Cow's milk allergy as a predictor of bronchial hyperresponsiveness and airway inflammation at school age.

BACKGROUND: Cow's milk allergy (CMA) has been found to be associated with an increased incidence of asthma at school age. However, prospective population-based studies of CMA and the development of airway inflammation and bronchial hyperresponsivess (BHR) are lacking. OBJECTIVE: The aims of this study was to evaluate CMA as a risk factor for BHR and airway inflammation presented later in childhood. METHODS: We followed prospectively 118 children with CMA and invited them to a clinical visit at a mean age of 8.6 years including the measurement of exhaled nitric oxide (FE(NO) ) and bronchial challenge with histamine. Ninety-four patients and 80 control subjects from the same cohort participated. RESULTS: At school age, children with a history of CMA had higher FE(NO) levels (P=0.0009) and more pronounced responsiveness to histamine (P=0.027) than their controls. Stratified analysis showed a significant difference only in IgE-positive CMA. Multinomial logistic regression analysis showed that IgE-positive CMA [odds ratio (OR) 3.51; 95% confidence intervals (CI) 1.56-7.90; P=0.002] and a history of wheeze during the first year of life (OR 2.81; 95% CI 1.16-6.84; P=0.023) were independent explanatory factors for increased FE(NO) , and IgE-positive CMA (OR 3.37; 95% CI 1.03-10.97; P=0.044) and parental smoking (OR 3.41; 95% CI 1.14-10.22; P=0.028) for increased BHR, whereas for IgE-negative CMA, no associations with FE(NO) or BHR were found. In the CMA group, those exposed to CM very early at the maternity hospital, had less BHR (P=0.002). CONCLUSIONS: Compared with their controls, children with a history of IgE-positive CMA show signs of airway inflammation, expressed as higher FE(NO) , and more pronounced bronchial responsiveness to histamine at school age. In contrast to IgE-negative CMA, IgE-positive CMA is a significant predictor of increased FE(NO) and BHR at school age. Very early exposure to CM was associated with less BHR.

Duration of clinical reactivity in cow's milk allergy is associated with levels of specific immunoglobulin G4 and immunoglobulin A antibodies to beta-lactoglobulin.

BACKGROUND: 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. OBJECTIVE: We investigated whether specific antibody responses to CM proteins differ over time between patients who recovered from cow's milk allergy (CMA) by the age of 3 years and those who developed tolerance only after the age of 8 years. METHODS: The study population comprised of 83 patients with IgE-mediated CMA. They belonged to a cohort of 6209 healthy, full-term infants followed prospectively for the emergence of CMA. Serum samples were available at diagnosis (median age 7 months), 1 year later (median 19 months) and at follow-up (median 8.5 years). Age-matched control subjects with no history of CMA (n=76) participated in the follow-up. Serum levels of IgE antibodies to CM were measured using UniCAP. Levels of IgA, IgG1 and IgG4 antibodies to beta-lactoglobulin and alpha-casein were measured using ELISA. RESULTS: 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.

A dual long-term effect of breastfeeding on atopy in relation to heredity in children at 4 years of age.

BACKGROUND: The long-term effect of early feeding on atopic sensitization is still unsolved. The aim of this study was to evaluate the long-term effect of breastfeeding on atopy in groups of 4-year-old children stratified by atopic heredity. METHODS: We collected four groups of 4-year-old children from a birth cohort: two groups with differing backgrounds of atopic heredity, all exclusively breast-fed for at least 3 months; and two groups with differing atopic heredity, but all fed with cow's milk-based formula during their first weeks. The data were collected with a questionnaire, skin prick testing, and measurement of serum total and allergen-specific IgE levels. RESULTS: Breastfeeding significantly decreased the risk of allergic rhino-conjunctivitis [odds ratio (OR) 0.41, 95% confidence interval (CI) 0.18-0.95] and sensitization to furred pets, as measured by skin prick results, in children with atopic heredity, whereas in children without atopic heredity, breastfeeding was related to an increased risk of symptomatic atopy (OR 2.57, 95% CI 1.16-5.70), and high serum IgE values. A significant interaction was found between heredity and breastfeeding. CONCLUSIONS: The long-term effect of breastfeeding was dual: in children with atopic heredity, breastfeeding protected against atopy, whereas in children without atopic heredity, it increased the risk of atopy.

Diagnostic value of skin-prick and patch tests and serum eosinophil cationic protein and cow's milk-specific IgE in infants with cow's milk allergy.

