Supplemental Material can be found at: http://jn.nutrition.org/content/suppl/2008/07/11/138.1.145S.D C1.html The Journal of Nutrition The Use of Whey or Skimmed Milk Powder in Fortified Blended Foods for Vulnerable Groups: A Literature Review

The Use of Whey or Skimmed Milk Powder in Fortified Blended Foods for Vulnerable Groups1,2

Camilla Hoppe, Gregers S. Andersen, Stine Jacobsen, Christian Mølgaard, Henrik Friis, Per T. Sangild, and Kim F. Michaelsen*

Department of Human Nutrition, Faculty of Life Sciences, University of Copenhagen, DK-1958 Frederiksberg, Denmark

Abstract Fortified blended foods (FBF), especially corn soy blend, are used as food aid for millions of people worldwide, especially malnourished individuals and vulnerable groups. There are only a few studies evaluating the effect of FBF on health outcomes, and the potential negative effect of antinutrients has not been examined. Different lines of evidence suggest that dairy proteins have beneficial effects on vulnerable groups. Here we review the evidence on the effects of adding Downloaded from whey or skimmed milk powder to FBF used for malnourished infants and young children or people living with HIV or AIDS. Adding whey or skimmed milk powder to FBF improves the protein quality, allowing a reduction in total amount of protein, which could have potential metabolic advantages. It also allows for a reduced content of soy and cereal and thereby a reduction of potential antinutrients. It is possible that adding milk could improve weight gain, linear growth, and recovery from malnutrition, but this needs to be confirmed. Bioactive factors in whey might have beneficial effects on the immune jn.nutrition.org system and muscle synthesis, but evidence from vulnerable groups is lacking. Milk proteins will improve flavor, which is important for acceptability in vulnerable groups. The most important disadvantage is a considerable increase in price. Adding 10–15% milk powder would double the price, which means that such a product should be used only in well-defined at ARLA FOODS on January 27, 2016 vulnerable groups with special needs. The potential beneficial effects of adding milk protein and lack of evidence in vulnerable groups call for randomized intervention studies. J. Nutr. 138: 145S–161S, 2008.

Introduction delivery to recipients of U.S. food aid commodities. The project This article is one component of a Food Aid Quality Enhance- is coordinated by SUSTAIN, a U.S. nongovernmental organiza- ment Project to enhance product quality and improve nutrient tion that uses science and technology to improve nutrition in developing countries. The article will assess the value of adding whey protein (WPRO)3 to fortified-blended foods (FBF) to im-

1 Published in a supplement to The Journal of Nutrition. The review was sup- prove their nutritional value. The potential impact of using other ported in part by funding from Sustain as part of a Food Aid Quality Enhancement dairy products, especially skimmed milk powder (SMP), will Project and an unrestricted grant from the United States Dairy Export Council. also be evaluated, as it has been used in many other food aid Guest Editor disclosure: Writing of the review was in part supported by funding products and is widely available. from SUSTAIN and an unrestricted grant from the US Dairy Export Council, FBF is used on a very large scale to feed populations in low which is also stated in the acknowledgments. K. F. Michaelsen has received research grants from the Danish Dairy Research Foundation to perform research income countries, especially malnourished individuals and vul- on the effect of milk whey on growth. nerable groups. The most common FBF are corn soy blend (CSB) 2 Author disclosures: K. F. Michaelsen, C. Hoppe, and C. Mølgaard have received and wheat soy blend (WSB). They are made from wheat or corn research grants from the Danish Dairy Research Foundation to perform research as the main staple, soy flour to improve the protein quality, a on the effect of milk whey on growth. P. T. Sangild has received research funding from Arla Foods amba. G. S. Andersen, S. Jacobsen, and H. Friis, no conflicts of vegetable oil source, and a mix with mineral-vitamins to fortify interest. the blend. Most of the FBF is donated by the United States and 3 Abbreviations used: AA, amino acid; BCM, body cell mass; b-LG, b-lactoglobulin; delivered by the World Food Program (WFP). BMD, bone mineral density; CSB, corn soy blend; CSM, corn soy milk; DSM, dried The recipes are developed to provide a balanced intake of skim milk, same as NDM and SMP; F-100, therapeutic milk; FBF, fortified blended essential nutrients for growth and development of young food; GMP, glycomacropeptide; GSH, glutathione; IGF, insulin-like growth factor; IOM, Institute of Medicine; MT, metric ton; NDM, nonfat dry milk, same as DSM children and for malnourished individuals. They were originally and SMP; PDCAAS, protein digestibility corrected amino acid score; PE%, protein developed by the U.S. Agency for International Development in energy percentage; PLWHA, people living with HIV and AIDS; RUTF, ready-to-use the 1960s. They are designed to be energy and nutrient dense, therapeutic food; SMP, skimmed milk powder, same as DSM and NDM; WFP, and, as they are precooked, they are easily prepared into an World Food Programme; WP, whey powder; WPC, whey protein concentrate; WPI, whey protein isolate; WPRO, whey protein; WSB, wheat soy blend; WSM, energy-dense porridge that is easy for children to eat. However, wheat soy milk. very few studies have evaluated the effect of FBF in malnour- * To whom correspondence should be addressed. E-mail: [email protected]. ished and vulnerable groups. Raw soy contains considerable

0022-3166/08 $8.00 ª 2008 American Society for Nutrition. 145S amounts of antinutrients (such as antitrypsin) that potentially FBF interfere with protein digestibility and mineral absorption. The FBF consist of a mixture of cereals, pulses, fats, vitamins, and processing of FBF is designed to reduce antinutritional factors, minerals intended to provide a balanced intake of essential but the actual decrease in antinutritional factors has not been nutrients for vulnerable groups. These comprise the original FBF, documented clearly. The efficacy of cereal- and legume-based namely corn soy blend (CSB) and wheat soy blend (WSB). supplementary feeding in large-scale programs has not been However, other types of FBF exist based on sorghum and soy, conclusively demonstrated (1–3). bulgur, wheat and soy, or combinations of cereals with heat- WFP held a technical review on its FBF in Rome in July 2005, treated soy in its full fat form or as defatted flour. There are also which also dealt with the potential use of milk or milk products FBF that contain milk, corn soy milk (CSM) and wheat soy milk in FBF. The objective was to review the appropriateness of the (WSM), described in more detail below, but they are not widely product specifications vis-a`-vis nutritional requirements of spe- used, mainly because of the higher cost. WFP has also supported cific target groups, including protein content and qualities, the manufacture of locally designed and produced FBF, includ- keeping the overall cost of the products in mind. One point of ing Unimix in Kenya, Famix in Ethiopia, Likin Phali in Malawi, discussion was a number of recent studies highlighting the role and Indiamix in India. of foods of animal origin in ensuring child growth and devel- WFP distributed almost 300,000 metric tons (MT) FBF in opment. The level of antinutritional factors in the blends was 2006: .207,000 MT was bought in Italy, Belgium, and develop- also discussed. One conclusion was the need to develop special ing countries, and 88,000 MT was received as in-kind donations, ‘‘convalescent’’ foods for moderately undernourished children. mainly from the United States (WFP, personal communication). Also, it was concluded that the benefits of including SMP in FBF Assuming that FBF provided ;25% of the energy intake [500 kcal and in new foods for malnourished children should be reviewed. (2.1 MJ)] of those receiving it, the amount would be sufficient to In terms of formulation, it was recommended that FBF form supply ;6.5 million people for a whole year. Downloaded from 25% of the total ration/diet, and it was suggested that a conva- The nutritional quality of FBF is improved through the lescent food should supply a minimum of 50% of energy intake addition of soy, and the product is fortified with essential micro- during an initial phase of 1–6 wk. nutrients. Because they are precooked and distributed as flour, The main aim of this review is to evaluate whether or not they require only limited amounts of fuel for cooking and are there is research to support substituting some of the vegetable or simple to prepare and microbiologically safe. Furthermore, they

legume protein in the blends with dairy protein. Two central can be produced relatively inexpensively. However, WFP is at jn.nutrition.org areas are covered. One is to evaluate data on the potential effects present reconsidering the formulation to upgrade the nutritional of improved protein quality on health outcomes, and the other value. is to assess evidence on potential positive health effects of bio- The ingredients (cereals and legumes) are heat treated before logically active compounds in milk, especially whey. milling to improve digestibility and to reduce levels of anti-

