Feasibility and compliance in a nutritional primary prevention trial in infants at increased risk for type 1 diabetes.

AIM: The international Trial to Reduce IDDM in the Genetically at Risk (TRIGR) was launched to determine whether weaning to a highly hydrolysed formula in infancy reduces the incidence of type 1 diabetes in children at increased genetic disease susceptibility. We describe here the findings on feasibility and compliance from the pilot study. METHODS: The protocol was tested in 240 children. The diet of the participating children was assessed by self-administered dietary forms, a structured questionnaire and a food record. Blood samples were taken and weight and height measured at birth and at 3, 6, 9, 12, 18 and 24 months. RESULTS: A majority of the subjects (84%) were exposed to the study formula at least for 2 months. Linear growth or weight gain over the first 2 years of life was similar in the two study groups. The levels of IgA and IgG antibodies to cow's milk and casein were higher in the cow's milk-based formula group than in the hydrolysed formula group during the intervention period (p<0.05), reflecting the difference in the intake of cow's milk protein. CONCLUSION: This randomized trial on infant feeding turned out to be feasible, and dietary compliance was acceptable. Valuable experience was gained for the planning and sample size estimation of the study proper.

A multi-centre study of candidate genes for wheeze and allergy: the International Study of Asthma and Allergies in Childhood Phase 2.

BACKGROUND: Common polymorphisms have been identified in genes suspected to play a role in asthma. We investigated their associations with wheeze and allergy in a case-control sample from Phase 2 of the International Study of Asthma and Allergies in Childhood. METHODS: We compared 1105 wheezing and 3137 non-wheezing children aged 8-12 years from 17 study centres in 13 countries. Genotyping of 55 candidate single nucleotide polymorphisms (SNPs) in 14 genes was performed using the Sequenom System. Logistic regression models were fitted separately for each centre and each SNP. A combined per allele odds ratio and measures of heterogeneity between centres were derived by random effects meta-analysis. RESULTS: Significant associations with wheeze in the past year were detected in only four genes (IL4R, TLR4, MS4A2, TLR9, P<0.05), with per allele odds ratios generally <1.3. Variants in IL4R and TLR4 were also related to allergen-specific IgE, while polymorphisms in FCER1B (MS4A2) and TLR9 were not. There were also highly significant associations (P<0.001) between SPINK5 variants and visible eczema (but not IgE levels) and between IL13 variants and total IgE. Heterogeneity of effects across centres was rare, despite differences in allele frequencies. CONCLUSIONS: Despite the biological plausibility of IgE-related mechanisms in asthma, very few of the tested candidates showed evidence of association with both wheeze and increased IgE levels. We were unable to confirm associations of the positional candidates DPP10 and PHF11 with wheeze, although our study had ample power to detect the expected associations of IL13 variants with IgE and SPINK5 variants with eczema.

Dietary manipulation of beta cell autoimmunity in infants at increased risk of type 1 diabetes: a pilot study.

AIMS/HYPOTHESIS: We aimed to assess the feasibility of a dietary intervention trial with weaning to hydrolysed formula in infants at increased risk of type 1 diabetes and to study the effect of the intervention on the emergence of diabetes-associated autoantibodies in early childhood. METHODS: We studied 242 newborn infants who had a first-degree relative with type 1 diabetes and carried risk-associated HLA-DQB1 alleles. After exclusive breastfeeding, the infants underwent a double-blind, randomised pilot trial of either casein hydrolysate (Nutramigen; Mead Johnson) or conventional cow's milk-based formula until the age of 6-8 months. During a mean observation period of 4.7 years, autoantibodies to insulin, anti-glutamic acid decarboxylase and insulinoma-associated antigen-2 were measured by radiobinding assays, and islet cell antibodies (ICA) by immunofluorescence. RESULTS: The feasibility of screening and identifying a cohort of first-degree relatives with HLA-conferred disease susceptibility, enrolling them in a dietary intervention trial and following them for seroconversion to autoantibody positivity is established. The cumulative incidence of autoantibodies was somewhat smaller in the casein hydrolysate vs control formula group, suggesting the need for a larger well-powered study. After adjustment for duration of study formula feeding, life-table analysis showed a significant protection by the intervention from positivity for ICA (p=0.02) and at least one autoantibody (p=0.03). CONCLUSIONS/INTERPRETATION: The present study provides the first evidence ever in man, despite its limited power, that it may be possible to manipulate spontaneous beta cell autoimmunity by dietary intervention in infancy.

