CMA is the most common food allergy in children under 5 years of age [3American College of Asthma and Immunology: Milk allergy affects half of US food-allergic kids under age 1: Most children with a milk allergy don’t carry epinephrine. ScienceDaily 2020. Available at: https://www.science daily.com/releases/2018/11/181116083208.htm]. It is defined as an abnormal and undesired immune response triggered in a sensitized individual after exposure to Cow’s Milk Proteins (CMPs), typically casein and whey proteins such as β-lactoglobulin [4Jo J, Garssen J, Knippels L, Sandalova E. Role of cellular immunity in cow’s milk allergy: Pathogenesis, tolerance induction, and beyond. Mediators Inflamm 2014; 2014249784
[http://dx.doi.org/10.1155/2014/249784] [PMID: 25002754] ]. Cow’s milk, however, contains more than 20 protein allergens prone to cause reactions, and although casein fractions (α-S1-casein, α-S2-casein, β-casein) and β-lactoglobulin are the main allergens in cow’s milk, reactions to Bovine Serum Albumin (BSA) and α-lactalbumin have also been reported [5Elagamy EI. Milk Protein Allergy Reference Module in Food Sciences 2015; 1-5.]. In the United States alone, it is estimated that 2% of the population under 5 years of age [3American College of Asthma and Immunology: Milk allergy affects half of US food-allergic kids under age 1: Most children with a milk allergy don’t carry epinephrine. ScienceDaily 2020. Available at: https://www.science daily.com/releases/2018/11/181116083208.htm](464,000 children) [6Duffin E. Number of children aged between 0-5 years in the US 2000-2020 Statista 2019. Available at: https://www.statista.com/statistics/690946/ children-zero-to-five-years-of-age-america-us/] have CMA. Based on different cohort studies, the prevalence of CMA ranges between 1.9% and 7.5% for all infants and children [7Høst A, Halken S, Jacobsen HP, Christensen AE, Herskind AM, Plesner K. Clinical course of cow’s milk protein allergy/intolerance and atopic diseases in childhood. Pediatr Allergy Immunol 2002; 13(s15): 23-8.
[http://dx.doi.org/10.1034/j.1399-3038.13.s.15.7.x] [PMID: 12688620] -12Flom JD, Sicherer SH. Epidemiology of Cow’s Milk Allergy. Nutrients 2019; 11(5): 1051.
[http://dx.doi.org/10.3390/nu11051051] [PMID: 31083388] ].

According to the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN), it is estimated that about 50% of children with CMA will develop tolerance to CMPs by the age of 12 months, more than 75% by the age of 3 years, and more than 90% by the age of 6 years [13Koletzko S, Niggemann B, Arató A, et al. Diagnostic approach and management of cow's-milk protein allergy in infants and children: ESPGHAN GI Committee practical guidelines. J Pediatric Gastroenterol Nutrition 2012; 55(2): 221-9.]. Two years prior to the publication of the ESPGHAN guidelines for the management of CMA, the World Allergy Organization’s (WAO) Diagnosis and Rationale for Action against Cow’s Milk Allergy (DRACMA) guidelines provided information on CMP tolerance development in children from two populations: (1) general public with no medical treatment before the study; and (2) referral patients with medical treatment before the study. Study findings showed that 56% of children develop CMP tolerance by the age of 1 year [14Fiocchi A, Brozek J, Schünemann 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.
[http://dx.doi.org/10.1097/WOX.0b013e3181defeb9] [PMID: 23268426] ]. Furthermore, 77%, 87%, 92%, 92%, and 97% of children may develop CMP tolerance by the age of 2, 3, 5, 10, and 15 years, respectively [14Fiocchi A, Brozek J, Schünemann 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.
[http://dx.doi.org/10.1097/WOX.0b013e3181defeb9] [PMID: 23268426] ].