The review focuses on 2 important vulnerable groups, nutrients and cooking times. The FBF is fortified with a vitamin at ARLA FOODS on January 27, 2016 namely people living with HIV and AIDS (PLWHA) and and mineral mix. malnourished infants and young children. Both groups have increased nutritional needs because of infections and different Types of FBF. CSB and WSB are by far the most widely used degrees of malabsorption, have a low muscle mass and thereby FBF. They contain cornmeal or wheat flour, soybeans, and a increased nutritional needs for catch-up growth, and also often mineral-vitamin mix. CSB consists of ;80% maize and 20% have poor appetites. soy, and WSB consists of ;75% wheat and 25% soy. WFP has A spectrum of nutritional conditions pertain to the popula- given specifications for the energy, protein, and fat content of the tions receiving food aid, including nonmalnourished individuals blends (Table 1). However, according to the U.S. specifications in need of food, vulnerable groups and individuals with mod- (8), the energy content is somewhat lower [CSB 376 kcal/100 g erate malnutrition, and those with severe malnutrition. FBF (1.57 MJ/100 g) and WSB 355 kcal/100 g (1.49 MJ/100 g)], and without any animal foods will be sufficient to support those the protein content also differs (CSB 16.0 g/100 g and WSB 21.5 without malnutrition. SUSTAIN is currently assessing their g/100 g). In recipes for CSB and WSB, the content of soy flour suitability as complementary foods for nonmalnourished and (defatted) is 22 and 20%, respectively (9). moderately malnourished infants, and preliminary findings suggest that dilution of the cooked FBF may negatively impact TABLE 1 Nutritional value of commonly used food-aid energy and nutrient density and infants’ ability to consume commodities according to WFP1 adequate quantities based on their average stomach capacity. During the last decade, a special diet (therapeutic foods, F-100, Energy Fat Fat Protein Protein produced by several manufacturers) in which the only protein kcal/100 g MJ/100 g E% g/100 g E% source is milk has proven to be very effective in hospital-based FBF treatment of severely malnourished children and has reduced CSB 380 1.60 14.2 18.0 18.9 mortality considerably (4). Recently, a new kind of therapeutic WSB 370 1.55 14.6 20.0 21.2 food, ready-to-use therapeutic food (RUTF), has been used in CSM 380 1.60 14.2 20.0 21.1 home-based treatment programs of both severely and moder- Ingredients ately malnourished children (5–7). Most of the RUTF contains a Wheat (cereal) 330 1.39 4.1 12.3 14.9 considerable amount of milk powder. If FBF fortified with dairy Corn (meal) 360 1.51 8.8 9.0 10.0 protein is introduced as a special food or a ‘‘convalescent’’ food Soy (flour, full fat) 380 2.00 41.6 37.2 31.0 to selected vulnerable groups, it may fill a gap between plant- Dairy products based FBF and RUTF wherein about half of the protein or more SMP 360 1.51 2.5 36.0 40.0 is dairy protein. Consequently, this review also briefly summa- Dried whole milk 500 2.10 48.6 25.0 20.0 rizes the composition and main results obtained using thera- peutic foods including RUTF. 1 Adapted from (150).

146S Supplement FBF with milk as SMP are available but have not been used cheese-making process. The remnant whey is high in both very much, mainly because of the price. Recipes for both CSM lactose and minerals (13). Currently there are 2 major basic and WSM have been developed. Both of these have 15% (wt:wt) types of whey available, sweet and acid (sour) (14). Acid whey is SMP.In both recipes, the amount of soy has been reduced by ;4– obtained during the production of acid-coagulated cheeses such 5% to compensate for the higher protein content. We have not as cottage and cream cheese, and sweet whey originates from the been able to find any studies evaluating the effects on growth or manufacture of rennet-coagulated and hard cheese. The biolog- recovery from malnutrition with these milk blends or studies that ically active casein glycomacropeptide is present only in sweet have compared effects of CSM or WSM with FBF with no milk. whey (14). The concentration of calcium in acid whey is ;2-fold higher than that in sweet whey. Therapeutic foods Therapeutic foods are mainly intended for the treatment of Whey powder, concentrates, and isolates. WP, which is severe malnutrition in children and are outside the scope of this dried whey, has a typical protein content of 11–14.5% and a article. They will, however, be described briefly, as the protein lactose content of 63–75%. WPRO is, however, processed into source in these products is either 100% milk protein (therapeutic whey protein concentrate (WPC) with different concentrations, milk or F-100) or mainly based on milk protein (RUTF). F-100 usually ranging from 34–80%, and as whey protein isolate consists of 42% milk powder (SMP), equivalent to 11% of (WPI) containing at least 90% protein. energy from proteins. Thus, all protein is milk protein. RUTF nutritional composition is quite close to that of the F-100 Protein quality therapeutic milk, but the major difference is that F-100 is given as One of the main arguments for adding whey or SMP to FBF is to a milk with an energy density of ;1 kcal/g (4.2 kJ/1 g), whereas improve the protein quality. Improved protein quality allows for a reduction of the total amount of protein needed, which is RUTF is fat-based pastes with a very low water content and an Downloaded from energy density that is ;5 times as high [5 kcal/g (21 kJ/g)]. Some beneficial both for economic reasons, as the amount of soy might manufacturers add whey powder (WP) to RUTF together with be reduced, and for metabolic reasons, as metabolizing surplus SMP. The rationale for adding WP is not the potential biological nitrogen is not efficient. effects of whey but rather that WP is less expensive than SMP, has a better protein quality, and might have some technological Protein quality indexes. High protein quality is defined as

advantages. Therapeutic milk/F-100 and RUTF have been very protein that supports maximal growth. The various protein jn.nutrition.org successful in supporting growth and reducing mortality in quality indexes include 1 or more factors related to the AA pro- severely malnourished children, and it is plausible that part of file, digestibility, and the presence of inhibiting or biologically this effect could be related to the high milk content, as discussed active components in the food ingested. later. Until recently, protein efficiency ratio was the most widely

used index for evaluating protein quality. It is defined as body at ARLA FOODS on January 27, 2016 Milk and powdered dairy products weight gain divided by the amount of test protein consumed by a Milk is an excellent source of a number of nutrients, and its young growing rat. Consequently, different growth patterns proteins are easily obtained and used in various contexts, which between rats and humans are a concern when protein efficiency positions them among the best-characterized proteins chemically, ratio is used (15). physically, and genetically. Mature bovine milk contains ;3.5% Protein digestibility-corrected amino acid score (PDCAAS) is protein (10,11). The main protein fractions of bovine milk are a more recent evaluation method of protein quality and has been casein and whey, which account for ;80% and 20%, respectively. adopted by FAO and WHO (16) as the preferred method of The major casein products are as1-, as2-, g-, and k-casein. The evaluating protein quality in human nutrition. major WPRO include b-lactoglobulin (b-Lg), a-lactalbumin, PDCAAS represents the AA available after protein digestion, immunoglobulins (Ig), serum albumin, and lactoferrin, all of that is, the content of the first limiting essential AA in a test which possess specific biological activity (11,12). There are also protein divided by the content of the same AA in a reference several minor proteins with specific biological activities. pattern of essential AA (17). The index further includes true digestibility defined as the true digestibility of the test protein, Whole milk powder. The main difference between whole milk measured in a rat assay, thereby taking into consideration fac- powder and the other powdered products is the fat content. An tors influencing the digestion of the protein (15). The maximum important reason that whole milk powder is not used much in PDCAAS value is 1.0, meaning that 100% or more of the food aid is the short shelf life because the fat gets rancid easily. requirement of essential AA is achieved. A score above 1.0 is The alternative to milk fat, vegetable oil, has a longer shelf life rounded down to 1.0. However, several limitations must be and is less expensive. considered when PDCAAS is used: the validity of using the protein requirement of children in a reference AA pattern and SMP. SMP, which is also called nonfat dry milk (NDM) or dried the validity of using true digestibility and the truncation of skim milk (DSM), is characterized by having a low fat (0.8 g/100 values above 100%, which limits the information provided g) content. SMP has a high nutritional value and is a source of about the potency of a specific protein source to counteract and high-quality animal protein (36 g/100 g). SMP has a carbohy- balance inferior proteins in mixed diets (17). drate content of 52 g/100 g, which is predominantly lactose. When stored in cool conditions with low humidity, it has an Protein quality of FBF and ingredients. Plant protein sources average shelf life of 3 y. provide 65% of the world’s supply of edible protein, with the main contributors being cereal, especially wheat, rice, and corn. Whey. Whey is a collective term referring to the serum or liquid Soy is also used as a source of protein in blends designed for food part of milk that remains dissolved in the aqueous portion after aid programs, such as WSB and CSB, because of its favorable the coagulation of casein into curd during the manufacture of content and constitution of AA. Although plant products are a cheese, where most of the fat and casein have been used in the good source of protein and certain plant products contain much

Milk proteins in fortified blended foods 147S higher levels of some AA than animal sources, no plant source more, when milk is a considerable part of the protein, the provides optimal levels of all 9 essential AA. When the AA digestibility and, thereby, the bioavailability of the protein will profiles of the major plant staple food sources are compared be higher as reflected in the higher PDCAAS. with human muscle tissues, it appears that the limiting AA of In general, blends containing 10% WPC80% possess slightly corn is tryptophan, and in soy the sulfur-containing AA methi- higher PDCAAS than blends containing 20% WPC34% as 10% onine and cysteine. Further, all plant sources with the exception WPC80% contain slightly more protein than 20% WPC34%. of soy have a uniformly lower lysine content. In low-income Soy flour has approximately the same protein content as countries, problems with satisfying AA needs are mainly related SMP and WPC34%. Thus, exchanging soy for 1 of the 2 milk to monotonous diets. However, for mixed diets based on, for powders will result in approximately the same protein energy example, both cereals and legumes, requirements are often fully percentage (PE%), but the protein quality will increase from the achieved because the products complement each other and com- higher PDCAAS of milk products. pensate for the insufficient protein quality (18). It is beyond the scope of this article to develop detailed The PDCAAS of corn, wheat, and soy are 0.35, 0.37, and recipes. This can be done by linear programming where protein 0.93, respectively (Table 2). However, in the blended foods, the energy percentage, protein quality (PDCAAS), fraction of AA patterns of the ingredients complement each other, resulting protein that should be milk protein, lactose content, and fat in relatively better PDCAAS values, e.g., the PDCAAS of CSB energy percentage should be taken into consideration. and WSB are 0.65 and 0.64, respectively. If milk is added, as in CSM and WSM, the PDCAAS increases to 0.81 and 0.76, Antinutritional factors. Antinutritional factors are mainly respectively. Digestibility of protein in traditional diets from present in pulses, grain, and legumes and can impair intake, low-income countries is considerably lower than that of a typical uptake, or utilization of other food and feed components (19). Western diet. This is a result of the presence of less refined cereal These factors can be difficult to measure, and the Codex Com- Downloaded from and grain legumes, which contain less digestible protein mission has not yet set standards for these factors. Important fractions and high levels of insoluble fiber. antinutrients include lectin, hemagglutinins, saponins, antitryp- sin, antichymotrypsin, thiaminase, and phytate. The influence of adding whey or SMP to FBF on protein Raw soy is the most concentrated source of trypsin inhibitors. quality. To evaluate the potential effects of adding powdered Trypsin inhibitors are not restricted to their effect on trypsin but

milk to protein quality, we calculated the quality (PDCAAS) and may also inhibit other proteases that contain serine in the active jn.nutrition.org amount of protein of theoretical blends of FBF where the cereal site. Tannins are present in various plants, including cereal grains or soy has been replaced by different amounts of either whey or and legume seeds and possess the ability to precipitate proteins SMP (Table 3). in aqueous solutions, making them less available for digestion PDCAAS is partly based on the content of the first limiting and absorption. Phytates are found primarily in seeds, nuts, and