The diagnosis of cow's milk allergy is based on a clinical response to an elimination-challenge test with cow's milk. We studied the usefulness of the skin-prick and patch tests and measurement of cow's milk-specific IgE and eosinophil cationic protein in serum as diagnostic tools for cow's milk allergy in a cohort of 6209 unselected infants followed from birth for the development of cow's milk allergy. Of the 239 infants challenged with cow's milk, 118 showed a positive and 121 a negative response at a mean age of 6.9 months. A positive reaction to a skin-prick test with cow's milk (> or = 3 mm) was seen in 72 (61%) and 29 (24%) infants with positive and negative challenges, elevated serum cow's milk-specific IgE (> or = 0.7 kU/L) in 52 (45%) and 15 (13%) infants, a positive reaction to patch test with cow's milk protein fractions in 26 (26%) and eight (8%) infants, and elevated serum eosinophil cationic protein (> or = 20 microg/L) in 22 (21%) and seven (13%) infants, respectively. Parallel use of the four tests with the above-mentioned cut-off values correctly classified 73% of the infants with a sensitivity of 0.76 and a specificity of 0.67. An immediate reaction to cow's milk challenge correlated with skin prick test positivity and elevated serum milk-specific IgE, and tended to correlate with patch test positivity. No single test or parallel use of the four tests could predict the challenge outcome acceptably in this prospectively followed, unselected cohort of 6209 infants. A positive reaction to one or more tests needs to be confirmed by a challenge test and a negative response to all four tests does not rule out the possibility of cow's milk allergy.

Breast-feeding and the development of cows' milk protein allergy.

Early feeding with cows' milk (CM) may cause cows' milk allergy (CMA). Breast milk contains many immune factors which compensate for the undeveloped defence mechanisms of the gut of the newborn infant. We studied the effect of supplementary CM feeding at the maternity hospital on the subsequent incidence of CMA, the effects of formula and breast feeding on the subsequent immunologic types of CMA, and the importance of immune factors present in colostrum in the immune responses of infants with CMA. In a cohort of 6209 infants, 824 were exclusively breast-fed and 87% required supplementary milk while in the maternity hospital: 1789 received CM formula, 1859 pasteurized human milk, and 1737 whey hydrolysate formula. The cumulative incidence of CMA, verified by a CM elimination-challenge test, was 2.4% in the CM, 1.7% in the pasteurized human milk and 1.5% in the whey hydrolysate group. Among these infants, exposure to CM at hospital and a positive atopic heredity increased the risk of CMA. Of the exclusively breast-fed infants, 2.1% had CMA. Risk factors for the development of IgE-mediated CMA were: exposure to CM at hospital, breast-feeding during the first 8 weeks at home either exclusively or combined with infrequent exposure to small amounts of CM and long breast-feeding. The content of transforming growth factor-beta1 (TGF-beta1) in colostrum from mothers of infants with IgE-mediated CMA was lower than from mothers of infants with non-IgE-mediated CMA. In infants with CMA, TGF-beta1 in colostrum negatively correlated with the result of skin prick test and the stimulation of peripheral blood mononuclear cells to CM, but positively with infants' IgA and IgG antibodies to CM proteins. Feeding of CM formula at maternity hospital increases the risk of CMA, but exclusive breast-feeding does not eliminate the risk. Prolonged breast-feeding exclusively or combined with infrequent exposure to small amounts of CM during the first 8 weeks induces the development of IgE-mediated CMA. Colostral TGF-beta1 may inhibit IgE- and cell mediated reactions and promote IgG-IgA antibody production to CM in infants prone to developing CMA.

Infant feeding patterns affect the subsequent immunological features in cow's milk allergy.

