Cows Milk Protein Allergy (CMPA) Road to Management

Cows Milk Protein Allergy (CMPA) Road to Management

Dedication JNMC SGPGIMS Late Dr S K BHATNAGAR

Learning Objectives Understand CMPA and its different types
Discuss epidemiology, risk factors, and immunopathogenesis of CMPA Food Allergy and CMPA: An Overview Understand clinical evaluation and diagnostic procedures for CMPA Describe different strategies to prevent CMPA Discuss general principles for the management of CMPS Diagnosis, Prevention, and Management of CMPA Learning objectives of this presentation include: Understand cow’s milk protein allergy and its different types Discuss the epidemiology, risk factors, and immunopathogenesis of cow’s milk protein allergy Understand the clinical evaluation and diagnostic procedures for cow’s milk protein allergy Describe different strategies to prevent cow’s milk protein allergy Discuss general principles for the management of cow’s milk protein allergy Understand the types of lactose intolerance and their pathophysiology Discuss the signs and symptoms and differential diagnosis of lactose intolerance Describe nutritional interventions for the management of lactose intolerance CMPA: Cow’s milk protein allergy

Case presentation I

14 months/Boy Multiple courses of antibiotics including ATT VPIMS
No history of Fever Edema Rec. resp or skin infections Blood transfusions Hospitalization Blood/mucus in stools Development: normal Immunized for age BCG scar + Diarrhea 8-10 times/day, watery, large volume 4 mo 6 mo 10 mo 14 mo

Family History Bronchial asthma No Consanguinity No family h/o
TB, IBD, Recurrent infections

Dietary history Cow’s milk - undiluted Exclusively
VPIMS Cow’s milk - undiluted Exclusively Breast Fed Dal ,Daliya ,biscuits mashed fruits 4 mo 6 mo 10 mo 14 mo

No signs water/ fat soluble vitamin def.
Examination Weight: 9.5 Kg Height: 78 cm Pallor + No icterus ,clubbing, edema No signs water/ fat soluble vitamin def. P/A: No organomegaly PR: normal Other systems: normal

Diarrhea Anemia Problems 14 months old Watery Blood Large volume Mucus
Small Bowel Large bowel Diarrhea Anemia +

Possibilities CMPA IBD – Crohn’s Large and small bowel involvement
No Failure to thrive CMPA f/h/o allergy , asthma Coinciding with introduction of cow’s milk Immunodeficiency No other systemic infections

Work-up Hb: 9.4 g/dL ( ) TLC: 8,300/mm3 N-58% L-28% E-8% M-8%
Absolute eosinophil count: 660/mm3 ( ) Platelet: 2,23,000/mm3 ESR: 5 mm/ 1st hr S.Alkaline phosphate:749 U/L ( ) S. Calcium: 8.6 mg/dl S. Phosphorus: 4mg/dl

Proctosigmoidoscopy Apthous ulcers

Histopathology: Rectal Biopsy
Eosinophils

Cow’s milk protein allergy
Colitis (bloody diarrhea) Family history of asthma Cow’s milk protein allergy Aphthous ulcers on proctosigmoidoscopy 12 eos/HPF in the rectal Bx

Adverse Food Reactions (any untoward reaction after ingestion of a food)
Toxic Non- toxic Food Intolerance** (Non Immune mediated) Food Allergy (Immune mediated) **(MC adverse food reaction) Enzymatic Pharmacological Idiopathic IgE Mediated Non IgE Mediated

Typical Symptoms Associated With IgE- and Non-IgE-mediated Reactions
IgE-mediated Symptoms Urticaria Angioedema Vomiting Diarrhea Eczema Rhinitis Anaphylaxis Non-IgE-mediated Symptoms Gastroesophageal reflux Constipation Malabsorption Villous atrophy Eosinophilic proctocolitis Enterocolitis Typical immunoglobulin E reactions include urticaria, angioedema, vomiting, diarrhea, eczema, rhinitis, and anaphylaxis. Non-immunoglobulin E-mediated reactions include gastroesophageal reflux, vomiting, constipation, malabsorption, villous atrophy, eosinophilic proctocolitis, and enterocolitis. Reference Vandenplas Y, Abuabat A, Al-Hammadi S, et al. Middle east consensus statement on the prevention, diagnosis, and management of cow’s milk protein allergy. Pediatr Gastroenterol Hepatol Nutr. 2014;17(2):61–73.(p.62,66) IgE: Immunoglobulin E Vandenplas Y, et al. Pediatr Gastroenterol Hepatol Nutr. 2014;17(2):61–73.

Lactose intolerance is same as CMPA
Myth 1 Lactose intolerance is same as CMPA

Lactose intolerance Case 6 months old Top fed
Watery diarrhea, Colic, passing excessive flatulence, perianal excoriation , Acidic stools , reducing substance in the stools Lactose intolerance

Stool reducing substance > 0.5 gm% (++) – 32 %
Stool pH < 5 – 10%, < % Treat lactose intolerance only if above associated with severe diarrhea Lactose free is not synonymous as Soya (Trace – 100 mg%, mg%, mg%, 4+ - > 1gm%)

Lactose intolerance is same as CMPA
Myth 1 Lactose intolerance is same as CMPA Both are entirely different entities CMPA being immune mediated requiring complete avoidance of milk and milk products for varying duration Lactose intolerance is non-immune mediated (enzymatic) and is transient.