AA, as previously discussed. In accordance with the general grains and interfere with zinc and iron absorption as well as the at ARLA FOODS on January 27, 2016 knowledge that limited lysine can pose a problem in vegetable- bioavailability of other essential mineral nutrients. Furthermore, based food sources, the first limiting AA of blends in Table 3 is phytates are able to bind proteins in the gastrointestinal tract and generally lysine because of the low lysine content in either corn negatively influence the activity of digestive enzymes. or wheat. There is, however, an exception in 2 blends (see Although it has often been mentioned that soy contains high footnote 5 of Table 3), where the first limiting AA is tryptophan, levels of antinutrients, we have not been able to identify studies which is a consequence of the content of fairly concentrated with FBF that have clearly demonstrated a negative effect of such whey, which balances out the lack of lysine. antinutrients. Studies on infant formula based on soy protein In general, CSB has a slightly higher PDCAAS than WSB. show that there are no major differences in growth compared Also, blends with reduced soy content have a lower PDCAAS with cow’s milk-based formula (20). However, soy-based infant than blends in which soy is not reduced. It is not surprising that formulas contain soy protein isolates that have a low content products adding the same amount of WPC80% as WPC34% of phytate (1–2%), which is considerably lower than that in have considerably higher PDCAAS, as it contains more than FBF using crude toasted soy. In a recent comment from the double the amount of protein. The lower PDCAAS of blends ESPGHAN Committee on Nutrition, it was recommended that containing SMP in comparison with whey-containing blends is soy formulas be used for specific reasons only, as they may have explained by a lower content of lysine in SMP. nutritional disadvantages and contain high levels of phytate and The addition of the milk powders results in considerable phytoestrogens with unknown long-term effects (20). Addition- increases in protein energy percentages as expected, from the ally, in piglets, WPRO stimulate small intestinal and body level of 17.2–21% in CSB and WSB in blends with no milk up to growth relative to a corresponding isocaloric and isoproteinous levels ;20–25% when 5–20% milk powder is added. Further- diet with soy hydrolysate (21).

TABLE 2 Products and their protein quality indexes

WPI . 90% WPC80% WPC34% SMP F-100 CSM WSM CSB WSB Soy-flour Cornmeal Wheat Amino acids (151) (152) (151) (151) (153) (153,154) (153,154) (153,154) (153,154) (raw) (153) (153,154) flour (153)

g/100 g protein Total essential 47.79 46.33 48.43 44.22 44.21 39.71 36.91 37.87 34.17 37.52 38.35 30.05 Total BCAA 22.82 21.69 22.51 21.46 21.48 19.38 17.51 18.47 15.98 17.00 20.97 15.12 Total sulfur-containing AA 5.07 5.41 4.23 3.27 3.26 3.20 3.35 3.21 3.35 2.82 3.92 4.04 Protein, g/100 g product 100 79.89 35.00 33.50 15.97 19.97 20.62 17.43 20.02 36.54 9.44 10.65 Protein indices (PDCAAS) (17) 1.14–1.67 1.14–1.61 1.14–1.49 1.24 1.24 0.81 0.76 0.65 0.64 0.93 0.35 0.25–0.37

148S Supplement TABLE 3 PDCAAS of different blends with and without milk powder1

Blends with reduced cereal content1 Blends with reduced soy content2 Blends with no soy content3 CSB2 WSB CSB WSB Corn Wheat

PDCAAS (PE%)

Basic blend4 0.65 (17.2) 0.64 (21.0) 0.65 (17.2) 0.64 (21.0) 0.35 (9.5) 0.37 (13.9) 1 5% WPC34% 0.73 (18.5) 0.71 (22.0) 0.69 (16.5) 0.67 (20.3) 0.50 (10.8) 0.49 (14.9) 110% WPC34% 0.80 (19.7) 0.77 (23.1) 0.73 (15.8) 0.71 (19.7) 0.62 (12.1) 0.60 (15.9) 120% WPC34% 0.92 (22.2) 0.89 (25.2) 0.82 (14.5) 0.78 (18.4) 0.82 (14.5) 0.78 (18.1) 1 5% WPC80% 0.82 (20.8) 0.80 (24.4) 0.80 (18.9) 0.77 (22.6) 0.67 (13.1) 0.64 (17.3) 110% WPC80% 0.925 (24.4) 0.92 (27.3) 0.885 (20.5) 0.88 (24.4) 0.81 (16.8) 0.83 (20.6) 1 5% SMP 0.71 (18.4) 0.69 (22.0) 0.67 (16.6) 0.65 (20.3) 0.46 (10.8) 0.46 (14.9) 110% SMP 0.76 (19.6) 0.74 (23.1) 0.68 (15.8) 0.66 (19.6) 0.56 (12.0) 0.54 (15.9) 120% SMP 0.85 (22.1) 0.82 (25.1) 0.72 (14.4) 0.69 (18.3) 0.72 (14.4) 0.68 (18.0)

1 The amount of dairy powder (WPC or SMP) added to the blend replaced by the same amount of cereal (corn in CSB and wheat in WSB), whereas the amount of soy is unchanged. 2 The amount of dairy powder (WPC or SMP) added to the blend replaced by the same amount of soy, whereas the amount of cereal (corn in CSB and wheat in WSB) is unchanged. 3 The blends consist only of cereal (corn or wheat) and dairy powder (WPC or SMP) in different ratios. 4 Basic blends: CSB; 80% corn, 20% soy. WSB; 79% wheat, 21% soy. 5 The limiting amino acid is tryptophan. In the other blends lysine is the limiting amino acid. Downloaded from

Cost of milk, types of whey, FBF, and FBF components with recurrent acute or chronic infections such as those with TB The price of commodities used for FBF and relief feeding is an and HIV/AIDS. During the last few decades, the number of essential factor in deciding the composition of blends and rations. PLWHA has increased dramatically, and it has been realized that

Table 4 presents typical prices of milk products, FBF, cereals, and this group has considerable nutritional problems. jn.nutrition.org legumes as of March 2007. In recent years there have been con- siderable fluctuations of the world market prices on dairy prod- PLWHA. According to United Nations Programme on HIV/ ucts, and during the first half of 2007, there have been marked AIDS (22), as many as 4.1 million people became newly infected increases. Whey has traditionally been an inexpensive surplus with HIV during 2005, bringing the total number of people product from cheese production and has been used to feed pigs. living with HIV to 38.6 million. With .23 million AIDS deaths at ARLA FOODS on January 27, 2016 SMP and WPC (34 and 80%) are the products that may be rel- so far, and many more weakened by HIV infection, the epidemic evant to add to FBF, as they are the cheapest per unit protein. Up has consequences that are already brutally felt in most families to 2006, WPC34% has been ;25 to 33% cheaper than SMP. and communities in the hardest-hit countries and has a devas- Other whey types are more expensive per kilogram protein, and tating impact on social and economic development. unprocessed WP with 13% protein is more expensive than SMP Based on considerable animal and human data, conceptual and WPC34%, when compared as price per kilogram protein. frameworks describing possible 2-way relations between nutri- Based on a simple calculation of the amounts, not taking tion and specific infectious diseases have been developed. In brief, extra costs of mixing and other technical aspects into account, most infectious diseases may impair nutritional status, and im- adding for example 10% SMP or WPC34% to CSB will increase paired nutritional status or decreased intake may affect the risk the price of the product by about two-thirds to US$0.58/kg and and severity of infectious diseases (23). US$0.60/kg. The conceptual framework also applies to various nutrients and HIV infection. However, because it has become clear that Vulnerable groups oxidative stress—an effect of the infection in the absence of In many low-income countries, large proportions of the popu- adequate intake of antioxidants—directly leads to increased lation are nutritionally vulnerable, and food aid is often aimed replication of HIV in the cells, HIV-specific conceptual frame- mainly at vulnerable groups. Traditionally, infants and young works have been developed, and the current data on the relation children, pregnant and lactating women, and the elderly are between nutrition and HIV have been reviewed (24). regarded as nutritionally vulnerable. Other groups are patients HIV infection may affect the nutritional status of individuals in various ways. It may have a direct biological effect on TABLE 4 Typical prices of SMP, WP, and FBF. March 20071 nutritional status, and it may have indirect effects that are mediated through reduced food production or cash income, and, Commodity US$/kg product US$/kg protein hence, reduced access to food. The biological effects result from HIV disease causing an acute-phase response or local lesions, SMP 2.35 6.73 which may reduce intake and absorption and increase utilization WPI . 90% 7.26 8.07 and loss of nutrients. There is evidence to suggest that even early WPC80% 6.27 7.84 asymptomatic HIV infection affects absorption of nutrients and WPC34% 2.64 7.76 also increases resting energy expenditure. WP (13%) 1.10 9.17 Based on a WHO consultation, it is recommended that 2 CSB 0.38 (0.36–0.40) 2.18 asymptomatic HIV-infected individuals increase their energy 2 WSB 0.47 (0.40–0.54) 2.35 intake by 10% and that those with symptomatic disease increase 1 Sources: USDA, National Agricultural Statistics Service and WFP. their intake by 20–30%. However, regarding proteins, the WHO 2 Values are means (ranges). consultation concluded (25):

