United Pharmaceuticals SAS

How the type of protein influences particle morphol. remains a hot topic of debate.In this study we focused on the drying behavior of two major milk protein types; i.e., whey protein and native micellar caseins.To improve understanding of the role of each protein in the particle-forming mechanisms, seven mixtures containing different whey proteins to caseins ratios were investigated.A monodisperse spray dryer (MDSD) was used to produce uniform particles by drying monodispersed droplets in a hot, dry air flow.Single particles were also obtained from the same material using single droplet drying in a pendant configuration.Powders were characterized according to their phys. characteristics and their rehydration properties.It was demonstrated that particle morphol. was mainly governed by the type of protein matrix, almost regardless of the drying kinetics, which differed considerably between MDSD and single droplet drying.Controlling product formulation thus represents a potential means by which to tune particle morphol. and therefore the functional properties of powder.

Breast-feeding is generally accepted as the ideal food for infants. This commentary focuses on alternative choices of infant feeding and does not discuss breast-feeding. Many reviews conclude that the effect of breast-feeding in the prevention of allergic diseases has not been conclusively demonstrated; however, this statement should be formulated in the opposite way because the breast-fed baby is the criterion standard. Rather, the correct postulation should be that it is not demonstrated that cow's-milk–based infant feeding induces a higher risk for the development of allergic disease than breast-feeding. Discrepancies in the literature can, most of the time, be explained at least in part by differences in the time frame in which the effect is measured: Although some focus on the short-term effect of the method of feeding (eg, cow's-milk allergy, atopic dermatitis), others focus on the long-term effect (allergy prevention in general). The Cochrane report on the use of hydrolyzed formula for the prevention of allergy concluded that for nonbreast-fed infants, the use of hydrolyzed formula for at least 4 months of life reduces the incidence of allergy, especially atopic dermatitis (1). Moreover, the American Academy of Pediatrics and the European Society for Pediatric Allergy and Clinical Immunology recently stated that there is modest evidence that the use of extensive or partial hydrolyzed formula prevents atopic dermatitis and food allergy (2,3). Hays and Wood (4) published a critical review of the literature and came to similar conclusions. In the present issue of JPGN, Alexander and Cabana (5) present a meta-analysis evaluating the effect of partial whey hydrolysate versus intact cow's-milk protein on atopic dermatitis. The authors reviewed 18 articles, representing 12 independent study populations, and concluded that there is a 44% (square root of relative error [SRRE] = 0–56, 95% confidence interval [CI] 0.40–0.77) statistically significant reduced risk of developing atopic manifestations, including atopic dermatitis (5). Four articles identified methodologically strong studies, especially focused on atopic dermatitis; the incidence of atopic dermatitis was reduced by 55% (SRRE = 0.45, 95% CI 0.30–0.70) with partially hydrolyzed whey compared with intact protein formulae. Szajewska and Horvath (6) have recently published a meta-analysis on a similar topic in a different journal, with similar conclusions. They (6) stated that “partial hydrolyzed formula compared to standard formula is effective in allergy prevention in children at high risk for allergy.” They included a comparison between partial and extensive hydrolysate formulae and concluded that there is no benefit for extensive over partial whey hydrolysate (except for the cumulative incidence of all of the allergic diseases from 0–36 months of age) (6). All of the studies included in the meta-analysis by Alexander and Cabana (5), with 1 exception, regard infants as being at “high risk for allergy” based on family history. The EuroPrevall review (7) concluded that there is little evidence to support the current recommendations on infant feeding with the objective of reducing the prevalence of allergic disease (beyond atopic dermatitis): “The use of milk based hydrolysates is also widely recommended although the evidence supporting this is weak” (7). An important bias in methodology in meta-analyses may be induced by pooling data obtained with different hydrolysates. In other words, interventional prevention studies conclude that in “high-risk” infants, the hydrolysates that have been tested have a short-term preventive effect, decreasing the incidence of cow's-milk allergy and, to some extent, atopic dermatitis. There are no data to suggest that there is a preventive effect on other allergic manifestations, but one can also state that there is an absence of evidence, or even absence of a trend, in the literature to suggest that infants that have been fed hydrolysates are (at a later age) at increased risk to develop allergy. The latter had been hypothesized in the beginning when prevention of hydrolysates was launched as a concept because of a possible lack of induction of tolerance. Some may argue that it cannot be denied that, to some extent, a potential bias exists in many studies in that they are funded by the formula manufacturers themselves. The study by Exl et al (8) is the only study in a general not-at-risk-for-allergy population, but it is funded and published by Nestle. Moreover, the meta-analysis in the present issue of JPGN and the one by Szajewska and Horvath (5,6) are funded (partially) by Nestle (Nutrition Institute). The German Infant Nutritional Intervention (GINI) study (9) is an exception to this because it has been independently funded. Therefore, it is reassuring to observe that the results of the GINI study are in line with the majority of the data from the other trials. This is confirmed in the meta-analysis by Szajewska