IgE to cross-reactive carbohydrate determinants (CCD) in childhood: Prevalence, risk factors, putative origins.

BACKGROUND: IgE antibodies to cross-reactive carbohydrate determinants (CCD) are usually clinically irrelevant but they can be a cause of false positive outcomes of allergen-specific IgE tests in vitro. Their prevalence and levels have been so far cross-sectionally examined among adult allergic patients and much less is known about their origins and relevance in childhood. METHODS: We examined CCD with a cross-sectional approach in 1263 Italian pollen allergic children (Panallergen in Paediatrics, PAN-PED), as well as with a longitudinal approach in 612 German children (Multicenter Allergy Study, MAS), whose cutaneous and IgE sensitization profile to a broad panel of allergen extracts and molecules was already known. The presence and levels of IgE to CCD were examined in the sera of both cohorts using bromelain (MUXF3) as reagent and a novel chemiluminescence detection system, operating in a solid phase of fluorescently labelled and streptavidin-coated paramagnetic microparticles (NOVEOS, HYCOR, USA). RESULTS: IgE to CCD was found in 22% of the Italian pollen allergic children, mainly in association with an IgE response to grass pollen. Children with IgE to CCD had higher total IgE levels and were sensitized to more allergenic molecules of Phleum pratense than those with no IgE to CCD. Among participants of the German MAS birth cohort study, IgE to CCD emerged early in life (even at pre-school age), with IgE sensitization to group 1 and 4 allergen molecules of grasses, and almost invariably persisted over the full observation period. CONCLUSIONS: Our results contribute to dissect the immunological origins, onset, evolution and risk factors of CCD-sIgE response in childhood, and raise the hypothesis that group 1 and/or 4 allergen molecules of grass pollen are major inducers of these antibodies through an antigen-specific, T-B cell cognate interaction.

A singleplex IgE test to a mixture of molecules from multiple airborne allergen sources: Innovating in vitro screening of respiratory allergies.

BACKGROUND: In vitro immunoglobulin E (IgE) tests can be better standardized if based on molecules rather than extracts. However, singleplex screening tests for respiratory or food allergies are still based on extracts only. TARGET: To validate a novel singleplex IgE screening test for respiratory allergies, based on a mix of major allergenic molecules Der p 1, Der p 2, Fel d 1, Can f 1, Can f 2, Can f 3, Can f 5, Bet v 1, Phl p 1, and Art v 1 (Molecular SX01, NOVEOS, HYCOR, USA), and requiring only four microliters (µl) of serum. METHODS: We examined six subsets of sera from participants of the German Multicenter Allergy Study (MAS) birth cohort enrolling 1314 newborns during 1990: (1) monosensitized (n = 58); (2) polysensitized (n = 24); (3) nonsensitized, with total IgE levels above (n = 24) or (4) below (n = 24) 300 kU/L; (5) sensitized to milk and/or egg but not to airborne allergens (n = 24); and (6) sera of children aged ≤5 years at their earliest IgE monosensitization to airborne allergens (n = 41). Sera were analyzed with the novel molecular SX01 test (NOVEOS) and with three categories of comparators: ImmunoCAP Phadiatop SX01, extracts, and molecules of D. pteronyssinus, cat, dog, grass, and birch. Sensitivity, specificity, positive and negative predictive values were calculated. Quantitative interrelationships were determined using Spearman's rank-order correlation coefficient and Bland-Altmann plots. RESULTS: The molecular SX01 test predicted the outcome of IgE tests based on molecules, extracts, or Phadiatop in 188 (96.4%), 171 (87.7%), and 171 (87.7%) of the 195 sera, respectively. Accordingly, sensitivity was 93.5%, 89.0%, and 82.4%, whereas specificity was 100%, 97.6%, and 96.1% when compared with molecular, extract, and Phadiatop tests, respectively. Inconsistent outcomes were largely confined to sera with IgE-Ab levels around the cutoff value of 0.35 kU/L, except for 5/195 (2.5%) sera, containing high levels of IgE to Phl p 5 and/or Alt a 1 only. IgE levels measured by the molecular SX01 test and with IgE tests to molecules, extracts, and Phadiatop were highly correlated (rho 0.90; p < .001), (rho 0.87, p < .001), (rho 0.84, p < .001), respectively. The novel molecular SX01 test detected IgE-Ab in 27/28 (sensitivity 96.4%) of the sera of preschool children at their earliest IgE sensitization to the same molecules. DISCUSSION: Our study validates the prototype of a novel category of IgE test, based on molecular mixes. The test's rather good precision and accuracy in early screening IgE sensitization to airborne allergens in German children may be further improved by adding a few other molecules, such as Phl p 5 and Alt a 1.

