Non–IgE-mediated Gl Food Allergy (FA) Dr. Raga Sirror, MBBS, FRCPC Thunder Bay Regional Health Sciences Centre Pediatrics, Allergy

Conflict of Interest Declaration: Presenter: Dr. Raga Sirror Title of Presentation: Non IgE mediated Gastrointestinal Food Allergy I have no financial or personal relationship related to this presentation to disclose.

Objectives: To identify different types of Non IgE mediated FA. To discuss the management of Non IgE mediated FA. To discuss the possible associations between common GI issues & FA.

History of Food Allergy Hippocrates noted: cow’s milk (CM) caused GI symptoms, as well as urticaria, and that some infants fed CM had diarrhea, vomiting, and FTT that resolved only after removal of CM from their diets Wuthrich B. History of food allergy. Chem Immunol Allergy 2014

Classification of gastrointestinal hypersensitivities to food IgE mediated Mixed Non IgE mediated Immediate GI symptoms Oral Allergy syndrome EoE Eczema Food protein induced allergic proctocolitis (FPIAPC) Food protein enteropathy (FPE) Food protein induced enterocolitis(FPIES)  

Case No.1 2 m old, Frank A. Peter, breastfed with bloody stool. Aside from the diaper, the baby is well. What’s Frank A. Peter diagnosis? FPIAP FPIES FPE You start asking mom about symptoms and checking on growth

Case No.1 2 m old, Frank A. Peter, breastfed with bloody stool. Aside from the diaper, the baby is well. What’s Frank A. Peter diagnosis? FPIAP FPIES FPE You start asking mom about symptoms and checking on growth

Food Protein Induced Allergic Proctocolitis (FPIAP) Clinical presentation: Mucousy, bloody stools in otherwise healthy infant No vomiting No FTT No malabsorbtion Occasional colic or diarrhea Elizur A. et al. Pediatr Allergy Immunol 2012

What is one physical exam you don’t want to miss in an infant with suspected FPIAP?

60% of cases occur in breastfed infants FPIAP Epidemiology: 60% of cases occur in breastfed infants Personal or FHx of atopy is not Mean age: 2 -8 wks,. Food most implicated: CM, soy 20% react to CM & soy or multiple foods Odze RD,et al . Hum Pathol 1993 described as early as first wk

FPIAP Epidemiology (cont’d) A prospective population-based study from Israel, reported CM FPIAP prevalence of 0.16 % in 13,019 infants. Prevalence was much lower when infants were challenged at 3 m after initial presentation Elizur A, Cohen M, Goldberg MR, et al. Pediatr Allergy Immunol. 2012   The best data regarding prevalence Lack of symptom reoccurrence in the majority of infants speaks either to the transience of sensitivity to milk in FPIAP or to the possibility that milk sensitivity did not account for rectal bleeding in these infants.

The symptoms recurred in all cases with reintroduction of CM FPIAP in Children Ravelli et al. reported 16 cases of rectal bleeding in children 2-14 yr; resolved with elimination of CM The symptoms recurred in all cases with reintroduction of CM Endoscopic and histologic findings were consistent with FPIAP Ravelli A et al. Am J Gastroenterol, 2008

Dietary Ag complexed to breast milk IgA → eosinophil activation FPIAP Pathogenesis Largely unknown Dietary Ag complexed to breast milk IgA → eosinophil activation Unknown, partly related to rare scopes performed to dignose. Important piece of diagnosis is to rechallenge after elimintation

Typical presentation and resolution of symptoms with elimination FPIAP Diagnosis: Typical presentation and resolution of symptoms with elimination Rechallenge in 4-8 wks is recommended Endoscopy – generally not needed Patchy erythema, loss of vascularity in rectum, sometimes extending to colon ↑ eosinophils (5-20/hpf) Lozinsky AC,et al. J Pediatr (Rio J). 2014 Unknown, partly related to rare scopes performed to dignose. Important piece of diagnosis is to rechallenge after elimintation

Is Is FPIAP over diagnosed?

The etiology of small and fresh rectal bleeding(RB) in not-sick neonates: should we initially suspect FPIAP? Eur J Pediatr. 2012. Jang HJ1, et al. 16 , not sick neonates with fresh RB 10, satisfied endoscopic findings of FPIAP ECT in cases with over 4 d of persistent RB Only two confirmed as FPIAP by food ECT. In 14 , RB disappeared at 4 (1-8) d idiopathic neonatal transient colitis (INTC). Spontaneusly disappear Endoscopy in all 16, In absence of other etiology We prospectively analyzed neonates with small and fresh rectal bleeding who were clinically normal. We investigated age at symptom onset, feeding at onset of bleeding, the time of bleeding disappearance, stool smear and culture, endoscopic findings, and histopathologies in the biopsy specimens of 16 not-sick neonates. FPIPC should be carefully confirmed through food ECT.

