eosinophilic gastroenteropathies comprise a for the physician to sort the diagnosis out from an group of disorders characterized by an intense eosin- extensive differential diagnosis list. ophilic infiltration of the esophagus, stomach, or October 2005 GASTROINTESTINAL MANIFESTATIONS OF FOOD ALLERGIES Lunch 1 529 small bowel mucosa. It can present as early as ture), and sleep pattern disturbance. The esopha- infancy and finds its peak in the second and third geal and gastric inflammation does not respond well decade of life.12 The depth of eosinophilic infiltration to H-2 blockers. When tested, their serum IgE is in the organ wall relates to the manifestation of found to be normal or slightly elevated, and signifi- symptoms and their severity. cant peripheral eosinophilia has only been observed The etiology of eosinophilic gastroenteropathy is in about 50% of cases.14,15 Finally, the diagnosis will not well understood. A relation with food sensitivity need to be confirmed with a tissue biopsy to docu- can be found in some patients but not in others. In ment the pathologic mucosal infiltration with eosin- those with no identifiable relationship to food, the ophils (Ͼ20 eosinophils per high-power field). initiating factor is not determined in most. The Proteins that have been incriminated in allergic diagnosis of eosinophilic enteropathy can only be eosinophilic esophagitis are cow’s milk, wheat, soy, made after excluding other pathologic conditions peanut, and egg.16 Often, there are multiple anti- that can trigger an eosinophilic response, in conjunc- gens responsible for the reaction, and there is poor tion with histologic (biopsy) findings indicating tis- correlation with skin testing in helping to identify sue eosinophilia. In eosinophilic gastroenteropathy, them. it is believed that the pathologic response involves 1 The treatment of allergic eosinophilic esophagitis T-cell- and IgE-mediated mechanisms. includes the use of hydrolyzed protein formula in the In eosinophilic gastroenteritis, the gastric infant, with around an 80% response. The use of antrum and small bowel are frequent sites of the elemental diets with L-amino acid formulas has eosinophilic infiltration. There are 3 categories of yielded excellent results. Patients have responded to the disorder: (1) mucosal, (2) muscular, and (3) serosal. elemental diets even in absence of any identifiable ● In the mucosal form, there is nausea, vomiting, food allergy. Dietary manipulation can in fact decrease the severity of the inflammation, but this abdominal pain and diarrhea; it may be associ- 17,18 ated with occult blood loss, iron deficiency ane- has been shown not to be curative in all cases. mia, protein losing enteropathy, and failure to Should dietary restriction not prove to be satisfac- thrive; tory, a trial of prednisone, methylprednisolone, or ● inhaled steroids that are swallowed has been proven In the muscular (transmural) form, there may 18,19 be obstructive symptoms, mimicking pyloric to be efficacious. stenosis or thickening of the gastric outlet. ● In the serosal form, patients may present with Other Eosinophilic Gastroenteropathies ascites and abdominal pain. (Eosinophilic Gastritis and Gastroenterocolitis) Treatment includes elimination of pathogenic Allergic eosinophilic gastritis and enterocolitis foods; if that fails, some give a trial of an elemental can present with symptoms of abdominal pain, diet; oral cromolyn may also be added. If the above anorexia, early satiety, failure to thrive, pyloric measures fail, corticosteroids can induce a remis- stenosis, bleeding, anemia, protein-losing enteropa- sion. The patients frequently flare on corticosteroid tapering, and they may require repeated courses or thy, colitis, intestinal obstruction, pseudo-Crohn’s continuous low-dose corticosteroids. disease, intestinal perforation, and eosinophilic ascites.20–22 In about 70% of cases, atopy is identi- fied, and laboratory tests show elevated IgE and Eosinophilic Esophagitis peripheral eosinophilia. The age of onset ranges from infancy to adolescence, and the most commonly Eosinophilic esophagitis is a chronic inflamma- implicated foods are cow’s milk, egg, corn, cod, and tory condition affecting the esophagus. It is a mem- ber of the family of eosinophilic gastroenteropathies. soy. Often a single antigen is identified and skin Teitelbaum et al13 demonstrated increased presence testing has been found to have a specificity of of CD3 and CD8 lymphocytes in the esophagus of approximately 50% in these cases. children with eosinophilic esophagitis. These cells These disorders are characterized by marked stimulate T-cell proliferation and production of eosinophilic infiltration of the mucosa and submu- eosinophil chemotactic agents such as eotaxin, cosa of the esophagus, stomach antrum, duodenum, attracting more of these cells that, after their acti- and the colon. Response to acid blocking medication, vation, will produce cytotoxic substances. These like H-2 blockers or proton pump inhibitors has little agents can also cause smooth-muscle contraction or no effect. Intervention with restriction of the producing dysphagia, abdominal pain, or respira- offending protein is successful in about 50% of those tory symptoms. affected; treatment with hydrolyzed formula seems Allergic eosinophilic esophagitis can produce to be very effective in those younger than 2 years of symptoms indistinguishable from gastroesophageal age. Response to L-amino acid–based formulas is reflux disease. The age of onset ranges from infancy excellent. In patients not responding to dietary pro- to adolescence. These patients may present with tein restriction, a trial of low-dose systemic cortico- emesis, failure to thrive, food refusal, abdominal steroids yields good therapeutic results. About 75% pain, irritability, dysphagia (with esophageal stric- of those affected will experience resolution of symp- 530 GARCIA-CAREAGA AND KERNER Vol.Lunch 20, No.1 5 toms over several years, and in the other 25%, their only with cow’s milk protein and soy but to other disease will extend into the adult years. solid foods like turkey, lentils, rice, oat, barley, and The long-term prognosis of eosinophilic enterop- vegetables. The offending vegetables have included athies is unknown in the pediatric population.23 In sweet potatoes, squash, string beans, and peas. adult patients with eosinophilic esophagitis (treated Symptoms may appear during the first month of life separately in this document, although still consid- and can be seen in association with faltering of ered an eosinophilic enteropathy), the persistence of growth. Symptoms occur with a median time of symptoms is the common rule, with dysphagia the appearance of 2 hours after ingestion of the protein prevalent problem. During a mean of 7.2 years’ fol- and include vomiting, diarrhea, lethargy, and dehy- low-up of adult patients with eosinophilic esophagitis, dration. The severity of this reaction can lead to dysphagia persisted, but there was not an associated acidemia, methemoglobinemia, and shock.27–29 increase risk of malignancy or premalignant lesions. It The immune mechanism responsible for the re- is necessary that a long-term follow-up of these action appears to be T-cell mediated. There has patients be done to assess whether there is a risk of been no association with IgE antibodies, and at the malignancy associated with this condition.24 level of the affected tissue there is a diffuse in- flammation with predominant plasma cell infiltrate, crypt abscess formation, villous injury, and in some Non–IgE-Mediated GI Disorders cases it leads to focal erosive gastritis and esophagi- Proctocolitis tis with prominent eosinophilia infiltrating the tis- sue.25 Treatment is with a hypoallergenic formula Proctocolitis, as a result of cow’s milk protein (casein hydrolysate), which is usually effective (if allergy, is usually seen during the first 6 months of not, an amino acid–based formula can be used). life. The infant presents with a history of mucousy Most infants outgrow the allergy by age 2 or 3 years, bloody stools. It could be specks of blood mixed with and some seem to maintain hypersensitivity into the stools or a more significant presence of blood. Up childhood.16 to 60% of the cases occur in breastfed infants. It also can manifest in formula-fed infants and in patients 25 fed soy formulations. Although extensively hydro- Dietary Food Enteropathy lyzed formulas are use as the first line of therapy, allergic reactions to these formulas have been rarely Dietary food enteropathy presents in infancy with described.26 In patients who have such an allergic symptoms of diarrhea, vomiting, and failure to gain reaction, treatment with an amino acid–based (non- weight. This disorder can ultimately lead to a state allergenic) formula results in resolution of symp- of protein-losing enteropathy, edema, and GI blood toms. Management of breastfed infants is more loss. Reaction to cow’s milk protein is the most difficult. Restriction of cow’s milk (and, more rarely, common etiology, although other proteins like soy, other foods such as soy or egg) from the mother’s diet egg, fish, and cereal grains have been associated usually results in resolution of symptoms. The for- with this condition. As with the previous 2 disorders, mulas stated above are required if maternal dietary it is mediated by a T-cell-mediated immune reac- restriction fails. tion, and IgE antibodies do not play a role. Diagnosis Although the diagnosis is almost always reached is based on the combined findings from endoscopy/ on clinical grounds, if confirmation of the disease is biopsy, allergen elimination, and challenge. Biopsy sought, a flexible sigmoidoscopy can be performed. reveals variable small bowel villus injury, increased The gross finding, on endoscopic mucosal inspection, crypt length, and intraepithelial lymphocytes. usually reveals patchy erythematous lesions, edema Treatment is dietary restriction of the offending of the mucosa and friability, and may be accompa- allergen. Dietary food enteropathy usually resolves during the first 2 years of life, although it may nied by lymphonodular hyperplasia, which could be 16 limited to the rectum and sigmoid colon, but it can persist into the childhood years. For a comparison also involve the entire colonic mucosa. between these 3 entities, please refer to Table 2. Biopsies obtained from the mucosa of the rectum or colon show the presence of an abnormally high Constipation number of eosinophils infiltrating the mucosa and penetrating as deep as the muscularis mucosa.25 Allergy to cow’s milk has been associated with the Cow’s milk protein proctitis/proctocolitis is a dis- development of constipation. The inflammation that ease of infancy and will resolve after elimination of develops as a result of an allergic response could the offending protein. The disorder should resolve lead to the formation of an anal fissure, causing between the ages of 6–9 months and 1–2 years. painful defecation. The response to the painful act can lead to a retentive pattern. Anal lesions will disappear after discontinuation of cow’s milk and Food Protein–Induced Enterocolitis Syndrome reappear after rechallenge in a significant number Infantile food protein–induced enterocolitis syn- of patients. In the study by Iacono et al,30 specific drome (FPIES) is a severe manifestation of a food IgE antibodies to cow’s milk were found in 31 out of hypersensitivity reaction. It has been associated not 44 patients with constipation. The presence of other October 2005 GASTROINTESTINAL MANIFESTATIONS OF FOOD ALLERGIES Lunch 1 531

