Allergic or Other?

Gillian Lam, M.D. Assistant Professor of Pediatrics Division of OHSU Doernbecher Children’s Hospital OHSUJune 2021

S Disclosures OHSUS None Objectives

S Milk Protein Allergy

S Colic vs Reflux vs Milk Protein Allergy

S Common Etiologies for GI OHSUS Allergic vs IBD S Very Early Onset IBD Cow Milk Protein Allergy (CMPA)

S Allergic to cow’s milk protein, with high cross-reactivity to soy

S Major Flag: poor weight gain, with mucousy/bloody stools

S Minor Flag: vomiting, fussiness, frequent reflux S Milk Protein Allergy vs Colic vs Reflux OHSUS Growing well with normal stools? Colic/Reflux S Calprotectin may not be helpful

S Diagnosis clinically Calprotectin in healthy infants OHSU

Feng Li, Jingqiu Ma, et al. Fecal Calprotectin Concentrations in Healthy Children Aged 1-18 Months. PLoS One. 2015; 10(3): e0119574. Published online 2015 Mar 5. Colic

S Baby is clinically well, but fussy and crying

S Reassuring parents can be hard, especially when they are desperate to try things

S Trialing different formulas S Soy-based formula OHSUS Partially-Hydrolyzed Formula (Not hypoallergenic) S Similac Total Comfort, Enfamil Gentlease, Gerber Gentle/Smooth S ?Extensively-Hydrolyzed Formula Gastroesophageal Reflux OHSUS Frequent transit relaxation of lower esophageal sphincter Gastroesophageal Reflux

S GER vs GERD S GER is a normal physiologic process with passage of gastric contents into the S GERD is GER when it causes issues, like symptoms, esophageal injury, poor weight gain, etc SOHSUGER in infants is normal baby spit up S Formula changes and medications may not help S Reflux precautions, small frequent feeds, keep upright/inclined after eating, thickened feeds Gastroesophageal Reflux

S Thickening milk for Reflux S Oatmeal cereal over rice cereal S Enfamil A.R is thickened with Rice starch S Gel-Mix (carob bean gum) OHSUS Reflux medications don’t stop reflux from occurring S Medications only decreases the acidity, so helpful with GERD Reflux Medications

S H2-Blocker S Ranitidine (Zantac), Famotidine (Pepcid), Cimetidine

S Proton Pump Inhibitors S Omeprazole (Prilosec), Pantoprazole (Protonix), Lansoprazole (Prevacid), Esomeprazole (Nexium) OHSUS Try to avoid long term usage S Decreases absorption of Calcium, Iron, B12, Mag S Increased risk of pneumonia, Cdiff, dementia, acute kidney drug injury Colic vs Reflux vs CMPA

S Poor weight gain or mucousy/bloody stools -> Tx for CMPA

S Growing well with normal stools, but baby fussy/vomiting S Reassure/Treat for Colic and/or Reflux

S Trial of extensively hydrolyzed formula helped fussiness/vomiting OHSUS Continue treating as CMPA, but consider earlier re- introduction or trial back to regular formula CMPA – Change Formula

S No Soy-based formula due to high cross-reactivity

S Jump straight to extensively-hydrolyzed formula S Alimentum, Nutramigen, Pregestimil

S 10% require amino-acid based OHSUS Elecare, Neocate, Alfamino S Hypoallergenic formulas taste and smell BAD

S They are expensive ($20 vs $30 vs $45), can lasting ~2-3 days CMPA - Elimination Diet

S Breastfeeding Mom/Child must avoid all foods containing milk and Soy

S Must read labels S Milk, Dairy, Whey, Casein S Soybean, Soybean oil, Soy lecithin OHSUS Milk and Soy in MANY foods S Soy in many shelf-stable foods (esp baked goods) Common Misconception

S Milk Protein Allergy is NOT the same as

S Babies DO NOT get lactose intolerance

S Lactose is the carbohydrate/sugar in all mammalian milk, including human breastmilk

S Lactose-intolerance starts earliest at age 2, but many develop it OHSUlater S Dairy-free diet is VERY different from lactose-free diet Chronic FPIES

S Other possible allergens S Beef, Eggs, Peanuts, Tree Nuts, Wheat S No testing available, so is “trial and error” S The more eliminations, the more restrictive the diet becomes OHSUS Ensure diet has enough calories, proteins and is complete S Iron? Vitamin D? Calcium? S Consider supplementing or temporary holding breastfeed S Can freeze breastmilk, label it and save for re-introduction What is left to eat?