Lactose intolerance vs. CMPA
Congenital or acquired absence of lactase enzyme Usually it is secondary to insult to intestine after an episode of acute gastroenteritis Presentation is profuse watery diarrhea > 14 days duration It responds to reduction of lactose load in 90% cases and only 10 % cases require total withdrawal Milk products are allowed Treatment for 2-4 weeks is sufficient Lactose free diet works CMPA is allergic reaction to milk protein of animal source 1-3 months after introduction It present as proctocolitis, colitis or gastroenteritis Usually, Bleed PR and diarrhea Treatment include complete avoidance of animal milk & milk products Milk products also not allowed Treatment for at least 1 yr post diagnosis or till age of 2 yrs whichever is older All or none phenomenon

What makes CMPA challenging ?

Myth 2 Diagnosis can be made by atopy patch test, Total IgE and intradermal tests.

Myth 2 Diagnosis can be made by atopy patch test, Total IgE and intradermal tests. Atopy patch test : No agreement on standardization about the preparation and application of antigen Subjective nature. Total IgE : Not included diagnostic workup of CMPA. Nor the ratio of specific IgE to total IgE offers a benefit over specific IgE alone Boyce et al J Allergy Clin Immunol 2010;126:S1–58. Mehl et al Allergy 2005;60:1034–9.

Myth 2 Diagnosis can be made by atopy patch test, Total IgE and intradermal tests. Determination of IgG antibodies or IgG subclass antibodies against CMP : No role in diagnosing CMPA Serum IgE against whole milk/ specific milk protein by RAST has role. Intradermal testing not recommended. gold standard Double blind placebo controlled food challenge Boyce et al J Allergy Clin Immunol 2010;126:S1–58 Vanto et al:Allergy 1999,54,

Oral Food Challenge Test: ESPGHAN/NASPGHAN Guideline Recommendations
Confirm the diagnosis of CMPA by an elimination diet followed by oral challenge test Two common procedures: Open challenge and DBPCFC Type of milk for oral challenge Dose of milk for oral challenge Age <1 year: Formula based on cow’s milk Age >1 year: Fresh pasteurized cow’s milk Age >3 years: Lactose-free milk containing cow’s milk protein Initial dose should be lower than that causing allergy, with a gradual increase up to 100 mL If no allergic reactions, at least 200 mL milk to be consumed daily for two weeks CMPA is excluded and no elimination diet is needed No allergic symptoms CMPA is confirmed; prescribe therapeutic elimination diet Objective symptoms and positive for specific IgE Perform DBPCFC to reduce bias Uncertain symptoms and moderate-to-severe eczema Even when a significant improvement is documented with the elimination diet, the diagnosis of CMPA needs be confirmed by conducting a standardized oral challenge test. The clinical assessment with elimination diet and challenge within four weeks is the fundamental basis for an accurate diagnosis of CMP. This test can be carried out in either inpatient or outpatient settings, where documentation of symptoms, recording of the milk volume that elicits symptoms, and provision of symptomatic treatment if required are possible. Two common procedures for oral challenge test include open challenge and double-blind, placebo-controlled food challenge. A blinded study is the reference standard and the accurate test for diagnosis of CMPA, but it is expensive and time-consuming. An open challenge is usually the first step, if there is a low probability of a reaction. For infants, the challenge test is performed with infant formula based on cow’s milk. For children over one year, fresh pasteurized cow’s milk may be used. For children over three years, lactose-free milk containing cow’s milk protein can be used to rule out lactose intolerance. The initial dose of the milk for the oral challenge test should be less than the quantity that can induce an allergic reaction. Gradually the dose is increased up to 100 mL. In children with severe reactions, doses may be started by 0.1 mL and progressed further at 30-minute intervals. When the child shows tolerance with no allergic reactions, at least 200 mL milk has to be consumed at home everyday for two weeks. If no symptoms are reported within two weeks, CMPA can be excluded and the elimination diet is no longer required. If the patient has objective symptoms and is positive for specific IgE, then CMPA is confirmed and a therapeutic elimination diet is prescribed. Reference Koletzko S, Niggemann B, Arato A, et al. Diagnostic approach and management of cow’s milk protein allergy in infants and children: ESPGHAN GI committee practical guidelines. JPGN. 2012;55:221–229.(p.224,225) CMPA: Cow’s milk protein allergy; DBPCFC: Double-blind, placebo-controlled food challenge. Koletzko S, et al. JPGN. 2012;55:221–229.

A disease entity seen in western children alone.
Myth 3 A disease entity seen in western children alone.

A disease entity seen in western children alone.
Myth 3 A disease entity seen in western children alone. In the west, it’s prevalence is 2–5%. Cause of malabsorption in 13% children below 2 years of age. Accounts for chronic diarrhea among 30-35% of children in less than 5 yr of age. Indian data Yachha et al Ind J Gast 1993;12:120-5 Poddar et al JGH Oct 2009 Poddar et al J Trop Pediatr Jun

DR J.R.SRIVASTAVA AWARD at UP Pedicon 2011
Chronic Diarrhea In Children: An Etiological Spectrum In The State Of Uttar Pradesh Int J Contemp Pediatr. 2014; 1(1): Received DR J.R.SRIVASTAVA AWARD at UP Pedicon 2011 Authors Dr Shrish Bhatnagar, Dr Romesh Gauttam

Spectrum

Comparatively etiological profile of chronic diarrhea
< 3 YRS > 3 YRS

Onset of cow milk allergy can occur after 5 yr of age.
Myth 4 Onset of cow milk allergy can occur after 5 yr of age.

Myth 4 Onset of cow milk allergy can occur after 5 yr of age. Almost always CMPA onset is seen in the first few years of life - majority in the 1st year. Debut of CMPA after 12 months of age is extremely rare. In 2 - 6% of children it’s onset is seen in <3 yrs. of age and it’s prevalence falls to <1% in children 6 years of age and older. The prognosis for CMPA in infancy and young childhood is good. Sicherer et al. J Allergy Clin Immunol 2011;127:594–602.