Table 2 Non–IgE-mediated gastrointestinal disorders

Enteropathy FPIES Proctitis

Age at onset 1–18 mo 2d–6 mo 2d–3 mo Duration 18–36 mo 9–36 mo 6–9 mo Presentation Indolent Acute Acute, mild FTT Moderate/severe Moderate No Irritability Mild Moderate Minimal Emesis Mild Moderate No Diarrhea Moderate Severe Mild Rectal bleeding Minimal Moderate Mild/moderate Fecal PMN’s No Common Common Anemia Moderate Moderate Mild Main etiology Cow’s milk Cow’s milk Breast milk Other etiology Soy, wheat, egg, cod Hydrolyzed casein, rice, nut Soy, corn, egg

Duration, once the offending allergen is removed; FPIES, food protein–induced enterocolitis syndrome; FTT, failure to thrive; PMNs, polymorphonuclear cells. signs of CMA, like bronchospasm, dermatitis, and aphthoid erosions can be seen throughout the rhinitis, increases the chance that constipation will colonic mucosa in a patchy distribution. respond to a cow’s milk–free diet.30 Kokkonen and Kaurttunen33 conducted a retro- spective analysis of 140 children using colonoscopy Celiac Disease and upper endoscopy and review of the histopathol- ogy and clinical symptomatology. They concluded Celiac disease, or gluten enteropathy, is an that lymphonodular hyperplasia of the colon and immune response to the gliadin component found in terminal ileum is not an innocent finding as previ- wheat, rye, and barley (gliadin in oats is no longer ously thought, having a significant correlation with implicated by most experts). Celiac disease is con- food allergy as a result of an up-regulated immune sidered a multifactorial disease in which not only response. Lymphonodular hyperplasia is not an the exposure to gliadin is necessary but also the exclusive finding of food allergy; other entities like presence of a genetic susceptibility as well. Gluten inflammatory bowel disease can have the same find- enteropathy is a T-cell-mediated chronic inflamma- ings on endoscopy. The authors pointed to the fact tory process with an autoimmune component and that the true prevalence of lymphonodular hyper- can manifest with extraintestinal manifestations as 31 plasia in the general population without symptoms well. is unknown.33 The prevalence of celiac disease in the general Another study has shown an association between unselected population of North America and West- the presence of lymphonodular hyperplasia and ern Europe ranged from 152 to 2670 per 100,000. abnormalities in Th1 and Th2 function in non-IgE Among the studies conducted in the United States, food allergy. More studies in this area are needed to the prevalence ranged from 1:320 (only child popu- 34 32 better understand this association. lation in this group) to 1:105. The resolution of the Lymphonodular hyperplasia has been incrimi- inflammation and symptoms occurs upon complete nated as a disorder causing diarrhea, low-grade GI avoidance of products containing gliadin. bleeding, anemia, abdominal pain, and protein-los- ing enteropathy. Its onset can occur in infancy, Lymphonodular Hyperplasia causing proctitis, and in the toddler age group can The significance of lymphonodular hyperplasia, present with low-grade colitis. In most cases, the in relation to a pathologic process, is not clear. The etiology is idiopathic, and in others, a relation with small and large intestine is an organ rich in lym- cow’s milk, soy, and even hydrolyzed formula has phoid tissue. Aggregation of lymphoid follicles, also been found. Resolution of symptoms is anticipated known as Peyer’s patches, will give rise to sub- with puberty. mucosal nodules. It is thought that the appearance of lymphoid nodules corresponds to an enhanced immunological response. Its gross appearance in Diagnosis And Management colonoscopy or upper endoscopy is that of small The evaluation of children with food allergies raised nodules. Sometimes it can give a cobblestone starts with the process of a thorough history and appearance to the mucosa. During colonoscopy and complete physical examination. The physician must distal ileal intubation, it is not uncommon to find analyze the presenting symptom or symptoms and prominent lymphoid hyperplasia, which is very their relation to food. The temporal relation of the frequently regarded as a normal finding. Also, reaction after exposure to food is of paramount 532 GARCIA-CAREAGA AND KERNER Vol.Lunch 20, No.1 5 importance. Approaches to diagnosis of GI food labels is mandatory with special attention to “hid- allergies are depicted in Table 3. The IgE-mediated den food.” How to read food labels is part of the reactions are easier to detect and diagnose, but parental education in order to prevent cross-contam- unfortunately, the non–IgE-mediated food allergies ination of products (eg, the same mill may be used to present a challenge for the clinician. Specific immu- process wheat and corn). Joshi showed that most nological testing is not available for many of the parents were unable to identify allergens in food categories of non–IgE-mediated food allergy reac- labels. He also found that only 7% of 60 parents were tion. The exclusion of other pathologic conditions, able to identify milk protein in 14 sample labels.35 whether infectious, noninfectious inflammatory, The Food