Page 1  - Page 2

B. More information:

Cow's milk contains at least 30 different proteins. Most milk-allergic individuals react to more than one milk protein.1

The type of adverse reactions that can be induced by cow's milk can be classified as follows:

  • Toxic reactions: Naturally occurring substances found in various plants are eaten by cows and secreted into their milk. These substances can be toxic to humans. Examples of these are quinolizidine alkaloids, pyrrolizidine alkaloids, piperidine alkaloids, sesquiterpene lactones and tremetol/tremetone.

  • Psychological reactions

  • Non-toxic reactions

    • Immune-mediated/allergy

      • IgE-mediated

      • Non-IgE-mediated

        • Cell-mediated

        • Protein enteropathy

    • Non-immune mediated/intolerance

      • Lactose intolerance (due to an inability to produce sufficient lactase, the enzyme responsible for splitting lactose into its constituent monosaccharides, glucose and galactose)

    It must also be remembered that milk can contain other substances such as antibiotics and iodine, as well as substances added in the manufacturing of processed milk such as colourants, flavourants and emulsifiers. These could also cause adverse reactions in susceptible individuals. In this issue of the newsletter, however, we will focus mainly on non-IgE-mediated milk allergy.

    There are various classifications for the many manifestations of milk allergy. The main ones are:

    • according to the type of hypersensitivity reaction (i.e., Type I, III and IV reactions)

    • according to time of onset of the symptoms (i.e., immediate, intermediate and late-onset or acute and delayed symptoms)

    • according to the organ/bodily system involved

    At present, evidence for type I (IgE-mediated), III (immune complex) and IV (cell-mediated) reactions against cow's milk protein has been demonstrated. 2,3

    The Melbourne Milk Study4,5 has shown that there is a relationship between the time of onset of symptoms, the minimum volume of milk ingested that provoked symptoms, and the type and specific cause of symptoms. Three groups are identified. (Other studies that took a similar approach are also quoted.)

    Group 1:

    • Immediate reaction (within minutes)

    • Small volumes (up to 20ml)6

    • Mainly gastrointestinal symptoms7 and cutaneous manifestations4,8 such as urticaria and angioedema9,10,11 with or without signs of anaphylaxis

    • High levels of serum-specific IgE antibodies to cow's milk

    Group 2:

    • Intermediate reaction (occurring from 1 to 24 hours after ingestion)

    • Moderate volumes (less than 120ml)6

    • Predominantly gastrointestinal symptoms4, including vomiting and diarrhoea, but also atopic dermatitis, infantile colic, gastro-oesophageal reflux, oesophagitis, infantile proctocolitis, food-associated enterocolitis and constipation10

    • No indication of IgE sensitisation

    Group 3:

    • Late onset of symptoms (between 24 hours and 5 days)

    • Large volumes (more than 120ml)6

    • Gastrointestinal and cutaneous symptoms (such as eczema and atopic dermatitis), but also the development of coughing, wheezing, infantile colic, gastro-oesophageal reflux, oesophagitis, infantile proctocolitis, food-associated enterocolitis and constipation10

    • Varying degrees of IgE sensitisation. The late-reacting non-IgE-sensitized cow's milk-allergic patients demonstrate elevated T-cell reactivity to milk proteins.4,5,8,9,10

    The first 2 groups can be classified as involving relatively rapid-onset reactions, whereas Group 3 involves slowly evolving reactions with features such as eczema, colic, failure to thrive and chronic gastrointestinal or atopic symptoms.4 The exact mechanisms of these disorders are poorly understood.10

    Cow's milk allergy can present with a variety of symptoms including systemic, skin, respiratory and gastrointestinal reactions. Non-IgE-mediated reactions that have been recorded include food protein-induced enterocolitis syndrome,12,13 eosinophilic proctocolitis,14 generalized malabsorption with villous atrophy,15 Melkersson-Rosenthal syndrome,16 pulmonary hemosiderosis17 and esophagitis.18 It has been suggested that there is an association between children with previous rotavirus infection and non-IgE milk enteropathy.19 (These and other adverse reactions to milk will be discussed in more detail in the next issue.)

