The Role of Partially Hydrolyzed Whey Formula for the Prevention of Allergic Disease

Evidence and Gaps

Adrian J Lowe; Shyamali C Dharmage; Katrina J Allen; Mimi LK Tang; David J Hill


Expert Rev Clin Immunol. 2013;9(1):31-41. 

In This Article

Changing Theories on the Causes of Allergic Disease

In the 1980s and early 1990s, evidence emerged that high exposure rates to house dust mite (HDM) levels was associated with increased risk of sensitization to HDM and asthma.[19,20] There was also evidence that infants who were exposed to intact cows' milk were at greater risk of developing eczema[21] and asthma[22] when compared with children who were breastfed. This and other evidence lead to the concept of 'avoid allergens – prevent allergic disease'. This concept dominated the thinking concerning allergic disease for many decades. In support of this concept, it has been argued that infants are relatively vulnerable to developing sensitization to allergens, either due to increased mucosal permeability[23] or tendency to mount Th2 type responses[24] to allergens, which in turn increases the risk for developing allergic disease. According to this theory, exposure to allergenic dietary proteins (in particular cows' milk, egg and peanut) may promote the development of allergic disease. It was hoped that allergen avoidance (withholding food allergens for a number of months) might have long-term benefits for the child's health and reduce the risk of developing allergic disease.

The 'avoid allergens – prevent disease' concept inspired a large number of allergen avoidance trials for a variety of allergens.[25–27] While some small studies that combine multiple forms of allergen avoidance in infancy to prevent allergic disease have shown promising results,[28] larger studies using HDM avoidance as a sole intervention[29–31] have not shown a clear reduction in the incidence of allergic disease. Despite limited evidence,[26] maternal avoidance of food allergens during pregnancy and lactation is generally not recommended due to insufficient evidence that it reduces allergic disease risk, and for concern that it may adversely affect the mother and child's nutrition status.[26] However, this issue remains controversial.[32] Given the inconsistency of results for the studies inspired by the 'avoid allergens – prevent allergic disease' paradigm, there has been waning interest in this avenue of research.

In recent years, there has been a dramatic and exciting shift in thinking on how allergic diseases may be prevented. There is increasing dominance in the notion that there may be a window of opportunity, between approximately 4 and 6 months of life, which may be critical in the development of tolerance to allergens in our environment.[10] This is, in part, based on our growing understanding of the importance of immune regulatory responses,[10] and due to a number of important observations:

  • Introduction of cereal grains prior to 4 months and after 6 months is associated with increased risk of parent-reported wheat allergy;[33]

  • In a population-based cross section study, children exposed to cooked egg between 4 and 7 months have the lowest risk of food challenge confirmed egg allergy compared with introduction after 7 months;[34]

  • Delayed introduction to cows' milk products (after 9 months) has been associated with an increased risk of eczema and recurrent wheeze, whereas delayed introduction of other foods was associated with increased risk of eczema, recurrent wheeze and sensitization to inhalant allergens;[35]

  • While a randomized controlled trial of brief exposure to cows' milk protein in the first 3 days of life has been shown not to influence risk of allergic disease,[36] an observational study has found that early introduction (<14 days) to cows' milk protein, which is probably also related to prolonged exposure, is associated with reduced risk of IgE-mediated cows' milk allergy;[37]

  • Early introduction of fish[38,39] has been associated with reduced risk of eczema, whereas early introduction of peanut has been associated with reduced risk of peanut allergy.[40]

The possibility of reverse causation having generated these results must be considered, as parents of children at the greatest risk of developing allergic diseases, either due to having a strong family history of these conditions or developing early signs of the conditions themselves, may decide to delay the introduction of various foods to the infant diet because of this risk.[41] The aforementioned studies have attempted to address this issue with varying degrees of success.

The potential for early dietary exposure to help induce tolerance is now being assessed in randomized controlled trials for peanut[102] and egg[103] in high-risk children.

It was during the 'allergen avoidance' era that research into hydrolyzed formula gained prominence.