In the complex interaction between certain environmental factors and genetic disposition, the early allergen exposure plays a major role in the development of allergic diseases. In aiming to reduce the allergen burden for the infant at risk during early infancy, cow's milk protein hydrolysate infant formulas (hypoallergenic infant formulas) are appropriate alternatives to breastfeeding for primary allergy prevention. The German Infant Nutritional Intervention-Program (GINI) was supported for the first 3 years by the German Ministry for Education and Research (BMBF) (FKZ 01 EE 9401-4). It is a birth cohort which was primarily scheduled until the children were 3 years old. The aim of the prospective, randomized, double-blind intervention study was to investigate the impact of different cow's milk protein hydrolysate infant formulas in the first 4 - 6 months on the development of allergic diseases in children at risk due to at least one parent or biological sibling with a history of allergic disease. The allocation to one of the 4 intervention formulas (partial whey hydrolysate, extensive whey hydrolysate, extensive casein hydrolysate or standard cow's milk formula) was randomised and stratified by family history (single/biparental) and the respective obstetric clinic. Recruitment was carried out by the three clinical centers (Research Institute Marien-Hospital Wesel, Children's Department, Ludwigs-Maximilians-University Munich and Children's Department Technical University Munich) in 18 obstetric clinics between 01.09.1995 and 30.06.1998. Along with the intervention study a non-interventional, complementary observational cohort of children with or without allergy risk was recruited and followed by annual self-reporting parental questionnaires. The GINI intervention study (GINI-I, N = 2.252) and the non-interventional observation study (GINI-NI, N = 3.739) are combined in the population-based GINIplus study (see article J. Heinrich et al. in this journal). The results of the GINI intervention study confirm that, cow's milk protein hydrolysate infant formulas have a preventive effect on allergic manifestation compared with a standard cow's milk formula, until school age. However, the dimension of the effect is different between the formulas. This effect, which is mainly driven by the effect on atopic eczema, develops in the first months of life and persists without rebound. In the formula groups the cumulative incidence of atopic eczema until school age is reduced between 26% and 45% compared with standard cow's milk formula. A beneficial effect of the hydrolysate formulas on the respiratory manifestations asthma and rhinoconjunctivitis, however, could not be shown. By comparing the GINI intervention and non-intervention arm of the GINIplus study it was demonstrated, that a family history for allergy doubles the risk for eczema in the offspring. Early intervention with cow's milk protein hydrolysate infant formulas is able to substantially compensate this risk for eczema until the age of 6 years. In contrast, by randomization to standard cow's milk formula this risk showed a trend towards a higher incidence compared with children at risk from the non-intervention group. Thus, the results of the GINIplus study have contributed to answer some of the controversially discussed questions.

The increasing prevalence of asthma, hay fever, and allergic sensitization in Western Germany after east-west division in 1949 and their rapid increase in East German children after re-unification in 1990 are strong indications for the role of life-style and/or environmental factors in the development of atopic diseases. Obviously, the perinatal period is crucial for priming the immune system. Therefore, explorations of determinants of atopic diseases need pregnancy or birth cohorts as the most appropriate epidemiological study designs. This review presents the design and selected results of the two German birth cohorts GINIplus and LISAplus. GINIplus and LISAplus recruited 5.991 and 3.097 healthy, term newborns, respectively, from Munich, Wesel, Leipzig, and Bad Honnef. Approximately 55% could be followed for the first 10 years. We analyzed the natural course of atopic diseases and the role of life-style, environmental, and genetic factors for disease onset, intermediate phenotypes, and genes involved in detoxification and oxidative stress. The results of these two large birth cohorts contributed substantially to the understanding of atopic diseases and their determinants.

Epidemiological studies indicate that asthmatic children are more susceptible to traffic-related air pollution exposure than non-asthmatic children. Local and systemic inflammation in combination with oxidative stress have been suggested as a possible susceptibility factor. We investigated effect modification by asthma status for the association between air pollution exposure and systemic effects using whole blood cytokine responsiveness as an inflammatory marker. The study was nested within the two German birth cohort studies GINIplus and LISAplus and initially designed as a random sub-sample enriched with asthmatic children. Using data from 27 asthmatic and 59 non-asthmatic six-year-old children we measured the production of Interleukin-6 (IL)-6, IL-8, IL-10, monocyte chemotactic protein-1 (MCP-1), tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in whole blood after ex-vivo stimulation with urban particulate matter (EHC-93). Air pollution exposure (nitrogen dioxide (NO2), nitrogen oxides (NOx), particulate matter with an aerodynamic diameter <10μm (PM10), particulate matter with an aerodynamic diameter <2.5μm (PM2.5mass), coarse particulate matter (PMcoarse) and PM2.5absorbance (PM2.5abs)) was modelled for children´s home addresses applying land-use regression. To assess effect modification by asthma status linear regression models with multiplicative interaction terms were used. In asthmatics exposure to NO2 was associated with higher production of pro-inflammatory cytokines: adjusted means ratio (MR) 2.22 (95% confidence interval 1.22-4.04) for IL-6 per 2.68µg/m³ NO2. The interaction term between asthma status and NO2 exposure was significant. Results for NOx, PM10, PM2.5mass and PM2.5abs were in the same direction. No association between air pollution and cytokine responsiveness was found in the group of non-asthmatic children and in the overall group. Traffic-related air pollution exposure is associated with higher pro-inflammatory cytokine responsiveness in whole blood of asthmatic children.

