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Home , Proctocolitis

10/3/2012

Childhood Objectives , Food intolerance, • To understand, diagnose and treat physiologic Eosinophilic or responses that cause diarrhea Something else? • To understand, diagnose and treat allergic processes that cause diarrhea - IgE, FPIES, cow's Chris A. Liacouras, MD • To understand, diagnose and treat food The Children’s Hospital of Philadelphia intolerances - lactose intolerance, food University of Pennsylvania School of Medicine hypersensitivity • To understand, diagnose and treat eosinophilic gastrointestinal disease

What is a normal bowel pattern Infant Bowel Pattern in children? • As in older children, stool patterns differ from • Everyone has their own normal pattern of baby to baby bowel movements • Some infants stool have a stool several times • Everyone’s bowels are unique to them, per day, some once a week - both are normal and what’ s normal for one person may not • Newborns commonly stool more frequently be normal for another than older babies, sometimes with every feed • A normal pattern can be 1-3 times a day at • Breast fed babies may have softer, more the most, or 2-3 times a week at the least, frequent stools than formula fed babies – and still be considered regular, as long as may change when solids are added it is the usual pattern for that person

What is diarrhea? Stool color

di·ar·rhe·a/ dīə rēə/ •Normal stool color varies quite a bit from black, dark A condition in which feces are discharged from the green, bright green, yellow or brown in color. bowels frequently and in a liquid form. Synonyms: diarrhoea – looseness •Stools that are white and chalk-like or stools that are bloody are not normal. • A change in normal consistency or frequency of stools

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Typical GI view of diarrhea Food • Bacterial infections - Campylobacter, Salmonella, Shigella, and Escherichia coli (E. coli). • Viral infections - Rotavirus, norovirus, cytomegalovirus, herpes simplex • Food hypersensitivity reactions affect virus, and viral – Up to 8% of children under 3 years of age • Post-viral • Parasites - Giardia lamblia, Entamoeba histolytica, and Cryptosporidium – At least 2.5% of the general population • Functional bowel disorders - . • Intestinal diseases/ - Inflammatory bowel disease, • 3x increase in prevalence of allergies over ulcerative , Crohn’s disease, celiac disease • Congenital disaccharridase deficiencies past 20 years • – Cystic fibrosis, Schwachman’s syndrome – Changes in environment • Food intolerances and sensitivities – Primary and secondary lactose intolerance – Changes in the processing of foods • Toddler’s diarrhea – Alteration of immunologic recognition • Reaction to medication - Antibiotics, cancer drugs, and antacids containing magnesium can all cause diarrhea – Use of antibiotics

Categorization Immune Mechanisms  Protein digestion  Antigen processing  Some Ag enters blood

IgEIgE--MediatedMediated IgEIgE--receptorreceptor APC Mast cell NonNon--IgEIgE Mediated  TNFTNF-- B cell T cell  ILIL--55

Cianferoni A and Sperfgel JM; Allergology International 2009; 58: 457-466.

Adverse Food Reactions Immunologic IgEIgE--MediatedMediatedNon- Non-IgEIgE Mediated

•Systemic CellCell--MediatedMediated (Anaphylaxis) • Eosinophilic • Food Protein-Induced • Oral Allergy (EoE) Syndrome • Eosinophilic • Food Protein-Induced Clinical Manifestations • Immediate • Eosinophilic gastrointestinal allergy • Food Protein-Induced Proctocolitis • Asthma/rhinitis • Atopic dermatitis • Dermatitis • Urticaria herpetiformis • Morbilliform rashes and • Contact dermatitis • Contact urticaria • Celiac disease

Sampson H. J Allergy Clin Immunol 2004;113:805-9. Chapman J et al. Ann Allergy Asthma & Immunol 2006;96:S51-68.

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Signs and Symptoms Case 1 IgE Non- Non-IgEIgE AcuteChronic

Skin Urticaria • 5 month old Angioedema • Within 15 minutes of eating developed Atopic dermatitis Respiratory rash, hives, abdominal pain, diarrhea, Throat tightness breathing difficulty Asthma Gut • Symptoms progressively worsening Vomit Diarrhea • Taken to ER Pain Anaphylaxis

•In ER • Anaphylaxis typically presents with many different symptoms over minutes or hours with an average onset of 5 to 30 minutes if exposure is intravenous and 2 hours for foods. The most common areas affected include: skin (80–90%), respiratory (70%), gastrointestinal (30–45%), heart and • After fluids and epinephrine vasculature (10–45%), and central nervous system (10–15%) with usually two or more being involved.

