Cow's milk protein allergy

What’s New in the Diagnosis and Management of Cow’s Milk Protein Allergy.
Distinguish IgE and non-IgE mediated aspects of cow’s milk allergy (CMA).
Review the clinical effects of formula in infants with CMA

1. بسم الله الرحمن الرحيم

2. بسم الله الرحمن الرحيم سورة البقرة الآية 32 صدق الله العظيم قالوا سبحانك لا علم لنا إلا ما علمتنا إنك أنت العليم الحكيم

3. COW MILK PROTEIN ALLERGY Professor Khaled Saad, MD, MSc, PhD

4. Cow milk Protein allergy n transfer into human breast milk (19).

5. Agenda What’s New in the Diagnosis and Management of Cow’s Milk Protein Allergy. Distinguish IgE and non-IgE mediated aspects of cow’s milk allergy (CMA). Review the clinical effects of formula in infants with CMA

6. Case 1 Vital Stats Girl 3 months old Length 50th percentile Weight 40th percentile Reason for visit Spitting up and irritability CMA-related symptoms Spitting up large volumes, irritability, seborrhea Other medical history/ family history None Current formula AR formula Feeding history Breastmilk for 1 month, cow’s milk formula thereafter Medications Proton pump inhibitor Birth history Uncomplicated term delivery Other considerations Normal bowel movements

7. Vital Stats Boy 4 months old Length 30th per-centile Weight 3rd per-centile Case 2 Reason for visit Ongoing blood and mucus in stools History Poor growth CMA-related symptoms Loose stools, mucus in stools, blood streaks in stools, poor weight gain Other medical history/ family history Older sister: allergy to egg Mother: asthma Current formula Intact cow’s milk–based, lactose-free formula Feeding history Began on routine formula, Then switched to intact cow’s milk–based, lactose-free formula Medications Simethicone Birth history Uncomplicated term delivery Other considerations Gassiness t.

8. Background

9. BREAST MILK Human breast milk contains IGs , antimicrobial enzymes. It also contains anti-inflammatory and tolerance-promoting compounds, such as IL-10. Exclusive breastfeeding for at least 3 to 4 months of age is associated with a reduced risk of atopy and lowered incidence of recurrent wheezing during the first 2 years of life.

10. BREAST FEEDING… MAMA!!

11. CMA is the most common food allergy of young children, affecting 2-6 % of infants. It results from an immunological reaction to one or more milk proteins. CMA may be immunoglobulin E (IgE) or non-IgE mediated, the involvement of two systems increases the probability of CMA. ESPAGHAN Guidelines for CMPA

12. Cow’s Milk Allergy (CMA): Key Concepts *The use of cow’s milk as a beverage probably began around 9000 years ago with the domestication of cattle. *US consumption is around 88 liter/ person/year. *As milk consumption increases, especially among infants, there is greater scope for adverse reactions. This may include behaviors such as:  

13. Classification of Adverse Reactions to Food

14. Adverse Reaction to Food Enzymatic Pharmacologic Other Nontoxic Toxic Non-Immune–Mediated Reaction 1,2 (Food Intolerance) Due to lack of particular enzyme Due to components of the food Immediate food allergy Oral allergy Food protein enteropathies Eosinophilic gastroenteropathies IgE-mediated Non-IgE mediated (e.g., T cell–mediated) Immune-Mediated Reaction 1-3 (Food Allergy) Neurologic IgE=immunoglobulin E. 1. Burks AW, et al. Pediatrics. 2011;128(5):955-965. 2. Burks AW, et al. J Allergy Clin Immunol. 2012;129(4):906-920. 3. Spergel JM. Allergy Asthma Clin Immunol . 2006;2(2):78-85.

15. Impact of Food Allergies Direct medical costs to the US health care system of $4.3 billion annually for childhood food allergies include clinician visits, emergency department visits, and hospitalization. Costs borne by the family of $20.5 billion annually for childhood food allergies. Quality of life decreased in UK, North American, European, and Asian studies. Risk of compromised nutrition. Long-term impact on feeding behaviors and risk of fatal reaction.

16. Family History and Physical Examination During Early Diagnosis Key observations for diagnosis: Learn about personal and family history of allergic disease. Identify and create a list of suspected foods. Document the precise description of reactions.