Die Prüfung der Lungenfunktion ist auch bei Kindern und Jugendlichen ein wichtiger Bestandteil zur Diagnose und Verlaufsbeurteilung von Atemwegserkrankungen [1]. Bei der klinischen Bewertung der Lungenfunktion ist die Qualität der verwendeten spirometrischen Referenzwerte entscheidend [2,3]. Geeignete Referenzwerte fehlen für Kinder und Jugendliche, vor allem für unter Sechsjährige, was die klinische Anwendung der Lungenfunktionsprüfung in dieser Altersgruppe zusätzlich erschwert [1]. Die bisher meist bei Kindern verwendeten spirometrischen Referenz-

BACKGROUND:Comparing children's lung function with reference values is important for diagnosing respiratory diseases. The values by Zapletal et al., commonly used nowadays, are not appropriate for the current stage of children's development. We have now developed new reference values and a lower limit of normal (LLN) for children in Germany, divided into small-range age and height categories.MATERIAL AND METHODS:We examined 4- to 18-year-old children in 3 German communities under field conditions. 1943 children were healthy and had a visually acceptable lung function which also fulfilled international quality criteria. We used the regression model LMS, which was introduced by Stanojevic and Quanjer in this context.RESULTS:There were significant differences between the measured lung function and the predicted values according to Zapletal et al. The lung function did not only depend on the child's height, but also in a non-linear way on the age. The variation coefficient did not depend on age.CONCLUSIONS:To avoid diagnostic errors, the currently often used reference values according to Zapletal et al. should no longer be used. The non-linear dependence on age corresponds to the recently published results by Stanojevic and Quanjer.

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.

Background: Spirometry reference values developed by Zapletal et al. (Zapletal A. et al., Basel: Karger 1987), although still clinically used, may no longer be appropriate. The Global Lung Initiative (GLI) (Quanjer P. et al. Eur Respir J 2012; 40; 1324-1343) developed new multi-ethnic reference values. The aim of the present analysis was to assess whether the GLI data are representative for our German population and the bias introduced if old reference equations continue to be used. Material and Methods: In our LUNOKID study, we examined 4- to 18-year-old children/adolescents in 3 German communities under field conditions. For analysis, we used the regression model LMS introduced by Quanjer et al. in the context of spirometry. Results: Of 3133 recruited healthy children 1943 had a lung function visual acceptable as well as meeting ATS/ERS criteria. Lung function did not only depend on the child’s height as supposed by Zapletal et al., but also in a non-linear way on age. Compared with the GLI data, we found that the variation coefficient in our LMS model did not depend on age. Furthermore, a significantly smaller percentage (0.9 to 1.8% depending on age) of children than the expected 5% had a FEV_1 below the lower limit of normal (LLN) predicted by Quanjer et al. Conclusions: To avoid diagnostic misconceptions, the conventional reference values according to Zapletal et al. should no longer be used. The non-linear dependence of lung function on age corresponds to the results recently published by Quanjer et al. Using the LLN as defined by the GLI data potentially leads to an underdiagnosis in a proportion of German children and adolescents.

Specific probiotic combinations during early feeding, via the mother or incorporated in early formula-feeding, mold the intestinal microbiota composition in infants. The objective was to analyze the impact of probiotic administration to mother or infant on gut microbiota composition in 6-month-old Finnish and German infants. In Finland probiotics were given to mothers (n = 79) for 2 months prior to and 2 months after delivery. In Germany probiotics were started in infants (n = 81) at weaning, at the latest at 1 month of age, and continued for 4 months. A breast-fed group of 6-month-old infants (22 from Finland, 8 from Germany) were compared. Gut microbiota were analyzed by FCM-FISH and qPCR methods. In breast-fed infants a trend toward higher counts of bifidobacteria was detected in Finland (p = 0.097) as against Germany, where a more diverse microbiota was reflected in higher Akkermansia (p = 0.003), Clostridium histolyticum (p = 0.035) and Bacteroides-Prevotella (p = 0.027) levels and a higher percentage of Akkermansia (p = 0.004). Finnish LPR + BL999 intervention group (Lactobacillus rhamnosus LPR and Bifidobacterium longum BL999) had higher percentages of fecal Lactobacillus-Enterococcus (9.0% vs. 6.1% placebo, p = 0.003) and lower bifidobacteria levels (10.03 log cells/g vs. 10.68 log cells/g placebo, p = 0.018). Probiotic treatment had different impacts on gut microbiota composition in Finnish and German infants due to differences in mode of feeding and the early commensal microbiota. Probiotic treatment had different impacts on gut microbiota composition in Finnish and German infants due to differences in mode of feeding and the basic commensal microbiota.