Milk proteins in fortified blended foods 149S There are insufficient data at present to support an TABLE 5 Safe level of protein intake for weaned infants, increase in protein intake for PLWHA above normal children, and adolescents per kilogram 1 requirements for health, i.e., 12% to 15% of total energy body weight intake. Participants were aware of the published nutri- tional guidance suggesting increased protein intake during All Girls Boys HIV infection, but they concluded that these recommenda- Age Safe levels2 Age Safe levels2 Age Safe levels2 tions were not based on rigorously conducted studies (25). y g/(kg d) y g/(kg d) y g/(kg d) Similarly, there are no recommendations regarding quality of 0.5 1.31 11 0.90 11 0.91 the protein. 1 1.14 12 0.89 12 0.90 It is likely that even early HIV infection leads to changes in 1.5 1.03 13 0.88 13 0.90 the structure and function of the intestinal tract, which is 2 0.97 14 0.87 14 0.89 accompanied by malabsorption of nutrients. An HIV enterop- 3 0.90 15 0.85 15 0.88 athy has been described, characterized by villous atrophy and 4 0.86 16 0.84 16 0.87 crypt hyperplasia (26). With more advanced disease and 5 0.85 17 0.83 17 0.86 frequent episodes of diarrhea, malabsorption becomes increas- 6 0.89 18 0.82 18 0.85 ingly common and contributes to wasting. 7 0.91 8 0.92 Infants and young children. Infants and young children are 9 0.92 especially vulnerable to malnutrition because of their high growth 10 0.91 velocities and consequent high energy and nutrient needs. 1 Adapted from (16). Downloaded from According to UNICEF, 31% of children under 5y suffer from 2 The safe level of protein intake is calculated as the mean requirement 1 1.96 SD. moderate or severe stunting, with 42% in the least-developed countries (27). About 10% of the children in low-income Recommended protein intake for vulnerable groups. There countries have moderate or severe wasting, and .10 million are 2 main methods of expressing recommendations for protein children die each year in low-income countries before they reach intake: as safe level of protein intake expressed as grams per the age of 5 y, equivalent to 7 of every 100 children (27). It has

kilogram body weight per day or as a safe range of PE% in the jn.nutrition.org been estimated that in more than half of the deaths, malnutrition diet. The safe levels of protein intake according to the new WHO/ is a contributing factor to mortality. FAO report on protein requirement (16) are given in Table 5. The ages up to ;18 mo are specifically vulnerable. There is a Safe ranges for protein energy percentage are given by the dramatic decline in nutritional status from birth up to ;18 mo in U.S. Institute of Medicine (IOM) (28). The ranges [acceptable weight for age (underweight), length for age (stunting), and macronutrient distribution ranges (AMDR)] are 5–20 PE% for at ARLA FOODS on January 27, 2016 weight for length (wasting) (Fig. 1). Thereafter, there is no children of 1–3 y, 10–30 PE% for children of 4–18 y, and 10–35 further decline, indicating that the children grow at a velocity at PE% for adults. The recommendations are developed for the same level as the reference population. healthy individuals living in industrialized countries. There is A very common complication to malnutrition in young considerable uncertainty in the lower values of these safe ranges. children is recurrent or persistent diarrhea. Long periods of A PE% based on the recommended protein intake, which should gastrointestinal infections will affect the mucosa of the intestine, be regarded as a minimum PE% in the diet, may be calculated resulting in an atrophic mucosa and thereby malabsorption of from the recommended protein intake and the mean energy nutrients, in a further deterioration of the nutritional status. requirements per kilogram body weight (29). The value is 5.3 Young children are also more sensitive to the effects of anti- PE% at 6 mo, gradually falls to 4.3 PE% at 2 y, and then nutrients, e.g., phytate, in that absorption of several minerals, increases gradually again to 8.7 PE% at 17 y. such as iron and zinc, is impaired. A basic assumption for recommendations on protein intake is that the energy requirement is met. Otherwise, some of the protein will be oxidized to provide energy. In a situation in which the total diet remains unknown, as when planning special foods for vulnerable groups, it makes more sense to give recommendations on protein content of diets as PE%. This is in accord with the approach suggested by Waterlow in 1992 (30). Waterlow also calculated the PE% needed for catch-up growth assuming different rates of catch-up. A young child would need a diet with 8 PE% for a catch-up of 5 g kg21 d21 and 10.4 PE% for a catch-up of 10 g kg21 d21. In the new WHO/FAO report on protein requirements (16), the corresponding values are somewhat lower; 6.9 PE% for a catch-up of 5 g kg21 d21 and 8.9 PE% for a catch-up of 10 g kg21 d21. For comparison, F-100, which is intended for treatment of severely malnourished children, has a PE% of 11 with a PDCAAS of 1.24. In several studies (31), it has been shown that it is possible to obtain mean weight gain ;10–15 g kg21 d21 in severely malnourished FIGURE 1 The nutritional status of children under 5 y in the world, children using F-100. expressed as SD scores (Z-scores) relative to the WHO growth ref- An important consideration regarding protein requirements erence that was used up to 2006 (155). Reproduced with permission to vulnerable groups is the fact that infections are common. from Pediatrics, American Academy of Pediatrics (155). According to the new WHO/FAO report on protein requirements

150S Supplement (16), estimates for the extra allowances needed in individuals as opposed to the more concentrated isolates (WPI90%), where with infectious diseases are between 10% for mixed intestinal it is ;1%. In WPC80% it is ;10%. Because the WPI are much parasites, .25% for untreated tuberculosis, and 50% in more expensive than WPC and therefore not relevant for low- individuals with symptom-free HIV. There are no differentia- cost food aid products, it is appropriate to consider to what tions in these figures according to age group. degree lactose maldigestion and intolerance are relevant prob- The focus of this article is on vulnerable groups with no or lems for feeding malnourished patients with high-lactose- moderate malnutrition. Thus, there is only a moderate need for content milk components. catch-up. A PE% of 8 in a blend of vulnerable groups would be Lactose maldigestion and intolerance develop after early sufficient if the PDCAAS were 1.0 and the whole diet were childhood, at about age 3–5 y in many populations. It is esti- covered by the blend. However, because the whole diet is not mated that lactose maldigestion is present in 75% of the world’s supposed to be covered, a PE% of 10–12 would compensate population (48). Lactose intolerance is characterized by symp- somewhat for a lower protein content and quality in the toms that are primarily gastrointestinal and include flatulence, remaining diet. Aiming for a PE% of 12 would also allow for a cramping, abdominal pain, nausea, distention, bloating, and PDCAAS below 1.0, e.g., at 0.80. In the following calculations, diarrhea. we will thus aim for a blend with a PE% ;12 and a PDCAAS not Solomons et al. (49) assessed the effect of using lactose- much below 0.8. containing and lactose-hydrolyzed formulas based on cow’s milk in the rehabilitation of severely malnourished children. More Potential effects of milk on vulnerable groups diarrheas were experienced by the group receiving the lactose- Animal-source foods in malnutrition. Whey is an animal containing formula, but the overall recovery was satisfactory in protein, and potential effects of interventions with whey could both cohorts, and there were no differences in rates of growth, be caused by the general characteristics of an animal food body protein repletion, restoration of energy reserves, or in- Downloaded from source, e.g., the AA pattern or the minerals. Therefore, it is testinal functions. In a meta-analysis of studies treating children relevant to discuss the general aspects of feeding animal foods to with diarrhea with either lactose-containing or lactose-free diets, malnourished individuals. it was concluded that most children with acute diarrhea can A number of studies have examined the association between safely be treated with undiluted lactose-containing milks. It was intake of animal-source foods and growth and development further stated that children should be fed continuously during

(physical and mental), morbidity (including nutritional anemia), illness with their usual diets (50). jn.nutrition.org and immune function (3,32–36). In an observational study from Miller et al. (51) observed that lactose malabsorption was a Kenya, Mexico, and Egypt, positive associations between intake common finding in HIV-infected children and was less common of animal-source foods and growth in weight and length were in an age-matched group of control children. However, lactose found, even after controlling for socioeconomic factors (37). malabsorption was not associated with higher rates of diarrhea

