CMPA 
Q&A

Extensively hydrolyzed formulas (eHFs) are manufactured by hydrolyzing whole proteins, cleaving them into small chain peptides, to reduce their allergenicity.¹ A well-designed hydrolysis process should markedly decrease, and ideally abolish, the allergenicity of the resulting peptides.¹ However, there is high variability in the level of hydrolysis between commercially available eHFs.¹ Although, there is no consensus on the degree of hydrolysis or how to assess residual allergenicity of eHFs,^2-5 several studies have reported allergic reactions to eHFs with variability in clinical efficacy.^2,4,6,7 This includes the Dutch cohort of the EuroPrevall study, where an eHF with 5-15% peptides above 1200 Da did not achieve adequate symptom control in 51% of infants with CMPA, resulting in the reintroduction of an amino acid-based formula.⁶ Differences noted in the safety and clinical efficacy of eHFs may be attributed to the presence of residual proteins or longer chain peptides.³ Our objective is to provide eHFs manufactured to the highest standards, including a patented ultra-filtration process, along with strict release criteria which includes testing for residual allergenicity in every batch.¹ Althéra® HMO is the most extensively hydrolyzed whey-based eHF available for the first-line management of CMPA.³ This is thought to explain why it was the only eHF to show similar efficacy and safety as that of an AAF in a randomized controlled trial. It was also significantly better tolerated than the AAF.⁸

<sup>1. Nutten S, et al. Adv Food Nutr Res. 2020;93:147-204. 
2. Muraro A, et al. EMJ Allergy Immunol. 2017;2(1):46-51. 
3. Nutten S, et al. Allergy. 2020;75(6):1446-9. 
4. Chauveau A, et al. Pediatr Allergy Immunol. 2016;27(5):541-3. 
5. Greer FR, et al. Pediatrics. 2019;143(4):e20190281. 
6. Petrus NCM, et al. Eur J Pediatr. 2015;174:759-65. 
7. Dupont C, et al. Br J Nutr. 2012;107(3):325-38 
8. Niggemann B, et al. Pediatr Allergy Immunol. 2008;19(4):348-54.</sup>

Our extensively hydrolyzed whey-based eHF Althéra® HMO and Alfaré® HMO are halal certified but they are not kosher certified.¹ The protein hydrolysate used in Althéra® HMO and Alfaré® HMO are uniquely produced with non-porcine enzymes.¹ These enzymes (proteases) are of plant and microbial origin. Both formulas meet hypoallergenicity criteria of the American Academy of Pediatrics (AAP) and can be recommended for the dietary management of CMPA.²

<sup>1. Data on file (Halal certification).
2. American Academy of Pediatrics (AAP). Committee on Nutrition. Pediatrics. 2000 Aug;106:346-9. (original - Kleinmann RE, et al. Subcommittee on Nutrition FDA. AAP 1990 & 1991).</sup>

Lactose intolerance is commonly confused with CMPA, especially because symptoms associated with the two conditions can overlap.¹ However, lactose intolerance is not immunological in origin like CMPA, and thus not an allergic condition. To make things even more confusing, the terms are mistakenly used interchangeably.¹ Lactose intolerance is clinically defined as lactose malabsorption with associated gastrointestinal symptoms.² CMPA is a reproducible immune-mediated allergic response to otherwise harmless cow’s milk protein, also associated with gastrointestinal symptoms, among others.³ Lactose intolerance and CMPA also differ in their mechanism. Lactose intolerance is due to low or absent lactase activity.¹ CMPA involves two different mechanisms, one mediated by immunoglobulin E (IgE) and the other non-IgE-mediated.⁴

<sup>1.Luyt D, et al. Clin Exp Allergy 2014;44(5):642-72. 
2. Heine RG, et al. World Allergy Organ J 2017;10(1):41. 
3. Flom JD, and Sicherer SF. Nutrients 2019;11:1051. 
4. Crittenden RG, and Bennett LE. J Am Coll Nutr 2005;24(6suppl):582-91.</sup>

Lactose is the dominant carbohydrate in breastmilk and the largest solid component, representing around 70g/Litre¹, and breastmilk is the best feed for all infants, including those with CMPA. Lactose also forms the backbone to almost all Human Milk Oligosaccharides (HMO), the 3rd largest solid component of human milk.^1,2

It has been suggested to provide beneficial effects for gut physiology, including prebiotic effects, as well as softening of stools, and enhancement of water, sodium and calcium absorption.³ The ESPGHAN expert group therefore considers it prudent to include lactose in infant formula.³ Previous concerns that infants with CMPA would react to residual protein traces in lactose have often resulted in complete avoidance of both lactose and cow’s milk protein.⁴ However, adverse reactions to lactose in CMPA infants are not supported by literature, and complete avoidance of lactose in CMPA is therefore no longer warranted.⁴

Francavilla and colleagues (2012) demonstrated that an eHF with added lactose confers prebiotic benefits in infants with CMPA. They reported that the addition of lactose shaped the composition of the gut microbiota by increasing total fecal counts of Lactobacillus and Bifidobacterium species, while decreasing levels of Bacteroides and Clostridia.⁵ Furthermore, lactose has been shown to be associated with better product palatability, which could improve acceptance/compliance.^6,7

Althéra® HMO is the only formula in our CMPA (AAA) range which contains lactose. Althéra® has been developed for the first-line management of CMPA and in hypoallergenicity studies was tolerated by 98.4% of infants with CMPA.8,9 Alfaré® HMO and Alfamino® HMO are lactose-free specialty formulas. Alfaré® HMO is indicated for children with CMPA and with severe gastrointestinal impairment. Alfamino® HMO is designed to support severe forms of CMPA, multiple food protein allergies or other conditions requiring an amino acid-based formula. Both Alfaré® HMO and Alfamino® HMO are suitable for cases of secondary (transient) lactose intolerance.