Allergy and Anaphylaxis Network (Fair- metabolic, endocrine, or anatomical, is frequently fax, VA; 1-800-929-4040; http://www.foodallergy. necessary. org) is an excellent resource for parents caring for In regard to laboratory testing, when the problem the food-allergic child. is that of an IgE-mediated sensitivity reactions, Some patients will need to take extensive hydro- RAST (radioallergosorbent test) testing and skin prick lyzed formulas or L-amino acid–based preparations tests could help in the confirmation of the suspected to maintain adequate nutrition and health. Oral diagnosis. In some instances, a direct challenge with systemic corticosteroids may be needed in the more the food protein is necessary. With skin testing and severe cases. For patients who are at risk of devel- RAST panels, false negatives are uncommon and, oping a life-threatening anaphylactic reaction, the therefore, have a good negative predictive value. On parents and the child need to receive training in how the other hand, false positives are common and have a to avoid, and if exposed, how to recognize a reaction poor positive predictive value. early enough to administer injectable epinephrine. In the case of non–IgE-mediated reactions, other Therapy in infants often requires selection of an nonspecific laboratory tests can be done. These alternative formula. In infants with IgE-mediated include stool examination for presence of blood, CMA, most (86%) will tolerate a soy formula,36 but eosinophils, and white blood cells. The atopy patch the rate of tolerance is lower (50%) for most of the test is a promising resource to identify non–IgE- cell-mediated disorders.28 Infants with true CMA mediated reactions. It involves the cutaneous expo- would be expected also to react to partially hydro- sure to a food protein for as long as 48 hours. A lyzed formula, lactose-free cow’s milk–based for- positive reaction indicates a delayed hypersensitiv- mula, and most mammalian milks (eg, sheep, ity reaction. The pitfall with this test is that at the goat),37 so none of these is a good alternative. In moment there are no standardized methods of appli- most cases (Ͼ95%), infants with CMA will tolerate cation and interpreting the results. The patch itself extensively hydrolyzed cow’s milk formula, but for can cause changes in the skin as a result of pro- the few who continue to react (presumably as a longed contact irritation.11 result of residual allergens), an amino acid–based An upper GI endoscopy or colonoscopy with biop- formula is required for therapy.38–40 sies could be helpful in suggesting the presence of a Prevention is the mother of all cures. Meta-anal- non–IgE-mediated disorder. yses of existing studies suggest a beneficial role for The gold standard for diagnosis of food-related al- breast-feeding high-risk infants for the first 3–6 lergies is the double-blind placebo control challenge. months of life in the prevention of atopic dis- Other tests, like single blind or open challenges, can ease.41,42 At this time, there are no conclusive stud- also be helpful. In a double-blind challenge, the ies indicating that the manipulation of the mother’s patient undergoes an elimination diet for at least 7 diet during pregnancy or while breastfeeding or the days. The patient should not be taking medications, restriction of allergenic foods from the infant’s diet specifically those that can blunt or ameliorate an will prevent the development of food allergy. There allergic response. The challenge should be under- is also some evidence that regular intake of peanuts taken in a facility where the child can be under by the pregnant mother may increase the chance of constant supervision, and medications to avert a life- a child developing a peanut allergy.43 threatening reaction should be immediately accessi- A large ongoing study in Germany comparing the ble. The child will initially receive a small dose of the use of various hypoallergenic infant formulas with suspected allergy-causing protein and then continue cow’s milk formulas as a supplement to breast- gradually increasing the amount of antigen over time feeding or as a weaning formula in high-risk infants until reaching a maximum without reaction.1 The suggests that extensively hydrolyzed casein formula period of observation may take as long as 4 hours for or partially hydrolyzed whey formula might be use- the non–IgE-mediated reactions, although some may ful in the prevention of some atopic disease and food manifest the reaction after Ͼ24 hours after exposure. allergy,44 as suggested by a recent meta-analysis.45 The treatment for food allergies is the avoidance In the year 2000, The American Academy of Pedi- of the offending antigen. It sounds simple but in atrics Committee on Nutrition published their recom- reality it is not, because hidden antigens in foods mendations for food allergy prevention (Table 4). will represent a challenge for these patients, and Their prevention guidelines were directed to the elimination diets may lead to malnutrition or high-risk infant (at high risk for food allergy), and dietary deficiencies.1 A meticulous attention to food there were no limitations imposed on the mother’s coe 2005 October

