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Internet Symposium on Food Allergens 4(1):2002
Allergen Data Collection - Update:
Cow's Milk (Bos domesticus)
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Authors in alphabetical order [contact information] Matthias BESLER (Hamburg, Germany)
Philippe EIGENMANN (Genève, Switzerland)
Robert H. SCHWARTZ (Rochester, NY, USA)
Abstract
Cow's milk allergy (CMA) can be defined as any adverse reaction mediated by immunologicalmechanisms to cow's milk proteins. CMA can be divided in IgE-mediated reactions (IgE-CMA) and non-IgE-mediated reactions (non-IgE-CMA) which may involve other immunoglobulins, immune complexesand cell-mediated reactions. Patients with non-IgE-CMA and digestive symptoms can present with thefollowing well defined clinical pictures: milk- induced enterocolitis, milk- induced proctitis, milk-induced enteropathy, or eosinophilic allergic gastro-enteritis. CMA should be differentiated from cow'smilk intolerance (CMI) reactions due to lactase deficiency or other non immune mediated causes whichare not subject of the present review. Most CMA has its onset in the first year of life, and becomesapparent at the time of weaning from breastfeeding. Prevalences of CMA range from 1.6% to 2.8% in randomly selected children younger than 2 years of age(elimination / challenge proven). Oral tolerance is frequently acquired in about 50 to 90% of childrenwith CMA within the first 6 years of life. However, severe CMA may persist into adulthood. Thefrequency of sensitization to cow's milk in adults has recently been estimated by RAST to be 0.7% and1.2% in Scandinavian countries. According to the onset of symptoms after milk ingestion CMA can be classified as immediate or delayed-type. The clinical picture can vary from mild to severe, involving the skin (eczema, hives, angioedema),gastrointestinal tract (oral pruritis, colic, vomiting, diarrhea, constipation), respiratory tract (cough,stridor, wheezing), and cardiovascular system (anaphylactic shock). No single laboratory test is diagnostic of CMA. Clinical manifestations supported by skin tests and invitro parameters are valuable. The diagnosis is confirmed by well-defined elimination and subsequentchallenge procedures. If there is evidence of anaphylaxis, challenge should be avoided. The inadvertentingestion of small amounts of cow's milk allergens hidden in foods can result in severe life- threateningclinical reactions. Cow's milk allergens could be present in breast milk, infant formulas, milk and milkproducts like cheese and yogurt, as well as in "non-dairy" foods occurring as contaminants or unlabeledadditives. The most effective treatment of CMA is allergen avoidance. Besides the optimal choice ofbreast milk, suitable milk substitutes in the nutrition of infants with CMA are soy hydrolyzed formulas,extensively casein and whey hydrolyzed formulas, and amino acid formulas. The exact frequency ofsensitization to soy protein in children with CMA is still controversial. Soy allergy seems to be rare inIgE-CMA, while approximately 60% of children with milk- induced enterocolitis are sensitive to soybean.
However, severe anaphylactic reactions to extensively hydrolyzed casein and partially hydrolyzed wheyformulas can occur in highly sensitized infants with IgE-mediated cow's milk allergy. Due to the highhomology of protein composition sheep's and goat's milk are cross-reactive in approximately 80% ofsubjects with CMA while mare's milk is only rarely cross-reactive with cow's milk (4% in subjects withCMA). In addition, sheep's milk may cause severe IgE-mediated allergic reactions in children notaffected by CMA. IgE antibodies from children allergic to cow's milk are capable of recognizing milkproteins from mammals bred in European countries (ewe, goat, buffalo). Cross-reactivity of camel's milkproteins has not been recognized. Therefore, due to clinically important residual allergenicity in somehypoallergenic formulas and milk allergen cross-reactivity between species, clinical testing in a safe Internet Symposium on Food Allergens 4(1):2002
medically-supervised environment is necessary in each cow's milk sensitive infant before use. In infants and children the major cow' s milk allergens are casein (CAS), beta- lactoglobulin (beta-LG),and alpha- lactalbumin (alpha-LA). Caseins (alpha-, beta-, kappa-CAS) are the most important inchildren and adults. Other allergens involved in CMA are bovine serum albumin (BSA) and bovineimmunoglobulins. Several IgE- binding epitopes of alpha-LA, beta-LG, alpha- and beta-CAS have beendescribed. Knowledge of the immunodominant epitopes of the major allergens may be useful inidentifying children who will have persistent CMA and children who are likely to outgrow CMA. The present data collection summarizes the following topics in tabular form: prevalences of CMA,diagnostic and therapeutic features, molecular biological and allergenic properties of cow' s milkallergens, stability and hidden presence of allergens, the use of infant formulas in therapy and preventionof CMA and other atopic diseases. (Internet Symposium on Food Allergens 2002, 4(1):19-106) 1 Prevalence of Cow's Milk Allergy
7.1 Sensitization to Cow's Milk
2 Outgrowing of Cow's Milk Allergy
7.2 Properties of alpha-Lactalbumin
3 Symptoms of Cow's Milk Allergy
7.3 Properties of beta-Lactoglobulin
4 Diagnostic Features of Cow's Milk Allergy
7.4 Properties of Bovine Serum Albumin
Family History / Maternal Factors
7.5 Properties of Caseins
Humoral Parameters
8 Isolation & Preparation
Cellular Parameters
Gastrointestinal Parameters
10 Stability of Cow's Milk Allergens
Diagnostic Significance of Tests
11 Allergen Sources
Other Features
12 Food Allergen Labeling
5 Therapy of Cow's Milk Allergy
13 Infant Formulas
6 Composition of Cow's Milk
7 Allergens of Cow's Milk
Disclaimer
The reference lists of the Allergen Data Collections are based mainly on searches of Medline and FSTA (Food Science &
Technology Abstracts) databases up to the related dates of publication. The scientific rigor of the studies listed is variable and
not subject of critique or evaluation by the authors or the editor of the Allergen Data Collections. The reader should be aware
of considerable problems in comparing data from different studies (eg. patient cohorts, diagnostic performances, possible
flaws in allergen preparations and methodologies for allergen characterization) and is encouraged to review the original
publications.
The information provided by the Internet Symposium on Food Allergens is for educational, communication and information
purposes only and is not intended to replace or constitute medical advice or treatments. Neither the authors nor the editorial
board of the Internet Symposium on Food Allergens is/are responsible for any use which might be made of the information.
copyright 2001 by matthias besler - ONLINE PUBLISHER Internet Symposium on Food Allergens 4(1):2002
1 Prevalence of Cow's Milk Allergy
1.1 General Population
Prevalences within the author's selected populations are listed. Those that are assigned randomly selected ("unselected") withnumbers more than 500 may be regarded as representative of the "general population". Inclusion criteria may involvecircumstances not related to atopic predisposition according to current knowledge. Country / Subjects
Sensitivity / Allergy to
Australia, Melbourne
Hill et al. 1997, 1999 620 unselected children (age of <2 years) Brazil, Campinas
cow's milk 1.8% (prospective follow-up) Lopez et al. 1999 114 newborns at term cow's milk 0.3% (case history) Collins-Williams 1956 3000 unselected children (private practice) cow's milk 7.5% (2 open challenges) Gerrard et al. 1973 787 unselected children (<3 years of age) Denmark, Odense
a) cow's milk 2.2% Host et al. 1988 a) 1749 unselected newborns b) cow's milk 1.0% (elimination/challenge) Host & Halken 1990 b) 52% exclusively brest-fed infants cow's milk 1.2%, 0.8% (SPT) at 6 and 12 Julge et al. 1997 251 consecutive born infants cow's milk 12, 21%, 26%, and 23%at 0.5, 1, 2, and 5 years of age (beta-LG Estonia, Tartu
specific RAST >/= class 1) Julge et al. 2001 237 consecutive born infants (1993-94) cow's milk 1.7%, 0.9%, and 0%at 0.5, 1, and 2 years of age (SPT) cow's milk 1.3-1.9% (with intestinal form Kuitunen et al. 1985 unselected children (<6 months of age) Finland, Helsinki
866 children from well-baby clinic (1-6 years
cow's milk 2-5% (open challenge) Finland, Helsinki
cow's milk 1.9% (challenge at a mean age Saarinen & Savilahti 2000 6209 infants followed prospectively from birth France
a) 33110 persons who answered a
questionnaire addressed to a representative
a) food allergy 3.2% sample of the French population (age of <61 b) cow's milk 8% (0.26% in group a) Kanny et al. 2001 (2 phase survey, questionnaires) b) 1121 persons with food allergies selectedfrom group a) received a second questionnaire(study period 1997-98) cow's milk 3.9% (SPT) Schäfer et al. 1999 1235 unselected preschool children (5-6 years) Germany, Augsburg
cow's milk 3.8% (SPT) cow's milk 2.3% (corresponding frequency 1537 subjects between 25 and 74 years of age Schäfer et al. 2001 estimates for the representative study base, (study period from 1997 to 1998) Iceland, Reykjavik
cow's milk 1.2% (RAST) Gislason et al. 1999 502 unselected adults Internet Symposium on Food Allergens 4(1):2002
Japan
1336 children in nusery school < 6 years of age cow's milk 4.0% (questionnaire)
Iikura et al. 1999 (12.6% reported symptoms of immediate-typefood allergy) Netherlands, Maastricht
cow's milk 2.8% (elimination / challenge 1158 unselected newborns (followed Schrander et al. 1993b prospectively from birth to 1 year of age) Norway, Oslo
2721 unselected children (population-based
a) cow's milk 1.1%* b) cow's milk 3.2% Eggesbø et al. 2001 a) point prevalence at age of 2.5 years c) cow's milk 0.2% b) cumulative prevalence at age of 2 years d) cow's milk 1.8% c) prevalence of CMA in children without * according to authors (parentally perceived reactions followed by parents perceived reactions to milk, but underestimate, as stepwise diagnostic procedure including unrecognized reactions were perceived reaction to other food (egg) and diet trials at home, SPT, and open challenge detected d) prevalence of CMA in children with no perceived reaction to any food, but reportedchronic conditions which could be due to food Spain, Valencia
cow's milk 0.36% (clinical history, SPT, 1663 unselected newborns (follow-up to 1 year Sanz Ortega et al. 2001 cow's milk 1.0% (RAST, questionaire) Björnsson et al. 1996 1397 unselected adults (20-44 years of age) Sweden, Linköping
cow's milk 0%, 4.6%, 9.0%, 0%, 1.2% healthy girls at birth and mean age of 3, 8, 25, Hattevig et al. 1984 and 48 months (n=57-86, all Rh negative) Sweden, Malmö
cow's milk in 1.9% (elimination / challenge 1079 unselected children (age at onset 2-44 Jakobsson & Lindberg 1979 Sweden, Uppsala
cow's milk 0.7% (RAST) Gislason et al. 1999 414 unselected adults Turkey, Adana
cow's milk in 1.6% (elimination / challenge Altintas et al. 1995 1348 unselected children (age 15 weeks) UK
cow's milk 0.71% (interview survey, 16420 randomly selected adults (age of >15 Emmett et al. 1999 UK, Isle of Wight
cow's milk 2.5% (case history) Hide & Guyer 1983 609 unselected newborns UK, Isle of Wight
a) cow's milk 4.1% (SPT) unselected children b) cow's milk appr. 1.5% (SPT at age of 4 (birth cohort of 1456 consecutively born b) Arshad et al. 2001 USA
cow's milk appr. 7% (case history) appr. 1000 unselected infants (private practice) USA
cow's milk 1% (history, skin test) Bachman & Dees 1957 403 unselected infants (well-baby clinic) USA
cow's milk 1% (history, skin test) Mueller et al. 1963 299 unselected newborns USA, Ann Arbor, MI
cow's milk 1.4% (questionnaire, school 66598 children from randomly selected public Rhim & Morris 2001 elementary schools USA, Denver, CO
cow's milk 2.2% (challenge tests) 480 unselected children (age of 0 to 3 years) Internet Symposium on Food Allergens 4(1):2002
1.2 Subjects with Atopic or Other Diseases
Country / Subjects
Sensitivity / Allergy to
cow's milk 12%, 9.3%, and 7.1% in Finland, Oulu
patients < 1 year, 1-3 years, and 3-15 years Hannuksela 1987 57, 43, and 42 children with atopic dermatits Finland, Tampere
113 infants with atopic eczema (age of 2-24
cow's milk 48% (oral challenge) Kekki et al. 1997 Moneret-Vautrin & Kanny 81 cases of anaphylactic shock to food (from cow's milk 6.3% (reported to CICBAA 80 cases of food- related anaphylaxis (from European Commission 1998 France
45 children with severe food allergies enrolled
11% cow's milk (SBPCFC or DBPCFC) Moneret-Vautrin et al. 2001 in a personalized care project in schools France, Pierre Benite
a) 580 patients with adverse reactions to food
a) cow's milk 18% Andre et al. 1994 b) 60 cases of anaphylaxis (study period 1984- b) cow's milk 3.3% France, Nancy and Toulouse
cow's milk 13%, goat's milk 0.55% (food Rance et al. 1999b 544 food allergic children France, Toulouse
cow's milk 9.2 % (labial food challenge) Rance & Dutau 1997 142 food allergic children France, Toulouse
cow's milk 12% (food challenge) Rance et al. 1999a 378 food allergic children Germany,Berlin
107 children with atopic dermatitis (and
cow's milk 51% (n=92, DBPCFC) Niggemann et al. 1999b suspicion of food allergy) Germany,Bonn
150 food allergic children (egg white, milk, cod cow's milk 52.0% (RAST)
Liappis & Starke 1999 fish, wheat, peanut and/or soybean) Italy, Bari
cow's milk 13% (case history), 21% Bonifazi et al. 1978 134 patients with atopic dermatitis Italy, Florence
54 episodes of food-dependent anaphylaxis in
Novembre et al. 1998 44 children (age of 1 month to 16 years) (from Italy, Milan
202 with chronic urticaria and suspected food
cow's milk 1.0% (DBPCFC) Pigatto & Valsecchi 2000 Italy, Palermo
cow's milk 9.3% (history) 204 children (median age of 6.3 months) with cow's milk 46% (RAST, SPT, eosinophils) Iacono et al. 1996 gastroesophageal reflux cow's milk 42% (challenge test) Italy, Rome
cow's milk 54% (RAST) Giampietro et al. 1992 371 children with food allergy Japan, Gifu / Nabu
cow's milk a) 8.1% (Nanbu), b) 19% (Gifu) children with asthma and/or atopic dermatitis Agata et al. 1994 from a) Gifu (n = 167) and b) Nanbu (n = 146) (RAST) Internet Symposium on Food Allergens 4(1):2002
Japan, Kochi
200 patients with atopic dermatitis and
cow's milk 52% (food challenge) Ogura et al. 2001 suspected food allergy Japan, Tokyo
cow's milk 28% (food challenge) Iwasaki et al. 1994 39 children with positive food challenge Malaysia, Kuala Lumpur
148 adults with symptoms of nasal congestion
cow's milk 12% (SPT) Gendeh et al. 2000 cow's milk 8.4% (survey, reported to the 131 cases of food- induced anaphylaxis TNO Nutrition and Food Research European Commission 1998 Netherlands, Rotterdam
cow's milk 47% (SAFT) Oranje et al. 1992 91 patients with atopic dermatitis cow's milk 64% (RAST) 163 food allergic infants Poland, Warshaw
153 hospitalized infants with respiratory
Maciejewski et al. 1995 cow's milk and/or egg 11% 124 children with food-induced anaphylaxis South Africa, Cape Town
112 children with atopic dermatitis (age of 5
cow's milk 20% (reported by parents) Steinman & Potter 1994 months to 13 years) Spain, Madrid
cow's milk 25% (SPT, RAST) Crespo et al. 1995 355 food allergic children Spain, Pamplona
cow's milk 37% (SPT, RAST, Histamine Resano et al. 1998 74 patients with atopic dermatitis a) cow's milk 20% (reported to the National a) 61 cases and b) 55 cases Food Administration) European Commission 1998 of food- induced anaphylaxis (from 1994-1996) b) cow's milk 5.5% (Hospital Reports) Switzerland, Geneva
cow's milk 19% (SPT) 74 children with atopic dermatitis (age of 6 cow's milk 15% (history, RAST, and Eigenmann & Calza 2000 months to 16 years, median 2.5 years) Switzerland, Zurich
402 food allergic adults (study period 1978-87) (cheese only 6.2%, milk only 3.5%) Switzerland, Zurich
383 food allergic patients (study period 1990- Etesamifar & Wüthrich 1998 Kongpanichkul et al. 1997 100 asthmatic children Turkey, Erdine
50 asthmatic children (age of 1.5 to 6 years)
cow's milk 18% (SPT) Yazicioglu et al. 1999 with specific serum IgE to foods (egg white,milk, codfish, wheat, peanut and/or soybean) UK, London
cow's milk 46%, cheese only 5% (repeated Lessof et al. 1980 100 patients with food intolerance UK, Manchester
cow's milk 1.7% (suspected cause of 172 patients expierenced anaphylactic reactions Pumphrey & Stanworth 1996 patients' worst reaction) to foods (from 1994-1996) Internet Symposium on Food Allergens 4(1):2002
USA, Baltimore, MD
196 food-allergic patients with atopic
cow's milk 50% (n=109, DBPCFC) Sampson & Ho 1997 USA, Baltimore, MD
cow's milk 73% (DBPCFC) Werfel et al. 1997a 11 beef-allergic patients (DBPCFC) USA, Baltimore, MD
cow's milk 11% (history, RAST, and 63 patients with atopic dermatitis (age of 6 Eigenmann et al. 1998 months to 20 years) USA, Boston, MA
279 adults with exercise- induced anaphylaxis
cow's milk 4% (reported trigger) Shadick et al. 1999 (study period 1980-98) USA, Denver, CO
a) cow's milk 57% (DBPCFC) a) 74 age of <3 years Bock & Atkins 1990 b) cow's milk 14% (DBPCFC) b) 111 age of 3-19 years USA, Durham, NC
a) 113 food allergic children with atopic
a) cow's milk 23% (SPT) Sampson & McCaskill 1985 b) cow's milk 17% (DBPCFC) b) 63 DBPCFC positive children of a) USA, Little Rock, AR
cow's milk 19% (SPT) from which 50% Burks et al. 1998 165 patients with atopic dermatitis were DBPCFC-positive USA, New Haven, CT
98 infants and children with multiple Gryboski & Kocoshis 1980 milk and gluten 3% USA, New Haven, CT
38 children with ulcerative colitis (age of <10
cow's milk 13% (history) USA, OH
148 respiratory-allergic children with
reproduced symptoms after food challenge 1.3 Prevalence of Associated Allergies
Country / Subjects
Sensitivity / Allergy to
Australia, Parkville
egg 67%, peanut 55% (challenge test) 42 children with CMA (followed for 2 years) Finland, Helsinki
Paganus et al. 1992 19 children with CMA sheep's milk: ovine CAS 98% (RAST) France, Gif Sur Yvette / Paris
goat's milk: caprine CAS 93% (RAST) 58 patients with CMA and specific IgE to Bernard et al. 1999 rat's milk CAS 59% (RAST) rabbit's milk CAS 57% (RAST) Internet Symposium on Food Allergens 4(1):2002