Similar findings have been obtained in Peru (38), in New Guinea or growth failure. at ARLA FOODS on January 27, 2016 (39), and in Central America (40). Iron, zinc, and vitamin B-12 F-100 is used extensively in the treatment of severe malnu- contents of animal-source foods in addition to good protein trition, a condition in which diarrhea is frequent and likely to quality may contribute to these findings. cause considerable intestinal atrophy and therefore low lactase. In a study in Kenya, the effect of meat and milk on growth Although it has not been strictly documented, there is a general was examined in schoolchildren who were randomized to a impression that lactose intolerance is not a major problem in meat, milk, or energy supplement compared with a control rehabilitation of severely malnourished children (52). F-100 group without a supplement (41). Children in each of the sup- contains 42% SMP, and with a lactose content of ;50% in SMP, plemented groups gained ;0.4 kg (10%) as compared with ;20% of the dry matter and 15% of the energy content in this children in the control group, but only those receiving the animal diet comes from lactose. Thus, it seems that a reduction of the foods gained more lean body mass. In the subgroup of children lactose content in milk-based diets for severe malnutrition offers with a lower baseline height-for-age z-score (#1.4), a positive no appreciable advantages, and the use of milk as the protein effect of milk supplements on height gain was shown, suggesting source for rehabilitation is not contraindicated (31,49,53). This that the effect of milk on linear growth may be superior to that is supported by the conclusion of a recent meta-analysis (54). It of other animal-source foods. should be kept in mind that ;40% of the energy in human milk comes from lactose, about twice as much as in cow’s milk, and Potential effects of milk protein constituents. The biological that human milk is considered an ideal food, even during periods activities of several bioactive proteins and peptides obtained of diarrhea. from milk proteins and their physiological roles have been ex- Some studies in piglets have shown a positive effect on amined in animal studies and in a limited number of intervention growth of adding lactose to a cereal-based diet, most likely studies in humans. Proposed functions of WPRO are mainly related because lactose is a carbohydrate with high bioavailability (55). to the immune or digestive system (42). It has been speculated In conclusion, the lactose content of FBF is not likely to be a that some of the effects of whey or other milk proteins could be problem. There is ;50% lactose in WPC34% or SMP, but the caused by peptides formed after digestion in the gastrointestinal amount of milk in FBF will be small, perhaps 10–20%, and the tract (43–47). There is an extensive interest in the potential use of FBF will constitute only a part of the energy intake, perhaps 25– bioactive milk components, such as b-lactglobulin, a-lactalbumin, 50%. Furthermore, such blends will not be intended for severely lactoferrin, and glycomacropeptide, in infant formula, clinical malnourished individuals, who have low levels of lactase. nutrition, and functional foods. Using specific bioactive milk components in FBF or other foods used in relief feeding is at Bone. Adding SMP or whey to the diet of vulnerable groups present not realistic because of the cost issue. living mainly on a vegetarian diet may have positive effects on bone mineralization. Lactose maldigestion and intolerance. The lactose content It has been shown that very low calcium intake in some areas, of both SMP and low whey concentrates (WPC34%) is ;50% especially in Africa, can be the main reason for bone diseases

Milk proteins in fortified blended foods 151S such as rickets despite high sun exposure and normal vitamin D Adding cow’s milk to the diet of stunted children is, therefore, status (56–61). Furthermore, supplementing with calcium can likely to improve linear growth. eliminate symptoms such as leg pain and radiological signs of Whey stimulates levels of insulin in circulation in both rickets (57). It may, therefore, be especially important to ensure postprandial (92) and fasting (93) states. However, because a sufficient calcium intake during periods with nutritional casein seems to increase circulating IGF-1 (93), it could be rehabilitation. Protein supplements for rehabilitation should, speculated that the entire milk protein with both whey and therefore, normally also contain calcium. However, the FBF is casein is needed to obtain the complete positive effect of milk on enriched with calcium as part of the mineral mix. linear growth. It was earlier believed that high animal protein intake had a negative influence on calcium balance because individuals with Muscle mass. PLWHA and malnourished infants and young high nondairy animal protein intake usually have higher urine children have decreased whole-body protein synthesis and net calcium excretion (62). However, newer studies have shown that mobilization of proteins into free AA. WPRO are easily digested animal protein also seems to have a stimulating influence on and have high metabolic efficiency, giving the protein a high calcium absorption, so the overall effect on calcium balance biological value compared with other milk proteins. WPRO normally will be neutral (63). Furthermore, in the elderly, with might influence body cell mass (BCM) in several ways. WPRO the appropriate intakes of vitamin D and calcium, giving protein contain the highest concentration of BCAA available from any supplements to correct an inadequate protein intake increases food protein source. BCAA must be present in the muscle cells to circulating insulin-like growth factor (IGF)-1 levels, improves promote protein synthesis (14). Circulating BCAA are unique clinical outcomes after hip fracture, and prevents bone mineral among AA because they are metabolized for energy by muscle density (BMD) loss at the proximal femur (64). rather than by the liver, thus helping to increase carbohydrate Some studies, mostly with animals, have examined the effect availability and counteract muscle protein breakdown. There- Downloaded from of WPRO on bone metabolism. In cells it has been shown that fore, BCAA might be exceptional among AA in their ability to WPRO may stimulate osteoblasts (bone-forming cells) (65) and provide an energy source during wasting and thus decrease inhibit osteoclasts (bone-resorbing cells) (66). It has also been muscle breakdown and aid recovery. However, this theory has, shown that WPRO may enhance bone strength in both growing to our knowledge, not been clinically studied. (67) and ovariectomized rats (66,68). In ovariectomized rat In addition, during starvation and malnutrition, the levels of

studies, the control diet protein was casein compared with casein insulin are greatly reduced, thus in part mediating the loss of body jn.nutrition.org plus some extra WPRO (66,68). Recently, rat studies have protein because insulin is known to inhibit proteolysis (94). In a shown an antiresorptive effect (69) and bone density-maintain- healthy individual, there is a rise in circulating insulin to initiate ing effect (70) of the acidic protein fractions isolated from the response to feeding, which is thought to be a major factor in bovine milk whey. Only a few human studies examining the controlling the retention of absorbed AA (95). Increases in AA effect of whey on bones have been published. In a study from concentrations, particularly of the BCAA, induce similar effects at ARLA FOODS on January 27, 2016 Japan, whey (a special type called the basic protein fraction, to those of insulin. In a healthy subject these 2 factors appear to MBP) has been shown to increase BMD in adult (71) and act synergistically. However, because insulin levels are decreased menopausal women (72). No studies on the effect of WPRO on during starvation and malnutrition, intake of BCAA might be BMD in adult men, children, or adolescents have been pub- more important for inhibition of body protein breakdown (94). lished. Also, as antiretroviral therapy and especially the group of AIDS From the literature it is not possible to state whether milk retroviral drugs, which are protease inhibitors, cause lipodystro- protein or whey, compared with other protein sources, will have phy and metabolic syndrome (96–98), an increased intake of a positive effect on the bones in malnourished individuals. A low BCAA may be especially beneficial for PLWHA. calcium intake from a diet with no animal foods could have a However, because glucagon levels also are decreased in negative influence on bones. However, the blends discussed in malnourished individuals, the insulin-to-glucagon ratios may be this review are fortified with a sufficient level of calcium. more important than the absolute concentration of either insulin or glucagon (94,99). Although the percentage of AA that Milk and linear growth. In a recent article (73) summarizing stimulate the secretion of insulin is the same in casein and human observational and intervention studies, it was concluded WPRO, the higher proportion of BCAA in whey results in a that cow’s milk seems to have a positive effect on linear growth. synergistic effect with insulin on protein metabolism (94). The strongest evidence that cow’s milk stimulates linear Moreover, the number of AA that stimulate glucagon secretion is growth comes from observational studies in both infants (74,75) substantially lower in WPRO than in casein. Hence, the and preschool children (32,76–78) and from intervention studies catabolic effect of glucagon, which counterbalances insulin in (79–86) in low income countries that show considerable effects. the acute control of protein, is less after a whey-protein meal. Additionally, observational studies from well-nourished popu- WPRO are also rich in arginine and lysine. Arginine and lysine lations show an association between milk intake and growth are among the AA thought to possibly stimulate growth hormone, (87). These results suggest that milk has a growth-stimulating which is an anabolic hormone. AA composition of WPRO is very effect even in situations where the nutrient intake is adequate. similar to that of skeletal muscle (100), providing almost all of the This effect is supported by studies showing that milk intake AA in approximate proportion to their ratios in muscle. Logically, stimulates circulating levels of the growth factors insulin (88) it can be supposed that this compatibility would position whey as and IGF-1 (89,90), which suggests that at least part of the an effective anabolic supplement, although it should be recog- growth-stimulating effects of milk occur through the stimulation nized that the nonessential AA contribute little to the overall of the IGF. Because the biological purpose of milk is to support response (101). the newborn during a period of high growth velocity, such an effect seems plausible, and the ‘‘milk hypothesis,’’ put forward Immune system and glutathione. Whey contains a relatively by Bogin (91), proposes that a greater consumption of milk high proportion of sulfur-containing AA, especially cysteine. during infancy and childhood will result in taller adult stature. This might be of particular value in conditions of immune