Rechallenged at 1 year and if positive, every 6m till 3y
N=1749 newborns 1995 Rechallenged at 1 year and if positive, every 6m till 3y Foll till 1 year for CMPA Høst et al ped allergy and immunology 2002:13(suppl 15):23-28

Myth 4 Onset of cow milk allergy can occur after 5 yr of age. Inappropriate or overly long dietary eliminations should be avoided. Such restrictions : Impair the quality of life of both child and family, Induce improper growth, and Incur unnecessary health care costs. Sicherer et al. J Allergy Clin Immunol 2011;127:594–602.

Milk from other animal sources can be given in a child with CMPA.
Myth 5 Milk from other animal sources can be given in a child with CMPA. Cross-reactivity is present among milk proteins obtained from cows, goats and sheep. Strong structural homology between milk proteins from different mammals. Only the whey fraction in the goat's milk differs from that in the cow's milk. Goat's milk is tolerated by only 40% of children who are allergic to cow's milk. All animal milk are to be avoided Bellioni et al J Allergy Clin Immunol. 1999;103:1191–1194

General Principles for Management of CMPA
Dietary elimination of CMP and replacement with hypoallergenic or soy formula Maternal CMP elimination The key principles in the management of cow’s milk protein allergy are the dietary elimination of CMP and replacement with a hypoallergenic or soy formula and maternal CMP elimination. Maternal CMP elimination may be beneficial because breast milk can contain intact cow’s milk antigen. Reference Allen K, Davidson G, Day A et al. Management of cow’s milk protein allergy in infants and young children: An expert panel perspective. Journal of Paediatrics and Child Health. 2009; (45):481–486 CMPA: Cow’s milk protein allergy Allen K, Davidson G, Day A et al. Journal of Paediatrics and Child Health. 2009; (45):481–486

Case scenario- 2 3 month old infant c/o visible specks of blood with mucus. Exclusively breast fed Non sick baby, wt gain acceptable Stool examination – Blood present What next?

Case scenario-3 Not otherwise pale, growth satisfactory
11 month old infant with on and off minor blood mixed with loose stools for 4 months. Not otherwise pale, growth satisfactory Diet – On cows milk at onset, changed to lactose free soya milk, multiple antibiotics, NO RESPONSE

Nutritional Interventions for Management of CMPA
Continued breastfeeding is the best treatment and mothers should avoid all dairy products in their diet1,2 Reassessment of maternal diet if symptoms are not resolved3 Egg, corn, and rice in maternal diet may also cause allergy in rare cases3 Infants may become normal only after a hypoallergenic formula or diet is initiated3 Iron deficiency anemia and Calcium deficiency should be considered in infants with long-term symptoms3 The common treatment strategy currently followed for cow’s milk protein allergy is the strict avoidance of cow’s milk protein in the diet.1 Continued breastfeeding is the best treatment for infants with cow’s milk protein allergy; however, mothers should be advised to avoid all dairy products in their diet.2 In some breastfed infants, the symptoms do not resolve despite maternal elimination of milk. In such cases, a thorough reassessment of maternal diet should be performed. Rarely, solid foods such as egg, corn, and rice may also cause allergy in this population. Some infants may become normal only after a hypoallergenic formula or diet is initiated. If there are long-term symptoms, assessment of iron levels may provide information about the incidence of anemia in infants.3 References Koletzko S, Niggemann B, Arato A, et al. Diagnostic approach and management of cow’s milk protein allergy in infants and children: ESPGHAN GI committee practical guidelines. JPGN. 2012;55:221–229.(p.224) Vandenplas Y, DeGreef E, Devreker T. Treatment of cow’s milk protein allergy. Pediatr Gastroenterol Hepatol Nutr. 2014;17(1):1–5.(p.3) Groetch M, Henry M, Feuling MB, et al. Guidance for the nutrition management of gastrointestinal allergy in pediatrics. J Allergy Clin Immunol: In Practice 2013;1:323–31.(p.326) Cow’s milk is hydrolyzed to eliminate allergenic epitopes of milk proteins that cause CMPA2 Koletzko S, et al. JPGN. 2012;55:221–229. Vandenplas Y, et al. Pediatr Gastroenterol Hepatol Nutr. 2014;17(1):1–5. Groetch M, et al. J Allergy Clin Immunol: In Practice 2013;1:323–331.

Alternatives to Cow’s Milk-based Formulae
Alternatives to cow’s milk-based products pHF AAF eHF with casein or whey Partially or extensively hydrolyzed rice formula Soy formula and soy hydrolyzed formula Partially hydrolyzed and extensively hydrolyzed formulas are available as alternative to cow’s milk formula. Further, amino acid formula is used to overcome sensitive reactions that may arise due to the presence of residual proteins in eHF. In amino acid formula and eHF, the allergenicity is completely removed and hence it is believed that they cannot induce oral tolerance. So, they are used for the treatment of CMPA and not commonly used for CMPA prevention. Rice hydrolysates and soy formulas are also found to be safe alternatives for the treatment of CMPA. Other mammalian milks are generally not indicated for the treatment of CMPA as they are nutritionally inadequate and have cross-reactivity with cow’s milk protein.2 Let us discuss clinical evidence on the role of a few of these alternatives in children with CMPA. Reference Vandenplas Y, DeGreef E, Devreker T. Treatment of cow’s milk protein allergy. Pediatr Gastroenterol Hepatol Nutr. 2014;17(1):1–5.(p.3) AAF: amino acid formula; eHF: extensively hydrolyzed formula; pHF: partially hydrolyzed formula Vandenplas Y, DeGreef E, Devreker T. Pediatr Gastroenterol Hepatol Nutr. 2014;17(1):1–5.(p.3)