Germany, Augsburg
59 subjects sensitized to cow's milk in SPT Schäfer et al. 2001 (25-74 years of age) (study period from 1997 to celery house duste mite 73% Italy, Rome
goat's milk 92% (DBPCFC) Bellioni-Businco et al. 1999 26 children with CMA (DBPCFC) Italy, Rome
mare's milk 8% (SPT) Businco et al. 2000 25 children with CMA (DBPCFC) mare's milk 4% (DBPCFC) Sweden, Malmö
Jakobsson & Lindberg 1979 20 infants with CMA (age of <12 months) Thailand, Bangkok
Harikul et al. 1995 cow's milk-sensitive children USA, New Haven, CT
98 infants and children with multiple Gryboski & Kocoshis 1980 milk and gluten 3% USA, San Diego, CA
Wilson & Hamburger 1988 cow's milk-sensitive infants soybean 14 % (DBPCFC, open challenge, or USA, San Diego, CA
convincing history of an anaphylactic Zeiger et al. 1999 93 children with CMA (<3.5 years) 2 Outgrowing of Cow's Milk Allergy
Country / Subjects
Australia, Victoria
47 with CMA (age of 3-66 months)
with onset of symptoms
Oral tolerance acquired at follow-up of 16 months in: a) <1 hour (n=15), a) 40%, b) 42%, c) 25% of patients b) 1 to 20 hours (n=24) or,c) >20 hours (n=8) Australia, Victoria
Tolerance in 28% by 2 years, in 56% by 4 years, and Bishop et al. 1990 97 children with CMA 78% by 6 years of age (DBPCFC) Tolerance in 6% by 1 year, 20% by 2 years, in 30% by 3 Gerrard et al. 1967 150 children with CMA years, and 53% by 12 years of age Total recovery in 56% by 1 year, 77% by 2 years, and Denmark, Odense
87% by 3 years of age; cow's milk allergy persisted in Host & Halken 1990 39 children with CMA 24% of patients with early IgE sensitization to cow'smilk Positivity to cow's milk proteins: Finland, Oulu
56 children with CMA in infancy (re- Tikkanen et al. 2000 examinations at the age of 10 years) 7.1% by clinical reactivity Internet Symposium on Food Allergens 4(1):2002
Finland, Tampere
Oral tolerance acquired at follow-up of 13 months in 37 patients with a history of CMA Isolauri et al. 1992 (mean age of 28 months) Sensitivity to cow's milk according to age groups:0-1 year in 22% France, Nancy and Toulouse
Rance et al. 1999b 68 children with CMA 3-6 years in 19%6-15 years in 2.9%(SPT and/or RAST, food challenge) Point prevalence of sensitization:1-3 years in appr. 5-6%5 years in appr. 6-7%6 years in appr. 5-6% Germany, Berlin and Freiburg
216 children of a prospective birth
Annual incidence of sensitization: cohort (sensitization rates were Kulig et al. 1999 1 years in appr. 5-6% estimated for the reference population 2 years in appr. 4% of 4082 children by weighted analysis) 3 years in appr. 3-4% 5 years in appr. 1-2%6 years in appr. 1-2%(Sensitivity to cow's milk during follow-up by RAST) Italy, Palermo
Oral tolerance acquired in 30%, 55%, and 70% of 86 consecutive children with IgE- children after 1, 2, and 3 years of cow's milk free diet, Carroccio et al. 2000b mediated or non-IgE-mediated CMA respectively (DBPCFC) (median age at diagnosis 4 months) Italy, Rome
Tolerance acquired in 68% at age of 2 years; 33% did Businco et al. 1985 37 children with CMA not tolerate cow's milk at age of 6 years Sensitivity to cow's milk
Israel, Tel-Aviv
Kornizky et al. 1999 347 subjects sensitized to food (n=347) 21-30 years Japan, Gifu
41% Improvement rate in children aged from <1 year to 22 children with CMA and atopic Netherlands, Groningen
Oral tolerance acquired in 13%, 48%, 74% and 78% of Olsder et al. 1995 23 children with CMA children at the age of 1, 2, 3 and 4 years, respectively Oral tolerance acquired in 15%, 22%, 51% and 67% ofthe children at the age of 1, 2, 3 and 4 years, Netherlands, Maastricht
Schrander et al. 1992 37 children with CMA 90% with initial IgE levels <10 kU/L and 47% withinitial IgE >/= 10 kU/L became tolerant Switzerland, Zurich
Oral tolerance acquired in 28% after 4 years of disease Stoger & Wüthrich 1993 34 adults with CMA Turkey, Adana
29% recovered within 2 years Altintas et al. 1995 21 children with CMA (age 15 weeks) USA
soy, egg, milk, wheat, and peanut: Sampson & Scanlon 1989 Food allergic patients 26% loss (after 1 year of onset, DBPCFC) USA, Baltimore, MD
Tolerance acquired in 38% at median age of 3 years James & Sampson 199 29 children with CMA Internet Symposium on Food Allergens 4(1):2002
3 Symptoms of Cow's Milk Allergy
Symptoms & Case Reports
systemic reactions anaphylaxis (20, 21, 24, 36, 40, 46, 44, 54, 55, 56, 64, 70, 71, 76, 78, 82, 92, 93***, 96, 100), excercise inducedanaphylaxis (55, 59, 62, 75), fatal reactions (47, 49**, 89) cutaneous symptoms angioedema (8, 18, 17, 44, 55, 78, 81, 100), angioneurotic edema (91), atopic dermatitis (22, 23, 24, 27, 35, 78, 87, 88, 92),contact urticaria (19), dermatitis (68), eczema (3, 6, 8, 9, 17, 25, 29, 30, 51, 69), eczematous lesions (91), erythema (29, 55,88, 96), exanthema (6), red itchy eyes (100), hives (100), lips edema (10, 100), pruritus (2), redness (55), swelling of eyelids(55), urticaria (2, 6, 8, 10, 17, 18, 22, 23, 26, 30, 39, 44, 51, 55, 69, 78, 81, 87, 88, 91, 92), generalized urticaria (100),localized urticaria (100***), acute-onset urticaria (86, 100***), chronic urticaria (63) gastrointestinal symptoms abdominal cramps (2), abdominal distention (42), abdominal pain (44, 91, 92, 96), colic (3, 51, 68, 91, 92), infantil colicsyndrome (1, 5, 6), colitis (57, 65), constipation (3, 68), chronic constipation (49, 52, 90), diarrhea (2, 3, 6, 10, 11, 15, 17,25, 29, 39, 42, 44, 51, 68, 69, 92), chronic diarrhea (12, 74), gastric dysrhythmia (98), delayed gastric emptying (98), foodprotein-induced enterocolitis syndrome (absence of specific IgE) (72, 95), protein-sensitive enteropathy (94), eosinophiliccolitis (31, 85), eosinophilic gastroenteritis (28, 99), gastroenteritis (11), gastro- oesophageal reflux (13, 58, 60, 67),morphologic lesion (15), nausea (44), proctitis (32), allergic proctocolitis (84), eosinophilic proctocolitis (97), progressivesmall bowel mucosal damage (26), occult intestinal bleeding (4), oropharyngeal itching / swelling (39, 44), oropharyngealpruritus (73), edema of tongue (10, 100), acute pancreatitis (33), loose stools (69, 91), vomiting (2, 3, 6, 11, 17, 22, 25, 68,69, 81, 83, 91, 92), protracted vomiting (92), in general (30, 78, 87) respiratory symptoms allergic alveolitis (7, 16), asthma (3, 10, 11, 18, 22, 39, 44, 45, 48, 50, 55, 70, 76, 83), bronchospasm (29), bronchialobstruction (91), bronchitis (6, 17), choking (100), conjunctivitis (76), conjunctival injection (100), cough (25, 51, 96),dyspnea (51, 55, 73), nasal blockade (73), allergic rhinitis (22), rhinitis (29, 44, 55, 81, 91), rhinoconjunctivitis (44, 45, 55),rhinorrhea (100), serious rhinorrhea (73), sneezing (73, 100), upper respiratory symptoms (100***), wheeze (25, 51, 68, 80,87, 81, 100) other symptoms association with cytomegalovirus colitis* (66), infantile autism* (53), aversion (91), anal fistula and fissures (49), growthretardation / failure to thrive (3, 6), insomnia (14), iron deficiency anemia in 20-70% (11), irritability (91), lactic acidosis(79), Melkersson-Rosenthal syndrome* (61), migraine* (38), necrotizing enterocolitis (43), steroid- resistant nephroticsyndrome (41), recurrent otitis media (77), pallor (17), psychological disturbance (3), pulmonary hemosiderosis (34), sleepdisturbances (91), tension-fatigue syndrome (37), lethargy (71) * controversial / hypothetical, ** possibly due to partially hydrolyzed whey formula, *** mediated by skin contact Internet Symposium on Food Allergens 4(1):2002
(1) Harris et al. 1977 (35) James & Sampson 1992 (68) Iacono et al. 1998c (2) Bonifazi et al. 1978 (36) Jones et al. 1992 (69) Jarvinen et al. 1998 (3) Buisseret 1978 (37) Kondo et al. 1992 (70) Kanny et al. 1998 (4) Ivady et al. 1978 (71) Laoprasert et al. 1998 (5) Jakobsson & Lindberg 1978 (39) Norgaard & Bindslev-Jensen 1992 (72) Sicherer et al. 1998 (6) Jakobsson & Lindberg 1979 (40) Sampson et al. 1992 (73) Vila Sexto et al. 1998 (41) Sieniawska et al. 1992 (74) Altuntas et al. 1999 (8) Firer et al. 1982 (42) Hayashi et al. 1993 (75) Fiocchi et al. 1999 (9) Taylor et al. 1982 (43) Michaud et al. 1993 (76) Goh et al. 1999 (10) Businco et al. 1983a (44) Stoger & Wüthrich 1993 (77) Juntti et al. 1999 (11) Podleski et al. 1984 (45) Bernaola et al. 1994 (78) Rance et al. 1999b (12) Businco et al. 1985 (46) Businco et al. 1994 (79) Rizk et al. 1999 (13) Forget & Arends 1985 (47) Malmheden Yman et al. 1994 (80) Yazicioglu et al. 1999 (14) Kahn et al. 1985, 1987 (48) Rossi et al. 1994 (81) Businco et al. 2000 (15) Kuitunen et al. 1985 (49) Tarim et al. 1994 (82) Eigenmann & Calza 2000 (16) Vergesslich et al. 1985 (50) Vargiu et al. 1994 (83) Nucera et al. 2000b (17) Hill et al. 1986 (51) Altintas et al. 1995 (84) Patenaude et al. 2000 (52) Iacono et al. 1995a (85) Rossel et al. 2000 (19) Salo et al. 1986 (53) Lucarelli et al. 1995 (86) Saarinen & Savilahti 2000 (20) Wüthrich & Hofer 1986 (54) Moneret-Vautrin & Kanny 1995 (87) Szabó & Eigenmann 2000 (21) Jarmoc & Primack 1987 (55) Wüthrich & Johansson 1995 (88) Schade et al. 2000 (22) Host & Samuelsson 1988 (56) Wüthrich et al. 1995 (89) Bock et al. 2001 (23) Prahl et al. 1988 (57) Armisen Pedrejon et al. 1996 (90) Daher et al. 2001 (24) Businco et al. 1989 (58) Cavataio et al. 1996 (91) Eggesbø et al. 2001 (25) Hill et al. 1989 (59) Guinnepain et al. 1996 (92) Järvinen et al. 2001 (26) Iyngkaran et al. 1989 (60) Iacono et al. 1996 (93) Kawano et al. 2001 (27) Cantani et al. 1990 (61) Levy et al. 1996a (94) Kokkonen et al. 2001a (28) Hill & Milla 1990 (62) Levy et al. 1996b (95) Marr et al. 2001 (29) Husby et al. 1990 (63) Paranos & Nikolic 1996 (96) Moneret-Vautrin et al. 2001 (30) Isolauri et al. 1990 (64) Tabar et al. 1996 (97) Pumberger et al. 2001 (31) Wilson et al. 1990 (65) Weisselberg et al. 1996 (98) Ravelli et al. 2001 (66) Jonkhoff-Slok et al. 1997 (99) Sicherer et al. 2001 (33) de Diego et al. 1992 (67) Iacono et al. 1998a, 1998b (100) Tan et al. 2001 (34) Fossati et al. 1992 Internet Symposium on Food Allergens 4(1):2002
Percentage of Reactions
Symptoms / Ref.
(1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (1) Goldman et al. 1963a
(2) Schwartz et al. 1987 Cutaneous [%]
(3) Bishop et al. 1990 (4) Host & Halken 1990 + Gastrointestinal (5) Schwartz 1991 (6) Schrander et al. 1993b All 3 organ systems (7) Stoger & Wüthrich 1993 (8) Sampson & Ho 1997 Atopic dermatitis (9) Hill et al. 1999 (10) Niggemann et al. 1999b Urticaria / Exanthema (11) Rance et al. 1999b Urticaria / Angio-oedema (12) Sporik et al. 2000 (13) Saarinen et al. 2001 Children with CMA
Generalized urticaria diagnosed by (1) clinical history, oral Contact urticaria (2) clinical history of anaphylactic reactions, RAST (3) parents reported Circumoral lesions (4, 6) elimination/challenge Gastrointestinal [%]
(5) clinical history, SPT (11) labial food challenge (12) DBPCFC; * together 21% (13) open challenge Adults with CMA
diagnosed by (7) clinical history, RAST Allergic rhinitis Other [%]
Failure to thrive Gastro-oesophageal reflux Internet Symposium on Food Allergens 4(1):2002
Symptoms, Onset and Doses for Elicitation of Symptoms
in IgE-mediated and non-IgE-mediated CMA
75 IgE-positive and 43 IgE-negative infants with CMA at open challenge (mean age of
6.7 months):
Anaphylactic reaction Atopic dermatitis Urticaria / Exanthema Immediate vomiting (<2 h) Continuous regurgitation Saarinen & Savilahti 2000 Allergic conjunctivitis Multiple organ symptoms Onset of Symptoms
Cumulative Dose of Cow's Milk
< 20 mL (appr. 750 mg protein) 20-200 mL (appr. 0.75-7.5 g protein) > 200 mL (appr. 7.5 g protein) Onset of Symptoms
Type of Reactions
(1) Björkstén et al. 1983 (2) Ventura & Greco 1988 delayed reactions (3) Sutas et al. 1997 (4) Niggemann et al. 1999b (5) Garcia-Ara et al. 2001 (6) Saarinen et al. 2001 Children with CMA
within 2-24 hours within 6-12 hours (1) clinical history within 12-24 hours (2) elimination / challenge (3, 4) DBPCFC (5, 6) open challenge * patients selected because of symptoms suggesting immediate-type CMA Internet Symposium on Food Allergens 4(1):2002
Onset of Symptoms
Type of Reactions
At diagnosis 1 year 2 years 3 years of follow-up
immediate (<45 min) intermediate (1-24 h) delayed (24-72 h) Carroccio et al. 2000b very delayed (>72 h)* No. of symptomatic patients 86 consecutive children with IgE-mediated or non-IgE-mediated CMA (median age atdiagnosis 4 months, DBPCFC)* symptoms of constipation, dermatitis, and wheezing Onset of Symptoms
Immediate onset reactions occurred in 43% of positive challenges after a cumulative time Sütas et al. 2000
of 36 min (3 min to 2.0 h) and late onset reactions in 57% of positive challenges after acumulative time of 54 h (2 to 192 h) (DBPCFC, 59 children with CMA) Age at Onset of CMA
(1) Savilahti 1981 Onset in 30% of children with CMA in the first month of life (1) and in 96% at <1 year Cluster Groups
3 clusters of patients with CMA using a K-means algorithm (data of case history and
effects of a standardized milk challenge):
predominantly urticarial positive skin tests, elevated and angioedematous total and milk specific serum (1) Hill et al. 1986 pallor, vomiting, or (2) Firer et al. 1987 relatively IgA deficient* (1) (3) Hill et al. 1989 positive skin tests and elevated eczematous or bronchitic specific IgE only in patients or diarrheal symptoms *milk- specific IgA, IgG and IgM levels similar in all groups and controls (2) (1) 100 cow's milk allergic children (mean age of 6 month) (2, 3) 47 cow's milk allergic children (age 4-66 months) Internet Symposium on Food Allergens 4(1):2002
Threshold for Elicitation of Symptoms
Challenge Tests:
Amounts of cow's milk inducing symptoms ranged from 5 g to 250 g (DBPCFC) (1) Amounts of milk (dry weight) inducing symptoms: </= 500 mg in 55% (including 26and 3 positive challenges with 250 mg and 100 mg, respectively) (DBPCFC, 196 foodallergic children with atopic dermatitis) (4) (1) Norgaard & Bindslev-Jensen A cumulative dose of 0.78 mg cow's milk powder (0.01 to 6.1 mg) elicited immediate onset reactions in 43% of positive challenges and a cumulative dose of 31.2 mg cow's (2) Malmheden Yman et al.
milk powder (4 to 100 mg) elicited late onset reactions in 57% of positive challenges (DBPCFC, 59 children with CMA) (5) (3) Laoprasert et al. 1998 A dose of 2 to 25 mL of cow's milk infant formula elicited symptoms in 58%, a dose (4) Sicherer et al. 2000 of 50 mL in 13%, of 100 mL in 9.2%, and a dose of >100 mL in 7.9% of 76 infants (5) Sütas et al. 2000 with CMA (age <1 year, open challenge) (6) (6) Garcia-Ara et al. 2001 A threshold of </= 0.1 mL and 1 mL of cow's milk observed in 1.7% and 5% of (7) Morisset & Moneret-Vautrin patients, respectively (59 patients with CMA, placebo-controlled food challenges) (7) Accidental Ingestion: Fatal anaphylaxis after ingestion of 100g of a sausage containing 60 mg CAS (2)The quantity of ingested whey proteins elicited anaphylactic reactions in a 3-year-oldboy was estimated to be 120-180 µg (equivalent to 23 to 24 µL of milk) (3) 4 Diagnostic Features of Cow's Milk Allergy

Family History / Maternal Factors
Family History
Family History
Subjects / Follow-up
Manifestation of CMA
of Atopic Disease
children (siblings with (1) Gerrard et al. 1973 formula fed infants (5th (2) Vandenplas & Sacre 1986 (3) Schwartz et al. 1987(4) Ventura & Greco 1988 formula fed infants (5th (5) Iacono et al. 1998c (6) Carroccio et al. 2000b 29 children with severe in 89% (1 parent) CMA (1 to 10 months) in 50% (both parents) with gastrointestinal *significance P <0.001 91 children (8 months) **symptoms at onsetpredominantly with extraintestinal 57 children (8 months) gastrointestinal, at the end of the study increased frequency 12 infants (birth to 5 years) persistent** (a) of wheezing, constipation, resolved within 1-2 years and delayed reactions 26 infants (birth to 5 years) (a, b) multiple foodintolerance in a) 92%, and b) 26 children (3 years) 12%, respectively 60 children (3 years) tolerance acquired (3) occurence of severe CMA in a pair of identical twins and HLA-identical siblings(4) family history of CMA in paranthesis(6) 86 consecutive children with IgE-mediated or non-IgE-mediated CMA (median ageat diagnosis 4 months) Internet Symposium on Food Allergens 4(1):2002
Maternal Parameters in Breast Milk
Total No.
Mothers from
6 infants with CMA 65 infants with IgE- 24 healthy infants (1) Savilahti et al. 1991 (2) Järvinen et al. 1999a (3) Saarinen et al. 1999b (4) Järvinen et al. 2000a 27 infants withchallenge-proven (5) Järvinen et al. 2000b CMA (0.25-8.0months) *in colostrum, ** in colostrum and breast milk, ***significance p=0.012(-) lower, (+) higher values, and (+/-) no difference as compared to controls# expression on breast milk macrophages (2) asymptomatic mothers (3) TGF-beta-1 positive correlation to beta-LG spec. IgA and CAS spec. IgG,negative correlation to SPT and lymphocyte stimulation with beta-LG or CAS(4) total and cow's milk specific IgA; levels of specific IgA positively correlatedwith levels of total IgA but not with the development of CMA in the infants(5) spontaneous and mitogen-induced TNF-alpha and IFN-gamma production ofhuman milk leucocytes Maternal Serum IgG
(1) Mothers of infants who a) developed allergy or b) presented no symptoms:
(1) Casimir et al.1989 Statistically lower serum IgG anti- beta-LG levels in a) than in b) (P <0.001) Risk Factors for Specific Serum IgE
Significant risk factors for the presence of cow's milk specific IgE in 75 infants with IgE-
(1) Saarinen & Savilahti mediated reactions to cow's milk (mean age of 6.7 months)*: - long breast-feeding- exposure to cow's milk at the maternity hospital * see Footnote (1) - breast-feeding during the first 2 months at home either exclusively or combined withinfrequent exposure to small amounts of cow's milk Footnote:
(1) All mothers should be encouraged to breastfeed their newborns in the first year of life. However, in the genetically
predisposed newborn, who can not yet be accurately identified prior to or at birth, exposure to cow's milk allergens via
breast milk, in the newborn nursery, and infrequent feeding of small amounts of cow's milk are significant risk factors for
the development of cow's milk specific IgE (and eventually IgE-mediated CMA). Evidence-based strategies to prevent this
from happening have not yet been developed.