Prevalence of self-reported food allergy and IgE antibodies to food allergens in Swedish and Estonian schoolchildren.

OBJECTIVE: To compare the prevalence of self-reported food allergy and IgE antibodies to food allergens in wheezing and non-wheezing Estonian and Swedish schoolchildren, in the light of the disparities in the standard of living, food consumption and prevalence of respiratory allergies that still exist between Estonia and the Scandinavian countries. DESIGN AND SETTING: As a part of the ISAAC Phase II study, children from a random sample of schools in Tallinn in Estonia and Linköping and Ostersund in Sweden participated in skin prick tests to inhalant allergens and the parents replied to questionnaires. IgE antibodies against a panel of food allergens (egg white, milk, soy bean, fish, wheat and peanut) were taken from children with questionnaire-reported wheezing and a random sample of nonwheezing children. SUBJECTS: Children aged 10-11 y. RESULTS: The prevalence of self-reported food allergy was similar in Estonia and Sweden and about twice as high in wheezing children than in nonwheezing children. In Estonia, however, 3% of the children with perceived food allergy reported reactions from at least four different foods, as compared to 31% in Sweden. The prevalence of sensitisation to food allergens was similar in wheezing and nonwheezing children in Estonia (8%) while, in Swedish children, IgE antibodies to food allergens were more likely among wheezing children (Linköping 38 vs 11%, crude OR 5.1, 95% CI 2.2-11.6, and Ostersund 24 vs 7%, crude OR 4.1, 95% CI 1.9-8.5). CONCLUSION: Our study suggests that IgE-mediated food reactions were less likely in Estonian schoolchildren. Moreover, the perception of food allergy and thereby the meaning of self-reported food allergy appears to be different in the two countries.

Atopic disorders among Estonian schoolchildren in relation to tuberculin reactivity and the age at BCG vaccination.

BACKGROUND: Published data about a relationship of atopic diseases to Bacillus Calmette-Guérin (BCG) vaccination and tuberculin responses are inconsistent. Our aim was to determine this association in a country with a low prevalence of allergies. METHODS: A random sample of 10-11-year-old schoolchildren in Tallinn was studied by a parental questionnaire (n = 979) and skin-prick tests (n = 643), according to the International Study of Asthma and Allergies in Childhood. Data about BCG vaccinations and tuberculin tests were obtained from school records (n = 723). RESULTS: The prevalence of allergic symptoms and atopy was similar in children vaccinated during the first month of life and later. Positive tuberculin responses (> or =5 mm) were inversely related to symptoms of asthma [odds ratio (OR) 0.10 (95% confidence interval 0.00-0.68) for exercise-induced wheezing; OR 0.37 (0.12-0.99) for night cough], and eczema [OR 0.53 (0.28-0.98)] but not to atopy. However, among BCG-revaccinated children, atopy tended to be more common in tuberculin responders, and the atopic children were significantly more likely to have a positive tuberculin response after the revaccination than would be predicted by their first test. CONCLUSIONS: We found no protective effect of early BCG vaccination against atopy in school age, although tuberculin responses and allergic symptoms were inversely related.

Wheezing in relation to atopy and environmental factors in Estonian and Swedish schoolchildren.

BACKGROUND: The prevalence of asthma and allergic diseases is significantly lower in post socialist Eastern Europe than in Western industrialized countries. The reason for this difference is largely unknown. Different types of childhood wheezing could be related to different risk factors. OBJECTIVE: To compare the prevalence of respiratory symptoms, asthma and atopic diseases among Estonian and Swedish schoolchildren and to evaluate characteristics for wheezing in the two countries. METHODS: In a prevalence study, population-based random samples of 10-11-year-old schoolchildren in Tallinn (n = 979), Estonia and in Linköping (n = 911) and Ostersund (n = 1197), Sweden were studied by a parental questionnaire and skin prick tests (SPT). All 275 children with wheeze in the past 12 months and 710 randomly selected controls within the original cohorts were invited to a case-control study involving a parental questionnaire, examination for flexural dermatitis and bronchial challenge with hypertonic saline. The study adhered to the International Study of Asthma and Allergies in Childhood (ISAAC) Phase II protocol. RESULTS: The prevalence of current wheezing was similar (8-10%) in the three centres, while diagnosed asthma and atopic symptoms were more common in Sweden and cold-related respiratory symptoms were more prevalent in Estonia. Frequent wheezing was more common in Sweden than in Estonia (but significantly so only in Ostersund). Wheezing children in Sweden had a high rate of positive SPT (49% in Linköping and 58% in Ostersund) bronchial hyper-responsiveness (BHR) (48% in Linköping and Ostersund) and anti-asthmatic treatment (63% in Linköping and 81% in Ostersund). In Estonia, the proportion of wheezing children with positive SPT, BHR and anti-asthmatic treatment was only 26%, 13% and 17%, respectively. Domestic crowding was inversely related to wheezing in one of the study areas (Ostersund). The mean baseline forced expiratory volume in one second (FEV1) was higher in Estonia than in Sweden, both in wheezing and non-wheezing children. CONCLUSIONS: Our study suggested that although wheezing symptoms were equally common in Estonia and Sweden, they were less severe in Estonia. More frequent symptoms and a high rate of atopy, BHR and anti-asthmatic medication characterized wheezing children in Sweden. In contrast, BHR, atopy and medication were uncommon among wheezing children in Estonia.