Acute alcohol intoxication among adolescents-the role of the context of drinking.

This study aims (1) to describe the context of drinking among adolescents with acute alcohol intoxication (AAI) by gender, (2) to explore temporal changes in the context of drinking and (3) to analyse the association between the context of drinking and blood alcohol concentration (BAC). A retrospective chart review of 12- to 17-year-old inpatients with AAI (n = 1441) of the years 2000 to 2006 has been conducted in five participating hospitals in Germany. Gender differences in the context of drinking were tested with t test and chi2 test. Differences over time were analysed using logistic regressions. Multivariate linear regression was used to predict BAC. Girls and boys differed in admission time, drinking situation, drinking occasion and admission context. No temporal changes in drinking situation and in admission to hospital from public locations or places were found. Higher BAC coincided with male gender and age. Moreover, BAC was higher among patients admitted to hospital from public places and lower among patients who drank for coping. CONCLUSION: The results suggest gender differences in the context of drinking. The context of drinking needs to be considered in the development and implementation of target group-specific prevention and intervention measures. What is known: • The context of drinking, e.g. when, where, why and with whom is associated with episodic heavy drinking among adolescents. What is new: • Male and female inpatients with acute alcohol intoxication differ with regards to the context of drinking, i.e. in admission time, drinking situation, drinking occasion and admission context. • Being admitted to hospital from public places is associated with higher blood alcohol concentration.

Allergies in high-risk schoolchildren after early intervention with cow's milk protein hydrolysates: 10-year results from the German Infant Nutritional Intervention (GINI) study.

BACKGROUND: The long-term effect of nutritional intervention with hydrolysate infant formulas on allergic manifestations in high-risk children is uncertain. OBJECTIVE: We sought to investigate the effect of hydrolysate infant formulas on allergic phenotypes in children with family history of allergies at school age. METHODS: We analyzed data from participants of the prospective German Infant Nutritional Intervention study after 10 years of follow-up. At birth, children were randomly assigned to receive, for the first 4 months, one of 4 blinded formulas as breast milk substitute, if necessary: partially hydrolyzed whey formula (pHF-W), extensively hydrolyzed whey formula (eHF-W), extensively hydrolyzed casein formula (eHF-C), or standard cow's milk formula. Outcomes were parent-reported, physician-diagnosed allergic diseases. Log-binomial regression models were used for statistical analysis. RESULTS: The relative risk for the cumulative incidence of any allergic disease in the intention-to-treat analysis (n = 2252) was 0.87 (95% CI, 0.77-0.99) for pHF-W, 0.94 (95% CI, 0.83-1.07) for eHF-W, and 0.83 (95% CI, 0.72-0.95) for eHF-C compared with standard cow's milk formula. The corresponding figures for atopic eczema/dermatits (AD) were 0.82 (95% CI, 0.68-1.00), 0.91 (95% CI, 0.76-1.10), and 0.72 (95% CI, 0.58-0.88), respectively. In the per-protocol analysis (n = 988) effects were stronger. The period prevalence of AD at 7 to 10 years was significantly reduced with eHF-C in this analysis, but there was no preventive effect on asthma or allergic rhinitis. CONCLUSION: The significant preventive effect on the cumulative incidence of allergic diseases, particularly AD, with pHF-W and eHF-C persisted until 10 years without rebound, whereas eHF-W showed no significant risk reduction. There is insufficient evidence of ongoing preventive activity at 7 to 10 years of age.

Is prevention of atopic eczema with hydrolyzed formulas cost-effective? A health economic evaluation from Germany.

OBJECTIVE: The German Infant Nutritional Intervention (GINI) trial, a prospective, randomized, double-blind intervention, enrolled children with a hereditary risk for atopy. When fed with certain hydrolyzed formulas for the first 4 months of life, the risk was reduced by 26-45% in PP and 8-29% in intention-to-treat (ITT) analyses compared with children fed with regular cow's milk at age 6. The objective was to assess the cost-effectiveness of feeding hydrolyzed formulas. PATIENTS AND METHODS: Cost-effectiveness was assessed with a decision tree model programmed in TreeAge. Costs and effects over a 6-yr period were analyzed from the perspective of the German statutory health insurance (SHI) and a societal perspective at a 3% effective discount rate followed by sensitivity analyses. RESULTS: The extensively hydrolyzed casein formula would be the most cost-saving strategy with savings of 478 € per child treated in the ITT analysis (CI95%: 12 €; 852 €) and 979 € in the PP analysis (95%CI: 355 €; 1455 €) from a societal perspective. If prevented cases are considered, the partially whey hydrolyzed formula is cost-saving (ITT -5404 €, PP -6358 €). From an SHI perspective, the partially whey hydrolyzed formula is cost-effective, but may also be cost-saving depending on the scenario. An extensively hydrolyzed whey formula also included into the analysis was dominated in all analyses. CONCLUSIONS: For the prevention of AE, two formulas can be cost-effective or even cost-saving. We recommend that SHI should reimburse formula feeding or at least the difference between costs for cow's milk formula and the most cost-effective formula.