Internet Symposium on Food Allergens 4(1):2002
Specific Serum IgE
Positivity and mean values of cow's milk specific serum IgE:
Patients / Reference
with history of CMA cow's milk tolerant children cow's milk DBPCFC positive (1) Dannaeus et al. 1977(2) Sampson & Ho 1997 cow's milk DBPCFC negative (3) Niggemann et al. 1999b (+) increased IgE levels, *significance P<0.0001, **significance P<0.001 (1) 69 children with food intolerance, IgG levels seemed to parallel IgE levels, nodifferences in IgA levels in allergic and control subjects(2) 196 children and adolescents with atopic dermatitis (90% family history of atopicdiseases)(3) 107 children with atopic dermatitis Specific IgE, Persistent Allergy
(1) Sicherer & Sampson Significantly elevated levels of milk- and CAS- specific IgE in children with persitent CMA (age of >9 years) as compared to children with CMA at the age of <3 years (RAST) (1) Total / Specific IgE, SPT, and Persistent Allergy
26 children with persistent CMA had significantly elevated levels of total serum IgE, and
cow's milk and cow's milk proteins specific IgE, and higher frequency of positive SPT to cow's Carroccio et al. 2000b
milk and proteins (86 consecutive children with IgE-mediated or non-IgE-mediated CMA,
median age at diagnosis 4 months)
Native / Denatured CAS, Specific IgE, Persistent Allergy
36 children with CMA: a) 11 became clinically tolerant, and b) 25 had persistent CMA; (6
controls without CMA). Compared to group b) children of group a) had significantly higher
ratios of specific IgE antibodies against linear (denatured by reducing agent) than against
conformational (native) epitopes of alpha-S1 and beta-CAS; none of group a) childrendeveloping tolerance and 9 of group b) children with persistent CMA possessed IgE to linearized beta-LG (immunodot-blots) CAS Specific B Cell Epitopes, Persistent Allergy
2 IgE-binding regions of alpha-S1-CAS (aa 69-78 and aa 173-194) detected by 67% and100% of sera from patients with persistent CMA (>9 years of age) but by none of childrenless than 3 years of age who are likely to outgrow CMA. No differences in IgG bindingobserved (24 children with CMA) (1) (1) Chatchatee et al. 2001a 6/10 children with persistent CMA detected a peptide from alpha-S1-CAS (aa 69-78) (2) Chatchatee et al. 2001b while none of 10 children who outgrew CMA had IgE binding to this epitope (immunodot- (3) Vila et al. 2001blot) (3)3 IgE binding regions on beta-CAS and 6 on kappa-casein detected by the majority of 15children with CMA (age of 4-18 years) with high levels of cow's milk specific IgE, but notby sera from children with CMA (age of <3 years) with low levels of specific serum IgE,who are likely to outgrow CMA (2) alpha-LA Specific B Cell Epitopes, Persistent Allergy
4 IgE-binding regions of alpha-LA detected with sera from 11 patients with persistent CMA
(4-18 years of age, IgE to cow's milk >100 kU(A)/L) none of these detected by sera from 8
(1) Järvinen et al. 2001 children <3 years of age (IgE to cow's milk <30 kU(A)/L) who are likely to outgrow CMA(SPOTs membrane technique) (1) beta-LG Specific B Cell Epitopes, Persistent Allergy
7 IgE-binding regions of beta-LG detected with sera from 11 patients with persistent CMA (4-
18 years of age, IgE to cow's milk >100 kU(A)/L) only 3 of these regions detected by sera from (1) Järvinen et al. 2001
8 children <3 years of age (IgE to cow's milk <30 kU(A)/L) who are likely to outgrow CMA
(SPOTs membrane technique) (1)
Internet Symposium on Food Allergens 4(1):2002
Specific IgE, Immediate Reactors, Tolerance
69 IgE- sensitized immediate reacting children with CMA (median age of 24 months) median (1) Hill et al. 1993b
study period of 2 years: 22% developed clinical tolerance, had lower specific IgE levels at thebeginning and the end of study period, and significant fall in SPT reactivity (1) beta-LG Specific B Cell Epitopes, Immediate and Delayed Type CMA
8 immediate type patients with CMA (systemic reactions) and 6 delayed type patients with
(1) Heinzmann et al. 1999 CMA (skin reactions) recognized same B cell epitope (beta-LG aa 95-113), no difference inIgE- binding peptide pattern (RAST inhibition, Pin-ELISA) (1) Specific Serum IgG and IgA
Percentage of positivity of specific serum IgA and IgG antibodies:
a) 43% b) 44% a) 57% b) 69% a) 71% b) 50% a) 43% b) 75% (1) Bottaro et al. 1992 a) 86% b) 44% a) 86% b) 69% (2) Vaarala et al. 1995(3) Juvonen et al. 1999 pooled alpha-LA, beta-LG, CAS a) 71% b) 38% a) 57% b) 63% NS = no significant differences (1) children (age of 3 months to 6 years): a) 7 with CMA (cutaneous symptoms), b) 16with CMA (gastrointestinal symptoms)(2) a) 10 infants fed cow's milk- based formula, b) 10 infants fed a CAS hydrolysateformula until the age of 9 months(3) 129 children a) cow's milk formula fed, b) CAS hydrolysate formula fed, c) breast fedduring the first 3 days of life, otherwise exclusively breast fed, follow-up for 2 years ('' at 8and 12 months) Specific IgE and IgG Subclass, IgA, Ratios
Cow's Milk CAS
+ (8)a) 90%, b) 0% (9) a) 50%, b) 0% (9) a) 20%, b) 0% (9) (1) Björkstén et al. 1983 c > d, e, f** (6); + (2) Schwartz 1991 a > b (4); + (8) (3) Tainio & Savilahti 1990(4) James & Sampson 1992 (5) Stoger & Wüthrich 1993 (6) Saalman et al. 1995 a) 80%, b) 30% (9) a) 80%, b) 20% (9) (7) Iacono et al. 1998c (8) Little et al. 1998(9) Szabó & Eigenmann a) 60%, b) 10%(9) a) 90%, b) 50% (9) a) 70%, b) 40% (9) IgE + IgG + IgG4 Internet Symposium on Food Allergens 4(1):2002
(+) increase, (-) decrease, (NS) no significant differences**ratios of IgG1/IgG, IgG1/IgG3 and IgG1/IgG4 same tendency (1) no relation to provocation test in 14 children with immediate reactions to cow's milk,15 cow's milk tolerant children(2) children with immediate type CMA, SPT positive to a) cow's milk (n=20), b) cow'smilk and whey hydrolyzed formula (n=17), c) cow's milk, whey and CAS hydrolyzedformulas (n=13)(3) 21children with challenge proven CMA(4) a) 18 children with CMA, b) 11 children acquired tolerance(5) 28 adults with CMA (aged from 16 to 58 years)(6) c) children with CMA predominantly gastrointestinal , or d) skin symptoms ofimmediate-onset, e) children with untreated coeliac disease and f) healthy children(7) a) 12 children with persistent CMA up to age of 5 years, b) 26 controls(8) 15 adults with CMA (average age of 39.5 years)(9) positivity in a) 10 children with CMA (age of 7 months to 68 months) and b) 10 age-matched non-allergics Symptoms and Prevalence of Specific IgE
Positivity of cow's milk specific serum IgE in 148 children with CMA according to symptoms:
Persisting diarrhea Ventura & Greco 1988 Urticaria / Anaphylaxis Failure to thrive Serum Eosinophilic Cationic Protein (ECP)
After 4 weeks of elimination diet; measurement of ECP before oral cow's milk challenge, 27
hours and 1 week after in 28 cow's milk allergic children (age of 5.8 to 43 months): Increased,
transient ECP serum levels during challenge in patients with skin manifestations but not in
patients with gastrointestinal symptoms (1)
(1) Suomalainen et al. 1994b After elimination diet; determination of ECP before milk challenge test, as well as 2 and 24hours after it in 35 cow's milk allergic children (average age of 16 months; 6-49 months): (2) Hidvegi et al. 2001 Basic ECP level significantly higher than in control group; ECP level significantly decreased2 hours after milk challenge test, after 24 hours back to basic ECP level; no significantdifferences in ECP levels of children with (n=10) and without clinical reactions (n=25), eitherbefore or after challenge test (2) Soluble IL-2 Receptor
Elevated serum levels of soluble IL-2 receptor in 16 children with non- IgE mediated CMA
(1) Blanco Quiros et al.
and in 8 children with IgE mediated CMA as compared to 19 children with other IgE- mediated food intolerance (1) IL-12 and sCD30
Increased serum IL-12 levels and normal sCD30 levels in children with CMA while pollen-
(1) Blanco Quiros et al.
sensitized children had normal IL-12 and higher sCD30 levels than controls; no differences in 1999 patients with asthma or allergic dermatitis (11 children with CMA, open elimination-challenge test, SPT, RAST) Specific TABM
Elevated serum levels of T-cell derived antigen- binding molecules (TABM) specific for
(1) Little et al. 1998 alpha-LA, beta-LG, and CAS in 6 to 7 of 15 adults with CMA (1) Eosinophil-related Markers
In a girl (at age of 12 months to 3 years) with CMA and multiple food allergies: high total
(1) Nilsson et al. 1999 eosinophil count, increased eosinophil activity, low IFN-gamma : IL-5 ratio, poor wheightgain, increasing respiratory symptoms (1) Internet Symposium on Food Allergens 4(1):2002
Lymphocyte Subclasses, Antigen Expression
7 children with CMA and atopic dermatitis children with CMA 37 children with CMA (+)* HLA-DQ7 24 children with CMA 9 children with IgE- 15 fed with cow's milk (1) Schwartz et al. 1987 (2) Abernathy-Carver et 7 breast fed children 12 patients with and (3) Nakajima et al. 1996 (4) Camponeschi et al.
1997 6 patients with CMA (5) Jarvinen et al. 1998 (+) increase, (-) decrease, * significant, (NS) no significant difference (6) Eigenmann et al. 1999 (7) Papadopoulos et al.
(1) preparations from unstimulated PBMC (2) in vitro stimulation with CAS(3) stimulation with alpha s1-CAS (8) Schade et al. 2000 (4) majority of HLA-DQ7 positive patients presented a high humoral response rather than (9) Ulanova et al. 2000 cellular response (stimulation with beta-LG)(5) challenge proven patients, compared to healthy controls (no stimulation)(6) mean age of 28 months (7 months to 9.3 years), beta-LG stimulated PBMC (7) children with IgE- mediated CMA (3-11 months of age), PCNA expression >/=10% asspecific and sensitive marker of CMA in cow's milk fed infants, low cow's milk antigen dietsare related with reduced lymphocyte reactivity in whey hydrolyzed fed and breast fed infants(stimulation with beta-LG)(8) patients with atopic dermatitis; stimulation with CAS, alpha-LA, and beta-LG(9) expression of CD1 in duodenal biopsy: CD1d positive cells found in lamina propriaduring symptomatic and asymptomatic periods, 6 healthy controls virtually devoid of CD1dexpression; localization of CD1d positive cells in areas where B cells, plasma cells anddendritic cells were present; positive correlation between the numbers of CD1d(+) andCD19(+) cells in the lamina propria CLA - cutaneous lymphocyte antigen (responsible for skin homing)PCNA - proliferating cell nuclear antigen T-Cells, Cell Surface Markers
Cow's milk protein specific T-cell clones (TCCs) were established from blood of infants with a)
CMA and atopic dermatitis, from b) atopic controls (atopic dermatitis, without CMA), from c)
nonatopic controls, and d) from infants with CMA after spontaneously developed tolerance:
(1) Schade et al. 2002 Expression Levels Internet Symposium on Food Allergens 4(1):2002
Lymphocyte* / PBMC** Proliferation
Cow's Milk
Patients / Stimulation with
beta-LG BSA
17 children with CMA children with CMA (challenge proven) a) children with CMA b) children with CMA (immediate type, RAST positive) children with CMA and atopic a) children with CMA (gastrointestinalsymptoms) b) children with CMA (skin or nosymptoms) 10 children with CMA a) <5 years, b) >6 years of age (1) Endre & Osvath 1975 a) 10 infants fed cow's milk- based (2) Tainio & Savilahti b) 10 infants fed a CAS hydrolysate (3) Kondo et al. 1992 (4) Kondo et al. 1993 a) 27 children with IgE mediated CMA (5) Suomalainen et al.
b) 9 children with milk induced (6) Eigenmann et al. 1995 enterocolitis syndrome (7) Iida et al. 1995 a) 22 patients with cow's milk (8) Vaarala et al. 1995 responsive atopic eczema (9) Hoffman et al. 1997 b) 66 patients with atopic eczema (non- (10) Werfel et al. 1997b (+) higher stimulation index or proliferation, (NS) no significant differences (1) significant proliferation with at least one milk antigen in 15 patients(2) in children without specific IgE(3) 3 children with CMA and tension- fatigue sydrome (cow's milk RAST scores in a)negative or slightly positive)(4) as compared to children with immediate allergic symptoms and controls(5) 44 children with CMA (mean age of 16 months) after 2-4 weeks of elimination diet,proliferation response abrogated after clinical challenge(6) as compared to control group ('' stimulation with whey hydrolyzed formula and proteins),lower stimulation with hydrolyzed formula(7) 22 children with CMA and atopic dermatitis, proliferative response decreased rapidlyafter elimination diet(8) fed until the age of 9 months ('' stimulation with alpha-CAS)(9) a) as compared to control group (significant, but extensive overlapp), group a) alsoresponded to soybean antigen(10) age of 16-67 years (median 28 years) Lymphocyte Transformation
Lymphocyte transformation test a) before and b) 30 days after elimination of cow's milk from
(1) Brarda et al. 1989 the diet: a) significantly increased lymphoblastogenesis (P <0.01), b) no differences in 19children with CMA (1) CBMC Proliferation, IFN-gamma
Stimulation of cord blood mononuclear cells (CBMC) with cow's milk proteins: pronounced
proliferation of cells stimulated with alpha-LA, beta-LG, and alpha-CAS; preferentially reduced (1) Szepfalusi et al. 1997
IFN-gamma levels in individuals with positive parental allergic history (39 randomly selected
newborns) (1)
Internet Symposium on Food Allergens 4(1):2002
Cytokine Production by Lymphocytes
Patients / Cytokines
IL-10 IL-13 Ref.
a) immediate- reactingb) late- reacting a) children with CMA b) children who acquiered tolerance children with CMA a) children with CMA b) children who acquiered tolerance a) immediate- reacting b) late- reacting children with atopic dermatitis (milk a) children with CMA (cutaneoussymptoms) b) children with CMA (predominantly digestive symptoms) (1) Hill et al. 1993a d) children who acquiered tolerance (2) Suomalainen et al.
31 children with CMA 1993a (3) Heyman et al. 1994 a) 6 infants with CMA b) 6 infants without CMA (4) Benlounes et al. 1996 a) 22 immediate-reacting children (5) Sutas et al. 1997 b) 29 late-reacting children (6) Werfel et al. 1997b d) cow's milk tolerant children (7) Benlounes et al. 1999 * significant, c) healthy control group, (+) positive response (8) Österlund et al. 1999 (9) Schade et al. 2000 (1) 75 (a) and 17 (b) children with CMA and 59 (c) tolerant children (age of 1-9 years) (10) Sütas et al. 2000 (stimulation with beta-LG)(2) 22 children(3, 4) stimulation of PBMC with cow's milk proteins(5) lower thresholds of stimulation in a) as compared to b)(5) 50 cow's milk allergic children (age of 2-60 months) (DBPCFC positive) with atopicdermatitis, after DBPCFC difference in IFN-gamma generation abolished(6) IL-4 production of CD4+ CAS specific T-cell clones (compared to house dust mitesensitive patients)(7) 83 children, measured in whole blood cultured with cow's milk proteins, day 1 ('')followed by TNF-alpha degradation, day 5: secretion peak in group b)(8) challenge proven children with either skin or gastrointestinal symptoms or bothcompared to healthy controls (age of 0.12-11.2 months), unstimulated PBMC and mitogen-induced production(9) infants with atopic dermatitis (age of 3.8-12.3 months); cow's milk protein-specific TCCderived from PBMCs stimulated with CAS, alpha-LA, and beta-LG; 2 patients with TCCreactivity to CAS and whey proteins and 2 patients with exclusive reactivity to CAS in bothgroups; CMA in infants with atopic dermatitis associated with production of TH-2 cytokinesby circulating antigen-specific CD4+ T cells; significant correlation with IL-4 of both IL-5and IL-13 production(10) stimulation of PBMC with cow's milk; IL-10 concentrations increased in response toDBPCFC in challenge-positive children Internet Symposium on Food Allergens 4(1):2002
Cytokine Secreting Cells in Blood and Duodenal Mucosa
Frequency of spontaneously cytokine secreting mononuclear cells in the
(1) Hauer et al. 1997 Children with a) CMSE, b) CMA, and c) age matched controls Cytokine secreting cells more frequently in duodenal mucosa than in the blood PBMC, Migration Inhibition Factor
In vitro assay of lymphocyte migration inhibition factor (MIF), stimulation of peripheral blood
(1) Ashkenazi et al. 1980 lymphocytes with beta-LG: significant higher MIF production in 24 children with CMA than incontrol subjects; most of 18 children recovered from CMA had negativ assay (1) Lymphocytes, Suppressor Activity
Decreased suppressor activity of isolated lymphocytes induced by either Concanavalin A or
(1) Suomalainen et al.
cow's milk in 10 children with CMA as compared to controls and patients who acquired cow's milk tolerance (1) Cell Mediated Cytotoxicity
Antibody- dependent cell- mediated cytotoxicity (ADCC) to beta-LG- coated cells rather
induced in most sera of children with CMA and predominantly gastrointestinal symptoms than
(1) Saalman et al. 1995 in sera of children with skin reactions (immediate- type), children with untreated coeliacdisease, or healthy children; ADCC reactivity of individual sera correlated with their IgG1antibody levels (1) Homing Receptor Expression
Stimulation of a) cord blood mononuclear cells and b) peripheral blood mononuclear cells (at
age of >3 months) with alpha-S1 CAS:
a) higher percentage of alpha-E-beta-7-positive T cells than in healthy controls; no difference in (1) Kohno et a. 2001
cord blood T-cell proliferation; CLA was not induced on T cells
b) no induction of alpha-E-beta-7-positive T cells; CLA was expressed on T cells
(4 infants with atopic dermatitis and CMA)
Salivary IgA
158 healthy mature infants at birth: Salviary anti-CAS IgA was significantly higher (P <0.05) in (1) Renz et al. 1990
high risk infants than in no risk or low risk infants; salviary anti-CAS IgA values correlatedwith maternal allergy, but not with paternal allergy (1) Pancreatic Enzymes
children with CMA (median age 3 months) fed with a) a hydrolyzed CAS- based formula or b) a
soy- protein based formula: No significant difference in pancreatic secretion between both
(1) Carroccio et al. 1997 groups for any of the enzymes studied (trypsin, chymotrypsin, lipase, and phospholipase) duringdiet of 6 weeks (1) Duodenal Fluid, Specific IgE and IgD
increased levels of cow's milk protein (and soybean agglutinin) specific IgE and IgD in basal and (1) Freier et al. 1983
pancreozymin- stimulated duodenal fluid in 13 children with various intestinal diseases (1)
Jejunal Fluid, Hyaluronic acid, Albumin
Jejunal fluid levels of hyaluronan (hyaluronic acid) and albumin increased after milk perfusion
(1) Bengtsson et al. 1996 challenges in 5 adults with CMA (DBPCFC positive, SPT and RAST negative, lactose tolerant)as compared with control group (1) Small Intestine Mucosa, IgE and IgM Plasma Cells
local reaginic reaction after ingesting cow's milk: increased mucosal IgE and IgM plasma- cells, (1) Shiner et al. 1975
increased degranulation of mast cells, staining of connective tissue and basement membraneswith antisera to IgG and C3 complement in 2 cow's milk sensitive infants (1) Internet Symposium on Food Allergens 4(1):2002
Small Intestine Mucosa and Serum, Alkaline Phosphatase
Levels of alkaline phosphatase (ALP) after cow's milk protein challenge: Significant depletion in (1) Iyngkaran et al. 1995
upper jejunal mucosa tissue and serum in infants with clinical and histological reactions (n=10);tissue ALP depressed in 3/5 patients with histological but no clinical reactions to cow's milk (1) Small Intestinal IgE Plasma Cells, Specific Serum IgE
Patients / Cow's Milk Specific
IgE Plasma Cells
Serum IgE
16 children with CMA (1) Schrander et al. 1993a (1) elimination / challenge proven CMA Intestinal Total Immunoglobuline Secreting Cells
Intestinal immune responses after diagnostic milk provocation:
Patients / No. of Secreting Cells
a) with CMA (acute urticaria) b) with CMA (gastrointestinal symptoms) c) with CMA (skin and gastrointestinal symptoms) (1) Isolauri et al. 1990 d) 13 with persistent CMA (2) Isolauri et al. 1992(3) Suomalainen et al.
e) 24 acquired tolerance d) 27 with CMA (age of 9-69 months) (+) significant increase during challenge, (-) no increase (1) IgM and IgA responses: in group b) > a)(3) increase in all isotypes associated with clinically positive cow's milk challenge; specificantibody secreting cells against beta-LG and CAS (and gliadin) increased in IgM class only Intestinal Eosinophils, Lymphocytes, Mast Cells
TIA-1** Mast Cells Ref.