CMA is mediated by 3 mechanisms: immunoglobulin E-mediated (IgE-mediated), non-IgE-mediated, and a mix of these two, each of which manifests a different set of symptoms. The symptoms are classified by severity, onset of the reaction (immediate or delayed), and the organ systems involved (respiratory, integumentary, gastrointestinal) [GI]. IgE-mediated reactions occur immediately or up to 2 hours after allergen exposure; whereas, non-IgE-mediated reactions may have a delayed response up to several days or weeks after allergen consumption [15Allen KJ, Davidson GP, Day AS, et al. Management of cow’s milk protein allergy in infants and young children: An expert panel perspective. J Paediatr Child Health 2009; 45(9): 481-6.
[http://dx.doi.org/10.1111/j.1440-1754.2009.01546.x] [PMID: 19702611] ]. For this reason, non-IgE reactions in CMA can be misdiagnosed and confused with lactose intolerance, gastroesophageal reflux disease (GERD), and other GI disorders. These reactions may require further elimination of the allergen from the diet coupled with oral food challenges to determine if the infant/child has an allergy to CMP [13Koletzko S, Niggemann B, Arató A, et al. Diagnostic approach and management of cow's-milk protein allergy in infants and children: ESPGHAN GI Committee practical guidelines. J Pediatric Gastroenterol Nutrition 2012; 55(2): 221-9.]. There are also clinical conditions where infants/children have a mix of IgE-mediated and non-IgE-mediated responses, such as atopic dermatitis and eosinophilic disorders [1Boyce JA, Assa’ad A, Burks AW, et al. NIAID-Sponsored Expert Panel. Guidelines for the diagnosis and management of food allergy in the United States: Report of the NIAID-sponsored expert panel. J Allergy Clin Immunol 2010; 126(6)(Suppl.): S1-S58.
[http://dx.doi.org/10.1016/j.jaci.2010.10.008] [PMID: 21134576] ].

Recognizing and implementing the best practices in CMA nutritional management by healthcare practitioners and caregivers is important to achieve optimal nutritional status, growth, and development. Symptom resolution is vital to achieve these outcomes. Practical tools, updated reviews, and accurate information describing the most optimal feeding methods based on the symptoms manifested by the infant/child are of utmost importance. Table 1 provides a summary of the most common CMA symptoms and clinical presentations.

Table 1
Common clinical presentations related to CMA.

In 2008, WAO Special Committee on Food Allergy recognized the need for an evidence-based approach to manage CMA. This committee conducted a systematic review of CMA literature, and used the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) methodology for evaluating the quality of evidence. In this system, the quality of evidence is assessed based on explicit methodological criteria and classified as either “high,” “moderate,” “low,” or “very low.” Formulation of the recommendations within the guidelines included consideration of the quality of evidence, benefits, harms, burden, cost and values/preferences. After the GRADE approach, the guideline panelists classified CMA recommendations as either “strong” or “conditional” (which is considered weak). In 2010, the DRACMA Guidelines were first published, [14Fiocchi A, Brozek J, Schünemann 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.
[http://dx.doi.org/10.1097/WOX.0b013e3181defeb9] [PMID: 23268426] ] with an update article in 2016 [25Fiocchi A, Dahda L, Dupont C, Campoy C, Fierro V, Nieto A. Cow’s milk allergy: Towards an update of DRACMA guidelines. World Allergy Organ J 2016; 9(1): 35.
[http://dx.doi.org/10.1186/s40413-016-0125-0] [PMID: 27895813] ]. The nutritional recommendations discussed in both documents are presented here.

The 2016 DRACMA publication continues to recognize the importance of breast milk for optimal nutrition and development of infants. When an infant is diagnosed with CMA, the pediatrician must recommend an “avoidance regimen”, which will substitute the infant’s diet with either an infant formula, or preferably, breastmilk with a mother’s diet free of CMP products [25Fiocchi A, Dahda L, Dupont C, Campoy C, Fierro V, Nieto A. Cow’s milk allergy: Towards an update of DRACMA guidelines. World Allergy Organ J 2016; 9(1): 35.
[http://dx.doi.org/10.1186/s40413-016-0125-0] [PMID: 27895813] ].