FPIAP Management: Exclusively breastfed: CM should be eliminated from maternal diet first, followed by soy, then egg Clinical bleeding typically clears within 3d after complete elimination, but may take up to 2 wk

Protein hydrolysate formula Soy formula not generally recommended Formula fed:   Protein hydrolysate formula Soy formula not generally recommended 5-10% of infants need to be switched to amino acid based formula Many infants sensitive to both proteins Loose green stools with hydrolysate formula does not generally indicate ongoing FPIAP

Majority resolve by age 12 m Reintroduction, over 3-5 d FPIAP Natural HX Majority resolve by age 12 m Reintroduction, over 3-5 d Some experts- reintroduce at 4-6 m Reintroduction can be done at home If symptoms recur, try in 5-6 m Elizur A, et al. JACI, 2012 Can be done at home May take few days for bleeding to recure Typically, re-challenge with the suspected offending food in FPIAP is not attempted until after 1 year of age [15, 33], although some experts advise 4 to 6 months after elimination, tolerance of the suspected inciting food in a majority of infants 1 to 3 months after diagnosis, clinicians may consider shorter duration of food avoidance.

Case No. 2 5 m old, Fred Pies, previously well, exclusively BF. At 4 m, introduced to CM formula 2 wks after, fed CM formula for 2nd time. 2 h later, he developed repetitive vomiting, looked lethargic, hypotensive Leucocytosis, Methemoglobimemia A full sepsis work-up, toxicology, and metabolic screening were negative He received IV fluids and antibiotics Blood-tinged diarrhea was noted only the first hospital day

What is Fred Pies diagnosis? FPIAP FPIES FPE

What’s Fred Pies diagnosis? FPIAP FPIES FPE

Intermittent exposure or re-exposure after a period of food avoidance Acute FPIES: Intermittent exposure or re-exposure after a period of food avoidance Severe, projectile emesis in 1 to 3 h, +/- diarrhea Pallor, lethargy Hypotension in 15% of reactions Cyanosis Hypothermia Methemoglobinemia may be caused by severe intestinal inflammation and reduced catalase activity resulting in increased nitrites Symptoms typically resolve within two to four hours with standard management

ER doc call Peds. re: an infant with possible septic shock: Hmm, This could be FPIES Allergist, on call for Peds

Chronic FPIES Infants with regular intake of the food, e.g. formula Intermittent, progressive emesis, bloody diarrhea FTT Dehydration

FPIES Supporting lab findings Leukocytosis,↑neutro Thrombocytosis Metabolic acidosis Methemoglobinemia Hypoalbuminemia Anemia Food skin prick test, +ve in 4 to 30% Hypo albumin in chronic Pts with positive skin test, more persistent fpies Methemoglobinemia may be caused by severe intestinal inflammation and reduced catalase activity resulting in increased nitrite, in ~ 1/3 of infants with severe reactions and Symptoms typically resolve within two to four hours with standard management

FPIES Implicated foods CM & soy (present 3 to 6 m) Rice, Oat Chicken, green bean, sweet potato Fish and shellfish FPIES observed in older children and adults Mehr S, et al. Pediatrics 2009 Eggs, corn Children with rice-induced FPIES were more likely to have multiple food sensitivities and severe symptoms requiring intravenous fluid resuscitation

FPIES Implicated foods (cont’d) Multiple food FPIES Up to 50% of pts react to both CM & soy in US studies 65% with CM or soy FPIES develop solid food FPIES 50% infants reacted to >1 grain Nowak-Wegrzyn A, Curr Opin Allergy Clin Immunol 2008;9:371-7 recent publications from a referral pulation in New York and an Israeli cohort report concomitant soy sensitization in 0 to 37 RICE, OAT, BARLEY

Israeli population based cohort: FPIES - Epidemiology Israeli population based cohort: CM FPIES in 0.34% of 13,019 infants (0.5% IgE mediated CMA) in 1st yr of life Slight male predominance 40-80% have FHx of atopy Personal Hx of atopy up to 30% Elizur A, et al. Pediatr Allergy Immunol. 2012

FPIES - Pathophysiology Mostly formula fed infants Immunologic mechanism unclear ? T cell mediated Food allergens may cause local inflammation, subsequent increased intestinal permeability and fluid shift

NIAID-sponsored panel in 2010 advise: FPIES Diagnosis NIAID-sponsored panel in 2010 advise: Diagnosis for FPIES based on typical presenting features, resolution with removal of the offending protein, and reoccurrence of symptoms with OFC OFC is not necessary when Hx is convincing or the reaction was severe Nonspecific symptoms & lack of definitive tests can contribute to the delay in diagnosis. Two typical episodes are needed to establish the definitive diagnosis without the need to perform an oral food challenge.