17. Family History and Physical Examination During Early Diagnosis Key symptoms to watch for during a physical examination: Cutaneous: Flushing, angioedema, and eczema GIT: Oropharyngeal pruritus and edema, abdominal cramping, nausea, vomiting, and diarrhea Pulmonary: Rhinorrhea, laryngeal edema, wheezing, coughing and shortness of breath Cardiovascular: Hypotension, tachycardia, and arrhythmias Behavioral: Irritability (preceding or in combination with other symptoms)

18. Gastrointestinal Manifestations Associated With Non-IgE–mediated Food Allergy 1. Eosinophilic esophagitis, GE 1,2 : Postprandial vomiting, anorexia, abdominal distention, steatorrhea, failure to thrive, weight loss, food impaction, and gastric outlet obstruction 2. Dietary protein enteropathy 2 : Diarrhea, failure to thrive, abdominal distention, and malabsorption, less frequent anemia, edema, and hypoproteinemia 3. Dietary protein enterocolitis 2 : Vomiting and diarrhea 4. Dietary protein proctocolitis 2 : Gross blood in stool + other symptoms 5. Celiac disease 1 : Diarrhea, steatorrhea, malabsorption, abdominal distention, flatulence, + nausea and vomiting, failure to thrive, oral ulcers, dermatitis herpetiformis Spergel JM. Allergy Asthma Clin Immunol . 2006;2(2):78-85. Burks AW, et al. J Allergy Clin Immunol . 2012;129(4):906-920.

19. Description of Allergic Reactions: Key items to note during an early diagnosis 1,2 : Timing of onset in relation to food ingestion. Symptoms, their severity and duration of reaction. Treatment of reaction. Reappearance of reactions after ingestion of suspected food Most recent reaction. 1. Sampson HA. J Allergy Clin Immunol . 1999;103(6):981-989. 2. Sampson HA et al. J Allergy Clin Immunol. 2014;134(5):1016-1025.e40.

20. Quick onset 1-3 Anaphylaxis, etc 1-3 Well-defined mechanism 1 Easier to diagnose 1 Validated tests 1-3,a Delayed onset 1-3 Eczema, reflux, etc 2 Mechanism unclear 2 Harder to diagnose 2 No validated tests 1,2 IgE Non- IgE a Not in infants. Burks AW, et al. J Allergy Clin Immunol. 2012;129(4):906-920. Burks AW, et al. Pediatrics. 2011;128(5):955-965. Wang J, Sampson HA. J Clin Invest. 2011;121(3):827-835 . IgE-Mediated Versus Non-IgE–Mediated Reactions

21. Burks AW, et al. Pediatrics. 2011;128(5):955-965. Sicherer SH, et al. Pediatrics. 2012;129(1):193-197. Quick onset : 20 minutes (but up to 2 hours) after food ingestion Reproducible Specific symptoms: urticaria, angioedema, rhinorrhoea, diarrhoea, vomiting Specific foods Positive tests Features of IgE-Mediated Allergy

22. Eosinophilic gastroenteropathies Food protein–induced proctocolitis Food protein–induced enteropathy Food protein–induced enterocolitis Eczema Reflux,colic Constipation Burks AW, et al. J Allergy Clin Immunol . 2012;129(4):906-920. Burks AW, et al. Pediatrics . 2011;128(5):955-965. Some Non-IgE–Mediated Reactions

23. Differential diagnosis

24. Most commercially available cow's milk contains two types of beta-casein: A1 and A2 types. Digestion of A1 type yield the peptide beta-casomorphin-7, which has been implicated in adverse gastrointestinal effects of milk consumption, similar to those in lactose intolerance

25. Milk Allergy Lactose Intolerance Cause An allergic reaction to the protein in milk and milk products A negative reaction to the sugar in milk and milk products. Symptoms Persistent diarrhea, Vomiting, Skin Rashes, Extreme fussiness, Low or no weight gain, Gassiness, Wheezing Bloating Gassiness Diarrhea Age of Onset First few weeks or months of life (usually not after age 2), Symptoms usually resolve at age 3 or 4. Can develop at any age, but usually not in infants, Usually does not go away. Treatment If the infant is breastfed: Mothers should remove all milk proteins from their diet. If the infant is bottle fed: Switch to a hypoallergenic amino acid-based formula . Avoid products with lactose Some amount of lactose may be tolerated by most persons.

