Background: Methods for predicting the clinical outcome of specific oral immunotherapy (OIT) would improve the safety of the therapy. Methods: We investigated 40 children aged 6-17 years with IgE-mediated cow's milk allergy (CMA) who either successfully completed OIT (n = 32) or discontinued the therapy due to adverse reactions (n = 8). From sera drawn before and after OIT, we analyzed specific IgA, IgG, IgG1 and IgG4 to cow's milk (CM), casein, β-lactoglobulin and ovalbumin (with enzyme-linked immunosorbent assay) and IgE to CM and hen's egg white [with enzymatic fluoroimmunoassay (Phadia ThermoFisher Scientific CAP system)]. As a reference, we also analyzed serum samples from 8- to 9-year-old children who either had no history of CMA (n = 76) or who had spontaneously recovered from IgE-mediated CMA (n = 56). Results: Levels of specific IgA, IgG, IgG1 and IgG4 to CM and casein, and CM-specific IgE prior to OIT were higher in children who discontinued the therapy than in those who achieved desensitization (p < 0.05). Adverse reactions in the entire population were associated with low IgG and IgG4, but high IgG1 levels to ovalbumin (p < 0.05). Specific IgA, IgG, IgG1 and IgG4 to CM proteins significantly increased and IgE to CM decreased during OIT in children who achieved desensitization (p < 0.01). In those who discontinued OIT, only IgG, IgG1 and IgG4 to CM increased significantly (p < 0.03) and CM IgE remained unchanged. Conclusions: High specific IgE, IgA and IgG-class antibodies to CM proteins appear to predict failure to achieve desensitization in CM OIT. Specific IgA and IgG-class antibodies to CM increase and CM IgE decreases during desensitization.

1.
Saarinen KM, Juntunen-Backman K, Jarvenpaa AL, Kuitunen P, Lope L, Renlund M, et al: Supplementary feeding in maternity hospitals and the risk of cow's milk allergy: a prospective study of 6209 infants. J Allergy Clin Immunol 1999;104:457-461.
2.
Saarinen KM, Pelkonen AS, Makela MJ, Savilahti E: Clinical course and prognosis of cow's milk allergy are dependent on milk-specific IgE status. J Allergy Clin Immunol 2005;116:869-875.
3.
Elizur A, Rajuan N, Goldberg MR, Leshno M, Cohen A, Katz Y: Natural course and risk factors for persistence of IgE-mediated cow's milk allergy. J Pediatr 2012;161:482-487.e1.
4.
Meglio P, Bartone E, Plantamura M, Arabito E, Giampietro PG: A protocol for oral desensitization in children with IgE-mediated cow's milk allergy. Allergy 2004;59:980-987.
5.
Staden U, Rolinck-Werninghaus C, Brewe F, Wahn U, Niggemann B, Beyer K: Specific oral tolerance induction in food allergy in children: efficacy and clinical patterns of reaction. Allergy 2007;62:1261-1269.
6.
Morisset M, Moneret-Vautrin DA, Guenard L, Cuny JM, Frentz P, Hatahet R, et al: Oral desensitization in children with milk and egg allergies obtains recovery in a significant proportion of cases. A randomized study in 60 children with cow's milk allergy and 90 children with egg allergy. Eur Ann Allergy Clin Immunol 2007;39:12-19.
7.
Skripak JM, Nash SD, Rowley H, Brereton NH, Oh S, Hamilton RG, et al: A randomized, double-blind, placebo-controlled study of milk oral immunotherapy for cow's milk allergy. J Allergy Clin Immunol 2008;122:1154-1160.
8.
Longo G, Barbi E, Berti I, Meneghetti R, Pittalis A, Ronfani L, et al: Specific oral tolerance induction in children with very severe cow's milk-induced reactions. J Allergy Clin Immunol 2008;121:343-347.
9.
Pajno GB, Caminiti L, Ruggeri P, De Luca R, Vita D, La Rosa M, et al: Oral immunotherapy for cow's milk allergy with a weekly up-dosing regimen: a randomized single-blind controlled study. Ann Allergy Asthma Immunol 2010;105:376-381.
10.
Martorell A, De la Hoz B, Ibanez MD, Bone J, Terrados MS, Michavila A, et al: Oral desensitization as a useful treatment in 2-year-old children with cow's milk allergy. Clin Exp Allergy 2011;41:1297-1304.
11.
Alvaro M, Giner MT, Vazquez M, Lozano J, Dominguez O, Piquer M, et al: Specific oral desensitization in children with IgE-mediated cow's milk allergy. Evolution in one year. Eur J Pediatr 2012;171:1389-1395.
12.
Vazquez-Ortiz M, Alvaro-Lozano M, Alsina L, Garcia-Paba MB, Piquer-Gibert M, Giner-Munoz MT, et al: Safety and predictors of adverse events during oral immunotherapy for milk allergy: severity of reaction at oral challenge, specific IgE and prick test. Clin Exp Allergy 2013;43:92-102.