Delayed allergic reactions to red meats

• Symptoms typically include generalized hives, • A novel and severe food allergy associated with IgE antibodies to the carbohydrate epitope -gal. itchiness, flushing or swelling of the lips. • Delayed symptoms (3-6 hours) of anaphylaxis, angioedema, or Swelling of the tongue or throat occurs in up to urticaria after eating beef, pork, or lamb. about 20% of cases. Respiratory symptoms and • SPT with commercial extract usually negative; improved signs that may be present, including shortness sensitivity if SPT with fresh mmeateat or with intradermal testing • Most of these patients report new-onset of symptoms to meat in of breath, wheezes or stridor. Gastrointestinal adulthood symptoms may include crampy abdominal pain, • All patients from Virginia, North Carolina, Tennessee, Arkansas, diarrhea, and vomiting. and Missouri; possibility of a sensitizing exposure that may be geographically isolated (areas endemic for ticks – Amblyomma • A feeling of anxiety or of "impending doom" has americanum). be described. Commins SP, et al. JACI 2009;123:426-33

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Case 2 Physical Exam

• 2 month old with 3 to 4 week history of • Normal baby exam diarrhea, bloody and mucus streaked • Benign abdominal exam stools • No , vomiting, jaundice • Labs and stool cultures normal • No medicines • No family history of GI disease • On milk based formula

Lower GI Bleeding in the Neonate Allergic Proctocolitis • May or may not need to perform sigmoidoscopy with biopsy • Infectious colitis Normal • Milk-protein allergy •NEC • Meckel’s, AVM, duplication cyst • Upper GI source

Allergic Proctocolitis Allergic Proctocolitis • Patchy eosinophilic infiltrate, variable in severity. • 2-6% of infants in developed countries • Neutrophilic cryptitis can be seen (not to extent of infectious colitis or IBD • Up to 60% breastfed • No chronic mucosal changes – β-lactoglobulin – Removal of dairy from mother’s diet – Small percentage have to stop breastfeeding • Cow’s milk protein formula fed – 30% cross-reactivity with soy – >80% respond to protein hydrolysate formula

Sampson HA, et al; J Pediatr Gastroenterol Nutr 2000; 30:S87-94

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Allergic Proctocolitis -- Allergic Proctocolitis Treatment Clinical features Laboratory features • Breastfed infants • Blood streaked stools • Mild peripheral – Maternal food restriction (mainly dairy) • Diarrhea eosinophilia – Infrequently other foods – Sometimes need to stop breastfeeding • Mucus in stool • Elev ated seru m IgE • Normal weight gain •Rare • Formula fed – Hypoalbuminemia – Skip soy formula (30-50% cross-reactivity) • Well-appearing – Mild anemia • Eczema, atopy - rare – Protein hydrolysate (75-80% respond) – Amino acid formula may be necessary

Allergic Proctocolitis – Summary Response to Treatment • 72 hrs: Improvement in clinic symptoms • Milk-protein allergy is a common cause of – Resolution of diarrhea, bleeding: Up to 3 bloody diarrhea in neonates weeks • Can be treated empirically with dietary restriction without diagnostic • 4-6 weeks: Histologic clearing sigmoidosocpy • Reintroduce milk at 12 mo? 18 mo? 24 • Usually resolves 18-24 months mo? – Can RAST, prick testing guide decision?