Soy Formula Approximately 25% infants in the USA are fed SIF at some point in their first year of life (AAP 2008)1 Concern over genistein content of soya formulas is due to their potential negative effects on sexual development and reproduction, neurobehavioral development, immune function, and thyroid function1 AAP: Literature reviews and clinical studies of infants fed SIF raise no clinical concerns with respect to nutritional adequacy, sexual development, thyroid disease, immune function, or neurodevelopment1 Approximately 25% infants in the USA are fed soya-based infant formulas (SIF) at some point in their first year of life. Soya is a product of the Asian plant, Glycine max, and used as a lactose-free option in the management of lactose intolerance. Phyto-estrogens (isoflavones) content in SIF is about 32–47 mg/L of isoflavones, whereas the mother's milk contains only 1–10 μg/L. The three main aglycones found in SIF are genistein, daidzein, and glycitein. The presence of genistein is of concern to many due to its potential negative effects on sexual development and reproduction, neurobehavioral development, immune function, and thyroid function. 1 According to the American Academy of Pediatrics, literature reviews and clinical studies of infants fed SIF do not have any clinical concerns in nutritional adequacy, sexual development, thyroid disease, immune function, or neurodevelopment. The US Food and Drug Administration has also approved these formulas safe for use in infants.1 Reference Vandenplas Y, Castrellon PG, Rivas R. et al. Systemic review with meta-analysis: Safety of soya-based infant formulas in children. Br J Nutr. 2014;111(8): US Food and Drug Administration has approved these formulas safe for use in infants1 SIF: Soya-based infant formulas; AAP: American Academy of Pediatrics. Vandenplas Y, et al. Br J Nutr. 2014;28;111(8):

Partially Hydrolyzed Formula
Partially hydrolysed formulas: Are developed mainly to minimize the number of sensitizing epitopes within milk proteins; however, they contain peptides with sufficient size and immunogenicity to stimulate oral tolerance. Thus, they are not suitable to treat CMPA, but are commonly used to prevent CMPA.1 According to the 2012 ESPGHAN gastrointestinal committee practical guidelines: Partially hydrolysed formula based on cow’s milk protein or other mammalian protein are not recommended for infants with CMPA.2 Partially hydrolysed formulas are developed mainly to minimize the number of sensitizing epitopes within milk proteins; however, they contain peptides with sufficient size and immunogenicity to stimulate oral tolerance. Thus, they are not suitable to treat CMPA, but are commonly used to prevent CMPA.1 Similac Senstive and Enfamil Gentlease According to the 2012 ESPGHAN gastrointestinal committee practical guidelines, partially hydrolysed formula based on cow’s milk protein or other mammalian protein are not recommended for infants with CMPA.2 References Vandenplas Y, DeGreef E, Devreker T. Treatment of cow’s milk protein allergy. Pediatr Gastroenterol Hepatol Nutr. 2014;17(1):1–5.(1,2,3) Koletzko S, Niggemann B, Arato A, et al. Diagnostic Approach and Management of Cow’s-Milk Protein Allergy in Infants and Children: ESPGHAN GI Committee Practical Guidelines. JPGN. 2012;55:221–229. CMPA: Cows milk protein allergy; ESPGHAN: European Society of Pediatric Gastroenterology, Hepatology, and Nutrition. Vandenplas Y, et al. Pediatr Gastroenterol Hepatol Nutr. 2014;17(1):1–5.(1,2,3) Koletzko S, et al. JPGN. 2012;55:221–229.

Extensively Hydrolyzed Formula: Safety, Efficacy, and Tolerance
Evolution of symptoms At inclusion, before challenge (n=30) At 1 month (n=30) At 2 months (n=24) At 3 months (n=22) Infants with episodes (%) 100 10 Infants with total symptoms (%) 21 Infants with cutaneous eruption (%) 87 Infants with pruritis (%) 33 7 Infants with vomiting (%) Infants with diarrhea (%) 3 Let us begin by discussing evidence on safety, efficacy, and tolerance of the extensively hydrolyzed formula in infants with CMPA. In a prospective, open, multicenter study by Matenico et al., 47 infants with CMPA received extensively hydrolyzed formula and were followed up for nearly 3 months. Out of the 47 infants, only one demonstrated a positive result in the oral food challenge provocation test, indicating that the extensively hydrolyzed formula was tolerated by 98% of participants. There were no reports of any serious adverse events related to the formula, at the end of the follow up period. Furthermore, during the 3-month study period, the weight-for-age and height-for-age increased and the infants exhibited normal weight gain, as evaluated using the WHO child growth standards. Based on the findings, the study concluded that extensively hydrolyzed formulas are well tolerated by infants and are useful for the nutritional management of infants with proven CMPA. Reference Matencio E, Maldonado J, Olza J, et al. A hypoallergenic infant formula comprising extensively hydrolyzed protein for the nutritional treatment of infants with cow’s milk allergy: Safety, tolerance, and efficacy. J Hum Nutr Food Sci. 2016;4(3): Extensively hydrolyzed formulas are well tolerated by infants and are useful for the nutritional management of infants with proven CMPA. CMPA: Cow’s milk protein allergy. Two Types : Casein or Rice Based Matencio E, et al. J Hum Nutr Food Sci. 2016;4(3):