12 children with CMA 47 children with coeliac children with CMA and (1) Kosnai et al. 1984 21 children with CMA/CMI (+) in 38% (2) Challacombe et al.
35 children with gluten (3) Kaczmarski et al.
1989 10 children with CMA/CMI (4) Hankard et al. 1997 * significant, (+) increase, (-) decrease**TIA-1 (= cytotoxic granule-associated protein) expressing lymphocytes (1) in lamina propria of jejunum(2) in lamina propria of duodenal mucosa(3) cellular infiltration of small intestinal mucosa(4) number of TIA1- expressing intraepithelial lymphocytes (IEL) and the TIA1/IEL ratio inpatients on cow's milk-free diet of various duration, negative correlation between theTIA1/IEL ratio and the duration of the diet (duodenal biopsies) Internet Symposium on Food Allergens 4(1):2002
Intestinal ECP, MBP, Histamine, VCAM-1
Histamine* VCAM-1** Ref.
5 adults with CMA 14 patients with cow's milk-sensitive enteropathy (+) increased, (-) decreased, *intestinal secretion, **expression on mononuclear cells (1) Bengtsson et al. 1997 (2) Chung et al. 1999 (1) DBPCFC positive, SPT and RAST negative, lactose tolerant patients (perfusionchallenges with milk, CAS, and whey)(2) Challenge positive, SPT and RAST negative patients, endoscopic duodenal biopsyECP = eosinophil cationic proteinMBP = eosinophil major basic proteinVCAM-1 = vascular cell adhesion molecule-1 Intestinal Epithelial Cells, CD23 Expression
CD23 expression on intestinal epithelial cells increased in 3 children with CMPI (age < 1 year)
Kaiserlian et al. 1995 associated by high levels of specific IgE Fecal alpha-1 Antitrypsin, TNF-alpha, ECP, IgE
Indicators of intestinal inflammation in jejunal fluid after cow's milk challenge:
13 children with CMA a) positive DBPCFC with cow's milk b) negative DBPCFC with cow's milk (+) in 11% (1) Kapel et al. 1999 15 children with CMA (2) Majamaa et al. 1996(3) Majamaa et al. 2001 (+) significant increase after challenge, (-) no increase*in challenge positive children**particularly in delayed type patients, ***particularly in immediate reactors (2) children with atopic eczema(3) out of 26 atopic infants with confirmed food allergy; all 9 patients with increased fecalconcentration of alpha-1-antitrypsin had positive challenge with cow's milk while only 6 inthose with normal alpha-1-antitrypsin concentration (fecal samples collected beforeelimination diet and 3 months later) Internet Symposium on Food Allergens 4(1):2002
Gastrointestinal Permeability
Alteration
Urinay Recovery / Test Substances Permeability
after cow's milk challenge polyethylenglycol (PEG) lactulose/mannitol excretion ratios cellobiose/mannitol excretion ratios lactitol/mannitol excretion ratios Jejunal Biopsy / Test Substances
(1) Falth-Magnusson et al.
horseradish peroxidase (HRP) *significantly changed, (+) increased, (-) decreased (2) Heyman et al. 1988 (3) Jalonen 1991 (1) 16 children with CMA (immediate- type), greatest alteration in children with most severe (4) Troncone et al. 1994 (5) Kalach et al. 2001 (2) 15 children with CMA (age of 1-24 months), jejunal transepithelial fluxes(3) 51 children with CMA (skin symptoms and patients with gastrointestinal symptoms), 3days after challenge(4) 32 children with CMA (age of 3-84 months), 24 hours after challenge(5) children with symptoms suggestive of CMA (age of 0.5-168 months): a) 95 children withproven CMA and b) 105 controls (challenge negative); defining a cut-off value intestinalpermeability exhibited a 68% sensitivity and a 77% NPV for CMA;. highest sensitivity(70%) at ages 6-12 months; abnormal intestinal permeability in 80% of CMA children withdigestive manifestations, in 43% with extra-digestive, 68% with mixed and 40% withanaphylactic manifestations; lactitol/mannitol ratio correlated negatively with age in controlgroup, no correlation in CMA group Protein / Allergen Absorption
Concentrations in blood serum samples
17 children with CMA (age 0.3 to 2 µg/L (in 29%) (1) Husby et al. 1990 3-4 days after birth 31 µg/L (2) Kuitunen et al. 1994 20 infants (followed up to 8 at 1 month 6 µg/L at 2 months 2 µg/L 1 week 7 µg/L (in 38%) at >3 months trace amounts 2 weeks 4 µg/L (in 21%) (1) 24 h after cow's milk challenge(2) median serum levels (per g alpha-LA or beta-LG given per kg body weight) Internet Symposium on Food Allergens 4(1):2002
Diagnostic Significance of Tests
SPT, Atopy Patch Test (APT), RAST
Patients / Reference
SPT - positive
(cutoff point, 3 mm) APT - positive
(1) Björkstén et al. 1983 (2) Norgaard et al. 1995 (3) Isolauri & Turjanmaa 1996 (4) Kekki et al. 1997 RAST - positive
(5) Rance et al. 1997 (6) Sampson & Ho 1997 (7) Majamaa et al. 1999 (8) Niggemann et al.
* mean age, (-) tendency of negative results, (+) association to positive results (1) 14 children with immediate reactions to cow's milk, 15 cow's milk tolerant children(2) 21 adults with cow's milk / egg allergy (DBPCFC, 5 different RAST systems)(3) 183 children with CMA and atopic dermatitis (DBPCFC or open challenge, 54%challenge positive)(4) 54 children with CMA and atopic dermatitis(5) 430 food allergic children and adolescents (labial food challenge positive) age from0.2 to 20 years(6) 54 of 109 DBPCFC positive to cow's milk (study population: 196 food allergicchildren and adolescents with atopic dermatitis, age from 0.6 to 17.9 years)(7) 72 children with CMA (challenge proven)(8) 107 children with atopic dermatitis (47 DBPCFC positive) age from 5 months to 12years Internet Symposium on Food Allergens 4(1):2002
SPT, Atopy Patch Test (APT), RAST (continued)
Patients / Reference
SPT - positive
(cutoff point, 3 mm) APT - positive
RAST - positive
(cutoff point,
(9) Vanto et al. 1999 (10) Sporik et al. 2000 (11) Garcia-Ara et al.
Serum ECP - positive
(cutoff point, >15 µg/L) (12) Roehr et al. 2001 (13) Saarinen et al. 2001 * mean age, (-) tendency of negative results, (+) association to positive results (9) 301 children with suspected CMA (176 DBPCFC positive)(10) 310 children with suspectd CMA (43% challenge positive), specifity of SPT inchildren less than 2 years of age was 91%(11) 170 children with suspected CMA age <1 year (mean 4.8 months); 4-year follow-up; SPT and RAST: at least one positive result for whole milk and/or major milkproteins (alpha-LA, beta-LG, or CAS)(12) 45 of 71 DBPCFC positive to cow's milk (study population: 98 children withatopic dermatitis and suspected food allergy, age from 2 months to 11.2 years);combination of positive APT with evidence of specific IgE or with a positive SPTresulted in a PPV of 100%(13) 239 children with suspected CMA (mean age of 6.9 months); 49% challengepositive; with a cut-off level in SPT of 8 mm sensitivity and NPV decreased (to 19%and 55%, respectively) while specificity and PPV increased (to 98% and 92%,respectively); using protein fractions (beta-LG, bovine serum albumin, CAS) in APTsensitivity and NPV were 26% and 57%, respectively, while specificity and PPVincreased (to 92% and 77%, respectively); with a cut-off level in RAST of >3.5 kU/Lsensitivity and NPV decreased (to 25% and 57%, respectively) while specificity andPPV increased (to 98% and 94%, respectively); serum ECP measured after challenge(day 4); with a cut-off level of 24.7 µg/L serum ECP sensitivity decreased to 13% whilespecificity, PPV, and NPV increased (to 98%, 93%, and 37%, respectively) Internet Symposium on Food Allergens 4(1):2002
Predictive Decision Points of Specific IgE
It should be noted that pedictive decision points are significantly affected by specific conditions
within each study population (e.g. atopic dermatitis or selection criteria)
Patients / Reference
Predictive Decision Point
>17.5 >17.5 Patients / Reference
(1) Sampson & Ho 1997 (2) Garcia-Ara et al.
2001 (3) Roehr et al. 2001 Predictive Decision Point
(4) Saarinen et al. 2001 * mean age, ** CAP system FEIA (1) 54 of 109 DBPCFC positive to cow's milk (study population: 196 food allergic childrenand adolescents with atopic dermatitis, age from 0.6 to 17.9 years)(2) 170 children with symptoms suggesting immediate-type CMA (age <1 year, mean 4.8months); 4-year follow-up(3) 45 of 71 DBPCFC positive to cow's milk (study population: 98 children with atopicdermatitis and suspected food allergy, age from 2 months to 11.2 years); combination ofpositive APT with evidence of specific IgE in a PPV of 100%(4) 239 children with suspected CMA (age of 6.3-7.5 months); 49% challenge positive(5) 100 children and adolescents with suspected IgE-mediated food allergy (age of 3 months to14 years); 61% with atopic dermatitis, appr. 50% with asthma, and 90% with atopic familyhistory, 21/62 DBPCFC positive to cow's milk Internet Symposium on Food Allergens 4(1):2002
Diagnostic Significance of Tests (continued)
Predictive Decision Points of SPT
It should be noted that pedictive decision points are significantly affected by specific conditions
within each study population (e.g. atopic dermatitis or selection criteria)
Patients / Reference
Predictive Decision Point
(wheal diameter in mm) (1) Sporik et al. 2000 (2) Saarinen et al. 2001 (1) 310 children with suspected CMA (age of 1-192 months; 120 children < 24 months);55% of challenges were positive, 37% negative, and 8% inconclusive (open oral foodchallenges)(2) 239 children with suspected CMA (age of 6.3-7.5 months); 49% challenge positive; SPTwith cow's milk formula Cut-Off Levels: Specific IgE vs. SPT
In EAST 62 children from 640 children with suspected food allergy (<2 years of age) were
CMA positive according to specific IgE levels grade 3+ and 4+ (>3.5 AEU/mL) while 63
children had IgE-mediated CMA by SPT (100% diagnostic SPT level: >6 mm) but not by
EAST;
in CAP RAST 4 children from 127 children with suspected food allergy (<2 years of age) wereCMA positive according to specific IgE levels grade 4, 5, and 6 (>17.5 kU(A)/L) while 11children had IgE-mediated CMA by SPT (100% diagnostic SPT level: >6 mm) but not by CAPRAST SPT, IgE and Oral Challenge
Diagnostic tests in comparison with oral challenge test in 11 children with CMA (1-15 years of
age):
Case History
Roger et al. 1994 SPT, IgE, APT, ECP and Oral Challenge
Positivity of tests in 239 children challenged with cow's milk at a mean age of 6.9 months:
Saarinen et al. 2001 Combination of the 4 tests correctly classified 73% of the infants with a sensitivity of 76% and aspecificity of 67% (cut-off levels: SPT >/ = 3 mm; RAST cow's milk-specific IgE >/ = 0.7 kU/L;ECP >/ = 20 µg/L) Internet Symposium on Food Allergens 4(1):2002
Clinical History, IgE, Oral Challenge
Children with atopic dermatitis:
Diagnosis of CMA by
(1) Eigenmann et al. 1998 (2) Eigenmann & Calza SPT and DBPCFC
Eigenmann & Sampson Significant differences in SPT (wheal sizes) between cow's milk allergic or tolerant individuals (DBPCFC) (P < 0.001); SPT cut-off values mean diameter 5 mm / surface area of wheal 29 mm2 Skin Tests, RAST, Histamine Release and Lymphocyte Stimulation
Positive results with cow's milk (and alpha-CAS*)
(1) Rasanen et al. 1992 Histamine Release Lymphocyte Proliferation a) 22 children with CMA (positive challenge test)b) 12 non- milk- allergic controls with atopic dermatitisPanel of tests detected 21/22 children positive and 5/12 false- positive Specific Serum IgG
Patients / Reference
16-58, median 26 years 1-48 (1-72) months cow's milk specific IgG
beta-LG specific IgG
(1) Stoger & Wüthrich (2) Iacono et al. 1995b NS no diagnostic significance (3) Keller et al. 1996 (1) 28 adults with CMA(2) 218 healthy children, 205 with CMA, 96 with other (atopic) diseases (commercialbetalactotest)(3) 702 infants divided into six groups of different feeding (breast fed, infant formulafed); the shorter the breast feeding period and the earlier cow's milk formula isintroduced, the higher the IgG levels SPT and RAST
41 children with suspected CMA (age of 3 months to 13 years; mean 2.6 years): 32% SPT
(1) Campbell et al. 1987 positiv, 61% IgE positiv; concordance of SPT and IgE results in 51% (1) Histamine Release, SPT and RAST
26 children with suspected CMA: 77% positive in oral challenge test; patients with urticaria:
(1) Prahl et al. 1988 high degree of correlation between histamine test, RAST and skin test; patients withgastrointestinal symptoms only a few positive results in histamine test, RAST and skin test (1) Internet Symposium on Food Allergens 4(1):2002
Positivity of Open Challenge and DBPCFC
in children with history of CMA
265 children suspected for 56% (n=155) 44% (n=110) CMA (mean age 3 months) (1) Baehler et al. 1996 (2) Kaila & Isolauri 1997 a) 16 probable immediate a) 62.5% with adverse reactions (up to 2 reactors (mean age 37 months) h after milk exposure) b) 28.8% with predominantly b) 53 probable delayed gastrointestinal symptoms (2h to 6 days (1) reactors (mean age 17 months) after milk exposure) Other Features
Parameters / Subjects
Gender of Adults with
Gender: 91% females, 39% of them experienced first CMA
symptoms during or soon after a pregnancy; Stoger & Wüthrich 1993 34 patients with CMA (aged 47% of patients were nonatopic and showed a monovalent from 16 to 58 years) sensitization to cow milk proteins First hour of life: hemorrhagic meconiumNext few days: bloody diarrheaDay 14: elevated total IgE, specific IgE to cow's milk andan eosinophilia in peripheral blood; symptoms disappeared Intrauterine Sensitization when milk feed was changed to extensively hydrolyzed
A newborn presenting Feiterna-Sperling et al. 1997 symptoms suggestive of CMA Day 30 and at 7 months of age: 2 challenges with cow'smilk formula followed by recurrence of vomiting, waterydiarrhea and failure to thrive.
Age of 17 months: cow's milk well tolerated well Intrauterine Sensitization Symptoms of food-induced enterocolitis occurred before
An infant with non-IgE Kalayci et al. 2000 any oral intake of antigen Sensitization / First
Symptoms
50 infants showed first adverse symptoms during exclusive 118 infants with challenge breast-feeding (37 had cow's milk specific IgE), and 32 Saarinen & Savilahti 2000 proven adverse reactions to infants were sensitized during exclusive breast-feeding (23 cow's milk (mean age of 6.7 had cow's milk specific IgE) Exposure to cow's milk formulas (significantly more often Cow's Milk Exposure
than in control group, p < 0.01): 25 children with CMA (age <1 16 during their first week of life Stintzing & Zetterstrom 1979 6 before fifth week of life 3 infants not exposed Differentiation of 3 groups by positive SPT to:A) cow's milk onlyB) cow's milk and whey hydrolysate formula SPT, IgE in Immediate
C) cow's milk, whey and CAS hydrolysate formula (1, 2, 3) (1) Schwartz et al. 1989 Type CMA
Significant differences in cow's milk specific serum IgE: A (2) Schwartz 1991 26 (1), 50 (2, 3), and 21 (4) < B < C (1, 2) (3) Schwartz et al. 1991 children with IgE mediated Significant differences in beta-LG and CAS specific serum (4) Amonette et al. 1993 acute reactions of CMA IgE: A < C and B < C (1, 2, 3)Most significant difference in intensity scores of IgE-binding to CAS and beta-LG in SDS-PAGE immunoblot:A < C (4) Internet Symposium on Food Allergens 4(1):2002
SPT, IgE and Delayed
Reactions
49 infants with clinical history
Reexamination of 24 children with negative SPT and suggestive of CMA, positive RAST at 1 year of age after exclusion diet: SPT and RAST (alpha-LA, 79% challenge negative Plaza Martin et al. 2001 beta-LG, and CAS) (age of <6 21% challenge positve (all presenting late reactions at mean of 7 days after milk ingestion) 94% had immediate reactions6% had delayed type reactions (>2 h after challenge) Frequencies of IgE- and
(SPT and/or RAST positive) 52 of 101 DBPCFC positive to non-IgE-mediated CMA cow's milk (study population of (SPT and RAST negative) Niggemann et al. 2001b 139 children with atopicdermatitis suspected for foodallergy) Adverse vs Allergic
Reactions
CMA in 1 patient, abnormal disaccharide absorption in 3 9 children with "unequivocal patients (gastrointestinal and immunoallergic Davidson et al. 1976 symptoms attributable to cow's reported milk-related gastro-intestinal response of intestinal symptoms* a) 53 10-year-old children who manifested CMA before 1 year Kokkonen et al. 2001b of age and achieved small-dosetolerance specific IgA and IgG b) age-matched control group of lactose malabsorption 90 school children * 4-week blind elimination-challenge test with 1 week oflow-lactose milk flour SPT: Commercial Extract Reexamination 1 year later:
vs. Fresh Food
SPT with commercial CAS, alpha-LA, and beta-LG 4-month-old infant with severe solutions all negative; in drop test with pasteurized cow's Di Berardino et al. 2001 atopic dermatitis and positive milk a severe generalized urticaria resulted within a few skin reaction upon contact with minutes 5 Therapy of Cow's Milk Allergy
Strict elimination diet: some 2/3 reported after 3-5 yearsthat a strict elimination diet had to be followed, otherwise Elimination Diet
prompt relapse of allergic symptoms was noted. About 1/3 Wüthrich & Hofer 1986 173 mainly adults with food allergy of patients, mainly with milk, cheese or egg allergy, showspontaneous desensitization by appropriate diet (casehistory, RAST) Elimination Diet
All cases improved on a milk free diet, in 18% a further 148 children with CMA (age of <1 modification of the diet was required after the first Ventura & Greco 1988 Internet Symposium on Food Allergens 4(1):2002
Elimination Diet
Remission of symptoms (severe colic) in 71% after 70 children with cow's milk protein elimination of cow's milk protein from the diet; successive Iacono et al. 1991 intolerance (mean age 30 days) challenges caused the return of symptoms in all infants Nutritional status of children was followed during anelimination diet (2 children soy- based formula, other Elimination Diet, Nutritional
children other foodstuffs and supplementary calcium):significant reduction in serum prealbumin values; low serum zinc values in 12 children; low serum iron in 2 Paganus et al. 1992 19 children with CMA (age of 0.6 to children; 2 had high serum alkaline phosphatase values; dietary intake of energy below recommendation in somechildren; protein intake high; low intakes of riboflavin insome children Calcium deficiency rickets caused by prolonged Elimination Diet, Calcium
elimination diet of cow's milk; adequate intake of calcium Davidovits et al. 1993 a 4 year old boy with CMA resulted in rapid improvement Clinical disappearance of symptoms after removal of milkfrom the mother's diet and/or elimination from the child's Elimination Diet
diet, significant correlation between alterations of Barau & Dupont 1994 intestinal permeability and ingestion of reputedlyhypoallergenic foods, breast milk, and hydrolyzed proteinformulas Mean length SD score and weight-for-length index ofpatients decreased compared with healthy controls; low Elimination Diet, Growth
serum albumin in 6% of patients, 24% had an abnormal 100 children (mean age 7 months) urea concentration, and low serum phospholipid Isolauri et al. 1998 with atopic dermatitis and challenge- docosahexaenoic acid in 8%; delay in growth more pronounced in subgroup of patients with early onset ofsymptoms Avoidance of all products containing milk, milk protein, Proposed Diet
lactoprotein, lactoserum protein, CAS, caseinate, Moneret-Vautrin 1999 lactalbumin, lactose, margarine, cream (contains a list of"allowed" and "prohibited" foods) In vitro stimulation of PBMC with milk proteins (beta-LG, Terfenadine / TNF-alpha
alpha-LA and CAS) with or without terfenadine: dose- Benlounes et al. 1997 children with CMA dependent decrease in TNF-alpha secretion in the presenceof terfenadine Food challenge before and after a seven- day pre- treatment Treatment with DSCG
period with oral sodium chromoglycate: Full protection in Businco et al. 1983a 8 children with CMA 6 children (asthmatic symptoms persisted in 2 patients) Treatment with DSCG
After 3 months of oral cromolyn therapy, the patient was 7-year-old child experienced acute, able to tolerate small amounts of milk and moderate severe anaphylaxis after ingestion of amounts of foods containing milk Pretreatment with sodium cromoglycate diminished the Treatment with DSCG
Falth-Magnusson et al.