S Vegans goods will be dairy and egg free, but most use soy or nuts as substitutes. Daiya is coconut based

S Pea, Hemp, Oat milk. Vegan protein shakes

S Most Fruits and Vegetables, Rice, Potatoes OHSUS Chicken, Pork, Beans, Seafood S Sunflower Butter, Avocado

S Hypoallergic Food Companies S Red Plate Foods, Enjoy Life, MadeGood Re-Introduction

S At at 9-10 months, Soy Lecithin/Oil then Protein S Goal of vegan birthday cake (using soy) S At 12 months, start “Milk Ladder” S Baked Dairy (cookie, muffin, pancake) S Cheese OHSUS Yogurt S Whole Milk Milk Alternatives

S At 12 months, switch infant formula to cow milk alternatives S Give either Soy, Hemp, Oat or Pea (SHOP) Milk

S Rice and coconut milk has almost no protein OHSUS Almond milk is low in both calorie and protein Not Improving?

S Still failure to thrive? S Is nutrition significant? S May need more than the average caloric needs for age S stool studies S Fat: Fecal fat and elastase OHSUS Protein: Alpha-1-antitrypsin (not serum) S Carbohydrates: Reducing substance S Most common cause of fat malabsorption is cystic fibrosis Not Improving?

S Still having bloody stools despite AA formula? S Consider Flexible Sigmoidoscopy OHSUS Ddx for bloody stools in children Blood or Not blood?

• Can appear as red blood if vomited or in stool • Foods containing red food coloring (Jelly, Kool Aid), tomatoes, strawberries, and beets

• Can appear as • Blueberries, spinach, licorice, grape juice, and certain medications such as Pepto-Bismol (due to bismuth) and OHSUIron • Question is best answered with a guaiac

“Bluerberry Poop” Guaiac

Guaiac is a colorless compound that turns blue when placed in contact with substances that have peroxidase activity (such as heme portion of hemoglobin) and hydrogen OHSUperoxide + = Guaiac

S “False-positives” with foods containing peroxidase activity S Red meat, melons, grapes, radishes, turnips, cauliflower, broccoli

S “False-negative” with anti-oxidant properties OHSUS Vitamin C Source: GI Tract or Not?

S Melena may be seen in patients who have swallowed blood S Maternal blood, post tonsillectomy, or epistaxis

S Females on their periods may appear to have hematochezia

S Hematuria may be mistaken for hematochezia OHSUS Can be difficult to distinguish hemoptysis and Where in GI Tract? Upper or Lower?

S Upper GI bleeding - proximal to the ligament of Treitz S Esophagus, stomach, S Melena – Black and tarry

S Lower GI bleeding - distal to the ligament of Treitz S Small bowel and colon OHSUS Hematochezia – Red blood S Melena can be seen with bleeding from proximal small bowel

S Hematochezia can be seen with massive UGI bleeding

S In infants, hematochezia may be due to an upper GI source owing to shorter intestinal transit time Etiologies of UGI Bleeding: In relative order of frequency

Newborn Infant Child-Adolescent Swallowed maternal Stress or ulcer Mallory-Weiss tear blood Vitamin K deficiency Acid-peptic disease Acid-peptic disease Stress gastritis or ulcer Mallory-Weiss tear Varices Acid-peptic disease Vascular anomaly Caustic ingestion Gastrointestinal Vasculitis (Henoch- OHSUVascular anomaly duplication Schonlein purpura) Coagulopathy Duodenal/gastric webs Dieulafoy lesion, Milk-protein sensitivity Bowel obstruction hemobilia Common Etiologies of Lower GI Bleed based on Age

Newborn Infant Preschool Age School Age (Birth – 1 mth) (1 mth – 2 yr) (2-5 yr) (>5 yr) Necrotizing enterocolitis Hemorrhagic disease Infectious colitis of the newborn Malrotation with Henoch-Schönlein purpura

Hirschsprung disease enterocolitis

OHSUInflammatory bowel Allergic Meckel diverticulum disease Lymphonodular hyperplasia