152S Supplement activation in that the high cysteine content of whey may spare models for human nutrition and for studies on milk diets in early tissue protein because acute phase proteins, which are produced life (120). At 3–5 wk of age, pigs are generally subjected to in response to immune challenge, are inordinately enriched in abrupt (premature) weaning from mother’s milk onto a vegetable- cysteine. based diet, often resulting in significant anorexia, gastrointes- Infection with HIV results in a progressive impairment of tinal disease (weanling diarrhea), and increased mortality. It is immune function, especially a decline in the amount of the likely that results from weanling pigs reflect the responses in membrane glycoproteins CD4, ultimately leading to opportu- malnourished and growth-stunted infants in the transition phase nistic infections and malignancies of AIDS (102). Impaired from milk to solid food. antioxidant defense may play a role in the immunopathogenesis It is widely recognized that young weanling pigs achieve of HIV infection (103–105). Also, in severe malnutrition, as in better growth performance with milk-based diets than with kwashiorkor, an impairment of the antioxidant defense is isocaloric diets containing similar amounts of nutrients derived observed (106–110). Reactive oxygen species and a consequent from corn-soy diets (55,121–123). The potential explanation for depletion of antoxidants have been suggested as the etiology of this positive effect includes a better overall PDCAAS value for kwashiorkor (111,112). Interestingly, it has been reported that milk protein (124), faster stomach emptying (120), lower blood levels of glutathione (GSH) are low, as in the case of HIV- antinutrient levels, and higher levels of milk bioactive substances positive patients. Based on the antioxidant hypothesis, a recent leading to better gut health (55,125). Part of the beneficial effect study from Malawi tested the effect of antioxidant supplemen- of milk products is also believed to arise specifically from the tation in children with kwashiorkor in Malawi but did not find high digestibility and beneficial luminal effects of milk lactose, an effect (110). which are present not only in the very nutrient-sensitive period GSH is a cysteine-containing tripeptide (g-glutamyl-cysteinyl- just after weaning (55) but also in older and healthier piglets, glycine) that is regarded as the major intracellular redox buffer- especially those showing slowest growth postweaning (126). Downloaded from ing principle (105,113). Finally, GSH provides reducing power The milk casein fraction has been shown to affect intestinal for the maintenance of other antioxidants, e.g., ascorbic acid structure and function in weanling pigs (127), and this could (vitamin C), vitamin E, and b-carotene (113). HIV patients are be via its content of immunomodulatory glycomacropeptides often depleted of GSH and other antioxidants (114), and GSH (128). Generally however, casein does not seem to explain the levels are reduced in children with kwashiorkor (106). high digestibility and growth performance in weanling pigs

WPRO is rich in the AA cysteine, which is the main source of reared on milk diets (129,130). More likely, it is the whey jn.nutrition.org the sulfhydryl group of GSH. Therefore, an increased intake of fraction that contains bioactive factors to exert improved gut whey may be beneficial in GSH-depleted indivduals, such as health, digestibility, and growth beyond the effects explained PLWHA and children suffering from kwashiorkor. solely by the contents of highly digestible lactose and protein. Oxidant/antioxidant imbalance can occur in obstructive Hence, spray-dried whey products have become widely used to airway disease as a result of ongoing inflammation. GSH plays enhance health and growth performance for weanling pigs. Even at ARLA FOODS on January 27, 2016 a major role in pulmonary antioxidant protection. A whey-based better performance and gut health are achieved when colostral oral supplement increased whole-blood GSH levels and pulmo- protein rather than whey-derived protein is included in weanling nary function in 1 patient who had obstructive lung disease and diets (131). This probably reflects even higher concentrations of low whole-blood GSH levels (115). The potential for such bioactive factors in colostral whey than in milk whey. supplementation in pulmonary inflammatory conditions de- The responses seen in weanling pigs may resemble those serves further study. in malnourished weanling infants but could also be valid during the entire period from birth. In immunocompromised, stunted Gastrointestinal development and recovery. Malnutrition newborn pigs, WPRO stimulated small intestinal and body and HIV infection have detrimental effects on the health of the growth, relative to a corresponding isocaloric and isoproteinous gastrointestinal tract. In a review by Playford et al. (116), it is diet with soy hydrolysate (21). The effects of casein on gut and mentioned that the growth and development of intestinal cells body growth were intermediate, but it is noteworthy that casein are positively influenced by components of milk and whey, increased bone mineral deposition, whereas WPRO exerted including growth factors and peptides. Glycomacropeptide effects mainly on soft tissue growth (organs, muscle, fat). The exhibits prebiotic activity (117), and lactose can be enzymati- results confirm not only that milk proteins are clearly superior to cally hydrolyzed to form monosaccharides, which are readily vegetable proteins (soy hydrolysate) in supporting growth in sick utilized by bifido bacteria, thus contributing to better function- newborns but also that whey and casein proteins exert differ- ing of the digestive tract (42). Glutamine (13% in casein and ential effects on the different parts of the body. 4.6% in whey) might be an important fuel source for the small Because the weanling pig is a very appropriate model for intestine, although results of its therapeutic effects indicate vulnerable infants and young children during the weaning limited efficacy (118,119). Thus, although there is a plausible period, and because these studies have been strictly controlled, mechanism whereby an individual with gastrointestinal dys- these results from animal studies are relevant and support the function may benefit from whey, this theory has not yet been hypothesis that there will be positive effects of adding whey or tested (101). SMP. However, the growth velocity of piglets is very high, and results seen in piglets may overestimate the effects in humans, Evidence from animal studies underlining the need for strictly controlled relevant studies in Numerous animal studies are available on the effects of bovine humans. milk products on early life growth patterns. Well-controlled animal studies clearly offer a potential to improve our under- Intervention studies with whey in standing of the mechanisms whereby milk components affect the vulnerable populations body during health and disease. PLWHA. The use of WPRO in vulnerable populations, such as As an omnivorous species with a gastrointestinal tract similar those affected by HIV infection, has been suggested as a means to that in humans, the pig is believed to be 1 of the best animal to improve health. If inadequate intake of protein increases the

Milk proteins in fortified blended foods 153S progression of HIV infection, increasing the intake or quality of In a study among 30 clinically stable HIV-infected individuals protein, from whey or other sources, may have beneficial effects with CD4 counts ,300 cells/mL, 45 g of WPRO was given daily on HIV infection. However, the question addressed here is for 14 d. Special commercial whey products were used called whether WPRO has specific effects on the course of HIV Protectamin or Immunocal (134). The production processes infection per se, i.e., effects that are not merely explained by the were distinct, with a lower isolation temperature (,72C) for provision of high-quality proteins. Providing whey to people Immunocal. The protein content ranged from 75 to 95% with a with inadequate intake of protein may be beneficial whether or fat content of 0–6%. Plasma GSH increased significantly in the not they have HIV infection. However, it may be useful to 15 patients receiving Protectamin but not in the 15 patients distinguish between 1) whether effects of whey are over and receiving Immunocal. The authors claim that the study was a above the effects of other high-quality proteins, and 2) whether double-blinded clinical trial and that short-term oral supple- effects are general or HIV-specific, i.e., affecting the course of mentation with WPRO increased plasma GSH levels. However, HIV infection. However, it is complex to distinguish whether because there was no control group and only before-after effects are general or HIV-specific. As for the latter, an effect on comparison, the conclusion does not seem to be valid. All the lean body mass is likely to be general, if not explained by HIV- patients receiving Immunocal were, therefore, openly switched 1 specific effects on CD4 count and viral load. to Protectamin for an additional 5 /2 mo (135). After the full 6 WPRO is rich in the AA cysteine, which is the main source of mo of supplementation, the mean plasma GSH was significantly the sulfhydryl group of the GSH. HIV patients are often depleted higher than at baseline. Again, because the study was in fact not of GSH and other antioxidants (114). When put on antiretro- a randomized, controlled trial, the increase in plasma GSH viral treatment, HIV infected patients will experience a pro- cannot be attributed to the intervention with whey. nounced decline in viral load and an increase in CD4 counts, Another small study was done among 30 HIV-infected which will be accompanied by an improvement in GSH-redox women with BCM ,90% of normal values and the same data Downloaded from status and increase in levels of antioxidant vitamins (132). published in 2 articles (136,137). The body composition of the However, if they are not on HIV treatment, the resulting oxida- patients was thoroughly assessed before and after a 6-wk control tive stress may increase viral replication and hence progression period before the intervention, and then the patients were of HIV to AIDS or death. Therefore, it has been suggested that randomized to WPRO, progressive resistance exercise, or both WPRO might increase GSH-levels and thus reduce progression for 14 wk. The authors claim that both interventions had effects

of HIV. on various outcomes. However, there was no proper control jn.nutrition.org Four studies have examined the effect of whey in PLWHA group, and, although data were not presented, there seemed to (Table 6). A pilot study was done on 3 HIV-infected individuals be no differences between the intervention groups. (133). The patients were clinically stable and given a WPC in A so-called prospective, double-blind trial was conducted amounts increasing from 8 to 39 g/d for 3 mo. The blood among 18 vertically HIV-infected children on antiretroviral mononuclear cell GSH content was below normal at baseline therapy (138). The children were between 12 and 72 mo. Half of at ARLA FOODS on January 27, 2016 but increased in all 3, whereas there were no effects on various the children received a WPC, and the other half received a serum protein concentrations. However, weight gains were placebo (maltodextrin, same amount of energy) or nothing. It is between 2 and 7 kg. According to the authors, this pilot study not clear how allocation to treatment was done, but the study will serve as a basis for a much larger clinical trial, which was apparently not randomized. Also, it is not clear to what apparently has not been conducted or published. extent the groups were comparable at baseline with respect to

TABLE 6 Whey intervention studies with PLWHA

Reference Study type n Subjects Study period Whey type (amount) Name Control Effect

Agin et al., Randomized 30 Women 14 wk Undenatured bovine Optimune 1) Exercise Weight gain as 2000, 2001 intervention (28–66 y) derived whey fat (P ¼ 0.002). (136,137) study protein powder 2) Exercise and No significant change in (1.0 g kg21 d21) whey combined BCM, skeletal muscle, strength or QOL. Bounous et al., Pilot study 3 White men 3 mo 75% WPC Immunocal None Weight gain. 1993 (133) (intervention) (8.4 g/d increasing No change in serum to 39.2 g/d) proteins. Increased GSH. Micke et al., Prospective 30 25 male, 5 female 2 wk 45 g whey/d Protectamin (P) GSH levels: Increased in 2001, 2002 double-blind (42 6 9.8 y) Immunocal (I) P-group (P ¼ 0.004), (134,135) randomized no change in I-group. No change in TNF-a, IL-2, and IL-12. Moreno et al., Prospective 18 10 boys, 8 girls 4 mo 79% WPC (20% of 1) Maltodextrin Increase in GSH in whey 2006 (138) double-blind (1.98–3.67 y) protein increasing 2) None group (P ¼ 0.018). clinical trial to 50% of protein) TCD4/CD8 increased nonsignificantly (P ¼ 0.116). Occurrence of coinfections lowered nonsignificantly (P ¼ 0.058).