Table 3 Gastrointestinal food hypersensitivities

Disorder Mechanism Symptoms Diagnosis

Pollen–food allergy syndrome IgE mediated Mild pruritis, tingling, or angioedema of the lips, Clinical history and positive SPT responses (oral allergy syndrome) palate, tongue, or oropharynx; occasional to relevant food proteins (prick-plus-prick ALLERGIES FOOD OF MANIFESTATIONS GASTROINTESTINAL sensation of tightness in the throat and rarely method); Ϯ oral challenge—positive systemic symptoms with fresh food, negative with cooked food Gastrointestinal anaphylaxis IgE mediated Rapid onset of nausea, abdominal pain, cramps, Clinical history and positive SPT responses vomiting, or diarrhea; other target organ or RAST results; Ϯ oral challenge responses (ie, skin, respiratory tract) often involved Allergic eosinophilic IgE mediated or Gastroesophageal reflux or excessive spitting up Clinical history, SPTs, endoscopy and esophagitis cell mediated or emesis, dysphagia, intermittent abdominal biopsy, elimination diet and challenge pain, irritability, sleep disturbance, failure to respond to conventional reflux medications Allergic eosinophilic IgE mediated or Recurrent abdominal pain, irritability, early Clinical history, SPTs, endoscopy and gastroenteritis cell mediated satiety, intermittent vomiting, FTT, or weight biopsy, elimination diet and challenge loss Food protein–induced Cell mediated Gross or occult blood in stool; typically thriving; SPT responses negative; elimination of proctocolitis usually presents in first few months of life food protein3clearing of most bleeding in 72 h; Ϯ endoscopy and biopsy; challenge induces bleeding within 72 h Food protein–induced Cell mediated Protracted vomiting and diarrhea (Ϯ blood) not SPT responses negative; elimination of enterocolitis infrequently with dehydration; abdominal food protein3clearing of symptoms in distention, FTT; vomiting typically delayed 24–72 h, challenge3recurrent vomiting 1–3 h after feeding within 1–2 h, ϳ15% have hypotension Food protein–induced Cell mediated Diarrhea or steatorrhea, abdominal distention Endoscopy and biopsy IgA; elimination enteropathy, celiac disease and flatulence, weight loss or FTT, Ϯ nausea diet with resolution of symptoms and (gluten-sensitive and vomiting, oral ulcers food challenge; celiac: IgA antigliadin enteropathy) and antitransglutaminase antibodies

Used with permission from J Allergy Clin Immunol. 2003;111(suppl):S540–547. FTT, failure to thrive; IgA, immunoglobulin A; SPT, skin prick test; RAST, radioallergosorbent test. Reprinted from the Journal of Allergy and Clinical immunology, Vol. 111. Sampson HA, Food Allergy, pp 5540–5547, © 2003, with permission from The American Academy of Allergy, Asthma and Immunology. Lunch 1 533 534 GARCIA-CAREAGA AND KERNER Vol.Lunch 20, No.1 5