Intussusception

From Walker – Lower Gastrointestinal Bleed Potential Etiologies of Lower GI Bleed based on History

Amount of Appearance Characteristics Pain Underlying disease blood loss of bleeding of stools Small Red Hard Yes Anal fissure Allergic proctocolitis, Small to Variable Red Loose infectious colitis, hemolytic moderate (abdominal) uremic syndrome, IBD Small to Normal, coated Red No Polyp moderate with blood Yes Moderate Red to tarry Normal Henoch-Schönlein purpura (abdominal) Red to tarry, Yes OHSUModerate Normal Intussusception currant jelly (abdominal) Yes Hirschsprung disease Moderate Red to tarry Loose (abdominal) enterocolitis Meckel diverticulum, Large Red to tarry Normal No

From Walker – Lower Gastrointestinal Bleed Infectious Colitis

Bacterial pathogens Parasitic pathogens Viral pathogens Infectious colitis Salmonella Shigella

Campylobacter jejuni Entamoeba Cytomegalovirus Yersinia enterocolitica histolytica (esp OHSUO157:17) Clostridium difficile Klebsiella oxytoca Allergic Proctocolitis

S Food protein (milk/soy) causes an inflammatory S Diagnosis clinically, doesn’t need endoscopy

S On colonic biopsies S Focal increase in the number of eosinophils OHSUS Mucosa architecture is preserved Inflammatory Bowel Disease

S Chronic architectural changes (atrophy, irregularity and shortening of crypts, thickening of the muscularis mucosae, metaplasia), small intestinal villous blunting, granulomas, OHSUincreased eosinophils S The peak incidence of IBD occurs the ages of 15 and 25 years

S ~25 -30% CD and ~20% of UC present before the age of 20 Inflammatory Bowel Disease

S Colitis phenotype is very common in pediatrics

S 90-95% of and 25% Crohn’s Disease present with and/or bloody diarrhea

S UC-like disease in younger children labelled with caution because of high probability of subsequent evolution to OHSUChron’s disease

Prenzel F Uhlig HH . Frequency of indeterminate colitis in children and adults with IBD─a meta-analysis. J CrohnsColitis 2009;3:277–81. Very Early Onset IBD (VEO-IBD)

S IBD in children <6 years of age

S Infantile IBD in children <2 years

S Very Rare S VEO-IBD representing 3% of pediatric IBD S 1/3 these VEOIBD patients are infantile OHSUS Disease severity often is higher S Likely associated with a gene defects that alter immune function or disturb epithelial barrier function

Bequet E Sarter H Fumery M et al. . Incidence and phenotype at diagnosis of very early onset compared with later onset paediatric inflammatory bowel disease: a population-based study [1988–2011]. J Crohn Colitis 2016 Very Early Onset IBD DDx/Assc

S Chronic granulomatous disease S Interleukin-10 (IL-10) signaling defects S Atypical severe combined immunodeficiency S Common variable immunodeficiency S Wiskott-Aldrich syndrome S Agammaglobulinemia S Hyperimmunoglobulin M syndrome S Familial hemophagocytic lymphohistiocytosis OHSUS IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) S Autoimmune enteropathy OHSU Primary Immunodeficiencies

S GI manifestations include intractable diarrhea, malabsorption, failure to thrive, or IBD

S Recurrent, severe or atypical infectious diarrhea S Defects in both B and T cells are susceptible to infections by bacterial, viral, and fungal organisms. S Bacterial infections are commonly observed in B cell defects. OHSUS Viral and fungal infections are characteristic of less severe T cell defects. S Impaired phagocytosis results in both bacterial and fungal infections. Primary Immunodeficiencies

S Increased risk for GI autoimmune and inflammatory diseases S IBD or IBD-like colitis, PSC, Celiac, Autoimmune , pernicious anemia

S Local dysregulation of the GI immune system may result in inappropriate immune responses that lead to autoimmunity or uncontrolled inflammation.