and Horvath, who conclude that “results should be interpreted with caution because of a lack of methodological rigor in many trials. Reassuringly, the strongest evidence comes from a well-designed and conducted, independently funded randomized controlled trial” (6). Alexander and Cabana (5) concluded that regardless of study design, infant population, follow-up time, and study location, individual study findings were consistent in reporting a reduced incidence of atopic dermatitis. The vast majority of the data have been accumulated in studies performed in atopic families, with 2 family members being atopic. Although epidemiologic data provide evidence that the risk of developing atopic disease in the offspring is related to the presence of atopic disease in the family, there are no epidemiologic data that focused specifically on cow's-milk allergy. Except for the study by Exl et al (8), all of the data have been accumulated in at-risk infants. Szajewska and Hovarth concluded that there is evidence to recommend the use of partial hydrolysate formula as an option for prevention of allergic disease, particularly atopic dermatitis/atopic eczema (6). In other words, at least 6 independent meta-analyses came to the same conclusion that in nonbreast-fed infants born in atopic families, partial whey hydrolysates (at least the ones studied) are preferred to standard formula (1–6); however, many questions are still unanswered. A more detailed examination of national recommendations shows that the main discrepancies among national recommendations are related to the use of hydrolyzed infant formulae (partial, extensively, or “proven reduced hypoallergenicity”), the age at which solids should be introduced, and whether the introduction of allergenic foods into the infant's diet should be delayed (7). It is stated in all of the recommendations that only the hydrolysates that have been clinically tested can be recommended. What has not been studied cannot be recommended. This does not mean, however, that hydrolysates that have not been studied or have only been poorly studied are not effective. The effectiveness is not known. Therefore, for now, clinical testing of the efficacy of hydrolysates has been recommended as mandatory to be able to make this claim. The relevance of the in vitro determination of residual allergenicity has been poorly validated. The relevance of animal testing has also been poorly studied. The question can be raised as to how strong the evidence is that clinical testing is mandatory. The GINI study is often cited as an example to strengthen the viewpoint that clinical testing is mandatory (9); however, the extensive whey hydrolysate that scored poorly at 1 and 3 years of age scored equal to the extensive casein and partial whey hydrolysate at the age of 6 years (10). This brings into question the information provided by 1 clinical trial and suggests the significant influence of confounding variables (known and unknown). If clinical testing is considered mandatory, then different well-designed studies are needed. How many studies are needed and where the funding for these trials comes from remains open for debate, as does the issue of optimal duration of intervention; no trials have yet compared different durations of preventive intervention. The question of when a formula should be retested can be raised as well because formula composition changes over time. If clinical testing of the hypoallergenic potential of a formula is mandatory, it seems logical to conclude that new studies are needed when or if the technique of hydrolysis changes. Fortunately, the technique of hydrolysis has not, to our knowledge, changed for most of the formulae used in prevention. But what about other changes in formula composition that may have an impact on the development of the immune response, such as the addition of long-chain polyunsaturated fatty acids, the addition of prebiotics, probiotics, and so on (11)? The effects of other changes in infant formula composition are not considered in most of the hydrolysate-prevention studies. Moro et al (12) showed that the addition of a specific oligosaccharide mixture (Immunofortis) to an extensive whey hydrolysate reduces atopic dermatitis about 50%. Although the population tested was at intermediate risk for atopic disease (single family member atopic disease) as opposed to most partial hydrolysate prevention studies (with biparental history of atopic disease), up to 50% of the infants fed an extensive hydrolysate had developed atopic dermatitis at the age of 6 months, versus only 25% in the group with the same formula with prebiotics (12). There are no clinical studies that evaluate the potential additional benefits of probiotics, long-chain polyunsaturated fatty acids, and other dietary changes that may influence the development of allergy. The few other preventive measures that have been shown to reduce the risk of allergic sensitization and atopic diseases in mother and child are the avoidance of smoking and alcohol consumption during pregnancy and lactation and the avoidance of impairment of gastric function (13). More studies are definitively needed to address the influence of certain foods, food components, and environmental factors on the prevention of allergic diseases in low- or high-risk infants (13). One of the frequently forgotten aspects is the recently acquired knowledge that antacid treatment can induce sensitization (14). What about the degree of hydrolysis? The broadly accepted concept of partial versus extensive hydrolysates is based on an arbitrary consensus. An extensively hydrolyzed protein has a lower median molecular weight than partial hydrolysates (although there is no consensus on a cutoff, and if there would be one, this would be arbitrary because the process of degree of hydrolysis is in fact a continuum between the intact protein at one end and amino acids at the other end), and thus has a more reduced potential allergenicity. The effect on treatment is beyond the scope of this document. It is obvious that a formula indicated in