<sup>1. Zivkovic et al., Proc Natl Acad Sci U S A. 2011;108(suppl 1) :4653‐4658. 
2. Zivkovic et al., Funct Food Rev. 2013;5(1):3-12..
3. Koletzko B, et al. J Pediatr Gastroenterol Nutr. 2005;41(5):584-99. 
4. Vandenplas et al. An ESPGHAN position paper. 2023. https://www.espghan.org/dam/jcr:7100468b-c6df-48bc-a566-6b13c427e756/CMA%20ESPGHAN%202022_V31.pdf;
5. Francavilla R, et al. Pediatr Allergy Immunol 2012;23(5):420-7. 
6. Maslin K, et al. Pediatr Allergy Immunol 2018;29(8):857-62. 
7. Miraglia Del Giudice M, et al. Ital J Pediatr 2015;41:42. 
8. Nowak-Węgrzyn A, et al. Allergy 2019;74(8):1582-4. 
9. Nowak-Wegrzyn A, et al. Nutrients 2019;11:1447.</sup>

There are 2 types of lactose intolerance (LI), primary and secondary. Importantly, primary LI does not usually manifest clinically before 5 years of age.¹ About 70% of the world’s population, more commonly adults, suffer from primary LI which is genetically predisposed, leading to a gradual decline in lactase expression over time.^1,2

Secondary LI can occur at any age; when there is villus damage, for example gut enteropathy, which can occur in some infants with CMPA.¹ Secondary LI is transitory and once the cause, commonly viral gastroenteritis (or gut enteropathy in CMPA), has been treated it resolves quickly.³ There is limited data supporting the removal of lactose from the diet of infants (in these clinical situations), knowing its potential benefits. The recommended feeding for infants, regardless of illness, is breastmilk, which contains a high concentration of lactose; and it is not recommended to stop breastfeeding in those with gastroenteritis.⁴ In fact, the WHO suggests that in infants with diarrhea breastfeeding should continue during rehydration therapy.⁵ Moreover, when lactose is fermented in the colon, it results in the growth of bifidobacteria which stimulates a healthy gut microbiota.⁴ In the recent opinion paper by ESPGHAN (2023) they propose that when CMA exists with severe diarrhoea and/or severe malnutrition, the transient use of a formula without lactose for 2- 4 weeks may be preferred.⁵

<sup>1. Heine RG, et al. World Allergy Organ J 2017;10(1):41. 
2. Harvey CB, et al. Ann Hum Genet 1998;62(Pt 3):215–23. 
3. Heyman MB. Pediatrics 2006;118(3):1279–86. 
4. Vandenplas Y. Asia Pac J Clin Nutr 2015;24(Suppl 1):S9-S13.
5. Vandenplas Y, et al. An ESPGHAN position paper. 2023. https://www.espghan.org/dam/jcr:7100468b-c6df-48bc-a566-6b13c427e756/CMA%20ESPGHAN%202022_V31.pdf;</sup>

Medium-chain triglycerides (MCT) are made up of a mixture of triacylglycerols consisting of saturated fatty acids with a chain length of 6–10 carbons.^1-3 MCT are easily absorbed because they are relatively soluble in water.³ Consequently, they are hydrolyzed both faster and more completely than long-chain triglycerides (LCT), the faster action of pancreatic lipase being facilitated by their small molecular weight.³ These benefits appear to be useful for infants with an immature gut or those with intestinal failure.⁴ MCT therefore provide a rapid energy source.⁵ Adding MCT to formulas has been shown to be beneficial in severe fat malabsorption, such as intestinal failure.⁴ Alfaré® HMO and Alfamino® HMO contain 40% and 24% respectively of MCT fats, which may support energy uptake in infants with severe GI impairment (including infants with severe enteropathy affecting fat absorption related to CMPA).

<sup>1. Bach AC, and Babayan VK. Am J Clin Nutr 1982;36(5):950-62. 
2. Marten B, et al. Int Dairy J 2006;16:1374-82.
3. Clegg ME. Int J Food Sci Nutr 2010;61(7):653-79.  
4. Delplanque B, et al. J Pediatr Gastroenterol Nutr 2015;61(1):8-17. 
5. Babayan VK. Lipids 1987;22: 417-20.
6. Vandenplas et al. Amino Acids 2010. Vandenplas Y, Plaskie K, Hauser B. Safety and adequacy of a semi-elemental formula for children with gastro-intestinal disease. Amino Acids. 2010;38(3):909-914. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2839472/</sup>