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

2. 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.

3. 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.

4. 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

5. 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)

6. 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

7. 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

8. 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

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

10. 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

11. 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.

12. 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

13. 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

14. 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

15. Is Is FPIAP over diagnosed?

16. The etiology of small and fresh rectal bleeding(RB) in not-sick neonates: should we initially suspect FPIAP?
Eur J Pediatr 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.

17. 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

18. 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

19. 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.

21. 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

22. What is Fred Pies diagnosis? FPIAP FPIES FPE

23. What’s Fred Pies diagnosis? FPIAP FPIES FPE

24. 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

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

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

27. 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

28. 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

29. 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

30. 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

31. 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

32. 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.

33. 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

34. 80% respond to hydrolysate formula
Management( cont’d)
Chronic FPIES
Food elimination
Sx resolved in 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

36. 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

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

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

39. What dietary intervention is a risk factor for FPE?

40. 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

41. 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

42. 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

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

44. Common GI Problems & Food Allergy

45. 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

46. 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

47. 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:

48. 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

49. 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

50. 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”

52. Thank you Comments, Questions?