154S Supplement relevant risk factors and how double-blinding was maintained. ugee conditions. In summary, RUTF, which has a high content of The supplements were given for 4 mo, and the effects on milk, seems to improve weight gain, but whether this is caused erythrocyte GSH, CD4 counts, and morbidity were assessed. by the higher energy density, the fact that RUTF is more con- An increase in erythrocyte GSH was observed in the whey- venient, or because of the milk content, is not known. supplemented group but not in the control group. No tests were In hospital-based clinical nutrition in industrialized coun- done to compare the change over time in the 2 intervention tries, there has been some interest in the differences in effects groups. There were no effects on CD4 count. of tube-feeding formulas based on whey or casein. Formulas In conclusion, there is no convincing evidence that whey has containing only whey or only casein and formulas with different beneficial effects on antioxidant status, immunological param- ratios of casein and whey are available in the market. However, eters, or HIV-specific outcomes. Most studies had not only most formulas for enteral feeding of children in the European inadequate power but also flawed design. For example, most market are made from casein or are casein predominant. We trials were based on before-after comparisons, and a beneficial have not been able to find studies with relevant comparison of change is, therefore, possibly attributable to the effects of other the effects of these formulas. From discussions with the exposures, e.g., season. Furthermore, details of composition or producers of formulas for enteral feeding, it is our impression processing of the supplements are not known. Some of the data that casein has been used traditionally because it was lactose- suggest that whey may increase GSH levels. If GSH depletion free. The reason for using whey in some formulas has mainly impairs immune function or increases viral load, whey supple- been the faster gastric emptying. As far as we are aware, it has ments might reduce progression of HIV, but this is speculative. not been because of other potential effects of WPRO. However, if the GSH depletion is secondary to oxidative stress in In conclusion, there are no studies showing specific effects the background of low dietary intake of antioxidants, then it of WPRO in infants and young children in either well-nourished seems likely that antioxidant supplementation will be equally or malnourished populations. A number of studies show the Downloaded from beneficial and probably less expensive. There is a need for positive effects of milk and animal foods on growth and de- soundly conducted intervention studies of the effect of WPRO velopment, especially in populations in low-income countries on HIV specific outcomes. with a diet mainly based on plant-source foods, and there are no studies that have compared weight gain in infants and young Infants and young children. A number of studies have children receiving FBF with and without the addition of milk.

evaluated the effects of adding milk to the diet of vulnerable However, the 5 times higher energy density and the convenience jn.nutrition.org groups of infants and young children. However, we have not of a RUTF could explain the differences. been able to find published studies that have examined the effect of adding whey to the diet, and especially not studies that have compared FBF with and without milk in infants and young Considerations for formulations of FBF with milk children. A crucial factor in the discussion of improving FBF is the cost of at ARLA FOODS on January 27, 2016 It is beyond the scope of this article to go through the the product. Adding milk-based powders will increase the cost of literature of the effects of adding milk to the diet. In the previous the products considerably. Adding 15% WPC34% will double sections ‘‘Animal-Source Foods in Malnutrition’’ and ‘‘Milk and the price of a CSB, based on prices in early 2007 (Table 4). Linear Growth,’’ we have summarized some of the literature Adding 15% SMP, which has approximately the same amount of suggesting that there might be specific positive effects of adding protein as WPC34%, will result in a slightly cheaper product. milk to diets of infants and young children, especially if their Whey is traditionally a surplus product from cheese production. diets are mainly vegetable based. Such effects are likely to be However, with the increasing interest in using whey in many much more pronounced in infants and young children who are different technical applications in the food sector, and also with not being breast-fed. an increasing interest in using whey as a food supplement in the It is not possible to evaluate to what degree the effects seen in ‘‘health food’’ sector, its cost has gone up. WPC34% was studies using milk or milk powder result from special effects of considerably cheaper than SMP, ;25–33% cheaper up to early the whey fraction, as whey constitutes only ;20% of the protein 2007. Other milk powder products, such as whey concentrates in milk powder, and milk is often covering only a limited part of with more protein or whey isolates, are considerably more the energy intake. expensive per kilogram protein than WPC34% and SMP. An increasing number of publications have reported that The increased price of a FBF with milk protein should be seen RUTF is very effective in home-based treatment of infants and in relation to the target groups and the potential beneficial young children with severe malnutrition. Although this article effects. The improved blends are aimed at vulnerable groups that does not focus on treatment of severe malnutrition, we find it are likely to be moderately malnourished and are at risk of relevant to describe in brief some of the studies that focus on developing severe malnutrition. We find it likely that blends more moderate malnutrition, which is common among vulner- containing SMP or WPC powder will be more effective in able groups such as infants and young children and HIV improving the nutritional status of the vulnerable children and patients. thereby also protect against development of severe malnutrition, The content of milk is high in most RUTF. Typically .50% which is associated with considerable morbidity and mortality of the protein comes from milk. In some of the products part of and is also expensive to treat. However, we acknowledge that the milk protein is WP (Plumpy Nut, Nutriset and BP-100, Com- there is a need for randomized studies to show whether FBF pact A/S). The reasons for adding whey to these products are containing milk protein has beneficial effects compared with basically lower price, better taste (high lactose content), and FBF without milk. technological. Studies in Malawi (5–7), Chad (139), Ethiopia (140), and Amount and type of milk protein. Replacing the 20% (wt:wt) Senegal (141) have shown that RUTF is readily consumed by soy in a CSB (almost all the soy) by 20% (wt:wt) WPC34% severely malnourished children and that they promote weight increases the PDCAAS from 0.65 to 0.82 (Table 3). If SMP is gain, both during regular nutritional rehabilitation and in ref- used instead, the PDCAAS would increase less, to 0.72.

Milk proteins in fortified blended foods 155S Adding SMP or WPC allows for a reduced content of soy or longer time. Whey is absorbed rapidly from the intestine, and cereal in the blend, which will increase the protein availability. this might potentially lead to better overall nitrogen balance and With a higher PDCAAS it is also possible to reduce the amount postprandial protein utilization (144). of protein. First, protein is expensive, and it is thus not feasible to use protein as an energy supply. Second, it might be a strain on Energy density, fat content, and quality. Because individuals the compromised metabolic systems in malnourished individuals in vulnerable population groups may need a high energy intake or PLWHA if surplus protein had to be metabolized to energy. for recovery, it is fundamental that the products have a high The nutritional quality of the FBF will, therefore, be improved if energy density. This has been considered in the formulation of SMP or WPC is added, both by an increase in the quality and a FBF, which aims at having an energy density of 1 kcal/g (4.2 kJ/g), decrease in the quantity of protein. which is usually regarded as being sufficient, but in reality the As discussed in an earlier section, a PE% of 8 in a blend to energy density is often lower. FBF may be provided with oil, but vulnerable groups would be sufficient, if the PDCAAS were 1.0 the dosage is critical because a too-high oil content will decrease and the whole diet were covered by the blend. A PE% of 8 would the nutrient density. However, increasing the energy density also allow for the extra need for moderate catch-up growth in further by adding more oil in the blends should be considered. In infants and young children. However, it might be marginal for CSB and WSB, the fat energy percentage is ;14, which is low individuals with infectious diseases (16). Because the whole diet compared with recommendations for feeding infants and young is not supposed to be covered by a fortified blend, a PE% of 10– children. Reviews focused on low-income countries have 12 would compensate somewhat for a lower protein content and suggested that there is a risk of a negative effect on growth if quality in the remaining diet. Aiming for a PE% of 12 would also the fat energy percentage of the whole diet is below 22 to 25 allow for a PDCAAS somewhat below 1.0, e.g., 0.80. (145,146). It is likely that a main reason for the very positive The fraction of protein that should come from milk is difficult effects of RUTF is the very high energy density of the product, Downloaded from to determine. The higher the fraction, the more likely it is that 5 times as high as a CSB-based porridge. there will be a positive effect on weight gain and linear growth, Another important aspect to consider when formulating an but the price will also increase considerably. If the milk protein is improved blend is the fat quality, especially the amount of whey, any potential bioactive effect of whey is also likely to be polyunsaturated fatty acids and the (n-3):(n-6) fatty acid ratio, higher if the whey content is higher. However, our literature as it might have effects on growth, cognitive development,