Similar prevalence of respiratory symptoms and atopy in Estonian schoolchildren with changing lifestyle over 4 yrs.

The prevalence of allergic sensitization and clinical manifestations is low in Eastern Europe, despite a continuous increase in industrialized countries with a market economy. The aim of the present study was to study changes in the prevalence of respiratory symptoms and atopic sensitization over time among schoolchildren in Estonia, in relation to environmental changes as the country transformed into a market economy. A cross-sectional study of 10-yr-old children was carried out between October 1996 and April 1997, employing a questionnaire regarding the prevalence of wheezing, rhinitis and itching rash (n=979) and skin-prick tests with seven inhalant allergens (n=640). The results were compared with those of a similar study performed in 1992-1993. The 12-month prevalence of wheeze was 8.3%, as compared to 9.4% in 1992-1993 (NS) and of asthma was 2.5 versus 3.2% (NS). The prevalence of a positive skin-prick test result was 14.3% in both studies. Furthermore, the prevalence of sensitivity to the individual allergens was similar, except for a significantly higher prevalence of dog sensitivity in 1996-1997 (4.7 versus 2.0%). The prevalence of respiratory and other potentially allergic symptoms, as well as the prevalence of atopic sensitization, remains low in Estonian 10-yr-old children, despite a changing lifestyle over the past 4 yrs. This could indicate that the time period was too short for environmental changes to affect the prevalence of allergy, or alternatively that risk factors associated with a "western lifestyle" are of particular significance earlier in life.

Prevalence of childhood asthma, rhinitis and eczema in Scandinavia and Eastern Europe.

There is evidence that the prevalence of allergies and asthma differs between populations in western and eastern Europe. This study investigated the prevalence of wheezing, rhinitis and eczema among schoolchildren in urban and rural areas of Scandinavia and the formerly socialist countries of Eastern Europe. A total of 79,000 children from two age groups (13-14 yrs and 6-7 yrs) in 18 study centres responded to a questionnaire within the International Study of Asthma and Allergy in Children (ISAAC). The 12 month period prevalence of symptoms of asthma, allergic rhinoconjunctivitis and atopic eczema was calculated. The prevalence of wheezing among the 13-14 yr old children was 11.2-19.7% in Finland and Sweden, 7.6-8.5% in Estonia, Latvia and Poland and 2.6-5.9% in Albania, Romania, Russia, Georgia and Uzbekistan (except Samarkand). The prevalence of itching eyes and flexural dermatitis varied in a similar manner between the three regions. The regional differences were less pronounced among the 6-7 yr old children in the seven participating centres. The highest prevalence of rhinitis was recorded in April-July in Scandinavia and during the winter months in the other countries. The prevalence of atopy-related disorders was higher in Scandinavia than in Estonia, Latvia and Poland, which in turn had a higher prevalence than five other countries of eastern Europe with a culture less similar to western Europe. This supports the hypothesis that "Western life style" is associated with a high prevalence of childhood allergy.

Prevalence of bronchial hyperreactivity as determined by several methods among Estonian schoolchildren.