Preventive effect of hydrolyzed infant formulas persists until age 6 years: long-term results from the German Infant Nutritional Intervention Study (GINI).

BACKGROUND: The long-term effect of nutritional intervention with hydrolyzed infant formulas on allergy development has not been sufficiently evaluated. OBJECTIVE: We performed a follow-up of the German Infant Nutritional Intervention study until 6 years of life to investigate the long-term allergy-preventive effect of 3 hydrolyzed infant formulas compared with cow's milk formula (CMF) in a randomized, double-blind trial. METHODS: Between 1995 and 1998, 2252 newborns with atopic heredity were randomly assigned at birth to receive one of 4 blinded formulas: partially or extensively hydrolyzed whey formula, extensively hydrolyzed casein formula, or CMF as milk substitute for the first 4 months when breast-feeding was insufficient. The cohort was followed from birth until 6 years of age with yearly questionnaires. Outcomes were physician-diagnosed allergic diseases (atopic dermatitis, food allergy, allergic urticaria, asthma, and hay fever/allergic rhinitis). Log-binomial regression modeled with generalized estimation equations was used for the statistical analysis. RESULTS: In the intent-to-treat analysis the relative risk of a physician's diagnosis of allergic manifestation (AM) compared with CMF was 0.82 (95% CI, 0.70-0.96) for partially hydrolyzed whey formula, 0.90 (95% CI, 0.78-1.04) for extensively hydrolyzed whey formula, and 0.80 (95% CI, 0.69-0.93) for extensively hydrolyzed casein formula. The corresponding figures for atopic eczema were 0.79 (95% CI, 0.64-0.97), 0.92 (95% CI, 0.76-1.11), and 0.71 (95% CI, 0.58-0.88), respectively. In the per-protocol analysis all effects were stronger and significant. No significant effect on other AMs was found. CONCLUSION: The data confirm a long-term allergy-preventive effect of hydrolyzed infant formulas on AM and atopic eczema until 6 years of age.

Solid food introduction in relation to eczema: results from a four-year prospective birth cohort study.

OBJECTIVE: To assess the association between the introduction of solid foods in the first 12 months and the occurrence of eczema during the first 4 years of life in a prospective study of newborns. STUDY DESIGN: Data were taken from annually administered questionnaires from a large birth cohort (recruited 1995-1998) comprised of an intervention and a nonintervention group. Outcomes were doctor-diagnosed and symptomatic eczema. Multiple generalized estimation equation models were performed for the 2 study groups. RESULTS: From the 5991 recruited infants, 4753 (79%) were followed up. The 2 study groups were different in their family risk of allergies and feeding practices. No association was found between the time of introduction of solids or the diversity of solids and eczema. In the nonintervention group, a decreased risk was observed for avoidance of soybean/nuts, but an increased risk was seen in doctor-diagnosed eczema for the avoidance of egg in the first year. CONCLUSION: The evidence from this study supports neither a delayed introduction of solids beyond the fourth month nor a delayed introduction of the most potentially allergenic solids beyond the sixth month of life for the prevention of eczema. However, effects under more extreme conditions cannot be ruled out.

Long-term effects of hydrolyzed protein infant formulas on growth--extended follow-up to 10 y of age: results from the German Infant Nutritional Intervention (GINI) study.