Extensively Hydrolysed Casein-Based Formula in Children with CMPA: Clinical Evidence
Parameter At inclusion At day 14 CoMiSS, mean (± SD) 7.4 (4.4) 3.2 (2.3)* Regurgitation scorea, mean (± SD) 1.6 (1.6) 0.9 (1.0)* Crying scorea, mean (± SD) 1.7 (1.1) 0.8 (0.6)* Stool consistency, % Formed stools 53.3% 66.7% Soft stools 13.3% 23.3% SCORAD index, mean (± SD)** 33.2 (14.8) 15.5 (6.7) *P-values vs. inclusion < (Wilcoxon’s test); a Sub-scores included in the calculation of the CoMiSS; CoMiSS: Cow’s Milk-related Symptom Score; SCORAD: Scoring Atopic Dermatitis index; ** values given are the reduction achieved from values noted at inclusion. Let us now discuss clinical evidence on the role of extensively hydrolyzed casein-based formula in children with CMPA. Alimentum Dupont et al. conducted a prospective, multicenter trial to determine the tolerance and hypoallergenicity of a thickened casein-based formula in 30 infants aged less than 12 months and with a diagnosis of CMPA. The infants were exclusively bottle fed with an extensively hydrolyzed casein-based formula for 4 months. The efficacy of the formula was evaluated by monitoring allergy symptoms and calculating the Cow’s Milk-related Symptom Score (CoMiSS) during the 4-month feeding period. There was a significant Reduction in CoMiSS, crying and regurgitation scores significantly decreased by 4.2 ± 4.0, 0.9 ±1.2 and 0.7 ± 1.1 respectively, after 14 days of feeding (p<0.001) Reduction in Scoring Atopic Dermatitis index by 15.5 ± 6.7 and 21.1 ± 11.2, after 14 and 45 days of feeding, respectively (p<0.001) Improvement in percentage of infants having normal stool consistency from 66.7% at inclusion to 90% after 14 days of feeding Improvement in growth z-scores which was negative at study inclusion There were no adverse events related to the use of the extensively hydrolysed casein-based formula. Based on the findings, the study concluded that the extensively hydrolysed casein-based formula is hypoallergenic, efficacious, safe, and has a positive effect on catch-up growth in infants with CMPA. Therefore, extensively hydrolysed casein-based formula can serve as an efficient and safe feeding formula in children with CMPA. Reference: Dupont C, Bradatan E, Soulaines P, et al. Tolerance and growth in children with cow’s milk allergy fed a thickened extensively hydrolysed casein-based formula. BMC Pediatrics. 2016;16:96. Extensively hydrolysed casein-based formula is hypoallergenic, efficacious, safe, and has a positive effect on catch-up growth in infants with CMPA. CMPA: Cow’s milk protein allergy. Dupont C, et al. BMC Pediatrics. 2016;16:96.

Extensively Hydrolyzed Rice-Based Formula: Safety and Tolerance
Evolution of the global symptom-based score Before challenge (n=38) At inclusion (n=38) 1 month (n=38) 3 months (n=36) 6 months (n=36) (A) (B) (C) (D) (E) Mean ± SD 8.6 ± 5.6 13.5 ± 5.2 3.5 ± 2.3 2.4 ± 1.9 1.5 ± 2.0 P value A-B, <0.0001a B-C, <0.001a B-D, <0.001b B-E, a symmetry test; b Paired Student’s t test Having discussed the efficacy of partially hydrolyzed rice-based formula, let us now discuss the safety and tolerance of an extensively hydrolyzed rice protein based formula for the management of infants with CMPA. Novarice Vandenplas et al. conducted a prospective trial to determine the hypo-allergenicity and safety of an extensively hydrolyzed rice protein formula in 40 infants with CMPA. The infants received the extensively hydrolyzed formula for 6 months during which time the clinical tolerance of the formula was evaluated using a symptom-based score and growth was evaluated using the WHO child growth standard reference charts. The formula was well tolerated by more than 90% of infants and the symptom-based score reduced significantly at each time point, compared to baseline scores. Furthermore, the formula facilitated a normalization of the weight-for-age, weight-for-length, and BMI z-scores during the 6-month study period. Based on the positive findings, the study concluded that the extensively hydrolyzed rice-based formula is an adequate and safe alternative to cow milk-based extensively hydrolyzed formula. Reference Vandenplas Y, De Greef E, Hauser B, et al. Safety and tolerance of a new extensively hydrolyzed rice protein-based formula in the management of infants with cow’s milk protein allergy. Eur J Pediatr. 2014;173: Extensively hydrolyzed rice-based formula is an adequate and safe alternative to cow milk-based extensively hydrolyzed formula. Vandenplas Y, et al. Eur J Pediatr. 2014;173:

Number of infants allergic to CMP over time Weight-for-height z-scores
Extensively Hydrolysed Formula: Clinical Tolerance and Impact on Growth Parameters Number of infants allergic to CMP over time Weight-for-height z-scores In this slide, we will discuss the efficacy of a partially hydrolyzed rice-based formula. Pascual et al. conducted a prospective, open, randomized study to compare the allergenicity and efficacy of a partially hydrolyzed rice-based formula with that of an extensively hydrolyzed formula in 92 infants diagnosed with IgE-mediated cow’s milk allergy. The infants were followed up at 3, 6, 12, 18, and 24 months and growth parameters were assessed at each visit. The first graph represents the number of infants allergic to CMP over time and the second graph represents the weight-for-height z-scores of infants in the two groups. The partially hydrolyzed rice-based formula was clinically well tolerated by more than 90% of infants with moderate-to-severe symptoms of IgE-mediated CMPA. Furthermore, as can be seen in the second graph, the growth of infants receiving the partially hydrolyzed formula was within normal ranges for weight and height when compared with the WHO growth standards, and there were no statistical differences in the growth parameters between the two groups tested. The study demonstrated that partially hydrolyzed rice-based formula could serve as an adequate and safe alternative to hydrolyzed formulas for infants with CMPA. Reference Pascual RM, Polanco FA, Rivero-Urgell M, et al. The effect of a partially hydrolysed formula based on rice protein in the treatment of infants with cow’s milk protein allergy. Pediatr Allergy Immunol. 2010;21: EHF: Extensively hydrolyzed formula; HRPF: Hydrolyzed rice protein formula. EHF: Extensively hydrolyzed formula; HRPF: Hydrolyzed rice protein formula. Extensively hydrolyzed formulas are clinically well tolerated and is associated with normal growth parameters. Pascual RM, et al. Pediatr Allergy Immunol. 2010;21:

Amino Acid-Based Formulas
WAO-DRACMA guidelines: AAFs rather than EHFs are recommended for infants at high risk of anaphylactic reactions. Fecal calprotectin and eosinophilic cationic protein before and after the DBPCFC Before challenge After challenge After 7 days After 14 days FC (Mean ± SD) 36.3 ± 22.1 μg/g 32.5 ± 23.8 μg/g 33.5 ± 21.6 μg/g ECP 0.93 ± 0.31 μg/g 0.92 ± 0.27 μg/g 0.90 ± 0.30 μg/g FC: Fecal calprotectin; ECP: Eosinophilic cationic protein; SD: Standard deviation. According to the World Allergy Organization Diagnosis and Rationale for Action against CMPA (WAO-DRACMA) guidelines, amino-acid based formulas rather than extensively hydrolysed formulas are recommended for infants at high risk of anaphylactic reactions. Canani et al. conducted the first study to determine the tolerance of the amino acid-based formula in children with documented IgE- or non-Ig-E-mediated CMPA and involved 60 consecutive patients aged ≤4 years. The concentrations of calprotectin and eosinophilic cationic protein in the feces were monitored to determine the optimal tolerance to the formula. The table on the slide presents the fecal calprotectin and fecal eosinophilic cationic protein before and after the double-blind, placebo-controlled challenge. After the double-blind, placebo-controlled challenge trials, none of the children presented with early or delayed clinical reactions. All of them tolerated at least 100 mL of the amino acid-based formula daily. There were no reports of any serious adverse events during the double-blind, placebo-controlled challenge trials, open challenge, or extended 7-day feeding period of amino acid-based formula. Parental reports of the acceptance and tolerance of the amino acid-based formula was good. Based on the findings, the study concluded that amino-acid based formula is well tolerated and could be used as a safe dietotherapy in children with IgE- or non-Ig-E mediated CMPA. Reference Canani RB, Nocerino R, Leone L, et al. Tolerance to a new free amino acid-based formula in children with IgE or non-IgE-mediated cow’s milk allergy: a randomized controlled clinical trial. BMC Pediatrics. 2013,13:24. Amino acid-based formula is well tolerated and could be used as a safe dietotherapy in children with IgE- or non-Ig-E mediated CMPA. WAO-DRACMA: World Allergy Organization Diagnosis and Rationale for Action against CMPA; DBPCFC: Double-blind, placebo-controlled, food challenge; CMPA: Cows milk protein allergy. Canani RB, et al. BMC Pediatrics. 2013,13:24.

Efficacy and Safety of AAF in Infants not Responding to EHF
Growth and allergic manifestations following 12 weeks of feeding* Parameter Baseline Visit 3 P value Weight, g (1210.4) (1146.2) n/a Weight z-score -1.6 (0.8) -1.1 (0.8) <0.001 Length, cm 65.32 (5.24) 69.96 (4.6) Length z-score -0.7 (1.1) -0.4 (0.9) 0.04 SCORAD (n) 13 7 SCORAD score 24.64 (13.25) 9.04 (5.94) 0.0156 GI symptom (n) 30 4 GI symptom score 24.2 (4.4) 8.4 (7.3) <0.0001 * Values listed as mean (standard deviation); GI: Gastrointestinal; n/a: not applicable; SCORAD: Scoring atopic dermatitis. Several studies have demonstrated the efficacy and safety of amino acid formulas in healthy infants. However, evidence on the role of amino acid formulas in infants not responding to extensively hydrolyzed formulas is limited. Therefore, Vanderhoof et al. conducted a prospective, observational study in which 30 infants aged 1-12 months with a history of weight loss and persistent allergic manifestations while on an extensively hydrolyzed formula, were initiated on an amino-acid based formula for 12 weeks. The table on the slide represents with growth and allergic manifestations following 12 weeks of feeding with amino acid-based formula. Initiation of the amino acid-based formula significantly reduced the incidence of atopic dermatitis and gastrointestinal symptoms and improved weight relative to the WHO reference population. The study demonstrated that initiation of amino acid-based formula significantly reduces atopic dermatitis and gastrointestinal complications and supports healthy weight gain, in infants with CMPA and not responding to extensively hydrolyzed formula. Reference Vanderhoof J, Moore N, de Boissieu D. Evaluation of an Amino AcidBased Formula in Infants Not Responding to Extensively Hydrolyzed Protein Formula. JPGN.2016;63: 531–533. AAF improves growth and allergic manifestations in infants not responding to EHF. AAF: Amino-acid based formula; EHF: Extensively hydrolyzed formula. Vanderhoof J, et al. JPGN.2016;63: 531–533.