Table 4 References Prevention of food allergy 46 1. Spergel JM, Pawlowski NA. Food allergy. Pediatr Clin North Am. 2002;49:73–96. American Academy of Pediatrics 2000 recommendations for 2. Marklund B, Ahlstedt S, Nordstro¨m G. Health-related quality of prevention of food allergy life among adolescents with all conditions, with emphasis on food Prevention limited to high-risk infants hypersensitivity. Health Qual Life Outcomes. 2004;2:65–80. No dietary restrictions during pregnancy, with the possible 3. American Gastroenterology Association Medical Position State- exception of peanut ment: evaluation of food allergies. Gastroenterology. 2001;120: Exclusive breastfeeding until 6 mo 1023–1025. Eliminate peanuts and nuts from lactation diet (consider 4. Hahn E, Bacharier LB. The atopic march: the pattern of allergic elimination of eggs, cow’s milk, fish) disease development in childhood. Immunol Allergy Clin North Supplemental calcium and vitamins during restricted- Am. 2005;25:231–246. lactation diets 5. Cantani A. The growing genetic links and the early onset of atopic diseases in children stress the unique role of the atopic march: a If bottle-fed, use hypoallergenic formula (extensive, or meta-analysis. J Investig Allergol Clin Immunol. 1999;9:314–320. possibly partial, hydrolysate) 6. Utter SL, Collier SB. Special diets. In: Walker WL, Watkins JB, Least allergenic solid foods at 6 mo; cow’s milk at 12 mo; Duggan C, eds. Nutrition in Pediatrics. 3rd ed. Ontario, Canada: eggs at 24 mo; peanuts, nuts, and fish at 36 mo BC Decker Inc; 2003;997–1016. 7. Stern M. Allergic enteropathy/food allergy. In: Walker WA, Durie PR, Hamilton JR, Walker-Smith JA, Watkins JB, eds. Pediatric Gastrointestinal Disease.3rd ed. Ontario, Canada: BC Decker Inc; nutrient intake, with the exception of avoiding eat- 2000:746–762. 8. Lehrer SB, Wilod LG, Bost KL, Sorensen RU. Food allergy: ing tree nuts and peanuts during the lactation current knowledge and future directions. Immunol Allergy Clin period. If the high-risk child is offered infant formu- North Am. 1999;19:563–581. las, the choice of a hydrolyzed formula (either an 9. Stenton GR, Vliagoftis H, Befus D. Role of intestinal mast cells in extensive or partial hydrolysate) is preferable. modulating gastrointestinal pathophysiology. Ann Allergy Asthma Immunol. 1998;81:1–15. With the exception of celiac disease and some food 10. Andre F, Pene J, Andre C. Interleukin-4 and interferon-gamma allergies that can persist into adulthood (eg, shell- production by peripheral blood mononuclear cells from food- fish and peanuts), the vast majority of food allergies allergic patients. Allergy. 1996;51:350–355. disappear over time. 11. Sampson HA. Update on food allergy. J Allergy Clin Immunol. 2004;113:805–819. 12. Kirschner B. Undetermined colitis and other inflammatory dis- Conclusion eases. In: Walker WA, Goulet O, Kleinman RE, Sherman PM, Shneider BL, Sanderson IR, eds. Pediatric Gastrointestinal Dis- In essence, gastrointestinal food hypersensitivi- eases.4th ed. Ontario, Canada: BC Decker Inc; 2004:850–865. ties can cause symptoms from mouth to anus. These 13. Teitelbaum J, Fox VL, Twarog FJ, et al. Eosinophilic esophagitis in children: immunopathological analysis and response to flutica- symptoms may be as subtle as mild pruritus, tin- sone propionate. Gastroenterology. 2002;122:1216–1225. gling of tongue and palate, to nausea, vomiting, 14. Talley NJ, Shorter RG, Phillips SF, Zinsmeister AR. Eosinophilic diarrhea, dysphagia, failure to thrive, gastrointesti- gastroenteritis: a clinicopathological study of patients with dis- nal blood loss, and the most ominous: anaphylaxis. ease of the mucosa, muscle layer, and subserosal tissues. Gut. 1990;31:54–58. Food allergies have become an increasing source of 15. Caldwell JH, Mekhjian HS, Hurtubise PE, Beman FN. Eosino- concern among both the lay public and health care- philic gastroenteritis with obstruction: immunological studies of givers. We now have a better understanding of the seven patients. Gastroenterology. 1978;74:825–828. different processes involved in the development of 16. Sicherer SH. Clinical aspects of gastrointestinal food allergies. Pediatrics. 2003;1609–1616. an allergic reaction, making recognition and treat- 17. Kelly K, Lazemby A, Rowe P, Yardley JH, Perman JH, Sampson ment choices easier for the physician. Anaphylaxis HA. Eosinophilic esophagitis attributed to gastroesophageal due to an IgE-mediated immune reaction is a life- reflux: improvement with an amino acid-based formula. Gastro- threatening event. The nonreaginic or T-cell-medi- enterology. 1995;109:1503–1512. 18. Orenstein SR, Shalaby TM, Di Lorenzo C, Putnam PE, Sigurds- ated allergic conditions can also have a significant, son L, Kokoshis SA. The spectrum of pediatric eosinophilic chronic, and deleterious effect in the health of an esophagitis beyond infancy: a clinical series of 30 children. Am J individual. Understanding these conditions and Gastroenterol. 2000;95:1422–1430. their differences is of paramount importance to be 19. Liacouras CA. Eosinophilic esophagitis in children and adults. J Pediatr Gastroenterol Nutr. 2003;37(Suppl):S23–S28. able to select the most appropriate therapy or com- 20. Whitington PF, Whitington GL. Eosinophilic gastroenteropathy bination of therapies. Of no less importance is the in childhood. J Pediatr Gastroenterol Nutr. 1988;7:379–385. education of patients with food allergies. This edu- 21. Khan S, Orenstein S. Eosinophilic gastroenteritis masquerading as pyloric stenosis. Clin Pediatr. 2000;39:55–57. cation should be delivered in clear terms in an effort 22. Hu˝ mmer-Ehret BH, Rohrschneider WK, Oleszczuk-Raschke K, to avoid potentially fatal reactions or chronic debil- Darge K, Nu¨ tzenadel W, Tro¨guer J. Eosinophilic gastroenteritis itating disease. mimicking idiopathic pyloric stenosis. Pediatr Radiol. 1998;28: 711–713. 23. Arora AS, Yamazaki K. Eosinophilic esophagitis: asthma of the Acknowledgments esophagus? Clin Gastroenterol Hepatol. 2004;2:523–530. The work was supported in part by the Carl and 24. Straumann A, Spichtin HP, Grize L, Bucher K, Beglinger C, Simon HU. Natural history of primary eosinophilic esophagitis: a Patricia Dierkes Endowed Fund for Nutrition and follow-up of 30 adult patients for up to 11.5 years. Gastroenterol- Home Care. ogy. 2003;125:1660–1669. October 2005 GASTROINTESTINAL MANIFESTATIONS OF FOOD ALLERGIES Lunch 1 535