The German Infant Nutritional Intervention Study (GINI) for the preventive effect of hydrolysed infant formulas in infants at high risk for allergic diseases. Design and selected results In the complex interaction between certain environmental factors and genetic disposition, the early allergen exposure plays a major role in the development of allergic diseases. In aiming to reduce the allergen burden for the infant at risk during early infancy, cow milk protein hydrolysate infant formulas (hypoallergenic infant formulas) are appropriate alternatives to breastfeeding for primary allergy prevention. The German Infant Nutritional Intervention-Program (GINI) was supported for the first 3 years of the study by the German Ministry for Education and Research (BMBF) (FKZ 01 EE 9401-4). It is a birth cohort which was primarily scheduled until the children were 3 years old. The aim of the prospective, randomised, double-blind intervention study was to investigate the impact of different cow milk protein hydrolysate infant formulas in the first 4 6 months on the development of allergic diseases in children at risk due to at least one parent or biological sibling with a history of an allergic disease. The allocation to one of the 4 intervention formulas (partial whey hydrolysate, extensive whey hydrolysate, extensive casein hydrolysate or standard cow's milk formula) was randomised and stratified by family history (single/biparental) and the respective obstetric clinic. Recruitment was carried out by the three clinical centers (Research Institute Marien-Hospital Wesel, Children's Department, Ludwigs-Maximilians-University Munchen and Children's Department Technical University Munchen) in 18 obstetric clinics between 01.09.1995 and 30.06.1998. Along with the intervention study a non-interventional, complementary observational cohort of children with or without allergy risk was recruited and followed by annual self-reporting parental questionnaires. The GINI intervention study (GINI-I, N = 2.252) and the non-interventional observation study (GINI-NI, N = 3.739) are combined in the population-based GINIplus study (see article J. Heinrich et al. in this journal). The results of the GINI intervention study confirm that, cow milk protein hydrolysate infant formulas have a preventive effect on allergic manifestation compared with a standard cow milk formula, until school age. However, the dimension of the effect is different between the formulas. This effect, which is mainly driven by the effect on atopic eczema, develops in the first months of life and persists without rebound. In the formula-groups the cumulative incidence of atopic eczema until school age is reduced between 26% and 45% compared with standard cow milk formula. A beneficial effect of the hydrolysate formulas on the respiratory manifestations asthma and rhinoconjunctivitis, however, could not be shown. By comparing the GINI-intervention and non-intervention arm of the GINIplus study it was demonstrated, that a family history for allergy doubles the risk for eczema in the offspring. Early intervention with cow milk protein hydrolysate infant formulas is able to substantially compensate this risk for eczema until the age of 6 years. In contrast, by randomisation to standard cow milk formula this risk showed a trend towards a higher incidence compared with children at risk from the non-intervention group. Thus, the results of the GINIplus study have contributed to answer some of the controversially discussed questions.

GINIplus and LISAplus. Design and selected results of two German birth cohorts about natural course of atopic diseases and its determinants The increasing prevalence of asthma, hay fever and allergic sensitization in Western Germany after division in 1949 and the rapid increase in East German children after re-unification in 1990 are strong indications for the role of life-style and/or environmental factors for development of atopic diseases. Obviously the perinatal period is crucial for priming the immune system. Therefore, explorations of determinants of atopic diseases need pregnancy or birth cohorts as most appropriate epidemiological study designs. This review presents the design and selected results of the two German birth cohorts GINIplus and LISAplus. GINIplus and LISAplus recruited 5.991 and 3.097 healthy, term newborns from Munich, Wesel, Leipzig and Bad Honnef. Approximatly 55% could be followed for the first 10 years. We analyzed the natural course of atopic diseases and the role of life-style, environmental and genetic factors for disease onset, intermediate phenotypes and for genes involved in detoxification and oxidative stress. The results of these two large birth cohorts contributed substantially to the understanding of atopic diseases and its determinants.