If the formula is warranted, the formula choice will depend on the infant’s symptoms and clinical presentation, as well as the availability of infant formulas in the market and financial resources of the family. DRACMA recommends EHF as option 1 for the treatment of non-severe and non-life-threatening CMA symptoms, such as immediate GI allergy, asthma, rhinitis, acute urticaria, angioedema, atopic dermatitis, CMP-induced enteropathy, GERD, constipation, severe irritability, colic, and CMP-induced gastroenteritis and proctocolitis. These guidelines do not specify the length of time the infant/child should consume the EHF before conducting an oral challenge to milk. However, they express that in earlier cohort studies using double-blind placebo-controlled food challenges (DBPCFC), 23% of infants suffering from CMA acquire tolerance after 13 months, and 75% after 43 months [14Fiocchi A, Brozek J, Schünemann 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.
[http://dx.doi.org/10.1097/WOX.0b013e3181defeb9] [PMID: 23268426] ]. This could be an indicator of the advised consumption length of a hypoallergenic formula depending on the symptoms. The guidelines remark that SF should only be used in infants older than 6 months. In infants presenting with non-severe and non-life-threatening symptoms, SF is option 2 of treatment. If the infant is at risk of sensitization to soy proteins, AAF is recommended.

For life-threatening CMA reactions such as anaphylaxis (with a negative Skin Prick Test [SPT] to a specific formula), FPIES (food protein-induced enterocolitis syndrome), Heiner syndrome, and allergic eosinophilic esophagitis, AAF is option 1 of treatment followed by EHF as option 2. Upon availability, RHF can be a substitute for EHF when the symptoms are non-severe and non-life threatening. Several studies, summarized by Bocquet et al. (2019), [26Bocquet A, Dupont C, Chouraqui JP, et al. Efficacy and safety of hydrolyzed rice-protein formulas for the treatment of cow’s milk protein allergy. Arch Pediatr 2019; 26(4): 238-46.
[http://dx.doi.org/10.1016/j.arcped.2019.03.001] [PMID: 30979632] ] have reported the safety and effectiveness of RHF in managing CMA and other gastrointestinal disorders (i.e., secondary lactase deficiency and chronic or acute diarrhea). The 2010 guidelines published by DRACMA recommended further research to be performed with RHF [14Fiocchi A, Brozek J, Schünemann 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.
[http://dx.doi.org/10.1097/WOX.0b013e3181defeb9] [PMID: 23268426] ]. In 2016, DRACMA published an update including new studies, and it was mentioned that upon availability, RHF could be a substitute for EHF when the symptoms are non-severe and non-life-threatening. If there is an anaphylactic reaction, RHF can substitute EHF as option 2 of treatment [25Fiocchi A, Dahda L, Dupont C, Campoy C, Fierro V, Nieto A. Cow’s milk allergy: Towards an update of DRACMA guidelines. World Allergy Organ J 2016; 9(1): 35.
[http://dx.doi.org/10.1186/s40413-016-0125-0] [PMID: 27895813] ]. SF is also option 2 to treat Heiner syndrome (after an AAF as option 1).

In April 2012, ESPGHAN published the Diagnostic Approach and Management of Cow’s Milk Protein Allergy in Infants and Children: ESPGHAN GI Committee Practical Guidelines [13Koletzko S, Niggemann B, Arató A, et al. Diagnostic approach and management of cow's-milk protein allergy in infants and children: ESPGHAN GI Committee practical guidelines. J Pediatric Gastroenterol Nutrition 2012; 55(2): 221-9.]. The authors, reviewers, and researchers included a wide range of experts from various institutions. Like DRACMA, these guidelines present a set of recommendations for the diagnosis and management of suspected CMA. Based on the evidence, the ESPGHAN guidelines also provide an algorithm to diagnose CMA. The nutritional recommendations after a confirmed CMA diagnosis are presented below.

The ESPGHAN guidelines advise that BF should be strongly encouraged for infants with CMA. In BF infants, the mother should start a strict CMP-free diet coupled with calcium supplements (1000 mg/day spread across the day), complemented with additional nutrition counseling.

ESPGHAN recognizes that most infants/children will tolerate EHF with whey or casein as the protein source. The formula recommendations vary depending on the age of the infant/child as well as the severity of the reaction. In infants <12 months of age with CMA and non-life-threatening symptoms, EHF is option 1 for nutritional management of infants of at least 6 months of age or until 9-12 months of age. Nevertheless, if the symptoms are severe, then EHF is recommended for 12-18 months of age before conducting an oral challenge in the child. ESPGHAN recommends AAF as option 1 for the nutritional management of anaphylaxis, EoE, and severe enteropathy.