26. COMISS score

27. COMISS Score Algorithm

28. What Factors May Help Explain an Increase in Food Allergy Prevalence? Changes in Diet Vitamin D: An association between low Vitamin D levels and increased risk of food allergy. Obesity: Obesity is associated with an inflammatory state; mostly studied in asthma Dietary Fat: Despite the earlier results, recent meta-analysis found no clear evidence to support the use of Omega 3 and Omega 6 fatty acids for the primary prevention of atopic allergic disease development or sensitization Hygiene Hypothesis: Lack of exposure to infectious agents and gut flora increases susceptibility to allergic diseases; limited data for FA, except for mild effect of cesarean delivery

29. Hygiene Hypothesis

30. Symptoms of Cow’s Milk Protein Allergy Can Mimic GERD in Infants Recent American Academy of Pediatrics (AAP) guidelines for the management of gastroesophageal reflux recognize that cow’s milk protein allergy may have a clinical presentation that mimics GERD in infants AAP treatment algorithm (2013) for recurrent regurgitation and weight loss Lightdale JR, et al . Pediatrics. 2013;131(5):e1684-e1695. Algorithm used with permission of American Academy of Pediatrics. Education Close follow-up 12 Improved? 11 No Yes Consider: Hospitalization: Observe parent/child interaction Consider: NG or NJ tube feedings Consultation with Pediatric GI Consider: Acid suppression therapy and/or prokinetics 13 Education Close follow-up 6 Evaluate further 4 Adequate calorie intake? 5 Are there warning signs? 3 No Yes No Yes CBC, U/A, electrolytes, creatinine, urea, celiac screen (> 6 months) Consider: Upper GI series 7 History and physical examination 2 Vomiting/regurgitation and poor weight gain 1 Manage accordingly 9 Abnormal? 8 No Yes Dietary Management: Maternal exclusion diet in breastfed infants (Protein/hydrolysate formula in formula-fed infants) Thickened feedings Increased caloric density 10 Accordingly , AAP recommends the following dietary modifications as a first-line approach to reflux management: Exclusion of cow’s milk and eggs from the diet of mothers who breast-feed their infants Protein hydrolysate formula in formula-fed infants Thickened feeding

31. DIAGNOSTIC PROCEDURES

32. The first step is a thorough history and physical examination. In most cases with suspected CMA, the diagnosis needs to be confirmed or excluded by an allergen elimination and challenge procedure. DIAGNOSTIC PROCEDURES

33. DIAGNOSTIC PROCEDURES Children with gastrointestinal manifestations of CMA are more likely to have negative specific IgE test results compared with patients with skin manifestations. Specific IgG Antibodies or Determination of IgG antibodies or IgG subclass antibodies against CMP has no role in diagnosing CMPA & not recommended.

34. Food Allergy Management Current management of food allergy includes PHARMACOTHERAPY (in case of accidental exposure to the antigen) STRICT ALLERGEN AVOIDANCE (exclusion diet) Chapman JA, et al. Ann Allergy Asthma Immunol . 2006;96(suppl):S1-S68.

35. Milk for atopic babies

36. The Long-term Effect of Nutritional Intervention With Hydrolysate Infant Formulas on Allergy in High-risk Children—The German Infant Nutrition Intervention (GINI) Study GINI was a study of 2,252 infants at high risk for atopy, enrolled at birth and followed through 10 years Infants randomized at birth to receive 1 of 4 formulas: an intact cow’s milk formula or 1 of 3 hydrolyzed formulas: pHF -W, eHF -W, eHF -C Strict intervention period as substitute for breast milk was 4 months to avoid modification of formula effect by solid foods Follow-up at 10 years with ISAAC questionnaire and invitation to study center for examination and blood sampling. eHF -C=extensively hydrolyzed casein formula; eHF -W=extensively hydrolyzed whey formula; ISAAC=International Study of Asthma and Allergies in Childhood; pHF -W=partially hydrolyzed whey formula. von Berg A et al. J Allergy Clin Immunol. 2013;131(6):1565-1573.

37. The GINI Study—10 Year Analysis 2 key takeaway points from the GINI study: Feeding with the pHF -W and eHF -C formulas in the first 4 months has a positive effect on cumulative incidence of atopic eczema/dermatitis in high-risk children, lasting until 10 years However, feeding cow’s milk protein hydrolysate formulas compared with cow’s milk formula has neither a positive effect on asthma and allergic rhinitis nor such an effect on allergic sensitization Physician diagnosed eczema [adj. %] Adjusted cumulative incidence of parent-reported physician-diagnosed eczema 45 40 35 30 25 20 15 10 9 8 7 6 1 2 3 4 5 6 7 8 9 10 Age [years] pHF-W eHF-C eHF-W CMF CMF=standard cow’s milk formula; eHF-C=extensively hydrolyzed casein formula; eHF-W=extensively hydrolyzed whey formula; pHF-W=partially hydrolyzed whey formula. Reprinted from J Allergy Clin Immunol . 2013;131(6):1565-1573. Von Berg A et al. Allergies in high-risk schoolchildren after early intervention with cow’s milk protein hydrolysates: 10-year results from the German Infant Nutritional Intervention (GINI) study. ©2013, with permission from Elsevier. Overall Study Conclusion: These results support the use of cow’s milk protein hydrolysate infant formula in high-risk infants to reduce the risk for atopic eczema but not for respiratory allergies

38. Babies at high risk for developing allergy First degree relatives with either : Food allergy Asthma OR moderate to severe atopic dermatitis (AD).