effect of milk challenge on gastrointestinal permeability, 16 children with CMA and usually decreased the severity of elicited symptoms Oral disodiumcromoglycate (DSCG) pretreatment did not Treatment with DSCG
alter the number of clinically positive challenges; 30 children with suspected CMA, significant increase in urinary lactose/mannitol ratio Van Elburg et al. 1993 a) with clinically positive challenge, b) with negative challenge permeability test) with placebo pretreatment as comparedb); no significant differences after DSCG pretreatment Treatment with Ketotifen
White blood cells were pretreated with Ketotifen: Podleski et al. 1984 1 patient with CMA inhibition of eosinophils degranulation Internet Symposium on Food Allergens 4(1):2002
Concept of specific immune treatment by antibodiescapable of specifically neutralizing anti-allergen antibodies; polyclonal antibodies against a peptide that is complementary to a major epitope of beta-LG were (In Vitro Study) Sélo et al. 2002 produced; these antibodies neutralized in vitro both well- 2 sera from patients with CMA characterized anti-beta-LG monoclonal antibodies frommice sensitized to beta-LG and anti-beta-LG IgE from 2patients with CMA * Studies may be experimental, unproved, or controversial. Please notice the disclaimer ! Oral Desensitization
Effective oral desensitization with milk or CAS extracts 2 cow's milk and cheese allergic Wüthrich & Hofer 1986 Complete milk tolerance was achieved after a treatmentperiod of 3-5 years in 50% of patients (partial tolerance in25%), in the other 25% desensitization was interrupted dueto repeated allergic reactions during treatment. Oral Desensitization
Desensitization protocol: starting dose established by SPT 16 female patients with IgE-mediated end point titration with milk diluted in water; oral CMA (study period 1980-95) desensitization starts with one drop given sublingually;dose increased daily up to 10 mL within 24 days; then thenext dilution was given and so on until 250 mL undilutedmilk were reached; maintenance dose of at least 1 dL ofmilk per day Diluted milk followed by increased pure milk wasadministered following a standardized protocol, at the Oral Desensitization
beginning pretreatment with oral sodium cromoglycate, 6 children with CMA (age 4-11 Patriarca et al. 1998 length of therapy 5 months, after therapy milk was tolerated (maintenance dose: 100 mL 2-3 times / week); 4 patientsfinished oral desentization successfully, 2 dropped Treatment was sucessfully completed in 3-8 months in 16 Oral Desensitization
cases; in 5 cases it was abandoned by the patients while in 3 24 patients with CMA (age 3-43 Nucera et al. 2000a cases the physicians decided to stop (same desensitization protocol as Patriarca et al. 1998) Desensitization accomplished in 4 month (same protocol asPatriarca et al. 1998); SPT at the beginning positive formilk, CAS, alpha-LA and beta-LG turned negative after 7months; specific IgE against milk proteins decreased, whilespecific IgG4 and IgA increased; reduced production of IL- Oral Desensitization
4 both in vitro (stimulated mononuclear blood cells) and in Nucera et al. 2000b 1 patient with CMA (age 6 years) serum; increased production of IFN-gamma by T-lymphocytes (both spontaneously and after stimulation withbeta-LG); results indicating a switch from a Th2 response(production of IL-4) to a Th1 response (with production ofIFN-gamma) during oral desensitization Oral Desensitization
Effective oral desensitization starting with diluted milk 12-year-old girl with persistent IgE- (under clinical conditions, 4-6 doses per day) for 5 days, Bauer et al. 1999 maintenance with daily intake of fresh milk Oral Tolerization
a) 10 infants fed cow's milk- based
Exposure to cow's milk proteins after the age of 9 months resulted in depressed cellular and humoral responsiveness Vaarala et al. 1995 b) 10 infants fed a CAS hydrolysate (beta-LG, BSA, CAS specific IgG and PBMC proliferation) formula until the age of 9 months * Studies may be experimental, unproved, or controversial. Please notice the disclaimer ! Internet Symposium on Food Allergens 4(1):2002
6 Composition of Cow's Milk
6.1 Distribution of Nutrients (Whole Milk)
For other milk products see: USDA Nutrient Database Nutrients: Content per 100 g
Energy 274 kJ (65 kcal) Carbohydrate 4.6 g Organic Acids 0.2 g Vitamin B1 35 µg Vitamin B2 180 µg Nicotinamide 90 µg Pantothenic acid 350 µg Vitamin B6 45 µg Palmitic acid 930 mg Vitamin B12 420 µg Stearic acid 400 mg Oleic acid 890 mg Linolic acid 90 mg Amino Acids
Linoleic acid 25 mg Cholesterol 12 mg Citric acid 210 mg Reference: Deutsche Forschungsanstalt für Lebensmittelchemie, Garching bei München (ed), Der kleine "Souci-Fachmann-
Kraut" Lebensmitteltabelle für die Praxis, WVG, Stuttgart 1991
6.2 Proteinfraction
Proteins / Glycoproteins
Amount of total protein
Concentration in Milk
Immunoglobulines References: Jensen 1995, Wal et al. 1995, Wal 1998 Internet Symposium on Food Allergens 4(1):2002
7 Allergens of Cow's Milk
Proteins / Glycoproteins
Goldman et al. 1963a, alpha-Lactalbumin [14.2 kDa] Gjesing et al. 1986 Goldman et al. 1963a, beta-Lactoglobulin [18.3 kDa] Gjesing et al. 1986 Goldman et al. 1963a, Serum Albumin [67 kDa] Gjesing et al. 1986 Gjesing & Lowenstein 1984,Gjesing et al. 1986, Immunoglobulin [160 kDa] Bernhisel-Broadbent et al.
1991 Goldman et al. 1963a, Caseins [20-30 kDa] Gjesing et al. 1986, Docena etal. 1996 Lactoferrin [80 kDa] 7.1 Sensitization to Cow's Milk Allergens
Country / Subjects
Argentina, La Plata
80 patients with CMA (3 months to 25 Docena et al. 1996 years, mean 6 years) (SDS-PAGE immunoblot, RAST) Australia, North Ryde, NSW
Adams et al. 1991 children with immediate-type CMA 50% (45%) 20% (76%) Denmark, Odense
63% (75%) 27% (88%) a) 21 infants with IgE-CMA b) 18 infants with non-IgE-CMA at 6 months (12 months)(specific serum IgE in CRIE after milk challenge) SPT RAST (>/= 2)
Finland, Turku
challenge proven patients with CMA Vanto et al. 1987 (age of <17 years) (n=11 in SPT, n=12 Internet Symposium on Food Allergens 4(1):2002
(1) Wal et al. 1995a France, Lille, Gif sur Yvette
(2) Lefranc-Millot et al. 1996 92 patients with CMA (3) Bernard et al. 1998 (RAST)Association of sensitivities (1):CAS in 87% of alpha-LA sensitive patientsbeta-LG in 78% of alpha-LA sensitive patientsBSA sensitivity seemed independentLactoferrin negative correlation to CAS Germany, Kiel
13 children with strongly suspected Kaiser et al. 1990 CMA (age of 8 months to 8 years) Italy, Milan
Restani et al. 1999 6 children with CMA (according to graded staining in SDS-PAGEimmunoblot) alpha-LA (14.2 kDa) Italy, Rome
beta-LG (18.3 kDa) Businco et al. 2000 25 children with CMA (DBPCFC) Lactoferrin (80 kDa) (SDS-PAGE immunoblot) Japan, Tokyo
Hasegawa et al. 2000 8 children with CMA Switzerland, Geneva
Szabó & Eigenmann 2000 10 children with CMA (SDS-PAGE immunoblot) Switzerland, Zurich
(1) Stoger & Wüthrich 1993 (1) 34 adults with CMA (2) Wüthrich & Johansson (2) 8 adults with CMA Internet Symposium on Food Allergens 4(1):2002
Taiwan, Taipei
30 children with suspected CMA (1 to 9 (RAST) multiple sensitization toalpha-LA and beta-LG in 13%CAS and alpha-LA in 27%CAS, alpha-LA and beta-LG in 37% USA, Baltimore, MD
Bernhisel-Broadbent et al.
bovine Immunoglobulins in 73% (RAST) 22 cow's milk- sensitive patients Skin Test
USA, Galveston, TX
(1) Goldman et al. 1963a 45 children with CMA (96% < 6 months BSA (2) Goldman et al. 1963b *frequencies in 27 oral challenge test (OCT)positive children RAST (>/= 3)
USA, Rochester, NY
(1) 29 children with CMA (age of onset (1) Schwartz et al. 1987 1 day to 10 months) (2) Amonette et al. 1993 (2) 21 children with CMA *SDS-PAGE immunoblot (graded scale >/= 2+) Internet Symposium on Food Allergens 4(1):2002
7.2 Properties of alpha-Lactalbumin
7.2.1 Molecular Biological Properties
(1) Allergen Nomenclature Sub- Allergen Nomenclature Bos d 4
Isoallergens and Variants
(1) Bell et al. 1970 Genetic variants A and B (1) Molecular Mass
(1) Docena et al. 1996 SDS-PAGE: 14.2 kDa (1), 13 kDa (2) (2) del Val et al. 1999 ESI-MS: 14178 Da (3) (3) Slangen & Visser 1999 Isoelectric Point pI 4.8
Amino Acid Sequence, mRNA, and cDNA
(1) Brew et al. 1970 X06366, M18780, J05147, M90645 (2) Hurley & Schuler 1987 (3) Vilotte et al. 1987 Amino acids
(4) Wang et al. 1989 703 bp (2), 724 bp (4) (5) Bleck & Bremel 1993 3090 bp (3), 2044 bp (5) recombinant Protein
expression in Escherichia coli:
expression of recombinant alpha-LA (1)
(1) Wang et al. 1989 expression in yeasts: (2) Viaene et al. 1991 expression of recombinant alpha-LA in Saccharomyces cerevisiae (2) (3) Soulier et al. 1994 expression in transgenic mice:expression of recombinant alpha-LA (3) 3D-Structure
X-ray studies of alpha-LA: significance of conformation for action in lactose
(1) Pike et al. 1996 (2) Sharma et al. 2001 3D-structures of alpha-LA compared with beta-LG and lactoferrin (2) Posttranslational Modifications
Disulfide Bridges:
4 disulfide bonds: 6-120, 28-111, 61-77, 73-91 (2)
Glycosylation:
Carbohydrate composition: GlcNAc, GalNAc, Man, Gal, Fuc, NeuAc (1) (2) Vanaman et al. 1970 Single glycosylation site: Asn-45 (3) (3) Hopper & McKenzie 1973 Detection of a glycosylated isoform (16-kDa in SDS-PAGE) with carbohydrate (4) Kim & Jiminzez-Flores 1994 detection kit (4) (5) Slangen & Visser 1999 Mixture of 14 different glycosylated isoforms and proposed composition ofmonosaccharides (15.8 to 16.7 kDa by ESI-MS) (5)Analysis of carbohydrates released from alpha-LA by mass spectrometry (5) Biological Function
alpha-LA belongs to the family 22 of glycosyl hydrolases (lysozyme c
superfamily), regulatory subunit of lactose synthase (1) (2) Hiraoka et al. 1980 Calcium binding properties (2), 2 Ca2+ binding sites one of which with high (3) Kronman et al. 1981 production in mammary gland (1) Internet Symposium on Food Allergens 4(1):2002
Sequence Homology
alpha-LA from water buffalo: aa sequence identity 99% (1)
alpha-LA from goat and sheep: aa sequence identities 95% and 94% (1)
human alpha-LA: aa sequence identity 78% (3) (2) Nitta & Sugai 1989 lysozyme from hen's egg white: alpha-LA evolved from the calcium- binding lysozyme along the mammalian lineage after the divergence of birds andmammals (2)lysozyme from various species: aa sequence identity up to 46% (1) 7.2.2 Allergenic Properties
Frequency of Sensitization
(1) see 7.1 Sensitization to Cow's Milk IgE-binding to alpha-LA in 0-80% of patients (1) B-Cell Epitopes
IgE binding sites located on alpha-LA:
Positivity
in Patients
1-16 (synthetic peptide) 5-18 (synthetic peptide) 6-10 :S-S: 115-123 (tryptic peptide) 13-26 (synthetic peptide) 17-58 (tryptic peptide) 47-58 (synthetic peptide) 59-94 (reduced tryptic peptide) (1) Adams et al. 1991 59-93 (native tryptic peptide) (2) Maynard et al. 1997(3) Järvinen et al. 2001 93-102 (synthetic peptide) 109-123 (tryptic peptide) (a) direct ELISA, EAST / RAST(b) EAST / RAST-inhibition(c) dot / immunoblot (SPOTs membrane technique) (1) 2 patients with CMA(2) 19 patients with CMA(3) 11 patients with persistent CMA (4-18 years of age, IgE to cow's milk >100kU(A)/L), positivity of 73% to at least 1 of the 4 IgE-binding epitopes; none ofthese epitopes detected by sera from 8 children <3 years of age (IgE to cow's milk<30 kU(A)/L) who are likely to outgrow CMA; 3 IgG binding regions identifiedusing 7 sera from patients with persistent CMA (1) Cross-Reactivity
sequence homology of beta-LG peptide 124-134 and alpha-LA 5-18, both IgE-
(1) Adams et al. 1991 PBMC Proliferation
(1) see Diagnostic Features of CMA: stimulation with alpha-LA (1) CBMC Proliferation Internet Symposium on Food Allergens 4(1):2002
T-Cell Clone (TCC) Reactivity
CMA in infants with atopic dermatitis associated with production of TH-2
cytokines; number of reactive TCC to alpha-LA (all TCC CD4+ and expressed
alpha/beta T-cell receptor):
(1) Schade et al. 2000 No. of TCC
2 patients with CMA 2 patients without CMA Alteration of Allergenicity
(1) Maynard et al. 1997 trypsin hydrolysis:IgE binding to different tryptic peptides of alpha-LA in 8/19 sera from cow's see also 10 Stability of Cow's Milk milk allergic patients (ELISA) (1) 7.3 Properties of beta-Lactoglobulin
7.3.1 Molecular Biological Properties
(1) Allergen Nomenclature Sub- Allergen Nomenclature Bos d 5
Isoallergens and Variants
(1) Braunitzer et al. 1973 Main genetic variants A (Asp-64, Val-118) and B (Gly-64 and Ala-118) (1, 3) (2) Brignon & Ribadeau-Dumas 1973 Minor genetic variants of subtype B with single substitution: variant C (Gln-59 > (3) Ebeler et al. 1990 His-59) (SWISS-PROT), variant D (Glu-45 > Gln-45) (2), variant W (Ile-56 > Leu- (4) Godovac-Zimmermann et al. 199056) (4), variants I (Glu-108 > Gly-108) and J (Pro-126 > Leu-126) (5) (5) Godovac-Zimmermann et al. 1996 (1) Docena et al. 1996 Molecular Mass Mr in SDS-PAGE: 18 kDa (1, 2)
(2) del Val et al. 1999 Isoelectric Point pI 5.3 (2)
(1) Fredriksson 1972 variant A: 5.13 (1), variant B: 5.23 (1) Amino Acid Sequence, mRNA, and cDNA
Variant B
(1) Braunitzer et al. 1973 M19088, X14712, M27732, K01086, X52581 (2) Jamieson et al. 1987 (3) Alexander et al. 1989 Amino acids
(4) Hyttinen et al. 1998 Internet Symposium on Food Allergens 4(1):2002
recombinant Protein
expression in Escherichia coli:
expression using a tac promoter vector, pTTQ18 (1)
expression of 2 site-directed mutants with an additional disulfide bond, increased
thermostability (3)
(1) Batt et al. 1990 expression in strain DH5alpha, positive IgE binding from 5 patients with CMA (4) (2) Totsuka et al. 1990 expression in a denatured form in periplasm using the pET26 vector (8)expression in yeasts: (3) Cho et al. 1994 expression of recombinant beta-LG (2) and a site directed mutant (6) in (4) Chatel et al. 1996 Saccharomyces cerevisiae, mutant inhibited the proliferation of CD4+ TCC from (5) Kim et al. 1997 (6) Totsuka et al. 1997 expression in native conformation in Pichia pastoris (5) (7) Hyttinen et al. 1998 epression in mouse cells: (8) Chatel et al. 1999 expression in native conformation in COS-7 cells and in vivo in mouse tibialismuscle (8)expression in transgenic mice:Bovine beta-LG gene was expressed mammary gland- specifically in transgenicmice, expression levels of beta-LG in milk > 1 mg/mL (7) 3D-Structure
X-ray studies of beta-LG (1)
(1) Brownlow et al. 1997 NMR studies of recombinant beta-LG (2) (2) Kuwata et al. 1998 3D-models of native and oxidized beta-LG, and partly and fully reduced beta-LG (3) del Val et al. 1999 (4) Sharma et al. 2001 3D-structures of beta-LG compared with alpha-LA and lactoferrin (4) Posttranslational Modifications
Disulfide Bridges:
(1) Brownlow et al. 1997 beta-LG occurs naturally as a mixture of monomers and 36-kDa dimers (2) 2 disulfide bonds: 66-160, 106-(119 or 121) (1) Biological Function
belongs to lipocalin family (2), binds retinol (1) (2) Virtanen et al. 1999 Sequence Homology
beta-LG from water buffalo and mouflon: aa sequence identies 98% and 95% (1)
beta-LG from goat and sheep: aa sequence identies 94% and 93% (1) (2) Arruda et al. 1995 cockroach allergen Bla g 4: aa sequence homology about 20% (2) Internet Symposium on Food Allergens 4(1):2002
7.3.2 Allergenic Properties
Frequency of Sensitization
(1) see 7.1 Sensitization to IgE-binding to in 13-76% of patients (1) Cow's Milk Allergens Allergenicity of Variants A and B
(1) van Beresteijn et al. 1995 No difference in IgE titers specific for genetic variants A and B of beta-LG (1) B-Cell Epitopes
IgE binding sites located on beta-LG:
inhibition of IgE
Positivity
3D-Location
in Patients
on beta-LG
to beta-LG [%]
1-16 (synthetic peptide) 1-8 (tryptic peptide) 8-24 (CNBr peptide) 9-14 (tryptic peptide) 15-26 (synthetic peptide) 44% (c) 25-107 (CNBr peptide) (1) Otani et al. 1989 (2) Adams et al. 1991 (3) Ball et al. 1994 25-40 (tryptic peptide) (4) Selo et al. 1998 (5) Heinzmann et al. 1999 31-48 (synthetic peptide) 45% (e)* (6) Selo et al. 1999 35-46 (synthetic peptide) 25% (c) (7) Järvinen et al. 2001 41-107 (fragment) 41-60 (tryptic peptide) 47-60 (synthetic peptide) 73% (e)* 49-60 (synthetic peptide) + (e) ** 62-107 (fragment) 67-78 (synthetic peptide) 55% (e)* 75-86 (synthetic peptide) 91% (e)* 78-83 (tryptic peptide) 84-91 (tryptic peptide) Internet Symposium on Food Allergens 4(1):2002
B-Cell Epitopes (continued)
IgE binding sites located on beta-LG:
inhibition of IgE
Positivity
3D-Location
in Patients
on beta-LG
to beta-LG [%]
85-96 (synthetic peptide) 92-100 (tryptic peptide) 95-113 (synthetic peptide) 97-108 (synthetic peptide) 102-124 (tryptic peptide) 108-145 (CNBr peptide) 117-128 (synthetic peptide) 13% (c) 119-128 (synthetic peptide) + (e) ** 124-134 (synthetic peptide) + (b) 125-145 (fragment) 125-135 (tryptic peptide) (1) Otani et al. 1989 127-144 (synthetic peptide) 82% (e)* (2) Adams et al. 1991 (3) Ball et al. 1994 129-138 (synthetic peptide) + (e) ** (4) Selo et al. 1998 141-152 (synthetic peptide) 55% (e)* (5) Heinzmann et al. 1999 143-152 (synthetic peptide) + (e) ** (6) Selo et al. 1999 (7) Järvinen et al. 2001 146-162 (CNBr peptide) 149-162 (tryptic peptide) 151-162 (synthetic peptide) 31% (c) (a) SDS-PAGE / immunoblot(b) direct ELISA, EAST / RAST(c) EAST / RAST-inhibition(d) Pin-ELISA(e) dot / immunoblot (SPOTs membrane technique) (1) 2 patients with CMA(2) 2 patients with CMA(3) 16 patients with CMA, * pooled serum(4) 19 patients with CMA(5) 14 children with CMA (age 6 months to 9 years)(6) 46 patients with CMA (location of epitopes in 3D-model of beta-LG)(7) * 11 patients with persistent CMA (4-18 years of age, IgE to cow's milk >100 kU(A)/L); ** 8 children <3 years of age (IgE to cow's milk <30 kU(A)/L) who are likely to outgrowCMA (pooled serum); positivity of 100% to at least 1of the 7 IgE-binding epitopes inpatients with persistent CMA; 6 IgG binding regions identified using 7 sera from patientswith persistent CMA (1) Adams et al. 1991 beta-LG peptide 124-134 and alpha-LA 5-18 (1) T-Cell Epitopes
Specific T-Cell Proliferation with:
(1) Piastra et al. 1994 beta-LG 145-161 (peptide) (1) PBMC Proliferation
(1) see Diagnostic Features of stimulation with beta-LG (1) Internet Symposium on Food Allergens 4(1):2002
PBMC Stimulation / Cytokines
PBMC stimulation with beta-LG:
(1) Hill et al. 1993 decrease in IFN-gamma production in cow's milk allergic children with atopic dermatitis ascompared to immediate- type allergic or tolerant children (1) T-Cell Clone (TCC) Reactivity
CMA in infants with atopic dermatitis associated with production of TH-2 cytokines;