treatment needs different composition than a formula indicated in healthy infants in prevention. After many years of debate as to which is best in prevention, consensus seems to be reached that both partial and extensive hydrolysates that have been studied score comparably in prevention. The concept of induction of tolerance has also recently become broadly accepted. Therefore, strict elimination and/or delayed introduction of certain foods may have more disadvantages than advantages (11,15). In theory, partial hydrolysates should induce better tolerance than extensive hydrolysates, and some in vitro data suggest this direction. Today, however, the data suggest that there is no clinically significant difference between partial and extensive hydrolysates on the induction of oral tolerance of cow's-milk protein. A relevant but yet unanswered question is, what is the rationale for feeding an infant intact cow's-milk protein? What are the arguments, except for the fact that mother's milk contains intact protein and not a hydrolysate? However, intact human (milk) protein cannot be compared with intact cow's-milk protein, neither chemicallynor immunologically. In some parts of the world (the United States), partial whey hydrolyzed formula is considered a formula for all infants. There is evidence that a formula with intact cow's-milk protein increases the incidence of atopic dermatitis, cow's-milk allergy, and wheezing in early childhood in comparison with breast-feeding for at least 4 months. In studies on infants at high risk for atopy who are not exclusively breast-fed for 4 to 6 months there is modest evidence that the onset of atopic disease may be delayed or prevented by the use of hydrolyzed formulas compared with formula made with intact cow's-milk protein, particularly for atopic dermatitis. Emphasis has switched recently to deliver functional benefits rather than compositional similarity to breast milk. Clinically relevant adverse effects of hydrolysates have not been reported (1–6,8,9), except for a possibly reduced acceptance (but also contradicted) because of the poor taste and higher cost. Moreover, there is a lack of evidence that transitory and limited ingestion of intact protein while the infant is generally fed a hydrolysate is potentially harmful. The theory of the “dangerous bottle” has been hypothesized but also contradicted (16). Guidelines now recommend the hydrolysates that have only been clinically tested in at-risk infants. Despite most studies having been performed in families with 2 atopic family members, 1 atopic family member is considered in the guidelines as an indicator to choose a formula with a hydrolysate instead of intact protein. In other words, the actual recommendations focus on a different target population than the population in which most data have been accumulated. The adherence to these guidelines seems extremely poor (17) (although it was probably evaluated only in 1 region in 1 study). Family history has a poor sensitivity and specificity for determining atopic risk. Up to now, there has not been any appropriate validated tool or questionnaire developed for assessing risk based on family history (18). Moreover, not 1 study focused on the question of whether a positive family history of atopic disease is a risk factor for cow's-milk allergy (all of the epidemiologic studies focused on family history as a risk factor for later atopic disease). It has been recognized by Bergmann et al (18) that “the preventive capacity of family history is not high enough to recommend it as a screening instrument for primary prevention.” More and more formulas contain protein hydrolysates, although their market positioning is not for treatment or prevention of allergy but rather for gastrointestinal discomfort and other nonspecific, vague indications. In Belgium, there is an antiregurgitation formula that is a (partial) hydrolysate. Because of the nonspecific positioning in the market, formulas with hydrolysates are being fed to infants without an allergy indication. New preventive and therapeutic strategies are being tested to induce specific food-allergen oral tolerance through the ingestion of progressively increasing doses of the offending food (19). The concept of hydrolysates with reduced (but not zero) allergenicity may fit into this concept. The criterion standard in infant feeding is the breast-fed infant. It has been shown in at-risk infants that with (partial) hydrolysates, compared to intact cow's-milk protein, the incidence of cow's-milk allergy and atopic eczema is reduced, and therefore closer to the criterion standard. It has to be acknowledged that there are more infants with cow's-milk allergy in nonatopic than in atopic families because the number of nonatopic families is much larger. Clinically relevant adverse effects of hydrolysates have not been demonstrated. Given the observation that clinically relevant differences between formula-fed and breast-fed infants are seen less frequently, maybe the relevant question regarding infant feeding should change. What is against changes in infant formula composition if clinical safety has been demonstrated beyond doubt and there are strong in vitro arguments in favor of this change? We could not demonstrate any significant difference in the development of basal immune parameters in breast-fed, standard formula-fed, and formula with prebiotics–fed healthy unselected infants (20). This does not mean that addition of these prebiotics is without benefit for the infant. Hydrolysates have been shown in at-risk infants to reduce cow's-milk allergy and atopic dermatitis and to be safe. As a consequence, broadening the use of hydrolysate formula to the general population is tempting. Before doing so, however, more data on cost efficacy and more general questions such as influence on taste development and acceptance and tolerance of diversification in large populations are needed. Key factors to determine the choice of the optimal infant formula include nutritional effect on the baby, acceptability, palatability, and cost.