review has not been able to find documentation for such effects. immune function, and oxidative stress. Soybean oil has a jn.nutrition.org The higher the milk protein fraction from milk, the lower any favorable fatty acid profile, so if soy is eliminated from blends potential effects of antinutrient effects from soy and the cereals where soybeans that are not defatted are used, it should be will be. Again, such effects are not well documented. A sug- considered to add soybean oil or other oils with a high (n-3) fatty gestion is that one-third to half of the protein should come from acid content, such as canola oil. milk to make an impact. In trials to test if there is a beneficial at ARLA FOODS on January 27, 2016 effect of adding milk to FBF, it is recommended to start the trials Lactose. Lactose maldigestion and intolerance are common in with blends with half of the protein from milk tested against many populations (48). However, it seems that milk consump- blends with no milk. tion allows adequate growth of children, even when they are A blend with a PE% of 12, a PDCAAS of 0.80, and with one- malnourished and have diarrhea (147). The content of lactose in third to half of the protein from milk seems to be a reasonable both SMP and WPC34% is ;50 g/100 g. Thus, assuming an compromise to aim for. A blend with 15% WPC34%, 85% energy content of 400 kcal/100 g (1.68 MJ/100 g) dry FBF, the corn, and no soy would result in 40% of the protein coming lactose content of such a blend will be 100 g/L if the blend from milk protein, a PDCAAS value of 0.73 and a PE% of 13.3. contains 20% SMP or WPC34%, which is equivalent to a For comparison CSB has a PDCAAS value of 0.65 and a PE% of lactose content ;10% of both weight and energy content. 17.2, and WSB has a PDCAAS value of 0.64 and PE% of 21.0, Adding 15% SMP or WPC34% will likewise result in a lactose according to U.S. specifications (8). content in the blend of 7.5%. We find it unlikely that such a low lactose content is a problem, even in individuals with lactase Flavor and satiating effect. Both flavor and the satiating effect deficiency. The lactose content will add sweetness to the taste, of a blend are likely to influence energy intake, which is crucial which is likely to be positive. in feeding vulnerable groups. Adding milk powder to the blends Studies in pigs have suggested that lactose could also have a influences flavor. Adding only 2–5% of SMP to a blend gives it a positive effect on growth because of its high digestibility, en- milky and also creamy flavor, even though there is no fat in SMP. hanced calcium absorption, and beneficial luminal effects (126). The flavor of whey is more neutral, but with no negative effects on the flavor of the blends. Both SMP and WPC34% have Minerals and vitamins. FBF is fortified with a mineral-vitamin ;50% (wt:wt) lactose, and the use of these products adds a mix. Different mineral-vitamin mixes are used. If WPC34% or sweet taste. Flavor is important for acceptability of the product SMP is added to FBF, the content of calcium, phosphorus, and for the vulnerable groups, and especially in malnourished young zinc especially will increase, especially if SMP is used because it children, the intake is likely to increase if the flavor is sweet. If contains almost twice the amount as WPC34%. If phosphorus is the addition of milk powder results in a considerable increase in not added to the mineral mix, the extra phosphorus is important protein intake, a high protein intake could also directly result in because a considerable part of the phosphorus in the blends is a blunting of the appetite (16). bound by phytate and thus not available. There are several Adding a milk protein powder to a blend is likely to affect studies showing a close inverse relation between plasma phos- satiety. WPRO are categorized as fast proteins and caseins as phate in the malnourished and death (148). If it is decided to add slow proteins, according to the pace at which AA emerge in the whey or SMP to the FBF, the composition of the mineral mixes circulation after ingestion (142). Whey appears to provide a should be evaluated to decide if there is a need for adjustments. more satiating effect than casein does (143) after a meal, but With vegetable sources in FBF, most of the phosphorus can be in there are no data available on the effect on energy intake over a the form of phytic acid, inositol hexaphosphate, which is the

156S Supplement storage form of phosphorus for the plant. Thus, approximate with a high proportion of protein being milk protein, which analysis of the FBF for total phosphorus is not sufficient. Because show a high weight gain and successful recovery. However, most dairy products contain bioavailable phosphorus, adding SMP or of these studies focus on young children with severe malnutri- WPC to FBF will be favorable if it is not included in the mineral- tion, and the RUTF typically contains a high milk protein con- vitamin mix. tent and energy density, and they often cover a large proportion The absorption of the minerals calcium, iron, and zinc is of the energy intake. Other important evidence comes from competitive. Therefore, it should be kept in mind that a high studies of young pigs. calcium content might decrease the absorption of iron and zinc. Because the addition of milk protein to FBF increases the This may affect the iron and zinc status in individuals whose sole price considerably, there is a need to document the beneficial or main diet for a period consists of FBF. effects before implementing these blends in programs to vulner- The mineral-vitamin mix used for blended foods includes able groups. It is beyond the scope of this article to suggest B-12, which is of special interest in low-income countries where detailed trial designs, but we will highlight some areas that need the intake of animal foods is often low or nil (149). The level of further studies. fortification is ;1.2 mg/100 g (Table 1). Furthermore, milk powder is a good source of B-12. If 15% SMP is added to a FBF, this will increase the B-12 content with ;0.6 mg/100 g. Recommendations on research There is a need to perform strict controlled intervention studies Technical aspects. There are technical issues to consider when comparing FBF with and without milk protein. These studies formulating new blends with milk protein. Most of these are not should be performed in vulnerable groups where it is likely that considered in this article. Whey contains many different specific adding milk protein would result in important health benefits proteins that may have specific beneficial effects. When produc- that would justify a considerably more expensive product. Such Downloaded from ing the blends, processing should be performed in a manner to groups could be moderately malnourished infants and young minimize protein denaturation. If FBF is made into porridge that children and PLWHA. should boil, e.g., for 10 min to overcome water contamination Animal studies should also be considered. Pigs are a useful issues, some denaturation might occur, thereby reducing poten- model for humans, especially regarding the gastrointestinal tial beneficial health effects of specific proteins. function. Piglets during the weaning period, when the gastro-

There are both advantages and disadvantages of adding milk jn.nutrition.org intestinal tract is vulnerable and mortality is high, present an protein (as either SMP or WPC) to FBF and advantages and especially relevant model for the weaning period in human popu- disadvantages of adding WPC in comparison to SMP (Table 7). lations where malnutrition and persistent diarrhea are common. From our study, it is clear that the scientific evidence for Flavor, satiating effect, fat content, and energy density are beneficial effects of adding milk protein to FBF is not very likely to affect energy intake, which is crucial in feeding of strong. The strongest evidence comes from the studies of RUTF at ARLA FOODS on January 27, 2016 vulnerable and malnourished groups. It will be possible to examine this in short-term crossover studies in relevant vulner- TABLE 7 Effects of adding WPC or SMP to FBF able groups fed different blends with and without whey or SMP ad libitum. The outcome in such studies would be the energy Adding WPC or SMP to FBF intake from the blends. Advantages Improves the protein quality, measured as PDCAAS. With improved protein quality it is possible to reduce the total amount of protein in the blend, which could have potential Acknowledgments metabolic advantages. Allows for a reduced content of soy and cereal and thereby a The following persons have helped us with important informa- reduction of potential antinutritional effects. tion and valuable discussions. We thank the staff at SUSTAIN, Likely to improve weight gain, linear growth, and recovery from especially Lisa Fleige; Alicja Budek and Pernille Kæstel, Department of Human Nutrition, and Helene Hausner and malnutrition, but studies are needed to confirm this. Are Hugo Pripp, Department of Food Science, University of Improves flavor; SMP more so than WPC. ˚ Disadvantages Increases the price considerably, which is an important limiting Copenhagen, Denmark; Gitte Graverholt, Arla Foods, Arhus, Denmark; Jan Are Heldal, Compact, Bergen, Norway; Antony factor in all relief feeding. Adds lactose to the product, which could potentially have Michalik and Hauke Kuhn, Fonterra (Europe), Hamburg, negative effects, but which is not likely to be important in Germany; Lars Børje Sjøberg, previously Semper, Sweden; Mamane Zeilana, Nutriset, France; Ceri Green, Josephine the amounts suggested. Garvey, and Martin von Eert, Nutricia, The Netherlands; Using whey (WPC34%) compared with SMP Advantages Has been 25–33% less expensive up to early 2007. Stuart Allison and Richard Lowe, Insta Products, Nairobi, Has a slightly better protein quality measured as PDCAAS, but Kenya; Tina van den Briel, World Food Program; Andre´ Briend, World Health Organization; Pieter Dijkhuizen, previously not likely to be important. Potential beneficial effects on the immune system and muscle World Food Program; Mark Manary, Washington University synthesis have been suggested, but convincing evidence is School of Medicine, St. Louis, MO; Michael Golden, Professor, Consultant, Ireland; Peter Garlick, Professor, Department of lacking. Relevant to perform studies to examine this further. We have not been able to identify studies suggesting that Animal Sciences, University of Illinois. casein-dominated milk powders such as SMP have advantages over whey. Disadvantages Might in the future be more expensive than SMP. Literature Cited Might not be as widely available as SMP. 1. Beaton GH, Ghassemi H. Supplementary feeding programs for young Does not improve flavor to the same degree as SMP. children in developing countries. Am J Clin Nutr. 1982;35:863–916.

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