number of reactive TCC to beta-LG (all TCC CD4+ and expressed alpha/beta T-cell
receptor):
(1) Schade et al. 2000 No. of TCC
2 patients with CMA 2 patients without CMA Alteration of Allergenicity
cyanogen bromide cleavage:
no alteration of IgE-binding in 50% of patients with CMA, in 10% increased IgE- binding
to CNBr- cleaved beta-LG (EAST inhibition) (2)
(1) Haddad et al. 1979 pepsin hydrolysis: (2) Selo et al. 1998 IgE-binding in 40% of 10 patients with CMA to native beta-LG and in 100% to peptic and (3) Selo et al. 1999 peptic- tryptic digested beta-LG (RAST) (1) (4) del Val et al. 1999 trypsin hydrolysis:reduced IgE binding (about <50%) in 75% and increased IgE binding in 9% of sera from 46 patients with CMA (3) 10 Stability of Cow's MilkAllergens reduction of disulfide bonds:no alteration of IgE-binding (1)increased pepsin digestibility and IgE- binding capacity (in animal model) of b-LG afterreduction of disulfide bonds with thioredoxin (4) 7.4 Properties of Bovine Serum Albumin
7.4.1 Molecular Biological Properties
Bovine Serum Albumin (BSA)
(1) Allergen Nomenclature Sub- Allergen Nomenclature Bos d 6
(1) Miller & Gemeiner 1993 Molecular Mass Mr in SDS-PAGE: 67.0 kDa (1), 66.3 kDa (2)
(1) Miller & Gemeiner 1993 Isoelectric Point pI 4.7-4.95 (1), 4.9-5.1 (2)
Amino Acid Sequence, mRNA, and cDNA
M73993, X58989, Y17769 Amino acids
583 residues (1), 607 (precursor) 2035 bp, 2061 bp, 1883 bp Internet Symposium on Food Allergens 4(1):2002
Posttranslational Modifications
Disulfide Bridges:
9 disulfide bonds (1) Biological Function
BSA belongs to the ALB/AFP/VDB family, main plasma protein (1)
3 homologous domains: I aa 4-177, II aa 196-369, III aa 388-567 (on precursor: I aa 28-
201, II aa 220-393, III aa 412-591 (1)good binding capacity for water, Ca2+, Na+, K+, fatty acids, hormones, bilirubin anddrugs, main function regulation of colloidal osmotic blood pressure (1) production in plasma, extracellular secretion (1) Sequence Homology
serum albumin from sheep: aa sequence identity 92% (1)
serum albumins from pig, cat, human, rhesus macaque, horse: aa sequence identities 74-79% (1) Other Properties
possible trigger of insulin-dependent diabetes mellitus: BSA peptide aa 126-144
(1) Karjalainen et al. 1992 (ABBOS) may be the reactive epitope (1) 7.4.2 Allergenic Properties
Bovine Serum Albumin (BSA)
Frequency of Sensitization
(1) see 7.1 Sensitization to IgE-binding to BSA in 0-88% of patients (1) Cow's Milk Allergens B-Cell Epitopes
IgE binding sites located on aa sequence of BSA:
aa 500-574 (of BSA) / aa 524-598 (of precursor) (1)
(1) Beretta et al. 2001 (1) tryptic peptides, SDS-PAGE immunoblotting, 5 beef allergic children Alteration of Allergenicity
heat treatment:
Negative reaction to cooked BSA (1.8 g) and positive reaction to uncooked BSA (55 mg)
in DBPCFC in a 19-year old woman (2)
(1) Alting et al. 1997 pepsin hydrolysis: (2) Kanny et al. 1998 ABBOS epitope (aa 126-144) not completely eliminated during digestion at pH 3-4 (mAbELISA inhibition)* (1) * no IgE-binding studies Internet Symposium on Food Allergens 4(1):2002
7.5 Properties of Caseins
7.5.1 Molecular Biological Properties
(1) Allergen Nomenclature Sub- Allergen Nomenclature Bos d 8
Isoallergens and Variants
(1) Mercier et a. 1971, 1973 (2) Grosclaude et al. 1972 (3) Grosclaude et al. 1979 (4) Visser et al. 1995 (5) Prinzenberg et al. 1998 Molecular Mass
(1) Docena et al. 1996(2) del Val et al. 1999 24 kDa (2) 32.4 kDa (1) 26.6 kDa (1) Isoelectric Point
Amino Acid Sequence, mRNA, and cDNA
(1) Mercier et al. 1971, 1973(2) Grosclaude et al. 1972 (3) Ribadeau-Dumas et al. 1972 (4) Brignon et al. 1977 (5) Nagao et al. 1984 M55158, X06359, M36641 (B2), (6) Stewart et al. 1984 M15132, M16645 X14908 (7) Gorodetskii et al. 1986 (8) Baev et al. 1987(9) Jimenez-Flores et al. 1987 Amino acids
(10) Gorodetskii & Kaledin (11) Stewart et al. 1987 (12) Alexander et al. 1988 (13) Bonsing et al. 1988 (14) Koczan et al. 1991(15) Chen et al. 1992 (16) Groenen et al. 1993 (17) Simons et al. 1993 recombinant Protein
(1) Kang & Richardson 1988 expression in
(2) Simons et al. 1993(3) Hitchin et al. 1996 (4) Jeng et al. 1997 (5) Rijnkels et al. 1998 3D-Structure
Micelle aggregation:
CAS subunits associate in solution forming complexes and ordered aggregates of micelles (1) SWISS-PROT
in lactoserum by colloidal calcium phosphate and phosphoserine interactions: ratio alpha- (2) Wal 1998 S1 / beta / alpha-S2 / kappa-CAS is 37% / 37% / 13% / 13% (2)Polymerisationkappa-CAS: monomer or multimer linked by disulfide bonds (1) Internet Symposium on Food Allergens 4(1):2002
Numbers of
Glycosylation sites (2) Saito & Itoh 1992 Glycosylation of kappa-CAS:O-glycosation sites: distribution of monosaccharide, disaccharide, trisaccharide (straight),trisaccharide (branched), and tetrasaccharide chains were 0.8, 6.3, 18.4, 18.5, and 56.0%,respectively (means of five kappa-CAS) (2) Biological Function
alpha-CAS: Calcium phosphate transport capacity of milk (1)
kappa: Micelle formation stabilizing, preventing CAS precipitation in milk (1) alpha-CAS, kappa-CAS: production in mammary gland, extracellular secretion (1) Sequence Homology
alpha-S1 and S2 CAS from cow's milk: aa identity 22.5% (2)
alpha-S1 CAS from sheep's and goat's milk: aa identity 87-89% (2)
alpha-S2 CAS from sheep's and goat's milk: aa identity 87-89% (2) (2) Spuergin et al. 1997 alpha-S1 and S2 CAS from sheep's and goat's milk: aa identity 97-98% (2) (3) Bernard et al. 2000b beta-CAS from sheep's and goat's milk: aa identity 91% (1)beta-CAS from cow's milk and human milk: aa identity 50% (3)kappa-CAS from sheep's and goat's milk: aa identity 84% (1) 7.5.2 Allergenic Properties
Frequency of Sensitization
(1) see 7.1 Sensitization to IgE-binding to CAS in 65-100% of patients (1) Cow's Milk Allergens Allergenicity of Subunits
Major IgE- binding CAS subunits in 4 patients with CMA and atopic dermatitis: in 1
patient alpha- and kappa-CAS, in 2 patients alpha-CAS, and in 1 patient kappa-CAS
(tested: alpha-, beta-, and kappa-CAS) (1)
(1) Shimojo et al. 1997 85% of 58 children presented IgE against each CAS, only 1 child was monosensitized (to (2) Bernard et al. 1998kappa-CAS), allergenic potencies according to statistical distribution of specific serum (3) Restani et al. 1999 IgE levels: alpha S1-CAS > beta-CAS >> alpha S2-CAS = kappa-CAS (RAST) (2) IgE-binding to alpha-CAS in 100%, beta + gamma-CAS in 50%, and kappa-CAS in 33%of 6 children with CMA (3) Internet Symposium on Food Allergens 4(1):2002
B-Cell Epitopes: alpha S1 CAS
IgE binding sites located on alpha S1 CAS:
Positivity
inhibition of IgE binding
in Patients
to alpha S1 CAS [%]
1-10 (synthetic peptide) 17-36 (synthetic peptide) 19-30 (synthetic peptide) 20-31 (synthetic peptide) 34-45 (synthetic peptide) 39-48 (synthetic peptide) 58-73 (synthetic peptide) 61-123 (fragment) 69-78 (synthetic peptide) 69-78 (synthetic peptide) 86-103 (synthetic peptide) (1) Otani et al. 1989 93-98 (synthetic peptide) (2) Spuergin et al. 1996(3) Nakajima-Adachi et al. 1998 93-102 (synthetic peptide) (4) Chatchatee et al. 2001a (5) Vila et al. 2001 109-120 (synthetic peptide) 123-132 (synthetic peptide) (b) EAST / RAST-inhibition(c) Pin-ELISA 124-135 (fragment) (d) dot / immunoblot (SPOTs 136-196 (CNBr fragment) membrane technique) 139-154 (synthetic peptide) 141-150 (synthetic peptide) 159-174 (synthetic peptide) 165-199 (fragment) 173-194 (synthetic peptide) 177-186 (synthetic peptide) 20% (+50%weak) (d) ** 181-199 (synthetic peptide) 92% and 30% (n=2) (b) 188-199 (synthetic peptide) (1) 2 patients with CMA(2) 12 patients with CMA, *similar IgG binding(3) 9 patients with CMA(4) * 9 patients with persistent CMA (4-18 years of age, IgE to cow's milk >60 kU(A)/L); ** 8 children <3 years of age (IgE to cow's milk <30 kU(A)/L) who are likely to outgrowCMA(5) 36 children with CMA: * 25 with persistent CMA, and ** 11 became clinicallytolerant Internet Symposium on Food Allergens 4(1):2002
B-Cell Epitopes: beta-CAS
IgE binding sites located on beta-CAS:
Positivity
in Patients
1-16 (synthetic peptide) 45-54 (synthetic peptide) 55-70 (synthetic peptide) 57-66 (synthetic peptide) 83-92 (synthetic peptide) 106-209 (fragment) 107-120 (synthetic peptide) 110-144 (fragment) 132-144 (fragment) 135-144 (synthetic peptide) (1) Otani et al. 1989 (2) Chatchatee et al. 2001b 149-164 (synthetic peptide) (3) Vila et al. 2001 151-160 (synthetic peptide) 40% (+10% weak) (b) * 50% (+50% weak) (b) ** 157-185 (fragment) 167-184 (synthetic peptide) 167-176 (synthetic peptide) 40% (+40% weak) (b) * 80% (+20% weak) (b) ** 175-184 (synthetic peptide) 50% (+10% weak) (b) * 60% (+40% weak) (b) ** 185-208 (synthetic peptide) 186-209 (fragment) 193-202 (synthetic peptide) 50% (+20% weak) (b) * (a) EAST / RAST(b) dot / immunoblot (SPOTs membrane technique) (1) 2 patients with CMA(2) * 15 patients with persistent CMA (4-18 years of age, IgE to cow's milk >60 kU(A)/L); ** 8 children <3 years of age (IgE to cow's milk <30 kU(A)/L) who are likely to outgrowCMA (pooled serum)(3) 36 children with CMA: * 25 with persistent CMA, and ** 11 became clinicallytolerant Internet Symposium on Food Allergens 4(1):2002
B-Cell Epitopes: kappa-CAS
IgE binding sites located on kappa-CAS:
Positivity
in patients
9-26 (synthetic peptide) 21-44 (synthetic peptide) 47-68 (synthetic peptide) 53-64 (synthetic peptide) 67-78 (synthetic peptide) (1) Chatchatee et al. 2001b 95-116 (synthetic peptide) 111-126 (synthetic peptide) 137-148 (synthetic peptide) 149-166 (synthetic peptide) (a) dot / immunoblot (SPOTs membrane technique) (1) * 15 patients with persistent CMA (4-18 years of age, IgE to cow's milk >60 kU(A)/L); ** 8 children <3 years of age (IgE to cow's milk <30 kU(A)/L) who are likely to outgrowCMA response inhibition
alpha S2 CAS (variant A) a) native and b) dephosphorylated form and c) alpha S2 CAS (variant D) lacking one major phosphorylation site beta CAS (variant A1) a) native and b) dephosphorylated a > b (1) Bernard et al. 2000a tryptic fragment (aa 1-25) from beta CAS a) native and b) dephosphorylated form 53 sera positive to native beta-CAS, 29 sera positive to alpha S2 CAS (variant A), and 28sera positive to variant D from 53 patients with symptoms of CMA and specific IgE(direct ELISA, and ELISA inhibition) (1) T-Cell Epitopes: alpha S1 CAS
alpha S1 CAS specific T-Cell Lines responsive to:
1-54 (CNBr fragment) (1)31-50 (synthetic peptide) (1)76-95 (synthetic peptide) (1) (1) Nakajima-Adachi et al. 1998 91-110 (synthetic peptide) (1)124-135 (CNBr fragment) (1)136-155 (synthetic peptide) (1) (1) 7 TCL from 2 patients with CMA PBMC Proliferation
(1) see Diagnostic Features of stimulation with CAS (1) Internet Symposium on Food Allergens 4(1):2002
PBMC Stimulation / Cytokines
PBMC stimulation with CAS:
Tendency of (4) and significantly higher (1) PBMC proliferation in cow's milk allergic
children with atopic dermatitis as compared to children with atopic dermatitis without
cow's milk allergy
16 of 28 CAS- or ovalbumin-specific TCC from cow's milk and egg allergic childrenwere CD8+; 75% of CD4+ TCC and 44% of CD8+ TCC secreted IL-4; all TCC secreted (1) Reekers et al. 1996 (2) Werfel et al. 1996(3) Werfel et al. 1997b 27% of CD4+ CAS- specific TCCs from adolescent or adult patients with cow's milk- (4) Schade et al. 2000 responsive atopic dermatitis, and the majority of house dust mite- specific TCCs,produced IL-4 on mitogen stimulation; INF-gamma was produced by the majority ofTCCs with both specificities (3) PBMC stimulation with kappa- CAS:25 of 31 TCC from patients with milk- responsive atopic dermatits responded to mixedCAS (alpha-, beta-, kappa-) and kappa- CAS (2) T-Cell Lines (TCL) / Cytokines
PBMC responsiveness to alpha s1- CAS activation was rather weak in cow's milk allergic (1) Nakajima al. 1996
patients; 26 alpha s1- CAS- specific T-cell lines were established; higher frequency ofCD8+ T cells which produced INF-gamma and IL-4 (1) T-Cell Clone (TCC) Reactivity
CMA in infants with atopic dermatitis associated with production of TH-2 cytokines;
number of reactive TCC to CAS fractions (all TCC CD4+ and expressed alpha/beta T-
cell receptor):
beta kappa
whole CAS
(1) Schade et al. 2000 4 patients with CMA 4 patients without Alteration of Allergenicity
heat denaturation acidic treatment (HCl) (1) Kohno et al. 1994 alkaline treatment (NaOH) see also 10 Stability of Cow's sodium dodecyl sulfate urea denaturation NS no significant difference in IgE-binding(1) patients with CMA 8 Isolation & Preparation
Extract / Purified
Review of purification and analytical methods by CAS and whey proteins Strange et al. 1993 chromatography and electrophoresis methods Spuergin et al. 1996 Purification of commercial CAS by IEC (DEAE Sepharose) Spuergin et al. 1997 Internet Symposium on Food Allergens 4(1):2002
Isoelectric precipitation of whole CAS from skimmed raw milkat pH 4.6; isolation of CAS fractions by successive, selective alpha S1-, alpha S2-, beta-, precipitations, followed by dissolving, dialysis and freeze Bernard et al. 1998 drying steps; further purification by IEC (purity assessed byRP-HPLC) glycosylated and non- Isolation from whey protein fraction by IEC (DEAE Sepharose) glycosylated alpha-LA Slangen & Visser 1999 followed by SEC (Sephadex G-75) Preparation from milk (1); purification by affinity (1) Wal et al. 1995b chromatography (antibovine IgG column) followed by IEC (Q (2) Selo et al. 1999 Sepharose), purity assessed by RP-HPLC and SDS-PAGE (2) Acid precipitation of colostral whey and concentration ofsupernatant, isolation of IgG by affinity chromatography (Avid Lefranc-Millot et al. 1996 Gel AL) and further purification by IEC, dialysis,lyophylization 9 Cross-Reactivities
Subjects / Methods
6 patients with cow's milk and 5 with cow's dander allergy: 4/6 patients with CMA showed serum IgE binding to danderallergens of 20, 22, 36, 50 and >200 kDa, dander cross- reactive Szepfalusi et al. 1993 cow's milk allergens were CAS (2 cases) and beta-LG (1 case); 1/5 cow's dander allergens cow's dander allergic patients showed serum IgE binding to milkallergens of 69, 92 and >200 kDa (immunoblot inhibition) Cow's Milk
16 children with CMA: high inhibition of IgE- binding to cow's goat's, sheep, and milk by goats', sheep, modified cows' milk formula and CAS modified cow's milk formula (RAST inhibition) Cow's Milk
9 milk allergic patients: IgE- binding to cow's and goat's milk Sabbah et al. 1996 proteins corresponding in Mr to beta-LG and CAS (immunoblot) Cow's Milk
8/11 beef allergic children presented concomitant reactivity to Werfel et al. 1997a cow's milk (DBPCFC)* Cow's Milk
Complete inhibition of IgE-binding to bovine IgG from beef by bovine IgG (160 kDa) cow's milk (immunoblot inhibition, pooled serum from 5 beef Ayuso et al. 2000 allergic patients) 26 children with CMA (DBPCFC positive); Cow's Milk
Sensitivity to goat's milk in 92% (DBPCFC); cow's milkcompletely extinguished IgE- binding to goat's milk allergens, Bellioni-Businco et al. 1999 goat's milk partially inhibited IgE- binding to cow's milk allergens(SDS-PAGE inhibition) 6 children with CMA: Cow's Milk
IgE- binding to milk allergens from cow, ewe, goat, and buffalo, Restani et al. 1999 ewe, goat, buffalo milk but not from camel (SDS-PAGE immunoblot, inhibition) 3 children with CMA: Cow's Milk
Up to 28% inhibition of IgE- binding to cow's milk allergens Businco et al. 2000 (CAS, alpha-LA, beta-LG, BSA, and lactoferrin) by mare's milkextract (SDS-PAGE immunoblot inhibition, densitometry) 6/9 egg allergic patients: 12-49% Inhibition of IgE- binding to lysozyme (hen's egg Walsh et al. 1987 lysozyme by alpha-LA (RAST inhibition) Internet Symposium on Food Allergens 4(1):2002
Inhibition of IgE- binding to goat's and sheep's CAS by cow's milk goat's, sheep's, and cow's Wüthrich & Johansson 1995 CAS in 1 adult (RAST inhibition) Sera from 58 patients with CMA and specific IgE to bovine CAS: specific IgE titers: whole casein fractions bovine > ovine > caprine CAS; Bernard et al. 1999 from cow, goat, ewe, 79% and 66% of sera showed IgE-binding to rabbit-CAS and rat- rabbit and rat milk * CAS of <10% intensity as compared to bovine CAS (ELISA) 17 children with CMA (immediate type): Inhibition of IgE alpha Caseins
binding to bovine alpha-CAS by alpha-CAS from cow, goat, and goat's, sheep's, and cow's Spuergin et al. 1997 sheep (RAST inhibition), lower specific IgE levels to goat- and sheep alpha-CAS (RAST) Exclusively breast-fed children with atopic dermatitis: cross- Cow's Milk
reactivity between lactoferrin, serum albumin, beta-CAS, and Cantisani et al. 1997 alpha-LA from human and cow's milk, no specific IgE against Bertino et al. 2000 bovine beta-LG; no clinical relevance of human milk proteins 20 patients with CMA and specific IgE against bovine whole Cow's Milk
CAS: 7 sera contained IgE specific for human beta-CAS; beta-CAS from cow's inhibition studies using native human and bovine beta-CAS as Bernard et al. 2000b milk and human milk well as bovine beta-CAS-derived peptides (aa 53-139, aa 106-209,and aa 1-52) demonstrated several common epitopes (ELISA) * multiple sensitization (not proved by inhibition-tests) Subjects / Methods
No inhibition of IgE- binding to goat's and sheep's CAS by goat's and sheep's vs cow's milk Wüthrich & Johansson 1995 cow's milk CAS in 1 adult (RAST inhibition) 1 cow's milk tolerant child with goat's and sheep's milkallergy: Decreased inhibition of IgE- binding to goat's milk and CAS by cow's milk and CAS, but not by goat's and goat's and sheep's vs cow's milk sheep's milk and CAS (RAST inhibition); IgE binding to Umpierrez et al. 1999 allergens in goat's milk at 22, 27, and 31 kDa, in sheep'smilk at 31 kDa and cow's milk at 34 kDa (SDS-PAGEimmunoblot) Cow's and Mare's Milk
16 and 18 kDa allergens (most
likely representing alpha-LA
1 mare's milk allergic adult (cow's milk tolerant) and beta-LG) from mare's milk (SPT, intracutaneous test, RAST, SDS-PAGE did not cross-react with corresponding cow's milkallergens Internet Symposium on Food Allergens 4(1):2002
10 Stability of Cow's Milk Allergens
Heat
Reduction of IgE binding to alpha-LA about 50%, to CAS boiling of skimmed milk, 10 fractions >66% and to beta-LG, BSA and bovine Ig binding Gjesing et al. 1986 abolished (CRIE score) Similar positive reactions in SPT and DBPCFC to 1), 2) and 1) raw untreated, 2) pasteurized 3), no reactions to 4) in 5 cow's milk allergic children Host & Samuelsson 1988 or, 3) homogenized and (immediate- type); tendency of lower thresholds of pasteurized cow's milk, and 4) a processed milkcommercial hypoallergenichydrolysed CAS infant formula Boiling of milk for 10 but not for 2 min eliminated SPT Heat