25. Sicherer SH. Enterocolitis, proctocolitis, and enteropathy. In: children with IgE-associated cow’s milk allergy. J Pediatr. 1999; Leung DYM, Sampson HA, Geha RS, Szefler SJ, eds. Pediatric 134:614–622. Allergy: Principles and Practice. St. Louis, MO: Mosby; 2003:510– 37. Bellioni-Businco B, Paganelli R, Lucenti P, Giampietro PG, Per- 517. born H, Businco L. Allergenicity of goat’s milk in children with 26. Vanderhoof JA, Murray ND, Kaufman SS, et al. Intolerance to cow’s milk allergy. J Allergy Clin Immunol. 1999;103:1191–1194. protein hydrolysate infant formulas: an underrecognized cause of 38. Kelso JM, Sampson HA. Food protein-induced enterocolitis to gastrointestinal symptoms in infants. J Pediatr. 1997;131:658– casein hydrolysate formulas. J Allergy Clin Immunol. 1993;92: 669. 909–910. 27. Levy Y. Food protein-induced enterocolitis. Pediatr Allergy Immu- 39. Frisner H, Rosendal A, Barkholt V. Identification of immunogenic nol. 2003;14:325–329. maize proteins in a casein hydrolysate formula. Pediatr Allergy 28. Sicherer SH. Food protein induced enterocolitis syndrome: case Immunol. 2000;11:106–110. presentations and management lessons. J Allerg Clin Immunol. 40. Isolauri E, Sutas Y, Makinen KS, Oja SS, Isosomppi R, Turjan- 2005;115:149–155. maa K. Efficacy and safety of hydrolyzed cow milk and amino 29. Nowak-Wegrzyn A. Food protein induced enterocolitis syndrome acid-derived formulas in infants with cow milk allergy. J Pediatr. caused by solid food proteins. Pediatrics. 2003;111:829–835. 1995;127:550–557. 30. Iacono G, Cavataio F, Montalto G, et al. Intolerance of cow’s milk 41. Gdalevich M, Mimouni D, David M, Mimouni M. Breast-feeding and chronic constipation in children. N Engl J Med. 1998;339: and the onset of atopic dermatitis in childhood: a systematic 1100–1104. review and meta-analysis of prospective studies. J Am Acad 31. Ma¨ki M, Lohi O. Enteropathy: celiac disease. In: Walker A, Goulet Dermatol. 2001;45:520–527. O, Kleinman RE, Sherman P, Shneider BL, Sanderson IR, eds. 42. Gdalevich M, Mimouni D, Mimouni M. Breast-feeding and the Pediatric Gastrointestinal Disease.4th ed. Hamilton, Ontario, risk of bronchial asthma in childhood: a systematic review with Canada: BC Decker Inc; 2004:932–943. meta-analysis of prospective studies. J Pediatr. 2001;139:261– 32. Dube´ C, Rostom A, Sy R, et al. The prevalence of celiac disease in 266. average-risk and at-risk western European populations: a sys- 43. Frank L, Marian A, Visser M, Weinberg E, Potter PC. Exposure to tematic review. Gastroenterology. 2005;128(4 suppl 1):S57–S67. peanuts in utero and in infancy and the development of sensiti- 33. Kokkonen J, Kaurttunen T. Lymphonodular hyperplasia on the zation to peanut allergens in young children. Pediatr Allergy mucosa of the lower gastrointestinal tract in children: an indica- Immunol. 1999;10:27–32. tion of enhanced immune response? J Pediatr Gastroenterol Nutr. 44. von Berg A, Koletzko S, Grubl A, et al. The effect of hydrolyzed 2002;34:42–46. cow’s milk formula for allergy prevention in the first year of life: 34. Bellanti JA, Zeligs BJ, Malka-Rais J, Sabra A. Abnormalities of the German Infant Nutritional Intervention Study, a randomized the TH-1 function in non-IgE food allergy, celiac disease, and ileal double-blind trial. J Allergy Clin Immunol. 2003;111:533–540. lymphonodular hyperplasia: a new relationship? Ann Allergy 45. Osborn DA, Sinn J. Formulas containing hydrolysed protein for Asthma Immunol. 2003;90:84–89. prevention of allergy and food intolerance in infants. (Cochrane 35. Joshi P, Mofidi S, Sicherer SH. Interpretation of commercial food Review). In: The Cochrane Library, Issue 1, 2004. Chichester, ingredient labels by parents of food-allergic children. J Allergy UK: John Wiley & Sons, Ltd., pgs 1–61. Clin Immunol. 2002;109:1019–1021. 46. American Academy of Pediatrics Committee on Nutrition: 36. Zeiger RS, Sampson HA, Bock SA, et al. Soy allergy in infants and Hypoallergenic infant formulas. Pediatrics 2000;106:346–349. Case 1: Eosinophilic Esophagitis – the controversies

Eliza is a 13-month old female being seen in clinic for persistent emesis. The emesis is post-prandial and can occur at any time of day. The vomitus is non-bilious and non-bloody and the emesis is non-projectile.

She is a product of a full term and normal pregnancy.

Her ROS and past medical history are negative except for mild atopic dermatitis.

In dietary history, she was nursed for the first 6 months of life and then switched to infant formula due to emesis. She is being introduced to age-appropriate solids.

Her physical examination is normal except for some patches of atopic dermatitis.

Her upper GI barium study was unremarkable; the anatomy was normal and there was mid-level gastro-esophageal reflux.

What would you do for her?

Thinking this is prolonged infantile GER, you elect a conservative path and treat her empirically with anti-GER therapy (PPI qam).

Her symptoms however do not improve as reported during a follow up visit at age 16 months.

You decide to buy some more time and step-up her therapy to PPI bid and a promotility agent.

On a follow up visit at age 20 months she is still vomiting though it is not as frequent. The mother however has noticed she is becoming a difficult feeder and wonders if the “terrible twos” are occurring a little sooner than normal.

What would you do at this time?

You endoscope her and the mucosa appears unremarkable – maybe slight blunting of esophageal mucosal vasculature. Biopsies are obtained and family is discharged from the endoscopy suite.

