Cow’s milk allergy. Aλλεργία στο γάλα της αγελάδας.

ΚΑΤΣΙΜΠΡΗΣ ΠΕΤΡΟΣ

Ιατρός, Ωτορινολαρυγγολόγος (MD. ORL, Msc, c PhD), Πανεπιστημιακό Γενικό Νοσοκομείο Αλεξανδρούπολης

Γρούτσος Χρήστος

Ιατρός, Ωτορινολαρυγγολόγος, Μέλος της Ελληνικής Εταιρείας ΩΡΛ Αλλεργίας και Ρογχοπαθειών, ΚΑΠΟΔΙΣΤΡΙΟΥ 14, Τρίκαλα, Θεσσαλία, τηλ: 2431039877

Γκολα Ε. Ελενη, ΜD

Ιατρός, Ειδικευομένη Ωτορινολαρυγγολόγος, Γεν. Νοσ. Ιπποκράτειο, Αθηνών.

Γκέλης Ν. Δημήτριος [Δρ]

Ιατρός, ΩΡΛ, Οδοντίατρος, Διδάκτωρ της Ιατρικής Σχολής του Πανεπιστημίου Αθηνών, με ιδιαίτερο ενδιαφέρον στην ΩΡΛ Αλλεργία. Φλάμπουρο Λουτρακίου Κορινθίας, 2744023768, τηλ. 6944280764, mail:pharmage@otenet.gr, http://www.gelis.gr

Cow's milk allergy affects 2-3% of young children, the economic impact of which necessitates search for simple diagnostic tools and affordable milk substitutes. Cow's milk is a major cause of allergy in infants. Cow's milk protein allergy is a condition commonly managed by general practitioners and paediatricians. The diagnosis is usually made in the first 12 months of life. Management of immediate allergic reactions and anaphylaxis includes the prevention of accidental food ingestion and provision of an adrenaline autoinjector, if appropriate. By contrast, the clinical course of delayed food-allergic manifestations is characterised by chronicity, and is often associated with nutritional or behavioural sequelae. Correct diagnosis of these non-IgE-mediated conditions may be delayed due to a lack of reliable diagnostic markers [1]. 

The signs and symptoms are nonspecific and may be difficult to objectify, and as the diagnosis requires cow's milk elimination followed by challenge, often, children are considered cow's milk allergic without proven diagnosis. Cow's milk allergy (CMA) has different clinical presentations according to age and  may be present as asthma, rhino conjunctivitis, dermatitis and gastrointestinal symptoms. 

Cow's milk allergy is shown to be a significant etiologic factor for constipation in infants and young children. Serum levels of IgE to cow milk proteins are helpful although not definitive for diagnosis. Based on the  limited study of El-Hodhod MA et al (2009) , tolerance is better achieved after 12 months of strict cow's milk elimination [2].

Milk contains about 80 percent casein and about 20 percent whey proteins.  Casein exists in milk as a colloidal complex with calcium phosphate. Casein is heat-stable. The major cow’s allergens belong to the casein fraction of proteins (αs1-, αs2-, β-, and κ-casein) and to whey proteins (α-lactalbumin and β-lactoglobulin) [7]. There is some cross-reactivity with soy protein, particularly in non-IgE-mediated allergy. There are immune and non-immune-mediated allergic phenomena. Immune-mediated adverse food reactions can be classified into four major categories: IgE-mediated, non-IgE-mediated, mixed, and cell-mediated reactions [8]. CMA is most frequently caused by a non-IgE-mediated mechanism.

Boiling is known to reduce the allergenicity of the whey proteins. Therefore, heat may reduce allergic reactions to milk in some patients, i.e. patients only allergic to whey proteins. Pasteurization reduces but does not eliminate the allergenicity of the caseins.

Beta-lactoglobulin is a major whey protein.  Beta-lactoglobulin is acid-sta­ble and will be absorbed through mucous membranes after ingestion. The allergenicity of beta-lactoglobulin will resist pasteurization.

Another major milk allergen is alpha-lactalbumin, also found in the whey fraction and which contains a single polypeptide chain.

Bovine serum albumin at 69 kDa is found in whey fraction as well and has a single polypeptide chain with a molecular weight of 67 kDa.  Colostrum may contain a higher quantity of bovine immunoglobulins.

Allergenic Proteins (with molecular weight):

Bos d 5 (Beta-lactoglobulin, 18.3 kDa);

Bos d 8 (Casein fractions (alpha, beta, gamma and deita), 20-30 kDa;

Bos d 4 (Alpha-lactalbumin, 14.2 kDa);

Bos d 6 (Serum albumin, 67 kDa);

Bos d 7 (immunoglobulin at 160 kDa)

In-House Clinical Evaluation Results: Sensitivity: 100%        Specificity: 82%
Efficiency: 92%  Number of Samples: 25.

Cow's milk is symbolized in RAST as F2.