Case 3

• 15 yo with a 4 year history of progressively • Labs – CBC, Chemistry panel, stool increasing abdominal pain and diarrhea cultures – negative • No weight loss (normal growth curve) • Abdominal xray – normal • NbldiNo bleeding, vom iting, ras h • Pain and diarrhea seem to increase after • Family history of similar problems in father eating and uncle

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Lactose Intolerance

• Lactose breath test significantly abnormal • Congenital Lactase Deficiency – Extremely rare – Neonatal diarrhea and malabsorption • Diagnosis - Lactose intolerance • Primary Lactase Deficiency – 70% of population – African, Asian descent: 90-100% – Decline in lactase levels starting after age 5

• Secondary Lactase Deficiency – Small bowel injury – Celiac disease, infection, Crohn’s disease, radiation or drug induced enteritis

Lactose Intolerance • Symptoms same as fructose intolerance Diagnosis • Food intolerances – Non-allergic food hypersensitivity is the • Hydrogen breath test medical name for food intolerance, loosely • Dietary trial referred to as food hypersensitivit y, or • Disaccharidase analysis previously as pseudo-allergic reactions. • Non-allergic food hypersensitivity should Treatment not be confused with true food allergies. • Dietary modification • Lactose free dairy products • Lactase supplementation

Other types of food intolerances Case 4

• Pharmacological responses to naturally • 10 year old occurring compounds in food, or chemical • Several years of intermittent but severe intolerance (caffeine, other organic abdominal pain chemicals occurring naturally in a wide • Ftltl(Frequent, loose stools (heme +) variety of foods • Decreased appetite • Food additives, preservatives, colourings and flavourings, such as sulfites or dyes

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Normal Eosinophilic Testing Antrum Gastroenteritis

• Heme + stools • Hemoglobin 10.5 • Albumin 3.3 mg/dL

• UGI/SBFT – gastric mucosal thickening

Eosinophilic Gastroenteritis Eosinophilic Gastroenteritis Clinical characteristics • Vomiting • Severe abdominal pain • Diarrhea, protein losing enteropathy • Gastrointestinal bleeding • Intestinal obstruction, perforation • Peripheral eosinophilia, (50%?) • Associated allergies: eczema, asthma, rhinitis, atopy Mucosal type Mural type

Eosinophilic Eosinophilic Gastroenteritis Gastroenteropathies • Very rare • Eosinophilic infiltrate through GI tract • GI symptoms Spectrum of disease or unique diseases? – Vomiting, diarrhea, abdominal pain, protein losing enteropathy, obstruction Colon • Exclusion of known causes of GI eosinophilia • Etiology unknown – Immunologic dysregulation Allergic proctocolitis – Food antigens NO DIARRHEA • Difficult to treat Eosinophilic gastroenteritis –Steroids – Dietary changes

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EoG - Treatment Case 5 • 1 year old • Diet • Exclusively breast fed (except formula first – Test for food allergies 3 wks) – Skin prick and Atopy patch – Solids introduced at 6 months (rice cereal, – Usually need amino acid based formulas fruits, vegetables) • Corticosteroids • Yogurt given for first time – Aggressive dosing – 1 hr later: Irritability and continuous emesis • Immunosuppresants – 2 hrs later: Brought to ED limp, listless – 6 mercaptopurine – Sepsis work-up negative – Returned to baseline after 2 hrs IVF and was discharged home 24 hrs later

Food Protein Induced Case 5 (continued) Enterocolitis (FPIES) • Two days later  Older brother gave him Clinical features yogurt again • Repetitive vomiting (~ 2 hours post ingestion) • Same symptoms • Diarrhea (~5 hours post ingestion) • In ED, limp and ill-appearing – Can have occult blood, WBCs • Afebrile, HR 157 bpm, BP 63/45 • Dehydration that may progress to: • Treatment: subcutaneous epinephrine – Lethargy without improvement and IVF which – Acidemia helped – Hypotension • Negative sepsis workup – Methemoglobinemia • Diagnosis is…? • Occasional hypoalbuminemia and FTT

Food Protein Induced Enterocolitis Food Protein Induced Syndrome (FPIES) Enterocolitis Syndrome (FPIES) st • Onset: Typically 1 year of life • Majority of patients become tolerant to • Milk most common inciting food by 3 years of age – 50% also react to soy • Not IgE mediated – 33% will react to solids • Diagnostic gold standard: Oral food • Multiple solid foods described challenge – 80% react to >1 food protein – 60% also react to milk, soy • Patch testing • May tolerate breast milk with maternal – Sensitivity 100%, specificity 71% in small restrictions study

– CHOP Allergy  Amino acid formulas • Oral food challenges requiredFogg MI, et al; Pediatr prior Allergy Immunol to food2006; 17:351-355