A few days later the biopsy report returns as significant eosinophilic inflammation of the mid- and distal-esophageal biopsies with 30 eosinophils/high power field, eosinophil degranulation, and layering of eosinophils along the luminal side. In addition there is basal cell hyperplasia upto 80% of epithelial thickness, and grade 2 lamina propria fibrosis.

What is your diagnosis and what are your additional diagnostic and therapeutic options?

You need to rule out GER – in this case it was done by the preceding anti-GER therapy. In other instances, options include pH probe study, Bravo monitoring, or anti-GER medical therapy.

Your other diagnostic options include visit with an allergist for prick/patch testing.

The allergy evaluation reveals positive results to apples, chicken, peas and watermelon.

What treatment would you place this child on?

Comparing PPI Responders and Non-Responders

PPI Responders 110 100 100 (n=17) 90 PPI Non-Responders 81 73 73 80 (n=26) 70 59 59 60 50 48 50 40 31 29 31 30 20 20 10 0 Male (%) Abnormal Furrows (%) Eos/hpf Abnormal pH Symptom Allergy Test test (%) Improvement (%) on PPI (%)

Dranove et al 2007; slide courtesy Dr Hirano

Topical Steroids 90 84.6 80 Pre-treatment 70 Post-treatment 60

50 43.4

40 33.3

Eos/hpf 400X 30 23 19.7 20

10 4.8 1 2.7 0 Koni kof f1 Noel R2* Tei tel baum34 Schaef er (n=18) (n=20) (n=13) (n=40)

Design: RCT Retrosp Prosp RCT Max Dose: 880 mcg/day 1320 mcg/day 880 mcg/day 1760 mcg/day

*Post treatment data on 16 patients.

1) Gastroenterology 2006; 2) Clin Gastroenterol Hepatol 2004; 3) Gastroenterology 2002; 4) Clin Gastroenterol Hepatol 2008

Eliza is placed on fluticasone inhaler to be swallowed, without an inhaler, at 2 puffs qid (110 mcg/actuation) with nothing to eat or drink for 30 minutes after and then to take a drink of liquid.

A repeat endoscopy 4 weeks later reveals normal appearing mucosa and normal biopsies.

How would you follow Eliza? You recommend a gradual wean off fluticasone over the next 2 months and establish a return visit. The child however is lost to follow-up.

They recently returned, and Eliza is now 6 years old, with complaints of periodic emesis, ongoing picky eating habits with texture issues, and “something not right”

You re-endoscope her and she has active EE – thickened esophageal mucosa with vertical lines and white specks in most of esophagus. There are no erosions, ulcers or evidence of a stricture or hiatal hernia.

The family follows up in clinic to discuss treatment options for EE. They are aware of a local support group of American Partnership for Eosinophilic Disorders (APFED.org) and googled some other treatments including montelukast, cromolyn sodium, systemic steroids, anti-IL-5 antibodies, and dietary modifications.

Histological Response to Diet

50 40 Before 30 After 20 Eos/HPF 10 0 t e iet Di D n al io t at en min em El Liacouras et al 2005 Eli

Oral Steroid Pre-treatment 40 Post-treatment 34.2 35 29 30

25

20

15 Eos/hpf 400X Eos/hpf 10

5 1.5 1.3 0 1 2 Liacouras Schaefer (n=20) (n=40)

1 mg/kg BID; max 30 mg BID

1) J Pediatr Gastroenterol Nutr 1998; 2) Clin Gastroenterol Heaptol 2008

Comparing Corticosteroids

120 100 97 Fluticasone 100 94 94 Prednisone 78 80 67

60 45.8 44.4 Percent 40 40

20 15

0 Symptom Resolution Histology Score <5 Eos/Hpf Side Effects*** Symptom Recurrence

•Systemic side effects in 40% of Prednisone; esophageal candidal overgrowth in 15% of Fluticasone. **Symptom recurrence in 44.4% of Prednisone and 45.8% of Fluticasone at Week 24 mark (i.e., received 12 weeks of drug and then monitored for 12 weeks off drug).

Clin Gastroenterol Hepatol 2008

Comparing Corticosteroids

— 80 patients randomized to prednisone or fluticasone — Relapse rates or time to relapse similar between the groups — Side effects: fewer with fluticasone — ? Reserve prednisone for severe cases

Schaefer et al. Clin Gastroenterol Hepatol 2008

Anti-Interleukin 5

z IL-5 is the predominant cytokine mediating eosinophil function; eosinophil lifeline

z 11 active EE adults randomized to mepolizumab (M) vs placebo

mepolizumab - M improved peripheral and

IL5 esophageal eosinophilia IL5 Y IL5 Y - no significant adverse events IL-5 receptors Y noted with M Eosinophil α chain β chain

Straumann et al. 2007

Case 2: Eosinophilic gastroenteropathy

11 year old Vietnamese female with upper abdominal pain, early satiety, emesis, and weight loss.

Screening laboratory studies normal/noncontributory including markers of inflammation.

Upper GI barium performed locally was read as unremarkable.

Endoscopy revealed a narrowed pylorus with ulcerations of the pyloric channel. The mucosa was friable. Biopsies of the antrum and the duodenum revealed significant eosinophilic inflammation.

What are your treatment options for this child?

Lowicki et al