BACKGROUND: Previous analysis in a prospective, population-based cohort reported reduced weight gain in children fed extensively hydrolyzed casein (eHF-C) formula during the first year of life but showed no effect on growth between 1 and 6 y of life. No studies have been conducted in children up to the age of 10 y. OBJECTIVE: The objective was to investigate potential differences in body mass index (BMI) over the first 10 y of life between infants fed within the intervention period of the first 16 wk of life with partially hydrolyzed whey (pHF-W), extensively hydrolyzed whey (eHF-W), eHF-C, or cow-milk formula (CMF) and infants exclusively breastfed (BF) within the intervention period. DESIGN: This was a prospective, randomized, double-blind trial in full-term neonates with atopic heredity in the German birth cohort German Infant Nutritional Intervention (GINI) followed through the first 10 y of life. Analyses of absolute and World Health Organization (WHO)-standardized BMI trajectories for 1840 infants [pHF-W (n = 253), eHF-W (n = 265), eHF-C (n = 250), CMF (n = 276), and BF (n = 796)] were conducted according to intention-to-treat principles. RESULTS: Except for the previously reported slower BMI gain in infants fed with eHF-C formula within the first year of life, no significant differences in absolute or WHO-standardized BMI trajectories were shown between the pHF-W, eHF-W, eHF-C, CMF, and BF groups thereafter up to the age of 10 y. CONCLUSIONS: Extension of the follow-up period from 6 to 10 y for this randomized controlled trial showed no long-term consequences on BMI for the 4 infant formulas considered. These data need to be confirmed in future studies.

Growth of infants fed formula rich in canola oil (low erucic acid rapeseed oil).

BACKGROUND & AIMS: Canola oil is a variety of rapeseed oil low in erucic acid (<2%). For many years, canola oil has been widely used as an ingredient in infant formula in Europe, but not in North America due to safety concerns. A number of studies have used variable canola content of infant formulas to investigate the effects of linoleic acid: α-linolenic acid ratio on visual function of infants. However, little published data is available to compare the safety of canola versus non-canola containing infant formula. The aim of this study is to investigate whether infant formulas containing canola oil support normal growth in infants as assessed by weight and length gain. METHODS: Re-analyses of data on infant weight and length gain from a prospective randomized double-blind trial in full-term infants in the German Infant Nutritional Intervention study (GINI). This analysis compared growth in infants receiving infant formulas with or without canola oil from week 4 to month 7. Absolute weight and length, weight and length gain in gram or cm per day and standardized weight and length measurements were analyzed by analyses of variance and a longitudinal random effects model. Standardization was conducted according to the new WHO 2006 age- and sex-specific child growth standards. RESULTS: Absolute and standardized weight and length measures did not differ between the formula groups with or without canola oil. This was true for both, analyses within each of the three anthropometric measurement periods (4-6 weeks, 3-4 months, 6-7 months) and for the longitudinal analyses over the whole period from 4 weeks to 7 months of life. Power analyses confirmed that sample size was sufficient to detect a difference of 3 g per day between 14 and 120 days between the two formula groups. CONCLUSIONS: Infant formula containing canola oil supports normal infant growth as assessed by weight and length gain.

Effect of hydrolysed formula feeding on taste preferences at 10 years. Data from the German Infant Nutritional Intervention Program Plus Study.

BACKGROUND & AIMS: There is some evidence that the type of infant formula received in early infancy has an influence on later food preferences. How long potential effects of taste programming persist is however not clear. Therefore, the aim of present study was to investigate whether feeding with different kinds of infant formula is associated with the acceptance of infant formula at 10 years of age. METHODS: Preference testing was conducted in 833 10-year old children being part of the interventional subgroup of the German Infant Nutritional Intervention Program Plus Study (GINIplus). If they were not exclusively breastfed, these children have been fed with either one of three hydrolysed formulas or a cow's milk formula during the first four months of life. RESULTS: Feeding with any kind of hydrolysed formula in infancy was positively associated with a higher acceptance of extensively hydrolysed casein formula (aOR: 1.88; 95% CI 1.08, 3.29) after adjusting for sex and study centre. CONCLUSIONS: Although this study did not show consistent associations and thus leaves some questions unanswered, it might stimulate further research on the potential programming effect of early infant feeding.

Short- and long-term effects of feeding hydrolyzed protein infant formulas on growth at < or = 6 y of age: results from the German Infant Nutritional Intervention Study.

BACKGROUND: The short- and long-term effects of feeding with hydrolyzed formulas on growth are uncertain. OBJECTIVE: Our aim was to investigate the potential differences in body mass index (BMI) over the first 6 y of life between infants fed with partially hydrolyzed whey (pHF-W), extensively hydrolyzed whey (eHF-W), extensively hydrolyzed casein (eHF-C), or cow-milk formula (CMF) and infants exclusively breastfed for the first 16 wk of life. DESIGN: We established a prospective, randomized, double-blind trial of full-term neonates with atopic heredity in the German birth cohort followed by the German Infant Nutritional Intervention Study through the first 6 y of life. Intention-to-treat and per-protocol analyses of absolute and World Health Organization-standardized BMI trajectories for 1840 infants (pHF-W: n = 253; eHF-W: n = 265; eHF-C: n = 250, CMF: n = 276; breastfed: n = 796) were performed. RESULTS: No significant differences in absolute or World Health Organization-standardized BMI trajectories were found among the pHF-W, eHF-W, CMF, and breastfed groups during the 6-y follow-up. However, in the eHF-C group, both intention-to-treat and per-protocol analyses showed a significantly slower sex-adjusted BMI gain through the 8th to 48th week of life (-0.1 to -0.2 lower BMI z score) but not beyond. Analyses of weight and length revealed that this difference is due to a slightly diminished weight gain in the first year of life because growth in length did not differ among study groups for the entire follow-up. CONCLUSIONS: To our knowledge, this is the first randomized trial investigating both short- and long-term effects of partially and extensively hydrolyzed formula (pHF-W, eHF-W, eHF-C), CMF, and breastfeeding on growth in one trial. Feeding with eHF-C led to a transient lower weight gain in the first year of life. No long-term consequences of different formulas on BMI were observed.