    How does one go about finding out what type of reaction is taking place?
    A thorough clinical history can be helpful in identifying the type of reaction.6 But it may not be clinically possible to differentiate between cow's milk allergy and other, non-immune-mediated reactions to milk solely on the basis of immediate clinical symptoms, as these can be quite similar.2,3

    A number of different diagnostic procedures can be done according to the clinical situation. These include skin prick testing, serum-specific IgE blood tests to milk, open challenge and double-blind placebo-controlled (DBPC) procedures.4 In research facilities, other tests such as T-cell activation are also available.

    Health professionals often think that diagnosing milk allergy is as simple as doing skin prick tests or blood tests. However, these tests are not always useful. Dr. David Hill has demonstrated that approximately 30% of milk allergies are non-IgE-mediated.5 Skin prick tests and blood tests may come up negative in the case of a genuine reaction to milk, yet some health professionals might rule out milk at that point.

    The traditional method of doing DBPC food challenges is seen as the "gold standard" of diagnostic tests, but does not diagnose delayed reactions due to a short observation period or a dose-dependent response. The results of DBPC challenges with milk are inconclusive in about 10% of cases. These children appear to tolerate milk after a challenge but develop adverse reactions up to 4 weeks after recommencing with normal volumes of milk. It has also been reported that some of these children develop exercise-induced anaphylaxis following ingestion of milk.6 However, through an amended style of DBPC challenges (in which the patient is observed for more than 24 hours and appropriate doses are offered), delayed reactions can be picked up.

    It might be helpful to keep in mind that it is unlikely for a patient to have milk allergy if:

    • Normal volumes (350-500ml per day) have been ingested for 6 months prior to the development of the symptoms.

    • A child has had symptoms attributed to milk allergy and appears to respond to milk exclusion, but subsequently ingests normal volumes of milk for 4 weeks without symptoms.4

    A thorough clinical history and elimination-challenge testing to identify a pattern in foods ingested and the symptoms experienced remain the only ways of confirming a diagnosis.6

      compiled by Karen du Plessis B.Sc. Diet.
    Food & Allergy Consulting & Testing Services (FACTS)
    PO Box 565
    Milnerton 7435
    South Africa

    C. Comments by our editors

    Prof Janice M. Joneja Ph. D., RDN
    This case study emphasizes two important aspects of food allergy practice: (1) Skin tests and blood tests for food-specific IgE on their own will not necessarily identify the specific foods, beverages or additives responsible for adverse reactions. Every test needs to be followed by elimination and challenge to confirm the results. (2) Double blind placebo controlled food challenge (DBPCFC) is not an infallible way to determine whether a food is causing the observed symptoms.

    The most effective way of determining which food is responsible for a person's symptoms is to eliminate all traces of the food(s) from the diet for a period of 2-4 weeks. If the symptoms resolve, the food is then reintroduced in a way that will detect both immediate and delayed-onset reactions. This is most efficiently achieved by using a sequential incremental dose challenge (SIDC) procedure over a period of two or four days. During the challenge phase, all of the foods allowed during the elimination phase can be eaten.

    On the first day of the challenge, a small amount of the test food is consumed about 2 hours after breakfast, and the patient is observed for a period of four hours. If no symptoms develop, double the original quantity of the test food is consumed. If again no symptoms develop, the test food is again doubled four hours later. Thus three doses of the test food are consumed on Day 1, four hours apart. Day 2 is a monitoring day for delayed reactions. None of the test food is consumed; all of the foods allowed on the elimination diet can be eaten.
    If no symptoms develop on Days 1 and 2, or if the reaction is so mild as to be equivocal, the same food is consumed on Day 3, increasing the quantities of the food, again in three incremental doses, four hours apart. Day 4 is again a monitoring day for delayed reactions when none of the test food is eaten.