Guideline Recommendations on Use of Formulas to Treat CMPA
2012 ESPGHAN, 2010 WAO-DRACMA, 2008 AAP:1 Use EHF based on cow’s milk protein to treat CMPA1,2 2012 ESPGHAN guidelines:1 If the EHF is not tolerated, then an AAF is recommended.1 2012 ESPGHAN guidelines:2 A soy formula may be considered to treat CMPA in infants aged >6 months if the EHF is not accepted or tolerated formulae are too expensive there is a strong parenteral preference for a vegan diet.1 WAO-DRACMA guidelines3 There is very sparse evidence suggesting a possible benefit from using eHF compared to soy formula The 2012 ESPGHAN, 2010 WAO-DRACMA, and the 2008 American Academy of Pediatrics guidelines recommend the use of extensively hydrolyzed formula based on cow’s milk protein for the treatment of CMPA.1,2,3 If the extensively hydrolyzed formula is not tolerated, then an amino acid based formula is recommended. A soy formula may be considered to treat CMPA in infants aged >6 months if the extensively hydrolyzed formula is not accepted or tolerated, if the formulae are too expensive, or if there is a strong parenteral preference for a vegan diet.1 However, according to the WAO-DRACMA guidelines, “There is very sparse evidence suggesting possible benefit from using extensively hydrolyzed formula compared with soy formula, but more research is needed to confirm these observations.”3 References Koletzko S, Niggemann B, Arato A, et al. Diagnostic Approach and Management of Cow’s-Milk Protein Allergy in Infants and Children: ESPGHAN GI Committee Practical Guidelines. JPGN. 2012;55:221–229. Bhatia J, Geer F. Use of Soy Protein-Based Formulas in Infant Feeding. Pediatrics. 2008;121:1062–8. Fiocchi A, Brozek J, Schunemann H, et al. World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) Guidelines. World Allergy Organ J. 2010; 3(4): 57–161. EHF: Extensively hydrolyzed formula; CMPA: Cows milk protein allergy; ESPGHAN: European Society of Pediatric Gastroenterology, Hepatology, and Nutrition; AAP: American Academy of Pediatrics; WAO-DRACMA: World Allergy Organization Diagnosis and Rationale for Action against CMPA. Koletzko S, et al. JPGN. 2012;55:221–229. Bhatia J, Geer F. Pediatrics. 2008;121:1062–8. Fiocchi A, et al. World Allergy Organ J. 2010; 3(4): 57–161.

Algorithm for Management of CMPA: 2012 ESPGHAN and NASPGHAN Guidelines (1/2)
Safest strategy: Strict avoidance of CMP Decide on the need for substitute formula and the best formula based on the age and presence of other food allergies. Infants up to 12 months of age If CMPA is confirmed, maintain on an elimination diet using a therapeutic formula (eHF) for at least 6 months or until 9-12 months of age. If severe immediate IgE-mediated reactions (AA), continue on elimination diet for 12/18 months of age; later rechallenge after repeated testing for specific IgE. The flow chart on the slide presents the approach put forth by the 2012 ESPGHAN and NASPGHAN guidelines for the management of CMPA. Accordingly, the safest strategy for the management of CMPA is to strictly avoid cow’s milk protein. The need for including a substitute formula to fulfill the nutritional needs in a child and the best choice of such a formula should be decided based on the age of the child and the presence of other food allergies. Infants up to the age of 12 months with a confirmed diagnosis of CMPA should be maintained on an elimination diet using a therapeutic formula for a minimum of 6 months or till they are 9 to 12 months old. Infants/children with severe immediate IgE-mediated reactions may be continued on elimination diet for 12 or even 18 months. Subsequently, they should be rechallenged after repeated testing for specific IgE. Reference: Koletzko S, Niggemann B, Arato A, et al. Diagnostic Approach and Management of Cow’s-Milk Protein Allergy in Infants and Children: ESPGHAN GI Committee Practical Guidelines. JPGN. 2012;55:221–229. CMP: Cow’s milk protein; CMPA: Cow’s milk protein allergy; ESPGHAN: European Society of Pediatric Gastroenterology, Hepatology, and Nutrition; NASPGHAN: North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Koletzko S, et al. JPGN. 2012;55:221–229.

Algorithm for Management of CMPA: 2012 ESPGHAN and NASPGHAN Guidelines (2/2)
Children beyond 12 months of age CMPA continues beyond 12 months of age First line therapy: Substitution of CMP by a therapeutic formula EHF, a formula based on a nonrelated protein with no cross-reactivity (e.g., casein /rice based infant formula), or AAF if neither options are tolerated. Provide calcium supplements if child does not consume sufficient formula. Re-evaluation: Challenge with cow’s milk after maintaining a therapeutic diet for at least 3 months Let us now discuss the approach put forth by the 2012 ESPGHAN and NASPGHAN guidelines for the management of CMPA in children beyond 12 months of age. When CMPA continues beyond 12 months of age, it is important to Provide individualized nutritional advice. Assess the dietary requirements of the child to determine whether nutrient supply while on elimination diet is adequate or whether the child needs therapeutic formula to support normal growth for age. Ensure that the child’s diet is supervised by a pediatrician or a specialist dietician. The first line therapy for the management of CMPA in children beyond 12 months of age is substitution of cow’s milk protein with a therapeutic formula. An extensively hydrolyzed formula or a formula based on a nonrelated protein with no cross-reactivity such as soy protein-based infant formula, or an amino-acid based formula can be considered if neither of the options are tolerated. The child should be provided calcium supplements if it does not consume sufficient quantity of formula. In order to avoid the continuation of restrictive diet for an unnecessarily long time, a challenge with cow’s milk may be performed after maintaining a therapeutic diet for at least 3 months up to at least 12 months. If the challenge is positive, then the child should be continued on elimination diet for 6-12 months. If the challenge is negative, cow’s milk should be fully reintroduced into the child’s diet. Nearly 50% of children affected with CMPA develop tolerance by 1 year of age, 75% children develop tolerance by 3 years of age, and >90% of children develop tolerance by 6 years of age. Reference: Koletzko S, Niggemann B, Arato A, et al. Diagnostic Approach and Management of Cow’s-Milk Protein Allergy in Infants and Children: ESPGHAN GI Committee Practical Guidelines. JPGN. 2012;55:221–229. Positive challenge test Negative challenge test Continue on elimination diet for 6-12 months Re-introduce cow’s milk to the diet CMP: Cow’s milk protein; CMPA: Cow’s milk protein allergy; EHF: Extensively hydrolyzed formula; AAF: Amino-acid based formula. Koletzko S, et al. JPGN. 2012;55:221–229.