13.
Salmivesi S, Korppi M, Makela MJ, Paassilta M: Milk oral immunotherapy is effective in school-aged children. Acta Paediatr 2013;102:172-176.
14.
Skripak JM, Matsui EC, Mudd K, Wood RA: The natural history of IgE-mediated cow's milk allergy. J Allergy Clin Immunol 2007;120:1172-1177.
15.
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 2010;40:251-256.
16.
Savilahti EM, Rantanen V, Lin JS, Karinen S, Saarinen KM, Goldis M, et al: Early recovery from cow's milk allergy is associated with decreasing IgE and increasing IgG4 binding to cow's milk epitopes. J Allergy Clin Immunol 2010;125:1315, 1321.e9.
17.
Wang J, Lin J, Bardina L, Goldis M, Nowak-Wegrzyn A, Shreffler WG, et al: Correlation of IgE/IgG4 milk epitopes and affinity of milk-specific IgE antibodies with different phenotypes of clinical milk allergy. J Allergy Clin Immunol 2010;125:695, 702, 702.e1-702.e6.
18.
Shek LP, Soderstrom L, Ahlstedt S, Beyer K, Sampson HA: Determination of food specific IgE levels over time can predict the development of tolerance in cow's milk and hen's egg allergy. J Allergy Clin Immunol 2004;114:387-391.
19.
Savilahti EM, Viljanen M, Kuitunen M, Savilahti E: Cow's milk and ovalbumin-specific IgG and IgA in children with eczema: low beta-lactoglobulin-specific IgG4 levels are associated with cow's milk allergy. Pediatr Allergy Immunol 2012;23:590-596.
20.
Savilahti EM, Saarinen KM, Savilahti E: Specific antibodies to cow's milk proteins in infants: effect of early feeding and diagnosis of cow's milk allergy. Eur J Nutr 2010;49:501-504.
21.
Cerutti A, Rescigno M: The biology of intestinal immunoglobulin A responses. Immunity 2008;28:740-750.
22.
Miranda DO, Silva DA, Fernandes JF, Queiros MG, Chiba HF, Ynoue LH, et al: Serum and salivary IgE, IgA, and IgG4 antibodies to Dermatophagoides pteronyssinus and its major allergens, Der p1 and Der p2, in allergic and nonallergic children. Clin Dev Immunol 2011;2011:302739.
23.
Francis JN, James LK, Paraskevopoulos G, Wong C, Calderon MA, Durham SR, et al: Grass pollen immunotherapy: IL-10 induction and suppression of late responses precedes IgG4 inhibitory antibody activity. J Allergy Clin Immunol 2008;121:1120-1125.e2.
24.
Pilette C, Nouri-Aria KT, Jacobson MR, Wilcock LK, Detry B, Walker SM, et al: Grass pollen immunotherapy induces an allergen-specific IgA2 antibody response associated with mucosal TGF-beta expression. J Immunol 2007;178:4658-4666.
25.
Saarinen KM, Vaarala O, Klemetti P, Savilahti E: Transforming growth factor-beta1 in mothers' colostrum and immune responses to cows' milk proteins in infants with cows' milk allergy. J Allergy Clin Immunol 1999;104:1093-1098.
26.
Kim JS, Nowak-Wegrzyn A, Sicherer SH, Noone S, Moshier EL, Sampson HA: Dietary baked milk accelerates the resolution of cow's milk allergy in children. J Allergy Clin Immunol 2011;128:125-131.e2.
27.
Bedoret D, Singh AK, Shaw V, Hoyte EG, Hamilton R, DeKruyff RH, et al: Changes in antigen-specific T-cell number and function during oral desensitization in cow's milk allergy enabled with omalizumab. Mucosal Immunol 2012;5:267-276.
28.
Shamji MH, Ljorring C, Francis JN, Calderon MA, Larche M, Kimber I, et al: Functional rather than immunoreactive levels of IgG4 correlate closely with clinical response to grass pollen immunotherapy. Allergy 2012;67:217-226.
29.
Shek LP, Bardina L, Castro R, Sampson HA, Beyer K: Humoral and cellular responses to cow's milk proteins in patients with milk-induced IgE-mediated and non-IgE-mediated disorders. Allergy 2005;60:912-919.
30.
Meiler F, Klunker S, Zimmermann M, Akdis CA, Akdis M: Distinct regulation of IgE, IgG4 and IgA by T regulatory cells and Toll-like receptors. Allergy 2008;63:1455-1463.
31.
Kukkonen AK, Savilahti EM, Haahtela T, Savilahti E, Kuitunen M: Ovalbumin-specific immunoglobulins A and G levels at age 2 years are associated with the occurrence of atopic disorders. Clin Exp Allergy 2011;41:1414-1421.
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