There is a lack of established criteria to identify asthma and bronchial hyperreactivity (BHR) in epidemiological studies, although both conditions appear to bear some relationship to atopy, at least in children. Recent studies indicate a low prevalence of atopy in former Socialist countries in Europe, yet the prevalence of BHR has been reported to be high. We have analysed the relationship between the outcome of various lung function tests, atopy and clinical symptoms of bronchial asthma in an epidemiological survey of Estonian 10-12 year old schoolchildren. Metacholine provocation test (four steps with the cumulative doses 100, 300, 700 and 1100 micrograms), exercise challenge test and PEF-variability over two weeks were done in 806 children in Tallinn (coastal, industrialised city) and 774 children in Tartu (inland, university town). A positive response to the metacholine challenge test was recorded in 19% in Tallinn and in 32% in Tartu (p < 0.001). A similar tendency was observed for a more than 15% decrease of FEV1 in the exercise challenge test, i.e. 6% in Tallinn and 18% in Tartu. There was only a weak relationship between BHR, as defined by either a positive metacholine challenge and/or exercise test, diagnosed asthma and reported wheezing. Thus, 47% of the wheezing children and 30% of the children with asthma had negative test results. Only 17% of the children with a positive metacholine challenge were atopic, as defined by at least one positive skin prick test. In conclusion, none of the methods employed to assess bronchial hyperresponsiveness were very useful for the identification of wheezing and asthmatic children in this epidemiological study. In contrast to the results of studies in Western Europe, most children with bronchial hyperreactivity in Estonia are not atopic.

The prevalence of atopic sensitization and respiratory symptoms among Estonian schoolchildren.

OBJECTIVES: To assess the prevalence of atopic sensitization, asthma and other respiratory disorders among Estonian schoolchildren in a coastal industrial city and an inland university town, i.e. Tallinn and Tartu. DESIGN: Prevalence surveys by self-completion of questionnaires by the children's parents and skin-prick tests (SPT) with eight common allergens. SUBJECTS: A total of 1519 schoolchildren aged 10-12 years. RESULTS: The prevalence of positive SPT was 11.0%, with significant differences between Tallinn (14.3%) and Tartu (8.1%), RR 1.89, 95% CI 1.13-2.73, P < 0.001. Dermatophagoides pteronyssinus, cat (6.1%) and timothy (4.8%) were the most prevalent sensitizing allergens in Tallinn. The prevalence of asthma diagnosed by a doctor was 2.9%, of wheezing 7.0% and of rhinoconjunctivitis 7.4%, as assessed by questionnaire. CONCLUSIONS: The prevalence of atopy as defined by a positive SPT, asthma and corresponding respiratory symptoms is low in Estonia similar to other post-socialist countries of Europe. The lower prevalence rates of allergic disorders are possibly explained with differences in lifestyle and living conditions. The relative significance of air pollution was apparently similar in Estonia and western Europe, however, as indicated by the higher prevalence of sensitization in the more polluted city, Tallinn than in Tartu.

Risk factors for respiratory symptoms and atopic sensitisation in the Baltic area.

Recent studies have indicated that atopic sensitisation is uncommon while respiratory symptoms are common among schoolchildren in Eastern Europe. Risk factors for respiratory symptoms and atopic sensitisation were evaluated in a cross sectional study involving 2594 schoolchildren (10-12 years) from Sweden (n = 665), Poland (n = 410), and Estonia (n = 1519). The measurements included parental questionnaires and skin prick tests with eight standardised allergens. Multiple logistic analyses demonstrated that atopic heredity was a significant independent risk factor for respiratory symptoms and atopic sensitisation in all the countries. Current dampness and maternal smoking were related to respiratory symptoms whereas domestic crowding, male gender, and passive smoking during infancy were related to atopic sensitisation. Current maternal smoking had a strong dose response association with current coughing attacks (nocturnal cough > 4 weeks or exercise induced coughing attacks) but only in Eastern Europe. A strong inverse relationship was recorded between domestic crowding and sensitisation as the risk for sensitisation increased with decreasing number of persons per room in the household (odds ratio (OR) 0.58, 95% confidence interval (CI) 0.43 to 0.77). Exposure to tobacco smoke at home during infancy was a risk factor for atopic sensitisation but only to animal dander and only in Eastern Europe (OR 1.41, 95% CI 1.03 to 1.93). In conclusion, there were small differences in the pattern of risk factors between Eastern and Western Europe. The only exception was environmental tobacco smoke being a risk factor only in Eastern Europe. The study also suggests that factors related to domestic crowding protect against atopic sensitisation in Estonia and Poland. A higher standard of living with less crowding may give rise to an increasing prevalence of atopic sensitisation also in Eastern Europe.