Like DRACMA, ESPGHAN does not recommend the use of SF in the first 6 months of age due to the high prevalence of cross-reactivity in young infants. However, after 6 months of age and in non-life-threatening scenarios, SF can be considered as option 2 in the following scenarios; if the infant manifests intolerance to EHF and AAF, if the latter two formulas are unaffordable, and in vegan families.

ESPGHAN recommends the use of RHF, but due to the limited availability in markets and limited data, the support for RHF use is limited to infants/children that are either refusing or not tolerating EHF, or in vegan families.

The AAP Committee on Nutrition published a policy statement in 2000, “Hypoallergenic Infant Formulas”, which provides recommendations on the use of different infant formulas for the management of CMA [24Baker S, Cochran W, Greer F, et al. Hypoallergenic infant formulas. Pediatrics 2000; 106(2 Pt 1): 346-9.
[PMID: 10920165] ]. In 2011, the NIAID published the “Guidelines for the Diagnosis and Management of Food Allergy in the United States” [1Boyce JA, Assa’ad A, Burks AW, et al. NIAID-Sponsored Expert Panel. Guidelines for the diagnosis and management of food allergy in the United States: Report of the NIAID-sponsored expert panel. J Allergy Clin Immunol 2010; 126(6)(Suppl.): S1-S58.
[http://dx.doi.org/10.1016/j.jaci.2010.10.008] [PMID: 21134576] ]. The NIAID guidelines are inclusive of all food allergies and are non-specific to CMA, hence, they only provide a general recommendation to use hypoallergenic formulas in infants with suspected CMA. NIAID gave general recommendations on the use of hypoallergenic formulas; therefore, it was decided to use the AAP policy statement on Hypoallergenic Infant Formulas in our comparative table as it more thoroughly discusses the nutritional recommendations. The AAP Committee on Nutrition stated that “The American Academy of Pediatrics is committed to BF as the ideal source of nutrition for infants” [24Baker S, Cochran W, Greer F, et al. Hypoallergenic infant formulas. Pediatrics 2000; 106(2 Pt 1): 346-9.
[PMID: 10920165] ]. This policy statement recognizes the importance of breastmilk as the ideal source of nutrition through the first 12 months of age or longer. When CMA is suspected, the maternal diet should be void of cow’s milk, egg, fish, peanuts, and tree nuts, and should be supplemented with calcium.

Infants who do not tolerate breastmilk despite the maternal avoidance of CMP may benefit from the use of a hypoallergenic formula such as EHF. If symptoms persist, then an AAF should be considered. The AAP policy statement remarks that when infants present with IgE-mediated reactions such as angioedema, urticaria, wheezing, rhinitis, vomiting, eczema, and even anaphylaxis, SF could be an option as an initial treatment or preferably after 6 months of age following the use of EHF or AAF [22Issues AAP. Recommendations for the Use of Soy Protein-Based Formulas in Infant Feeding - Special Medical Reports - American Family Physician. Am Fam Physician 1998; 57(11): 2876-6.
[PMID: 9636345] ]. Unlike IgE-mediated reactions, infants manifesting non-IgE-mediated symptoms such as enterocolitis, malabsorption syndrome, esophagitis, and proctocolitis should not use SF as the prevalence of concomitant reactions between soy and CMP is higher in infants (25% to 60%) with non-IgE-mediated symptoms [22Issues AAP. Recommendations for the Use of Soy Protein-Based Formulas in Infant Feeding - Special Medical Reports - American Family Physician. Am Fam Physician 1998; 57(11): 2876-6.
[PMID: 9636345] ]. RHF is not addressed by the AAP for a treatment option as it is not available in the United States. Milk from goats and other animals, or infant formulas containing large amounts of intact animal protein, are inappropriate alternatives for infants allergic to CMP.

Table 2
CMA nutritional management (BF, pHF, and other milks).

Table 3
CMA nutritional management (EHF, AAF, SF, and RHF): Comparative table of DRACMA, ESPGHAN and AAP guidelines.