    It would be most unusual for symptoms to develop later than the 96 hours, which this testing schedule allows. This method of testing will definitely identify both immediate and delayed reactions to the majority of food allergens or intolerance triggers.

    Sabine Spiesser B.Sc. Dip. Ther. Diet.
    All too often patients are dismissed after negative skin prick and RAST to food antigens without further exploration of offending symptoms.

    Persistence with repeated complaints can lead to a misdiagnosis as described in the case study. Patients and mothers especially often have an excellent instinct as to offending foods and their observations should be validated until proven otherwise. Many patients, who's needs have not been met, resort to consulting alternative practitioners who have no immunological training and often use unscientific if not fraudulent tests which lead to incorrect diagnoses and inappropriate diets. Malnutrition due to unwarranted multiple food avoidances is not uncommon. Dietitians are best placed to supervise elimination diets, food challenges and implementation of sound allergen free diets. Challenges and food re-introductions should never be rushed and should always include investigation for delayed reactions to individual foods and certain food chemicals.

    For more information on this subject and other allergy and intolerance related topics, visit:

    To join a professional food allergy discussion list where this subject can be discussed further, go to or

    We invite you to send us interesting case studies. We pay US$100 for each case study we use in our newsletter.

    To subscribe or unsubscribe, send an e-mail to and put "subscribe" or "unsubscribe" as the subject.

    D. References
    1. Savilahti E, Kuitunen M. Allergenicity of cow milk proteins. J Pediatr 1992;121:S12-S20.
    2. Host A. Cow's milk protein allergy and intolerance in infancy. Some clinical, epidemiological and immunological aspects. Pediatr Allergy Immunol 1994;5(5 Suppl):1-36.
    3. Host A, Jacobsen HP, et al. The natural history of cow's milk protein allergy/intolerance. Eur J Clin Nutr 1995;49:Suppl 1:S13-8.
    4. Hill DJ, Hosking CS. The cow milk allergy complex: overlapping disease profiles in infancy. Eur J Clin Nutr 1995 Sep;49 Suppl 1:S1-12.
    5. Heine RG, Hosking CS, Hill DJ. Food allergies in infants and children - two decades of research. Curr All Clin Immunol 2001;14(3):20-4.
    6. Hill DJ, Hosking CS. Cow milk allergy in infancy and early childhood. Clin Exp Allergy 1996;26:243-6.
    7. Foucard T. Development of food allergies with special reference to cow's milk allergy. Pediatrics 1985;75(1 pt2): 177-181.
    8. Ford RP, Hill DJ, Hosking CS. Cows' milk hypersensitivity: immediate and delayed onset clinical patterns. Arch Dis Child 1983 Nov;58(11):856-62.
    9. Firer MA, Hoskings CS, Hill DJ. Humoral immune response to cow's milk in children with cow's milk allergy. Relationship to the time of clinical response to cow's milk challenge. Int Arch Allergy Appl Immunol 1987;84(2):173-7.
    10. Heine RG, Elsayed S, Hosking CS, Hill DJ. Cow's milk allergy in infancy. Curr Opin Allergy Clin Immunol 2002 Jun;2(3):217-25.
    11. Hill DJ, Firer MA, Shelton MJ, Hosking CS. Manifestations of milk allergy in infancy: clinical and immunologic findings. J Pediatr 1986 Aug;109(2):270-6.
    12. Sicherer SH. Food protein-induced enterocolitis syndrome: clinical perspectives. J Pediatr Gastroenterol Nutr 2000;30 Suppl:S45-9.
    13. Powell GK. Milk and soy-induced enterocolitis of infancy: clinical features and standardization of challenge. J pediatr 1978;93:553-60.
    14. Machida HM, Catto Smith AG, Gall DG, Trevenen C, Scott RB. Allergic colitis in infancy: clinical and pathological aspects. J Pediatr Gastroenterol Nutr 1994:19:22-6.
    15. Kuitunen P, Visakorpi JK, Savilahti E, Pelkonen P. Malabsorption syndrome with cow's milk intolerance: clinical findings and course in 54 cases. Arch Dis Child 1975;50:351-6.
    16. Levy FS, Bircher AJ, Buchner SA. Delayed-type hypersensitivity to cow's milk protein in Melkersson-Rosenthal syndrome: coincidence or pathogenetic role? Dermatology 1996;192(2):99-102.
    17. Lee SK, Kniker WT, Cook CD, Heiner DC. Cow's milk-induced pulmonary disease in children. Adv Pediatr 1986;109:270-6.
    18. Kelly KJ, Lazenby AJ, Rowe PC, Yardley JH, Perman JA, Sampson HA. Eosinophilic esophagitis attributed to gastresophageal reflux: improvement with an amino acid-based formula. Gastroenterology 1995;109:1503-12.
    19. Firer MA, Hosking CS, Hill DJ. Possible role for rotavirus in the development of cows' milk enteropathy in infants. Clin Allergy 1988 Jan;18(1):53-61.

