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The treatment of cow’s milk allergy (CMA) relies on cow’s milk protein (CMP) avoidance with exclusive breast-feeding as a first option, which may be maintained when CMA symptoms in a breast fed infant occur close enough to the beginning of weaning. Maternal elimination of cow’s milk may be required but is not always mandatory; the decision is based on the persistence (or not) of clinical symptoms during exclusive breast-feeding.
The second and more common option is the use of CMP modified through hydrolysis, which results in so-called “hypoallergenic” and/or “anallergenic” formulas. Definitions of these formulas were criticized for containing potentially inappropriate medical claims and attempts were made to rely only on the degree of protein hydrolysis -- "extensive" or "high degree" protein hydrolysates as opposed to "partial" or "low degree" ones (Businco L et al, 1993, Aggett PJ et al, 1993). Extensively hydrolyzed formulas (eHFs) from different origins have been tested, including those derived from casein (Sampson HA et al, 1991, Ragno V et al, 1993) and from whey proteins (Halken S et al, 1993, Martin-Esteban M et al, 1998). One replacement formula also uses a soy and collagen based hydrolysate. Extensively hydrolyzed amino acid and peptide formulas with uniform distribution of molecular weight less than 1200 daltons may be suitable for most infants with CMA (AAP Committee on Nutrition, 1989), even though the numeric reduction of higher molecular weight molecules in enzymatic hydrolysis does not necessarily make the formula nonallergenic. Indeed, the optimal extent of hydrolysis is still doubtful (Poulsen OM and Hau J, 1987). Currently available methods for the calculation of molecular weight distribution in protein hydrolysates are limited (Bindels JG and Boerma JA, 1994). In addition, the hydrolysis per se may release biologically active peptides such as immunopeptide casein fragments (Britton JR, Kastin AJ, 1991) and traces of the original protein may be detectable in the final product (Mäkinen-Kiljunen S et al, 1993).
The regulations of the European Union for labeling infant formulas as having reduced allergenicity (or antigenicity) are based arbitrarily on a content of immunoreactive protein of less than 1 percent of total nitrogen containing substances (Commission of the European Communities, 1996), but there is no evidence that such a threshold of immunogenic protein would ensure a reduced clinical allergenicity. At present, a product’s potential for treatment and prevention of food allergy can only be determined by clinical trials using scientifically appropriate standards. It is accepted that the number of patients studied should be sufficient to project with 95 percent confidence that 90 percent of cow's milk-allergic patients will not react to the product (Kleinman RE, 1992). These recommendations (Kleinman RE et al, 1991, Kleinman RE, 1992), which should be met by hydrolysates in the treatment of patients with cow's milk protein allergy are based, from the clinical point of view, on results of a study reported in abstract in 1989, and published more extensively with some modifications in 1991 (Sampson HA et al, 1991). This study was carried out in older children (median age, 5.08 years) with a variety of clinical symptoms, mostly chronic manifestations (atopic dermatitis, rhinitis, or asthma) in addition to their cow's milk hypersensitivity. The European Society of Pediatric Allergy and Clinical Immunology (ESPACI) has stated that their recommendation for treatment of CMA is to use a formula that fulfills the criteria of 90 percent clinical tolerance (with 95 percent confidence limits) in infants with proven IgE-mediated CMA (Businco L et al, 1993).
Calculating that 90-95 percent of children allergic to CMP respond to eHFs, (Sampson HA et al, 1991, ESPGAN Committee on Nutrition, 1993, Businco L et al, 1993) implies that 5-10 percent still react to them. There are numerous reports on hypersensitivity reactions to eHFs in infants with cow milk allergy, both with immediate and delayed reactions (Businco L et al, 1989, Bock SA, 1990, Saylor JD and Bahna SI, 1991, Sampson HA et al, 1992, Kelso JM and Sampson HA, 1993). Thus other options are needed for those allergic to eHFs (Lake AM, 1997). The availability of an amino acid–based formula (AAF) (Neocate®, SHS International) (Sampson HA et al, 1992, Niggemann B et al, 2001) provided another option and offered the ability to refine the diagnosis of EHF allergy (De Boissieu D et al, 1997, Vanderhoof JA et al, 1997, Kelso JM and Sampson HA, 1993).