The impact of diet on cow's milk allergy (CMA) duration and whether exposure to residual amounts of cow's milk protein influences the onset of tolerance are unknown.

Patients not exposed to cow's milk protein residue achieve cow's milk tolerance earlier than patients who follow an extensively hydrolysed cow's milk diet. This may be due to residual antigenicity in hydrolysed milks. As the effect of dietary intervention is stronger in patients not sensitized to soy, we infer that when atopic disease has progressed to multiple sensitizations, the elimination of allergenic exposure may not be sufficient to reduce the duration of cow's milk allergy (CMA)[3] .

The development of tolerance in IgE-mediated allergies has been associated with lower cow's milk (CM)-specific IgE levels, increasing levels of specific IgG4 and, more contestably, IgA. Patients with persistent CMA at the age of 8 years (n=18 at diagnosis, n=16 at later time-points) had higher CM-specific IgE levels at all three time-points (P<0.001) compared with patients who became tolerant by 3 years (n=55 at diagnosis, n=54 a year later, n=40 at follow-up). They had lower serum IgA levels to beta-lactoglobulin at diagnosis (P=0.01), and lower IgG4 levels to beta-lactoglobulin (P=0.04) and alpha-casein (P=0.05) at follow-up. Conclusion High CM-specific IgE levels predict the persistence of CMA. Development of tolerance is associated with elevated levels of beta-lactoglobulin-specific serum IgA at the time of diagnosis, and later increasing specific IgG4 levels to beta-lactoglobulin and alpha-casein[4].

Dias A, et al (2009) In a retrospective study of children with persistent CMA diagnosed from January 1997 to June 2006, medical records were analysed regarding: clinical presentation, follow-up, treatment and acquisition of tolerance. Data analysis was performed using Excel 2007 for Windows. They included in their study seventy-nine children , with mean age at first symptoms of 3 months. The symptoms were immediate in 93%, with cutaneous (87.3%), gastrointestinal (55.7%) and respiratory (25.3%) manifestations.

During the follow-up period, 30% developed atopic eczema, 52% asthma and 35% rhinoconjunctivitis. A family history of atopy was identified in 53%. The majority presented increased serum total IgE (376+/-723 KU/l) and positive skin prick test (SPT) to cow's milk (CM) (79%). Skin prick tests (SPT) to goat's milk was positive in 2/3 of cases. Fifty-five percent had at least one accidental exposure to CM (severe reactions in 6%). During CM elimination diet, 35% were initially given an extensively hydrolysed formula, 17% a soy formula, and 48% both. By the age of 10 years, 44% of children persisted with CMA and this is  highlighting the importance of a multidisciplinary follow-up[5].

At present, the only proven treatment consists of elimination of cow's milk protein from the child's diet and the introduction of formulas based on extensively hydrolysed whey protein or casein; amino acid-based formula is rarely indicated. The majority of children will regain tolerance to cow's milk within the first 5 years of life[6].

Literature

1. Allen KJ, Davidson GP, Day AS, Hill DJ, Kemp AS, Peake JE, Prescott SL, Shugg A, Sinn JK, Heine RG. Management of cow's milk protein allergy in infants and young children: an expert panel perspective. J Paediatr Child Health. 2009 Sep;45(9):481-6.

2. El-Hodhod MA, Younis NT, Zaitoun YA, Daoud SD. Cow's milk allergy related pediatric constipation: Appropriate time of milk tolerance. Pediatr Allergy Immunol. 2009 Jun 25.

3. Terracciano L, Bouygue GR, Sarratud T, Veglia F, Martelli A, Fiocchi A. Impact of dietary regimen on the duration of cow's milk allergy: a random allocation study. Clin Exp Allergy. 2010 Jan 11.

4. Savilahti EM, Saarinen KM, Savilahti E. Duration of clinical reactivity in cow's milk allergy is associated with levels of specific immunoglobulin G4 and immunoglobulin A antibodies to beta-lactoglobulin. Clin Exp Allergy. 2009 Dec 2.

5. Dias A, Santos A, Pinheiro JA. Persistence of cow's milk allergy beyond two years of age. Allergol Immunopathol (Madr). 2009 Oct 21.

6. Kneepkens CM, Meijer Y. Clinical practice. Diagnosis and treatment of cow's milk allergy. Eur J Pediatr. 2009 Aug;168(8):891-6. Epub 2009 Mar 7.

7. Wal JM. Bovine milk allergenicity. Ann Allergy Asthma Immunol. 2004 Nov; 93(5 Suppl 3):S2-11. [PubMed]

8. Boyce JA, Assa’ad A, Burks AW, Jones SM, Sampson HA, Wood RA, et al. Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-sponsored expert panel. J Allergy Clin Immunol. 2010;126:S1–S58. doi: 10.1016/j.jaci.2010.10.008. [PMC free article] [PubMed]