    E. CPD Questions (for South African dietitians only)

    This CPD session is now closed. Please contact for more information.

    1. True or false: Most milk-allergic individuals are allergic to only one milk protein.
    (a.) True
    (b.) False

    2. What type of reaction can a person have to milk?
    (a.) Toxic reaction
    (b.) Allergic reaction
    (c.) Intolerance
    (d.) All of the above

    3. According to the Melbourne Milk Study, which of the following is not typical of Group 1:
    (a.) The adverse reaction takes place within minutes of ingesting milk.
    (b.) Only small volumes are necessary to provoke symptoms.
    (c.) The symptoms are mainly gastrointestinal and cutaneous.
    (d.) It is usually a non-IgE-mediated reaction.

    4. According to the Melbourne Milk Study, which of the following is not typical of Group 3:
    (a.) The adverse reaction takes place more than 24 hours after the ingestion of milk.
    (b.) Moderate volumes, of less than 120ml, provoke symptoms.
    (c.) Symptoms such as coughing, wheezing, colic, gastro-oesophageal reflux, oesophagitis, enterocolitis and constipation can be experienced.
    (d.) Varying degrees of IgE sensitisation are present.

    5. It has been suggested that there is an association between children with previous rotavirus infection and
    (a.) IgE-mediated allergic reaction
    (b.) Toxic reaction
    (c.) Non-IgE milk enteropathy
    (d.) Psychological reaction

    6. True or false: It may not be clinically possible to differentiate between cow's milk allergy and other, non-immune-mediated reactions to milk solely on the basis of immediate clinical symptoms.
    (a.) True
    (b.) False

    7. According to Dr. David Hill, what percentage of milk allergies are non-IgE-mediated?
    (a.) 10%
    (b.) 30%
    (c.) 50%
    (d.) 95%

    8. Which of the following is not true regarding the traditional method of doing double-blind placebo-controlled food challenges:
    (a.) Diagnoses immediate as well as delayed reactions
    (b.) Does not diagnose delayed reactions
    (c.) Results are inconclusive in about 10% of cases
    (d.) Seen as the "gold standard" of diagnostic tests


    1. a [ ] b [X]   2. a [ ] b [ ] c [ ] d [X]   3. a [ ] b [ ] c [ ] d [X]
    4. a [ ] b [X] c [ ] d [ ]   5. a [ ] b [ ] c [X] d [ ]   6. a [X] b [ ]
    7. a [ ] b [X] c [ ] d [ ]   8. a [X] b [ ] c [ ] d [ ]    

    1. b. False
    2. d. All of the above
    3. d. It is usually a non-IgE-mediated reaction
    4. b. Moderate volumes, of less than 120ml, provoke symptoms
    5. c. Non-IgE milk enteropathy
    6. a. True
    7. b. 30%
    8. a. Diagnoses immediate as well as delayed reactions

    Page 1  - Page 2