In a study published in 1997 (de Boissieu D et al, 1997), 16 children with presumed CMA, who presented with slowly evolving symptoms that persisted on an eHF diet, were switched to an AAF (Neocate®). This resulted in a good response in 13 cases, with a decrease in symptoms and an increase in weight gain. There was also a decrease in intestinal permeability, which probably corresponded to a decrease in local inflammation. These children relapsed on subsequent challenge with an eHF, confirming that they were allergic to cow’s milk hydrolysates. A similar study was carried out in the US by J Vanderhoof et al, in which 28 children with CMA and no response to eHF were given the same AAF for two weeks, resulting in symptom resolution in 25 cases (Vanderhoof JA et al, 1997). When the responders were later challenged with an eHF, 8 showed tolerance and 17 relapsed, confirming eHF allergy in nearly half of the patients
The time course of allergy to eHF may differ according to the presence or absence of associated food allergy (De Boissieu D and Dupont C, 2000). A recent study (De Boissieu et al, 2002) further depicts the evolution of infants allergic to both CMP and eHF and demonstrates that the time course of eHF allergy differs according to the association or not with allergy to several other foods. When allergy involves eHFs and several other foods, tolerance of eHFs and of CMP occurs later and a largely restricted diet based on AAF is required for a longer duration. This fits with the recent description of the use of EleCare® (Sicherer SH et al, 2001) in 31 consecutive children, of whom 29 had multiple food allergy and 13 had not tolerated eHFs. Those were enrolled in the study at a median age of 23.3 months (range 6 months to 17.5 years) and received their AAF for a median of 21 months (range 7 to 40 months).
The prevalence of concomitant soy intolerance during cow’s milk allergy probably occurs in 10 to 35 percent of infants. The prevalence of soy allergy in children with IgE-associated CMA was 14 percent (Zeiger RS et al, 1999). In children with non-IgE-associated CMA, the occurrence of intolerance to soy was more common, and the AAP Committee on Nutrition has recommended eHFs for these patients (AAP Committee on Nutrition, 1998). However, two studies (Zeiger RS et al, 1999, Klemola T et al, 2002) confirm that of infants with CMA, 70 percent tolerate soy formula without any symptoms, 10 percent have adverse reactions to soy formula, and that severe allergic reactions or development of IgE-mediated allergy to soy are uncommon. Soy formula may be considered as a first-choice alternative formula in infants with cow's milk allergy, with the exception, perhaps, of young infants (aged less than 6 months) who seem to react more that older children. The greater palatability and lower cost of soy formulas further increase their usefulness. Soy formula should nonetheless be introduced under physician observation to document tolerance.
An elimination diet may have adverse effects in children. The diagnosis of CMA has to be firmly established or suggested when infants with suspected CMA are referred to nutritionists and health workers for implementation of elimination diet. If the diagnosis of CMA has not been made with certainty, parents may resort to unreasonable dietary restrictions. In a cohort of children (mean age 7 months) with atopic dermatitis, challenge-proven CMA and clinical control of symptoms achieved, the mean length SD score and weight-for-length index of patients decreased compared with those in healthy age-matched children (Isolauri E et al, 1998). Low serum albumin was present in 6 percent of the patients, 24 percent had an abnormal urea concentration, and 8 percent had a low serum phospholipid docosahexaenoic acid. The delay in growth was more pronounced in a subgroup of patients with early onset than in those with later symptoms. A recent study (Christie L et al, 2002) shows that more children with CMA or multiple food allergies consumed dietary calcium below the recommended amount compared with children without CMA and/or one food allergy. The possibility of consuming a less than recommended intake of calcium and vitamin D in children with food allergy was less if the child received nutrition counseling (p<.05) or consumed a CMP free infant/toddler formula or calcium-fortified soy beverage.
See Also: Cow's Milk Allergy, Part 1.
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This material has been prepared by members of the IFM’s Advisory Committee on Child Health and Nutrition.
June 2004
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