reactivity to BSA and beta-LG, whereas CAS was heat Norgaard et al. 1996 boiling of milk, 2 and 10 min stabile (8 DBPCFC positive adults with CMA) Heat
No difference in IgE- binding to raw and cooked milk from Werfel et al. 1997a boiling of milk, 5 min sera of 2 patients with CMA (immuno-dot-blotting) Heat
boiling of extensively
Positive SPT to boiled and unboiled formula in a girl with Nilsson et al. 1999 hydrolyzed CAS formula Thermoaggregated (a) and reduced forms (b) exhibited a) heat 96°C, pH 8.0 anaphylactic effect on sensitized guinea pigs; allergenic Gmoshinskii et al. 1990 b) carboxymethylation properties of beta-LG appeared unaltered in food c) limited proteolysis hydrolyzates after thermal treatment and limited proteolysis ELISA inhibition using patients' IgE and rabbit IgGsspecific for alpha-CAS and beta-LG, respectively: reducedIgE-binding to irradiated proteins with different slopes of gamma Irradition
inhibition curves; rabbit IgG-binding increased up to a alpha-CAS, beta-LG certain dose of irradiation and then decreased; main bandsdisappeared in SDS-PAGE with increasing doses whileturbidity increased indicating a decrease of solubility (20patients with CMA) Percent inhibition of IgE-binding from sera of patients withIgE- mediated CMA to native proteins by respective hydrolysates of homologue protein: pepsin hydrolysis at
Whey Proteins
hydrolysis with pepsin (pH 2, 3,and 4, for 90 min) followed by Schmidt et al. 1995 hydrolysis with a mixture of pancreatic enzymes (pH 7.5 for 150 min) of beta-LG, alpha-LA,BSA, and bovine IgG (RAST inhibition) * beta-LG is barely hydrolysed by pepsin, but susceptible topancreatic enzymes Internet Symposium on Food Allergens 4(1):2002
Rate of hydrolysis: Duodenal Digestion
purified proteins > crude cow's milk or formula; in vitro digestion of cow's milk rates of alpha-LA, beta-LG, and CAS digestion were 0.03, (1) Jakobsson et al. 1982 proteins by duodenal fluid (1) 0.12, and 16.1 mg/mL duodenal juice/min (same capacity to (2) Jakobsson et al. 1983 and human trypsins and hydrolyze the milk proteins in infants with CMPI, celiac disease, or unclassified gastrointestinal disorder) Intestinal Digestion
Lower TNF-alpha production by stimulation of PBMC from intestinal digestion of beta-LG, cow's milk allergic patients with intestinal digested cow's Benlounes et al. 1996 alpha-LA and CAS (intestinal milk proteins as compared to intact proteins Cell-Envelop Proteinase
Elimination of IgE-binding epitopes by degradation of CAS specific hydrolysis of CAS and Alting et al. 1998 and removal of whey proteins by ultrafiltration 222 cow's milk intolerant / allergic patients: Pepsin Hydrolysis, beta-
Higher degree of IgG binding to native beta-LG than to LG
pepsin digested LG as compared to controls; almost Duchateau et al. 1998 pepsin hydrolysis of beta-LG complete discrimination between patient groups by cross-reactive experiments (ELISA) Lactic Acid Fermentation
lactic acid fermentation of
About 99% reduced antigenicity of whey proteins as sterilized cow's milk with a compared to raw milk (rabbit pAb, ELISA); allergenicity of mixed culture of meso- and alpha-LA and beta-LG only slightly attenuated (Skin Tests) thermophilic bacteria strains 11 Allergen Sources
Reported Adverse Reactions
Human Milk
Cow's milk taken by the mother precipitated allergic symptoms in 61 breast fed infants
(elimination/challenge in mother's diet) (1)
(1) Gerrard & Shenassa Proctocolitis triggered by cows' milk protein transferred to 11 infants via the breast milk; resolution of visible rectal bleeding within 72 to 96 hours after elimination of cow's milk from (2) Pumberger et al. 2001mother's diet (colonoscopy performed in 5 infants revealed benign eosinophilic proctocolitis)(2) "Non-dairy" Foods
Allergic reactions in 6 patients with CMA after ingestion of "non-dairy" products: tofu frozen
dessert (2 cases), beef hot dog (2 cases), bologna (2 cases), rice frozen dessert, tuna packed in
(1) Gern et al. 1991 aqueous solution; contents of milk proteins due to contamination by manufacturing facilities(37-2202 µg/mL) or to unlabeled adding of caseinate (136 µg/mL) (1) Cake, Cookie, Pastry
Near-fatal anaphylactic reactions in 2 children with CMA (age of 9 and 12 years) after
(1) Sampson et al. 1992 ingestion of a cookie, a cake or pastry containing the allergen (1) Chocolate, Candy
Occupational asthma and rhinoconjunctivitis in a chocolate candy worker (positive
(1) Bernaola et al. 1994 conjunctival and bronchial challenge tests with lactalbumin) (1) Internet Symposium on Food Allergens 4(1):2002
Several Food Products
9 Adverse reactions to unexpected cow's milk allergens in
a) Meatballs containing 1.1% CAS (undeclared)
b) Hot dog containing 0.04% CAS (contaminated)
c) Recombined ham containing 2.6% (undeclared)
Malmheden Yman et al.
d) Sausage containing 1.0% CAS (undeclared) e) Sausage containing 0.06% CAS (contaminated)f) Dark chocolate containing 0.8% CAS (contaminated)g) Ice cream (soy based) containing 0.2% CAS (contaminated)h) Lollipop, strawberry / cream containing 0.2% CAS (undeclared)i) Meringue containing 1.1% CAS (undeclared) Sorbets
Frozen desserts manufactured using the same equipment used for producing ice cream may
contain milk allergens:
(1) Jones et al. 1992 Anaphylaxis in a 2-year-old boy after ingestion of a "pareve"- labeled raspberry sorbet (kosher (2) Laoprasert et al. 1998 labeling to select dairy-free foods) (1)Anaphylaxis in a 3-year-old boy within 20 min after ingestion of a lemon sorbet (ca. 113 to170 g) containing trace amounts of milk allergens (whey proteins: 9 µg/mL) (2) (1) Foucard et al. 1997 Severe reactions after ingestion of sausage containing CAS (texturing agent) (1) (1) Wüthrich & Hofer 1986 Anaphylaxis after ingestion of cheese in a 23-year old woman (1) Goat's and Sheep's Cheese
Several allergic reactions after ingestion of feta (cheese made from sheep's milk) in a 15-year- (1) Wüthrich & Johansson
old boy, after ingestion of sheep's or goat's cheese in a 25-year old patient, both tolerated ingestion of diary procucts from cow's milk (1) (2) Umpierrez et al. 1999 Allergic reactions after eating goat's cheese and after touching of goat's and sheep's cheese in a2-year-old girl with tolerance to dairy products from cow's milk (2) Sheep's Cheese
(1) Calvani & Alessandri Several anaphylactic reactions after ingestion of food containing "pecorino" cheese made from 1998 sheep's milk in a 5-year-old atopic boy unaffected by cow's milk protein allergy (1) Mozarella / Ricotta / Parmesan Cheese
Asthma, urticaria and rhinitis in a boy with atopic dermatitis after ingestion of mozarella
(1) Fiocchi et al. 1999 cheese made from ewe's and cow's milk; several allergic reactions after ingestion of ricottacheese containing ewe's milk and parmesan cheese made from cow's milk, respectively (1) Baby Food
A baby food, cereal flour P, containing alpha- lactalbumin (although labeled guaranteed free of (1) Fremont et al. 1996
cow's milk), caused failure to thrive and diarrhea, vomiting, and coughing fits in a 22- month-old child with cow's milk allergy (1) Casein in Salmon
A 30 year-old woman with CMA (without fish sensitivity) experienced anaphylaxis within 1
hour after ingestion of a slice of bread with salmon, prepacked from a supermarket, the salmon (1) Koppelman et al. 1999
meat was restructured by microbial enzyme (transglutaminase) which crosslinks added CASand meat proteins, assuming a consumption of 10 to 50 g salmon, about 10 to 50 mg CASwere ingested (1) Casein-containing Product
A 25-year-old with asthmatic symptoms which were work-related to the production process of
candy making due to inhalation of Hyfoama DS (bronchial challenge, SPT, RAST); Hyfoama
DS is a colorless, water-soluble powder produced from CAS treated with calcium hydroxide
(1) Bader et al. 2001 solution and then dried. It is used as a substitute for egg white in a variety of baked goods. Themanufacturer recommends labeling of the final product as containing "hydrolyzed milkprotein." Casein in Tryptone Powder
Adult-onset sensitization to CAS in a 44-year-old male scientist after occupational exposure to (1) Vaswani et al. 1999
aerosolized tryptone powder (CAS product used in preparation of culture media); subsequentsystemic allergic reaction after ingestion of milk containing candy (SPT) Internet Symposium on Food Allergens 4(1):2002
Human Milk
16/17 of cow's milk allergic children showed allergic symptoms during cow's milk challenge
(1) Jarvinen et al. 1999b through human milk from asymptomatic mothers (age of children 1.8 to 9.4 months) see 12.2 Allergenicity / Safety of Infant Formulas Pharmaceuticals
Anaphylaxis in a 12 months-old boy after cutaneous application of a CAS containing ointment
to an inflamed diaper area (1)
Severe anaphylactic reaction in a 33-year-old woman during artificial insemination due to
(1) Jarmoc & Primack 1987 sperm- processing medium containing BSA (SPT, RAST) (2) (2) Wüthrich et al. 1995 Generalized anaphylactic reaction a few hours after tooth extraction in a 54-year-old woman, (3) Wüthrich et al. 1996 hemofibrine (a hemostatic sponge made of bovine fibrin) elicited symptoms (Scratch test, (4) Hasegawa et al. 2000 RAST) (3)3 out of 6 patients with positive RAST against CAS experienced allergic symptoms aftertaking antibiotics containing CAS (4) "Neutralizing" of Food Allergies
68-year-old woman with systemic mastocytosis was given "neutralizing" injections of milk and (1) Teuber & Vogt 1999
wheat and experienced flushing, palpitations, and lightheadedness with syncope (unproventechnique of provocation/neutralization) (1) Allergens in
Content / Products
Human Milk
Detectable amounts of immunoactive beta-LG (5-33 ng/mL) in Jakobsson et al. 1985 18/38 human milk samples Detectable amounts of beta-LG (5-800 ng/mL) in 40% of human Human Milk
milk samples, presence of symptoms in the infant such as diarrhoea, Axelsson et al. 1986 vomiting, colic, exanthema significantly correlated to high levels ofbeta-LG in the milk Detectable amounts of bovine beta-LG (up to 6.4 ng/mL) in 45% of Human Milk
samples; persisted up to 3 days after maternal dietary elimination of Machtinger & Moss 1986 57 breastfeeding mothers cow's milk Human Milk
Detectable amounts of bovine beta-LG (0.5-45 ng/mL) in 30% of 9 breastfeeding mothers Human Milk
36 samples of human
Detectable amounts of bovine IgG (mean 3.4 ng/ml) Maeda et al. 1993 Human Milk
beta-LG in human milk before and after oral cow's milk load (given 55 breastfeeding mothers after 24 hour milk free diet): beta-LG levels >2 ng/mL in 75% of Sorva et al. 1994 (cow's milk allergy in 46 samples, increased levels in 50% after load infants, oral challenge) Fat Substitutes
Allergenicity of microparticulated egg and cow's milk proteins in (1) Sampson & Cooke 1990 13 (16) egg and/or cow's fat substitues (Simplesse, Beta IL): No alteration of allergenic (2) Sampson & Cooke 1992 milk allergic patients potencies in SDS-PAGE immunoblot Positive skin test reaction to lactose containing seasoning (1 patient with CMA); CAS and whey proteins identified in this seasoning, Watson et al. 1995 dill-pickle seasoning and whey proteins in pharmaceutical grade lactose (containing lactose) alpha-LA content in "food quality" lactose 1-5 µg/g (RAST Fremont et al. 1996 15/30 commonly marketed natural rubber latex glove brands Latex Gloves
contained cow's milk CAS (rocket immunoelectrophoresis, ELISA Ylitalo et al. 1999 Internet Symposium on Food Allergens 4(1):2002
Specific affinity matrix: beta-LG coupled to Sepharose 4B used toremove beta-LG from milk, significant retardation in its elution Cow's Milk
because reversible polymerization with soluble beta-LG; beta-LG Chiancone & Gattoni 1993 depletion of beta-LG depleted milk proposed as hyposensitizing milk formula to be usedby lactating mothers Human Milk
No detection of beta-LG and bovine CAS in human milk (SDS- Restani et al. 2000 lactating mothers PAGE immunoblotting using mAb) 12 Food Allergen Labeling

Labeling / Regulation Status
International Regulations Mandatory labeling of prepackaged food /
(1) Codex Alimentarius Commission 1999 Milk and milk products advisary status (1) Labeling appropriate / recommendation (1) European Regulations
(1) Bousquet et al. 1998 Mandatory labeling of prepackaged food / Milk and milk products (2) European Commission 2001 proposal for directive (2) 13 Infant Formulas
13.1 Application of Infant Formulas in CMA
Parameters / Subjects
Nutritional Status
Diets based on soy or CAS hydrolysate formula (taken by 72%) 18 children with CMA (age of 1-3.5 supplemented with calcium and in 11 children with vitamins A Tiainen et al. 1995 and D resulted in adequate mean intakes of nutrients Improvement in 18% of children after receiving a soy formula, Infant Formulas
while symptoms were unchanged or worse in 53% (cow's milk Lothe et al. 1982 60 children with infantile colic formula and soy formula fed children), improvement withextensively hydrolyzed CAS formula (Nutramigen) Application of a) soybean and b) partially hydrolyzed milk Infant Formulas
Iwanczak et al.
36 children with CMA (age of 1 No improvement in a) 10% (Prosobee), b) 12% (Humana SL) month to 3 years) Partial or total relief of symptoms in a) 69% (Prosobee), b) 76%(Humana SL) Application of a) soybean and b) extensively hydrolyzed CAS Infant Formulas
100 children with CMA (age of 5 Korol et al. 1995 Partial or total relief of symptoms in a) 37% (Prosobee), b) 42% months to 9 years) Casein Hydrolyzed Formula Rectal bleeding resolved upon an extensively hydrolyzed CAS
a 4-day-old female with cow's milk formula, and endoscopy one week later showed improvement,
Wilson et al. 1990 induced eosinophilic colitis with only scattered areas of erythema, and no friability Application of 2 extensively whey hydrolyzed formulas (1 lactose Whey Hydrolyzed Formulas free): during application / follow-up of 10 weeks improvement of Verwimp et al.
79 infants with CMA / CMI (age of symptoms in about 80% of children and normal growth with both 1995 Internet Symposium on Food Allergens 4(1):2002
Whey Hydrolyzed / Amino
Atopic eczema improved significantly and progressively inextensively hydrolyzed whey and amino acid formula- fed groups; Acid Formulas
downward trend of serum total and milk- specific IgE levels Isolauri et al. 1995 22 infants with CMA (mean age of proving the efficacy of both formulas (follow-up study of 9 1-month study period: infants fed with extensively hydrolyzed Probiotics / Whey
whey formula a) fortified with Lactobacillus GG or b) not fortifiedformula Hydrolyzed Formula
clinical score of atopic dermatitis improved significantly in a); 31 infants with atopic eczema and decreased concentrations of alpha 1-antitrypsin and fecal TNF- alpha in a); concentration of fecal eosinophil cationic proteinunaltered in a) and b) Amino Acid Formula
12 infants with adverse reactions to Infant formula composed of individual amino acids: no symptoms Hill et al. 1995
soy formula, whey hydrolysate, orCAS hydrolysate Follow-up after successful use of an amino acid-based diet 11.8 Amino Acid Formula
+/- 8.7 months (3-30 months): 22 infants allergic to cow's milk Cow's milk protein tolerance occurred earlier in 9 patients whose proteins who did not tolerate allergy was limited to cow's milk proteins and to extensively extensively hydrolyzed protein hydrolyzed protein formulas (age of 11.8 +/- 3.9 months) as compared to 13 patients with associated allergies to other foods(age of 25.8 +/- 6.9 months) Amino Acid Formula
31 consecutive children with proven Amino Acid-based formula (EleCare) tested performing blinded
CMA (median age 23.3 months; 6 oral food challenges in nonrandomized feeding study (each child months to 17.5 years): serving as own control): 29 with multiple food allergies, 17 18 subjects with allergic eosinophilic gastroenteritis and/or Sicherer et al. 2001 with acute reactions and cow's multiple food allergies followed up while receiving formula for a milk-specific IgE, and 14 with median of 21 months (range, 7 to 40 months): formula was allergic eosinophilic gastroenteritis; hypoallergenic and effective in maintaining normal growth 13 did not tolerate extensivelyhydrolyzed formulas Prospective, controlled, multi-center trial: Amino Acid Formula /
Extensively Hydrolyzed
SCORAD index significantly improved in both groups after 6 months length standard deviation score significant increase in 73 infants (median age 5.7 months) Niggemann et al.
with CMA/CMI and atopic group a), no difference in group b) dermatitis (DBPCFC positive): weight-for-length values stable in both groups a) Amino acid formula fed group energy intake similar in both groups b) Extensively hydrolyzed formula significant clinical improvement in infants with early onset of symptoms CMA/CMI in both groups improved growth in group a) as compared to group b) Chestnut Formula
Supplemented chestnut formula: normal infant's development, 2 >50 infants with CMA or lactose Osvaath et al. 1976 cases of intolerance Soy Protein Formula
Cow's milk- free diet using as a soy protein formula improved the 20 children with CMA and atopic skin lesions, in addition to insuring a regular growth in all Cantani et al. 1990 infants; possible secondary sensitization to soy 1 infant Soy Milk Formula
Clinical tolerance to follow-up soybean formula in 16 children, 17 children with CMA / CMI (age one patient developed a severe diarrhoea within 72 hours after of 6 months to 3 years) introduction of the soybean formula Soy Milk
Incidence of allergic symptoms in 17% of infants fed a 2S protein Marano et al. 1989 20 infants with CMA fraction depleted soy milk Internet Symposium on Food Allergens 4(1):2002
Soy / Beef Hydrolyzed
Fed with lactose-free soy and beef hydrolysate based formula: improvement of symptoms in both groups, allergic symptoms in 1 (a) 12 infants with protracted Donzelli et al. 1990 (a) and 3 (b) infants who were previously fed with intact soy (b) 10 infants with atopic eczema Hypoallergenic Rice, Amino Biotin deficiency in an Japanese infant fed with an amino acid
Acid Formula
formula and hypoallergenic rice processed by protease; symptoms Higuchi et al. 1996 1child with cow's milk and soybean disappeared after oral supplementation with biotin allergy (age of 11 months) Lamp-Meat Based Formula
10 infants with adverse reactions to Application of a modular lamb- meat- based formula, prompt
Weisselberg et al.