Management: Acute FPIES (symptoms resolve in hrs) Rehydration IV Methylprednisolone Ondansetron Methylene blue when necessary Food avoidance Epinephrine is not of help Holbrook et al.J Allergy Clin Immunol,2013 Mild symtoms rehydrate at home, if sever symptoms Steroids Based on the presumed inflammatory pathophysiolog

80% respond to hydrolysate formula Management( cont’d) Chronic FPIES Food elimination Sx resolved in 3-10 days 80% respond to hydrolysate formula Soy formula can be introduced under supervision Rechallenge in 1-2 yr in hospital setting Soy formula used to be avoided as an alternative However, recent publications from a referral population in New York and an Israeli cohort report concomitant soy sensitization in 0 to 37, CaubetJC,FordLS,SicklesL,etal.Clinicalfeaturesandresolution of food protein-induced enterocolitis syndrome: 10-year experience. J Allergy Clin Immunol. 2014 Usually not necessary to avoid products with precautionary labeling

Case No. 3: 9 m old, Fae P. Edward, presented with recurrent vomiting, diarrhea, FTT, malabsorption and anemia. Negative celiac screen Endoscopy findings: villous atrophy

What’s Fae P. Edward diagnosis? FPIAP FPIES FPE

What’s Fae P. Edward diagnosis? FPIAP FPIES FPE

What dietary intervention is a risk factor for FPE?

FPE (Food Protein Enteropathy) Most likely to occur in infants fed intact CM prior to 9 m Described following gastroenteritis The prevalence of FPE is obscure Decline in the prevalence is noted Kleinman RE, J Pediatr,19991

FPE Clinical Presentation: Usually induced by CM Diarrhea, emesis, abdominal distension, FTT Distinguishing features from FPIES: Malabsorption with steatorrhea in 80% Lack of acute symptoms Eggs, rice, poultry, fish, or shellfish Malabsorption was due to damage to the jejunal mucosa: Varying villus atrophy was associated with inflammation in surface epithelium and lamina propria not lead to severe dehydration or metabolic de-arrangements that are seen in chronic-FPIES

Overlap with other enteropathies, e.g. celiac FPE Diagnosis Overlap with other enteropathies, e.g. celiac Endoscopy with biopsy to confirm villus injury with a cellular infiltrate Generally resolves spontaneously after age 2 Malabsorption was due to damage to the jejunal mucosa: Varying villus atrophy was associated with inflammation in surface epithelium and lamina propria

FPE Management: Food elimination Symptoms clear in 1-3 wk Rechallenge in 1-2 yr

Common GI Problems & Food Allergy

GERD A subset of infants with GERD can have CM allergy More likely in pts with severe and persistent regurgitation, FTT, and eczema . Distinction between infantile eosinophilic esophagitis (EoE) and GERD may be particularly difficult and requires endoscopy and esophageal biopsies (5% eos

GERD (cont’d) 204 infants diagnosed with GERD based on 24 h pH monitoring and histology CM free diet and two successive blind challenges confirmed CM allergy in 41.8% pts with GERD Giuseppe lacono, et al,Journal of Allergy Clin Immunol. 1996 Group from Italy. gastroesophageal reflux on the basis of 24-hour continuous pH monitoring and histologic examination of the esophageal mucosa.. Clinical history suggested diagnosis of cow's milk allergy in 19 infants, and 93 others had positive test results (serum IgE anti-lactoglobulin, prick tests, circulating or fecal or nasal mucus eosinophils) but did not have symptoms indicating cow's milk allergy

GERD (cont’d) Empiric trial of CM elimination for infants with problematic GERD can be considered Especially, those with gross or occult blood in stool, eczema, or a strong FHx of atopy . Vandenplas Y. Management of paediatric GERD. Nat Rev Gastroenterol Hepatol 2014:

Colic A subgroup of infants with colic can have intolerance to CM Specially, those with bloody stool, vomiting, and eczema The transient nature of colic make the investigations of effect of diet restrictions difficult David J. Pediatrics 2005 transient disorder resolving within few weeks, renders investigations of the effect of restrictive diet particularly difficult

Constipation 10 prospective clinical trials reported a CM protein free diet success rate 28-78% More likely in pts with coexistent atopy More likely to have anal fissures, perianal erythema and/or eczema Caubet et al. Pediatric Allergy and Immunology,2016 Increased anal pressure at rest. similar to FPIAP or FPIES may be involved (21, 176). Allergic inflammation may lead to increased anal pressure at rest and predispose to fecal retention (180). However, the potential effect of CM could also be explained by non-specific mechanisms that lead to change in stool consistency Allergic inflammation of the IS due to mucosal eoso & mast cells

Constipation and cow’s milk allergy: a review of the literature Miceli Sopo S, et al. Int Arch Allergy Immunol. 2014 “We believe that a CM-free diet for 2-4 wk should be proposed for children with chronic functional constipation, even if it is not severe or resistant to laxatives”

Thank you Comments, Questions?