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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.
- 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
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
There are various
classifications for the many manifestations of milk allergy. The main
- 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
reaction (within minutes)
- Small volumes
(up to 20ml)6
gastrointestinal symptoms7 and cutaneous manifestations4,8 such
as urticaria and angioedema9,10,11 with or without signs of
- High levels
of serum-specific IgE antibodies to cow's milk
reaction (occurring from 1 to 24 hours after ingestion)
volumes (less than 120ml)6
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
- Late onset
of symptoms (between 24 hours and 5 days)
- Large volumes
(more than 120ml)6
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
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
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
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.
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:
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
||compiled by Karen du Plessis
Food & Allergy Consulting & Testing Services (FACTS)
PO Box 565
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
Spiesser B.Sc. Dip. Ther. Diet.
too often patients are dismissed after negative skin prick and RAST
to food antigens without further exploration of offending symptoms.
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 http://groups.yahoo.com/group/AllergyDietitian
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Questions (for South African dietitians only)
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
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
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
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
ALL THE QUESTIONS
1. True or false: Most milk-allergic individuals are allergic to only
one milk protein.
2. What type of
reaction can a person have to milk?
(a.) Toxic reaction
(b.) Allergic reaction
(d.) All of the above
3. According to
the Melbourne Milk Study, which of the following is not typical of Group
(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
(a.) The adverse reaction takes place more than 24 hours after the ingestion
(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
(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.
7. According to
Dr. David Hill, what percentage of milk allergies are non-IgE-mediated?
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
||3. a [ ] b [ ] c [ ] d
|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
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