39. MANAGEMENT

40. What is the key to CMPA ?

41. Allergy march is a worldwide problem. Be proactive in preventing allergic diseases in infants and children rather than treating a current condition. Breast milk is the gold standard for feeding babies , either atopic or non atopic. Clinical Practice Treatment

42. Human milk is the optimal source of nutrition for term infants during the first 6 months of life. There is no evidence to support administration of a hydrolyzed formula, in preference to exclusive breastfeeding, to prevent allergy.

43. To prevent allergic diseases in high risk infants, who cannot be exclusively breastfed, an extensively hydrolyzed formula, in preference to a conventional cow's milk or soy protein formula can be offered.

44. Those breastfeeding infants who develop symptoms of food allergy may benefit from: a) maternal restriction of cow’s milk, egg, fish, peanuts and tree nuts and if this is unsuccessful, b) use of a hypoallergenic (extensively hydrolyzed or if allergic symptoms persist, a free amino acid-based formula) as an alternative to breastfeeding. Clinical Practice Treatment

45. Those infants with IgE-associated symptoms of allergy may benefit from a soy formula, either as the initial treatment or instituted after 6 months of age after the use of a hypoallergenic formula. Concomitant allergy to soy and cow’s milk in these infants is lower compared with those with non–IgE-associated syndromes such as enterocolitis, proctocolitis, malabsorption syndrome, or esophagitis. Benefits should be seen within 2 to 4 weeks and the formula continued until the infant is 1 year of age or older. Clinical Practice Treatment

46. Hydrolysed Formulas ALLERGENICITY Intact protein Partial hydrolysis Extensive hydrolysis Aminoacids TOLERANCE COST Palatability

47. MW ALLERNOVA CMA/ Nutramigen <1000 Da 82% 70% 1000-<2000 Da 15.6% 15% 2000-5000 Da 2.4% 15% COMPARISON OF EHF (EXTENSIVELY HYDROLYZED FORMULA)

48. Allernova : Double Mode of Action

49. Evaluation of an Amino Acid−Based Formula in Infants Not Responding to Extensively Hydrolyzed Protein Formula J Pediatr Gastroenterol Nutr . 2016 Nov; 63(5): 531–533.

50. Recommended management of CMPA includes the initiation of an extensive HF. Although 90% of infants exhibit healthy growth and reduced allergic symptoms on an EHF, 10% of infants with CMPA still react to the residual allergens in EHF. ESPGHAN guidelines indicate that the risk to react to EHF may be higher in the presence of severe enteropathy or with multiple food allergies. For that reason, AAF is considered as first-line treatment in infants who fail to thrive, suffer from macronutrients deficiencies and other life-threatening symptoms.

51. In a prospective, controlled study, atopic infants with CMPA receiving an AAF for 6 months demonstrated clinical improvement and proper growth compared with infants fed an EHF. In another study, data suggested that AAFs improved the gut barrier function and minimized GIT complications in atopic infants and improved long-term allergy management.

52. AMINOVA is the first thickened AAF for the dietary management of Severe CMPA & Allergy to EHF

53. Safety of a New Amino Acid Formula in Infants Allergic to Cow's Milk and Intolerant to Hydrolysates The 1st HEAD TO HEAD RCT study comparing Aminova and Neocate in the management of severe CMPA (Dupont et. al) ( JPGN 2015;61: 456–463)

54. Proven Efficiency

55. GERD

56. Taste acceptance

57. Parents satisfaction

58. Side effects of old AAF: Hypophastatemia Aktar et. al. 2019 Rickets/ fractures in 94% with High alkaline Phosphatase, low phosphate. Corrected with a change in phosphate supplement Creo et. al. 2018 Rickets/fractures after median (range) of 8mo. (3-15mo.) High alkaline Phosphatase, low phosphate. Corrected with phosphate supplement

59. Side effects of old AAF: Hypophastatemia Uday et. al. 2019 Children either on neocate , elecare , Showed Rickets/fractures in 23% with High alkaline Phosphatase, low phosphate. Corrected with a change in formula/phosphate supplement. These problems solved in new AAF Aminova with adjusted Ca++ to Phosphate ratio.

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