CAS hydrolyzed formulas (age of 6 resolution of symptoms (follow-up for 3 months to 5 years) months to 3 years) Ass' Milk
9 unweaned infants with multiple
Ass' milk plus medium chain triglycerides well tolerated by all Iacono et al. 1992 food hypersensitivity presenting severe symptoms of CMA Ass' Milk / Casein
Follow-up for a median period of 4 years (DBPCFC): Multiple food intolerance in 21/21of group a) (ass' milk group): Hydrolyzed Formula
more frequently to soybean, oranges, tomatoes and fish; goat's a) 21 infants (median age at milk intolerance in 5/6, and sheep's milk intolerance in 4/7 diagnosis 2 months) intolerant to receiving the respective food; these patients tolerated ass' milk; extensively hydrolysed proteins 3/21 patients in group a) became ass' milk intolerant; Carroccio et al.
treated with an ass' milk-based diet Multiple food intolerance in 20/70 infants of group b) (casein hydrolysate group); b) 70 cow's milk intolerant infants 52% of group a) and 78% of group b) became cow's milk-tolerant; (median age at diagnosis 3 months) age of children at tolerance was higher in group a) than in b) treated with casein hydrolysate Higher frequency of cases with elevated serum total IgE and cow's milk-based diet.
milk specific IgE in group a) Mare's Milk
Cow's Milk
Mare's Milk
25 children with IgE-mediated Businco et al. 2000 CMA (age of 19 to 72 months, median 34 months) higher percentage * SDS-PAGE immunoblotting 13.2 Allergenicity / Safety of Infant Formulas
Reported Adverse Reactions
see 11 Allergen Sources Infant Formulas
(1) Amonette et al. 1991 Acute allergic reactions in a 7-year old girl with CMA after challenge with 6 different partiallyand extensively hydrolyzed whey and CAS formulas (DBPCFC); anaphylactic reactions to a extensively hydrolysed CAS formula (Alimentum) (1, 2) Infant Formulas
20 children with CMA (age of 15 to 76 months) allergic reactions (challenge tests) to
a) extensively hydrolyzed CAS formula in 10%,
(1) Ragno et al. 1993 b) extensively hydrolyzed whey formula 13%,c) partially hydrolyzed whey formula in 45% Internet Symposium on Food Allergens 4(1):2002
Infant Formulas
4 children developed immediate anaphylactic symptoms after ingesting extensively hydrolyzed
whey and casein formulas, respectively, and 4 children demonstrated subacute or chronic
(1) Sotto et al. 1999 gastrointestinal symptoms. All children with anaphylactic symptoms had positive SPT and RASTto cow's milk and/or hydrolyzed proteins, while SPT and RAST were negative in 3 of 4 childrenwith chronic symptoms (1) Casein Hydrolyzed Formula
Anaphylaxis in a newborn infant after ingestion of extensively hydrolyzed CAS formula
(1) Lifschitz et al. 1988 (Pregestimil) (1) Casein Hydrolyzed Formula
Systemic urticaria in 1 of 11 children with CMA after DBPCFC with extensively hydrolyzed CAS (1) Oldaeus et al. 1991
formula (Alimentum) (1)
Casein Hydrolyzed Formula
(1) Saylor & Bahna Anaphylaxis in a newborn infant after ingestion of extensively hydrolyzed CAS formula Whey Hydrolyzed Formula
Anaphylaxis after ingestion of extensively hydrolysed whey protein formula (Alfa-ré) in infants
(1) Businco et al. 1989 aged 3 to 8 months (1) Whey Hydrolyzed Formula
Sytemic urticarial and respiratory reactions in 8 of 13 children with more severe sytemic IgE-
(1) Schwartz et al. 1991 mediated CMA (groups B and C: positive SPT to cow's milk, whey and CAS hydrolyzed formulas)when fed a partially hydrolysed whey formula (Good Start) (1) Whey Hydrolyzed Formula
(1) Ellis et al. 1991 Anaphylaxis after ingestion of partially hydrolyzed whey formula (Good Start) (1) (2) Businco et al. 1994 Anaphylaxis after ingestion of partially hydrolyzed whey formula in 2 infants (2) Extensively Hydrolyzed Formula
(1) de Boissieu et al.
13 infants allergic to extensively hydrolyzed cow's milk protein formulas fed for treatment of chronic digestive symptoms (1) Soy Hydrolyzed Formula
43 patients with possible milk- and/or soy-protein enterocolitis:
(1) Burks et al. 1994 23% had positive challenge with cow's milk, and 33% and 30% had positive challenge to 2hydrolyzed soy protein isolates Reportedly Safe Applications
Casein Hydrolyzed Formula
(1) Host & Samuelsson 1 extensively hydrolyzed CAS infant formula tested by DBPCFC in 5 children with IgE- mediated 1988 CMA, no symptoms occured (1) Casein Hydrolyzed Formula
1 extensivelyhydrolyzed CAS infant formula tested by SDS-PAGE immunoblot, ELISA and
(1) Sampson et al. 1991 DBPCFC in 25 cow's milk allergic children, even in open challenge no reactions occured (1) Whey Hydrolyzed Formula
All of 13 children with mild topical IgE- mediated CMA (group A: positive SPT to cow's milk,
(1) Schwartz et al. 1991 negative to whey and CAS hydrolyzed formulas) tolerated a whey hydrolysate formula (GoodStart) when fed for at least 2 weeks (1) Whey Hydrolyzed Formula
1 ultrafiltrated (<8 kDa) whey hydrolysate infant formula could be administered safely to 66
(1) Halken et al. 1993a children with CMA (elimination/challenge procedure) Casein / Whey Hydrolyzed Formula
(1) Eigenmann et al.
1 CAS-whey hydrolyzed infant formula tested by PBMC proliferation in 10 children with CMA: no significant T-cell activation (1) Casein / Whey Hydrolyzed Formula
(1) Martin-Esteban et al.
Hydrolysate well tolerated by 31/33 cow's milk allergic children (1) Internet Symposium on Food Allergens 4(1):2002
Several Infant Formulas
32 children with proven CMA (two-center study):
SPT positive
oral challenge tolerance
(1) Giampietro et al.
extensive hydrolysate whey formula (Nutrilon Pepti) extensive hydrolysate whey formula (Profylac) partial hydrolysate whey formula (Nan HA) Skin Tests and in vitro Tests of Infant Formulas
Allergens in Infant
Content / Products
Hydrolyzed Formulas
Positivity in SPT with 26 children with CMA (age of a) whey hydrolyed formula 69% Schwartz et al. 1989 1.3 to 13.8 years) b) extensively hydrolyzed CAS formula 38% Positivity in SPT (n=34-41) witha) partially and extensively hydrolysed whey formulas: Beba 24%and Profylac 15%b) extensively hydrolysed CAS formulas: 2.5% each (Alimentum Hydrolyzed Formulas
45 children with CMA (age of Positivity in RAST with Beba 24%, other hydrolyzed formulas 7- Oldaeus et al. 19913 months to 16 years) 13%Relative IgE- binding potency <0.06% for all tested formulas(RAST inhibition)Detectable amounts of bovine beta-LG in Beba 200 µg/g dryweight, other hydrolysed formulas 0.006-0.066 µg/g (ELISA) Positivity in SPT with Hydrolyzed Formulas
a) partially and extensively hydrolyed whey formulas: Beba 47% 15 children with CMA (age of and Alfare 6.7% (1/15) Oldaeus et al. 1992 b) extensively hydrolyzed CAS formulas: Nutramigen 0% (regular cow's milk formula 87%) Detectable amounts of bovine beta-LG in hydrolyzed formulas Hydrolyzed Formulas
from cows' milk whey or CAS, and from bovine collagen and soy Makinen-Kiljunen & 7 different infant formulas in (range 0.0056 to 200 µg/g dry weight, 0.84 to 31200 ng/mL ready-to-use product) Hydrolyzed Formulas
Serum IgE against protein hydrolysates in 6 children Plebani et al. 1990 13 children with CMA 6 hydrolyzed formulas tested: certain hydrolysates induced Hydrolyzed Formulas
positive skin reactions and allergic symptoms after oral Rugo & Wahn 1992 children with CMA challenge; CAS hydrolysates had the least residual allergenic 1 and 2 positive results to 2 extensively hydrolysed CAS Hydrolyzed Formulas
formulas; 7 positive results to a extensively hydrolysed whey 16 children with CMA Hydrolyzed Formulas
Positive SPT to a) extensively hydrolysed whey formula 1 girl with CMA (at age of 12 (Profylac) and b) extensively hydrolysed CAS formula Nilsson et al. 1999 Whey Hydrolyzed
Formula
35 patients with IgE- mediated 1 ultrafiltrated (<8 kDa), reactions: 6% had positive SPT, 11% positive RAST against Halken et al. 1993a extensively hydrolysed whey formula (no reactions in oral challenge test) Internet Symposium on Food Allergens 4(1):2002
5 children with CMA: Hydrolysate positive in 4/5 patients in SPT, inhibition of IgE-binding to cow's milk proteins by the formula ranged from 51- 1 ultrafiltrated, extensively Van Hoeyveld et al. 1998 Peptides of > 2600 Da positive in SPT and RAST inhibition; hydrolysed whey infant peptides of < 1400 Da negative in SPT but still able to inhibit to a small extent IgE- binding to thehydrolysate (SEC, SPT, RAST) Proliferative responses of PBMCs to hydrolysate formula: higher in 3 patients whose symptoms were not reduced by CAS Nishida et al. 1995 10 children with CMA hydrolysate formula 20 children with CMA (age of 15 to 76 months); positive SPT a) extensively hydrolyzed and specific RASTto a) in 15% and 15%, Ragno et al. 1993 b) extensively hydrolyzed b) in 15% and 20% c) in 45% and 65%, respectively c) partially hydrolyzed wheyformula 12 children with CMA: All hydrolysed formulas showed reduced IgE- binding capacity; 25% of patients sera showed IgE- binding to b) and c), and 42% a) non hydrolysed formula b) whey-based formula b) and d) contained bovine serum albumin, beta-LG, CAS and Gortler et al. 1995 c) whey-based and ultra- their fragments (3-67 kDa) filtrated formula c) contained CAS fragments (3-6 kDa) and beta-LG and its d) CAS/whey-based formula fragments (6-18 kDa)(RAST, immunoblot) Inhibition of IgE binding to (1) van Beresteijn et al.
11 whey and 1 CAS hydrolysed formulas (RAST inhibition) CAS- specific mAb: 0.05-0.67% CAS components in all partly (1) Restani et al. 1995, and 2 extensively whey hydrolysate formulas, not detectable in 2 1996 9 whey or CAS hydrolysed extensively CAS hydrolysate and the amino acid based formulas (2) Plebani et al. 1997 (SDS-PAGE immunoblot, ELISA inhibition) IgE-binding to residual protein fractions Hoffman & Sampson less than 20 kDa in several extensively hydrolyzed cow milk- children with CMA based formulae (RAST inhibition) Several Infant
Formulas
a) partially hydrolysed whey
formula
20 cow's milk allergic children (mean age 1.6 years): b) partially hydrolysed Inhibition of IgE- binding to cow's milk by cow's milk > a > b > Niggemann et al. 1999a c > d (RAST inhibition); SPT to d) all negative c) soy/pork collagenhydrolysated) amino acid formula Internet Symposium on Food Allergens 4(1):2002
Proteins with Mr of 7 to >30 kDa detected by gel filtration; proteins with Mr >20 kDa even detected in extensively hydrolyzed formulas by SDS-PAGE; residual beta-LG detected in Rosendal & Barkholt 12 different partially and all products by ELISA; by immunoblot and dot-immunoblot with 2000 extensively hydrolyzed cow's antibodies against total whey, caseins, or Kunitz soybean trypsin inhibitor antigenic material mainly detected in partiallyhydrolyzed products Cow's milk proteins see 11 Allergen Sources 13.3 Infant Formulas for Allergy Prophylaxis
It should be noticed that multiple parameters are involved in (food) allergy prevention. Nutritional intervention andenvironmental allergen avoidance are factors in allergy prevention. The role of infant formulas is controversial because theresults of several studies have not been reproduced and the objective experimental conditions are difficult to achieve andmaintain when studying human subjects. Please notice the disclaimer ! Feeding / Formula
Atopic Disease
Breast fed infants were found to have 328 children with a positive family history approximately one-half the incidence of atopy of of allergy (15 years follow up) cow's milk or soy based formula fed infants Development of atopic disease inBreast-fed group:38% with IgE > 0.8 U/ml Atopic Disease
12% with IgE < 0.8 U/mlSoy-fed group: 101 newborn infants of atopic parents Businco et al. 1983b 33% with IgE > 0.8 U/ml (total serum IgE) 16% with IgE < 0.8 U/mlCow's milk-fed group:90% with IgE > 0.8 U/ml17% with IgE < 0.8 U/ml Development of atopic eczemaBreast-fed group:22% (restricted maternal diet) Atopic Eczema
48% (no restricted maternal diet) Chandra et al. 1989a 97 brest fed and 124 non brest fed infants Soy-fed group: in 63%Cow's milk-fed group: in 70%CAS hydrolysate-fed group: in 21% Incidence of atopic eczema, wheezing, rhinitis,gastrointestinal symptoms, or colicBreast-fed group: in 20% Atopic Disease
Soy-fed group: in 37% Chandra et al. 1989b 72 infants with family history of atopy (each Cow's milk-fed group: in 36% Chandra & Hamed 1991 Partially hydrolysed whey-fed group: in 7% Cumulative incidence of atopic disease:breast-fed and whey hydrolysate-fed group < cow'smilk and soy-formula fed group Incidence of atopic symptoms (at 18 months) Atopic Disease
Extensively CAS hydrolysate fed group: in 51% Oldaeus et al. 1997 155 infants with family history of atopy Partially hydrolysate fed group: in 64%Regular cow's milk formula fed group: in 84% Internet Symposium on Food Allergens 4(1):2002
Development of atopic diseases similar in allgroups; development of cow's milk allergy /intolerance: Atopic Disease, Cow's Milk Allergy Exclusively breast fed group: none
91 high risk infants (follow-up to 18 months Odelram et al. 1996 Regular cow's milk formula fed group: in 3 infants with skin symptomsUltrafiltered, extensively hydrolysed whey-fedgroup: none Development of any atopic disease:a) in 29%, b) in 38%, c) in 50% (at 9 months) Atopic Disease, Humoral Response a) in 35%, b) in 48%, c) in 62% (at 18 months)
high risk infants (formula fed >3 months) associated to detection of spec. IgE and high spec.
a) 31 fed with extensively CAS hydrolyzed Oldaeus et al. 1999 Cow's milk specific IgE: b) 29 fed with partially hydrolyzed formula a) in 6.5%, b) in 10%, c) in 65% c) 34 fed with regular cow's milk formula beta-LG specific IgG:a < b < c Development of atopic dermatitis: Atopic Dermatitis, Cellular and
no differences in numbers and severity among Humoral Response
groups during first 12 months 72 infants from families with atopic PBMC proliferation: significantly decreased proliferation to CAS in b) Nentwich et al. 2001 a) fed with extensively hydrolyzed formula as compared to c) at 6 months of age b) fed with partially hydrolyzed formula Cow's milk specific IgE: c) breast fed (not received any formula at 6 a) in 9.5%, b) in 0%, c) in 13% at 6 months of age CAS specific IgG levels:b > a at 12 months of age Cow's Milk Allergy
Fed with whey protein hydrolysate formula: 21 infants with gastrointestinal symptoms of Merrit et al. 1990 improvement of symptoms cow's milk and/or soy protein intolerance Development of cow's milk allergy / intolerance: Cow's Milk Allergy
Exclusively breast-fed group: in 1/20Extensively hydrolysed CAS formula-fed group: in 158 high-risk infants (1 year of age, Halken et al. 1993b prospective study) Extensive whey hydrolysate-fed group: in 3/62(no symptoms to formulas occurred) Development of cow's milk allergy / intolerance Cow's Milk Allergy
at age of 6, 12, 36, and 60 months: 58 formula-fed "at risk" infants (all children Regular cow's milk formula fed group: Vandenplas et al. 1995 not breast-fed, formulas fed for first 6 in 43%, 53%, 57%, and 60% Partially whey hydrolysate-fed group:in 7%, 21%, 25%, and 29% Cow's Milk Allergy
unselected healthy, full-term infants
a) 1789 fed with cow's milk formula
18 to 34 months follow-up Saarinen et al. 1999a b) 1859 with pasteurized human milk Cumulative incidence of CMA: Saarinen et al. 2000 c) 1737 with extensively hydrolysed whey in a) 2.4%, b) 1.7%, c) 1.5%, d) 2.1% of infants formulad) 824 exclusively breast-fed Internet Symposium on Food Allergens 4(1):2002
Cow's Milk Allergy
478 infants with high-risk of atopy fed
Followed-up at the age of 12 and 18 months: during the first 4 months of life:a) 232 exclusively breast-fed Cumulative incidence of confirmed CMA: b) 79 extensively hydrolyzed casein formula a) 1.3%, b) and c) 0.6%, and d) 4.7% of infants c) 82 extensively hydrolyzed whey formulad) 85 partially hydrolyzed whey formula Halken et al. 2000 (study period 1994-95) Cumulative incidence of parental-reported CMA:b) 2.5, c) 0%, and d) 7.1% of infants Group a) children were exposed less to No significant differences in b), c), and d) tobacco smoke and pets at home andbelonged to higher social classes, whereas regarding the cumulative incidence of atopic groups b), c), and d) were dermatitis or respiratory symptoms identical concerning environmental factors Humoral Response
IgE, IgG, and IgG subclasses: infants at risk of atopy (age of 6 months) lower total IgE, cow's milk specific IgG, and alpha- a) breast fed group lactalbumin and beta- lactoglobulin specific IgG4 Chirico et al. 1997 b) regular cow's milk formula fed group in a) and c) than in b) c) partially whey hydrolysate fed group (no significant differences at 5 days of age) Humoral Response
129 unselected infants
Follow-up for 2 years: Exposure to cow's milk stimulated cow's milk b) cow's milk formula fed proteins specific IgG production, while feeding Juvonen et al. 1999 c) CAS hydrolysate fed with a CAS hydrolysate was associated with low during the first 3 days of life, otherwise specific IgG levels exclusively breast fed * Studies may be experimental, unproved, or controversial. Please notice the disclaimer ! 14 References [Recent Reviews]
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