Certain hydrolyzed formulas reduce the incidence of atopic dermatitis but not that of asthma: three-year results of the German Infant Nutritional Intervention Study.

BACKGROUND: Recommendations for primary prevention of allergic diseases in high-risk children include feeding with hydrolyzed formulas if breast-feeding is insufficient. OBJECTIVE: The primary objective of the German Infant Nutritional Intervention study was to investigate the allergy preventive effect of 3 hydrolyzed formulas compared with cow's milk formula in the first 3 years of life in a randomized, double-blind trial. METHODS: Between 1995 and 1998, 2252 newborns with atopic heredity were allocated to a group receiving cow's milk formula, partially or extensively hydrolyzed whey formula, or extensively hydrolyzed casein formula as a milk substitute for the first 4 months if breast-feeding was insufficient. Main outcome parameters were allergic manifestations, atopic dermatitis (AD), and asthma. RESULTS: After 3 years, 396 of 2252 children (17.6%) had dropped out. Breast-fed infants without formula feeding during the intervention (n = 889) were considered separately. A significant reduction of the incidence of AD was achieved with the extensively hydrolyzed casein formula in the intention-to-treat (ITT; n = 1363) and per protocol (PP; n = 904) analyses (ITT: population odds ratio [95% CI], 0.67 [0.45-0.99]; PP: adjusted odds ratio [OR(adj)], 0.53 [0.32-0.88]), and with the partially hydrolyzed whey formula in the PP analysis (ITT: population odds ratio, 0.76 [0.52-1.11]; PP:OR(adj), 0.60 [0.37-0.97]). None of the formulas reduced the incidence of asthma. CONCLUSION: The risk for AD, but not for asthma, can be reduced with certain cow's milk hydrolyzates in high-risk infants when breast-feeding is insufficient. CLINICAL IMPLICATIONS: Early nutritional intervention in high-risk children has significant influence on the incidence of AD, but not of asthma.

The effect of hydrolyzed cow's milk formula for allergy prevention in the first year of life: the German Infant Nutritional Intervention Study, a randomized double-blind trial.

BACKGROUND: The potential of extensively or partially hydrolyzed formulas to reduce the risks for allergies is controversial. OBJECTIVE: We sought to assess the preventive effect of differently hydrolyzed formulas compared with cow's milk formula (CMF) in high-risk infants. METHODS: Between 1995 and 1998, 2252 infants with a hereditary risk for atopy were enrolled in the German Infant Nutritional Intervention Study and randomly assigned at birth to one of 4 blinded formulas: CMF, partially hydrolyzed whey formula, extensively hydrolyzed whey formula, and extensively hydrolyzed casein formula (eHF-C). The primary end point at 1 year of age was the presence of allergic manifestation, which was defined as atopic dermatitis (AD), gastrointestinal manifestation of food allergy, allergic urticaria, or a combination of these factors. RESULTS: At 12 months per protocol, analysis was performed on 945 infants exposed to study formula: 304 (13.5%) infants had left the study, 138 (6.1%) infants were excluded because of noncompliance, and 865 infants were exclusively breast-fed the first 4 months of life. The incidence of allergic manifestation was significantly reduced by using eHF-C compared with CMF (9% vs 16%; adjusted OR, 0.51; 95% CI, 0.28-0.92), and the incidence of AD was significantly reduced by using eHF-C (OR, 0.42; 95% CI, 0.22-0.79) and partially hydrolyzed whey formula (OR, 0.56; 95% CI, 0.32-0.99). Family history of AD was a significant risk factor and modified the preventive effect of the hydrolysates. CONCLUSIONS: Prevention of allergic diseases in the first year of life is feasible by means of dietary intervention but influenced by family history of AD. The preventive effect of each hydrolyzed formula needs to be clinically evaluated.