Management Algorithm: Breastfed Infants With Suspected Non-IgE-mediated CMPA
Breast-fed infants with suspected reactions to cow’s milk: atopic dermatitis, vomiting, diarrhoea, stool blood, GORD, poor growth, infantile colic. Clinical evaluation, family history Mild symptoms Moderate-severe symptoms No diet Maternal diet without cow’s milk for 2-4 weeks. SPT/specific IgE, Stool eosinophils or stool blood. Improves ? Free maternal diet Give cow’s milk to the mother for 1 week. Symptoms ? Exclusion diet When it is necessary, breastfeeding should be supplemented with extensively hydrolyzed formula or soy formula (if > 6 months). Food challenge test after 6-12 months of avoidance. Yes No In exclusively breastfed infants, the suspected symptoms to cow’s milk proteins are usually non-IgE-mediated. If the symptoms are mild, there is no need for eliminating cow’s milk from maternal diet. In infants with bloody stools, there is no evidence that a maternal diet without egg and cow’s milk is helpful. In infants with moderate-to-severe symptoms, cow’s milk protein, eggs, and other foods should be eliminated from the mother’s diet only if her medical history suggests an unequivocal reaction. The infant should be referred to a specialized center. The maternal elimination diet should be followed for four weeks. If the absence of any improvement, the diet should be stopped. If improvement in symptoms is seen, it is recommended to feed the mother large volume of cow’s milk for one week. In case of symptoms occurring, the mother will continue the diet with supplemental intake of calcium. The infant can be weaned gradually, but cow’s milk should be avoided until 9 to 12 months of age and for at least six months from the beginning of the diet. If the volume of breast milk is insufficient, eHF or SF formula (if >6 months) should be administered. If after the reintroduction of cow’s milk in mother’s diet the symptoms do not occur, the excluded foods can be introduced one by one in the diet. Reference Caffarelli C, Baldi F, Bendandi B et al. Cow’s milk protein allergy in children: a practical guide. Italian Journal of Pediatrics 2010,36:5 Caffarelli C, Baldi F, Bendandi B et al. Italian Journal of Pediatrics 2010,36:5

Is there any way I could have prevented it? (Primary Prevention)
No evidence to restrict dairy avoidance during pregnancy At risk individuals – Maternal avoidance of dairy products – need more RCT Evidence of using hydrolyzed formula compared cows milk at high risk individuals – there is lot of evidence PRIMARY PREVENTION

Natural history of FA Most children with FA will eventually tolerate milk, egg, soy and wheat; far fewer will tolerate tree nuts and peanut. A higher initial level of IgE is associated with a lower rate of resolution of clinical allergy over time Earlier the age of intolerance, more is the chances of remission

Prognosis – CMPA Virtually all children manifest in first year
50 % tolerance by 1 year, 80 % tolerance by 5 years of age. Children with non-IgE-mediated CMPI have a good prognosis 35 % developed allergies to other food IgE mediated allergy may last longer

Protocol in CMPA - nutshell
Dairy free diet for child and mother(if being breastfed) for 4-8 weeks If improvement - rechallange with cows milk after 2 months If symptoms recur, confirms diagnosis. Rechallange after 1 year of age or after 6 mths of the reaction.

Pediatric Gastroenterology
Division of Pediatric Gastroenterology VPIMS Lucknow

Summary Cow’ s milk is the major cause of food allergy in children aged <3 years CMPA may be due to IgE- or non-IgE-mediated reactions and is the result of impaired oral tolerance For the prevention of allergies, breastfeeding without maternal allergen elimination is recommended as long as the infant is devoid of symptoms Clinical assessment with the elimination diet and challenge within four weeks are fundamental strategies for the accurate diagnosis of CMPA Continued breastfeeding is the best treatment for CMPA and the mother should avoid all dairy products in her diet eHF based on cow’s milk protein or AAF is a better choice over soy protein-based formula To summarize: Cow’ s milk is the major cause of food allergy in children aged <3 years. CMPA may be due to IgE- or non-IgE-mediated reactions and is the result of impaired oral tolerance. For the prevention of allergies, breastfeeding without maternal allergen elimination is recommended as long as the infant is devoid of symptoms. Clinical assessment with elimination diet and challenge within four weeks are fundamental strategies for the accurate diagnosis of CMPA. Continued breastfeeding is the best treatment for CMPA and the mother should avoid all dairy products in her diet. eHF based on cow’s milk protein or AAF is a better choice over soy protein-based formula. AAF: Amino acid formula; CMPA: Cow milk protein allergy; pHF: Partially hydrolyzed formula; eHF: Extensively hydrolyzed formula; IgE: Immunoglobulin E

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Cows Milk Protein Allergy (CMPA) Road to Management

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Cows Milk Protein Allergy (CMPA) Road to Management

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