BACKGROUND: The first exposure to food antigens provokes an immune reaction in an infant, its type depending on the quantity and frequency of doses and the age at introduction, and also being influenced by genetic factors. Most infants develop tolerance to food antigens, but in a small minority they provoke adverse symptoms. OBJECTIVE: To study the effects of breast and formula feeding and other environmental and genetic factors on the subsequent type of cow's milk allergy classified by the presence or absence of immunoglobulin (Ig) E antibodies to cow's milk. METHODS: A cohort of 6209 infants was followed prospectively from birth for symptoms of cow's milk allergy. The infant-feeding regimen was recorded at the maternity hospital and at home. At a mean age of 6.7 months, a total of 118 infants (1.9%) reacted adversely to a challenge with cow's milk. Before the challenge, the response to a skin-prick test with cow's milk and serum IgE cow's milk antibodies was measured. RESULTS: At challenge, 75 (64%) infants showed IgE-positive reactions to cow's milk, their most common symptom being acute-onset urticaria. Significant risk factors for the presence of IgE cow's milk antibodies in allergic infants were long breast-feeding (odds ratio [OR] 3.9, 95% confidence interval [CI] 1.6-9.8), exposure to cow's milk at the maternity hospital (OR 3.5, 95% CI 1.2-10.1) and breast-feeding during the first 2 months at home either exclusively (OR 5.1, 95% CI 1.6-16.4) or combined with infrequent exposure to small amounts of cow's milk (OR 5.7, 95% CI 1.5-21.6). Fifty infants had their first adverse symptoms during exclusive breast-feeding, and 32 infants were sensitized during exclusive breast-feeding. Most of the infants in both cases were IgE-positive: 37 and 23, respectively. CONCLUSIONS: In infants who are prone to developing cow's milk allergy, prolonged breast-feeding exclusively or combined with infrequent exposure to small amounts of cow's milk during the first 2 months of life induces development of IgE-mediated response to cow's milk.

Transforming growth factor-beta1 in mothers' colostrum and immune responses to cows' milk proteins in infants with cows' milk allergy.

BACKGROUND: Breast milk contains immune factors that compensate for the underdeveloped defenses of the gut of the newborn infant. OBJECTIVE: We sought to study the importance of these factors in the immune responses of infants with cows' milk allergy (CMA) to the proteins in cows' milk (CM). METHODS: We prospectively followed the development of CMA in 6209 healthy infants and collected samples of colostrum from mothers. Samples from mothers of infants with CMA and from control subjects were analyzed for immunoglobulins, CM-specific antibodies, and cytokines. In infants with CMA, correlations between the concentration of transforming growth factor (TGF)-beta1 in colostrum and the extent of the immune response to CM proteins were studied. RESULTS: The concentration of TGF-beta1 in colostrum samples from mothers of infants with IgE-mediated CMA (n = 65) was lower (mean, 589 pg/mL; 95% confidence interval [CI], 413-840) than from mothers of infants with non-IgE-mediated CMA (n = 37; mean, 1162 pg/mL; 95% CI, 881-1531; t = 2.57, P =.012). In 126 control subjects the mean concentration was 807 pg/mL (95% CI, 677-963). In the infants with CMA (n = 96-100), the concentration of TGF-beta1 in colostrum was positively correlated with IgA antibodies to beta-lactoglobulin and IgG antibodies to alpha-casein and whole formula and negatively with the diameter of a skin prick test response to CM and lymphocyte stimulation indices to alpha-casein and beta-lactoglobulin. CONCLUSIONS: In an infant prone to having CMA, the TGF-beta1 content of mother's colostrum may promote IgG-IgA antibody production and inhibit IgE- and cell-mediated reactions to CM.

Supplementary feeding in maternity hospitals and the risk of cow's milk allergy: A prospective study of 6209 infants.

BACKGROUND: Early feeding with cow's milk (CM) may increase the risk of cow's milk allergy (CMA). OBJECTIVE: We sought to examine prospectively whether supplementary feeding of CM at the maternity hospital would increase the risk when compared with feeding with pasteurized human milk or hydrolyzed formula. METHODS: We studied 6209 unselected healthy, full-term infants, of whom 5385 (87%) required supplementary milk while in the hospital. The infants were randomly assigned to receive CM formula (1789 infants), pasteurized human milk (1859 infants), or whey hydrolysate formula (1737 infants). The comparison group (824 infants) was composed of infants who were exclusively breast-fed. The infants were followed for 18 to 34 months for symptoms suggestive of CMA. The primary endpoint was a challenge-proven adverse reaction to CM after a successful CM elimination diet. RESULTS: The cumulative incidence of CMA in the infants fed CM was 2.4% compared with 1.7% in the pasteurized human milk group (odds ratio [OR], 0.70; 95% confidence interval [CI], 0. 44-1.12) and 1.5% in the whey hydrolysate group (OR, 0.61; 95% CI, 0. 38-1.00). In the comparison group, CMA developed in 2.1% of the infants. Among the infants who required supplementary feeding at hospital, both exposure to CM while in the hospital (OR, 1.54; 95% CI, 1.04-2.30; P =.03) and obvious parental atopy (OR, 2.32; 95% CI, 1.53-3.52; P <.001) increased the risk of CMA. CONCLUSIONS: Our data indicate that feeding of CM at maternity hospitals increases the risk of CMA when compared with feeding of other supplements, but exclusive breast-feeding does not eliminate the risk.