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FPIES Management Case 6

• 11 year old • IV fluid boluses • Poor weight gain, diarrhea, fatigue • Supportive care • No vomiting, regurgitation, no fever • Epinephrine typically NOT helpful • Avoidance

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Physical Examination Differential Diagnosis

• Pancreatic Insufficiency • Lethargic, irritable but otherwise normal • Lactose intolerance physical exam • Infection – bacterial, parasitic (Giardia) • CBC and Chemistryyp panel normal • Small bowel bacterial overgrowth • Stool cultures - normal • Biliary disease • Celiac disease • Crohn’s disease

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Further testing

• ANTI-ENDOMYSIAL IgA: Positive (1:160) •IgA: 50 • ANTI-TTG IAIgA: 133. 9

• Upper endoscopy performed

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Further Investigations Duodenal Biopsy - normal

• Upper endoscopy with biopsy performed

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Duodenal biopsy - case Celiac disease

• Immune-mediated enteropathy due to permanent sensitivity to gluten in genetically susceptible individuals – Wheat, rye , barley • 1:133 incidence in United States – First degree relative: ~1:20 • Can present with or without

Gold standard: Duodenal biopsies - Villous blunting, intraepithelial lymphocytosis gastrointestinal symptoms

The Celiac Iceberg Celiac Gastrointestinal Manifestations (“Classic”) Symptomatic Celiac Disease • Chronic or recurrent diarrhea Abnormal • Abdominal distention mucosa • Anorexia Silent Celiac Disease • FTT/loss of weight

Latent Celiac Disease Normal • Abdominal pain Mucosa • Vomiting

Genetic susceptibility: - DQ2, DQ8 • Positive serology • Irritability

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Celiac disease – Non Serological Test Comparison Gastrointestinal Manifestations Most common age of presentation: older child to adult Sensitivity % Specificity % • Dermatitis • Delayed Puberty Herpetiformis • Iron-deficient anemia AGA-IgG 69 – 85 73 – 90 resistant to oral Fe • Dental enamel AGA-IgA 75 – 90 82 – 95 hypoplasia of • Hepatitis EMA (IgA) 85 – 98 97 – 100 permanent teeth • Arthritis TTG (IgA) 90 – 98 94 – 97 • Osteopenia • Epilepsy with occipital • Short Stature calcifications

Farrell RJ, and Kelly CP. Am J Gastroenterol 2001;96:3237-46.

Celiac Disease Case 7

• 3 yo boy presents with abdominal pain and • Permanent intolerance to gluten diarrhea x 6 weeks associated with proximal small bowel mucosal disease – 4-6 loose, non-bloody BMs per day – “Never had a formed BM” • Removal of gluten leads to full clinical and histologic remission • No vomiting or weight loss • Highest prevalence amongst N. • Diet: “Normal” Europeans, esp W. Ireland (1 in 300) • Well appearing • 0.4% prevalence in healthy US blood donors • Infectious stool studies: Negative 63

Dietary Fructose

• Naturally occurring monosaccharide – Sucrose = Fructose + glucose More dietary history • Inexpensive sweetener • Patient constantly drinking from sippy cup – Sodas, fruit juices, candy • Also found in many fruits • You calculate 50-70 oz water/juice daily

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Dietary Fructose Intolerance Dietary Fructose Intolerance

• Mechanism of intestinal absorption poorly • Most common symptoms: Distention, understood gassiness, diarrhea • Non-absorbed fructose • Children with isolated abdominal pain – Osmotic load Diagnosis – Source for bacterial fermentation • Hydrogen breath test • Intestinal fluid shifts • Dietary trial – Distention – Bloating Treatment

– Diarrhea • Dietary modification Gomara RE, et al; J Pediatr Gastroenterol Nutr 2008; 47:303-308 Tsampalieros A et al; Arch Dis Child 2008; 93: 1078

Key Points • Consider allergic diseases in children presenting with diarrhea • Eosinophilic GI disease: Increasing in incidence • GI manifestations of food allergy often occur without typical allergic symptoms • EiidithEmpiric dietary changes can be expens ive an d difficult – utilize diagnostic tests whenever possible • Lactose & Fructose  Common cause of childhood diarrhea and abdominal pain • Lactose intolerance may be secondary to other GI disorders • Celiac disease – under-diagnosed

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