OHSUS Ineffective immune responses that do not fully clear invading pathogens, can further provoke further inflammation

S Selective IgA deficiency increased risk of celiac disease Chronic Granulomatous Disease (CGD)

S Defects in the phagocyte’s nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex, which generate reactive species of oxygen for its respiratory burst S Inability of phagocytes (neutrophils, monocytes, and macrophages) to destroy certain microbes S Recurrent bacterial and fungal infections caused by catalase- positive microorganisms OHSUS Aspergillus species S S. aureus S Burkholderia (Pseudomonas) cepacian complex S Serratia marcescens S Nocardia species Chronic Granulomatous Disease (CGD)

S Common infections: Pneumonia, Abscesses (skin, perianal, liver), Suppurative adenitis, Osteomyelitis, Bacteremia/fungemia, Cellulitis/impetigo

S Inflammatory granuloma formations, especially in hollow organs like lungs, GI and GU tracts OHSUS 30-40% of patients have colitis S Neutrophil Oxidative Burst Assay S Needs a control sample from a healthy un-related adult

S Treatment with prophylactic antibiotics and antifungals OHSU Monogenic IBD

S Rare genetic disorders that produce IBD-like intestinal inflammation and typically present in infancy -> VEO-IBD S Over 60 unique monogenic IBD disorders have been described, including: S Epithelial barrier and response defects (eg, IKBKG, TTC7, ADAM17) S Dysfunction of neutrophil granulocytes (eg, NCF2, NCF4, SLC37A4) S Hyper- and autoinflammatory disorders (eg, XIAP) S Complex defects in T- and B-cell function (eg, LRBA, CD40LG; WAS) OHSUS Regulatory T cells and IL-10 signaling (eg, IL10R, IL10, FOXP3) S Some gene defects affect predominantly hematopoietic cells (IL-10R, IL-10, XIAP, FOXP3), so respond to stem cell transplant IL-10 and IL-10 Receptor Defects

S Interleukin (IL)-10 plays downregulates the inflammatory processes S Inhibits production of proinflammatory cytokines like IL-12 and tumor necrosis factor (TNF) S Controls the growth and differentiation of a variety of cells in the immune system, including T and B cells, natural killer cells, granulocytes, and endothelial cells

S VEO-IBD with severe and progressive colitis, perianal involvement, OHSUextraintestinal manifestations including folliculitis and arthritis S IBD treatments often need to be very aggressive, and still not be sufficient

S Hematopoietic stem cell transplantation has been successful Common Etiologies of Lower GI Bleed based on Age

Newborn Infant Preschool Age School Age (Birth – 1 mth) (1 mth – 2 yr) (2-5 yr) (>5 yr) Necrotizing Anal fissure enterocolitis Hemorrhagic disease Infectious colitis of the newborn Malrotation with volvulus Henoch-Schönlein purpura Hirschsprung disease enterocolitis Polyp Intussusception OHSUInflammatory bowel Allergic proctocolitis Meckel diverticulum disease Lymphonodular hyperplasia

Intussusception

From Walker – Lower Gastrointestinal Bleed Nodular Lymphoid Hyperplasia (NLD)

S Benign condition found in many healthy individuals, especially children. Many consider it a normal finding if there’s no other abnormality

S But also a found in allergic enterocolitis and immunodeficiencies

S Lesions usually located in the , but sometimes in colon or stomach.

S Lesions can thin the mucosa and predispose it to ulceration and OHSUirritation, causing hematochezia S Blood loss is usually minimal and painless, but is present in multiple stools

S Resolves spontaneously over time/age Nodular Lymphoid Hyperplasia (NLD) OHSU Isolated NLD Allergic Colitis

Molnár K, Pintér P, Győrffy H, Cseh &, Müller KE, Arató A, Veres G. Characteristics of allergic colitis in breast-fed infants in the absence of cow’s milk allergy. World J Gastroenterol2013; 19(24): 3824-3830 Nodular Lymphoid Hyperplasia (NLD) OHSU

Duodenum Colon In patient with CVID and Refractory Giardiasis

Jung Hye Choi, et al. Diffuse Nodular Lymphoid Hyperplasia of the Intestine Caused by Common Variable Immunodeficiency and Refractory Giardiasis. Intern Med. 2017;56(3):283-287. Summary

S Growing well with normal stools -> Colic / Reflux

S Responded to hypoallergenic formula -> CMPA / FPIES

S Poor weight gain or mucousy /bloody stools -> CMPA / FPIES

S Bloody diarrhea despite AA formula -> VEO-IBD

OHSUS Diagnosed with VEO-IBD -> Immunodeficiency and Genetic w/u OHSUThank You!