Correction to: Vilnius Declaration on chronic respiratory diseases: multisectoral care pathways embedding guided self-management, mHealth and air pollution in chronic respiratory diseases.

An amendment to this paper has been published and can be accessed via the original article.

Respiratory symptoms, asthma and levels of fractional exhaled nitric oxide in schoolchildren in the industrial areas of Estonia.

OBJECTIVES: Exposure to air pollutants in the ambient environment has been associated with various respiratory symptoms, and with increased asthma diagnosis, in both children and adults. Most research to date has focussed on core pollutants, such as PM10, PM2.5, SO2 and NO2, and less attention has been given to the effects of industry-specific contamination. The current study aimed to examine the associations between respiratory symptoms, asthma, increased levels of fractional exhaled nitric oxide (FeNO) (as a marker of eosinophilic airway inflammation) and ambient levels of industrial pollutants (such as benzene, phenol, formaldehyde and non-methane hydrocarbons) for schoolchildren living near oil shale industries in Ida-Viru County, Estonia. METHODS: A total of 1326 schoolchildren from Ida-Viru, Lääne-Viru and Tartu Counties participated in a cross-sectional study, consisting of questionnaires on respiratory symptoms and asthma, as well as clinical examinations to measure FeNO. Dispersion modelling was used to characterize individual-level exposure to industrial air pollutants at each subject's home address. Associations between exposure and respiratory health were investigated using logistic regression analysis, and differences in results between regions were analysed using the Chi-squared test. RESULTS: The prevalence of respiratory symptoms (p < 0.05) in children living near (i.e. within 5 km) of an oil shale industry site in Ida-Viru County was 2-4 times higher than in children living in the reference area of Tartu County. Children exposed to 1 µg/m3 higher levels of benzene and formaldehyde had a higher odds ratio (OR) of having rhinitis without a cold (OR 1.03, 95% confidence interval (CI) 1.01-1.06), of ever having had attacks of asthma (OR 1.05, 95% CI 1.01-1.10) and of having a dry cough a few days per year (OR 1.05, 95% CI 1.01-1.10). Children exposed to 1 µg/m3 higher levels of benzene, formaldehyde, phenol and non-methane hydrocarbons had a higher odds ratio of having high FeNO levels (≥30 ppb): OR and 95% CI of 1.05, 1.01-1.09; 1.22, 1.06-1.41; 1.01, 1.00-1.01; and 1.75, 1.75-2.62, respectively.

Vilnius Declaration on chronic respiratory diseases: multisectoral care pathways embedding guided self-management, mHealth and air pollution in chronic respiratory diseases.

BACKGROUND: Over 1 billion people suffer from chronic respiratory diseases such as asthma, COPD, rhinitis and rhinosinusitis. They cause an enormous burden and are considered as major non-communicable diseases. Many patients are still uncontrolled and the cost of inaction is unacceptable. A meeting was held in Vilnius, Lithuania (March 23, 2018) under the patronage of the Ministry of Health and several scientific societies to propose multisectoral care pathways embedding guided self-management, mHealth and air pollution in selected chronic respiratory diseases (rhinitis, chronic rhinosinusitis, asthma and COPD). The meeting resulted in the Vilnius Declaration that was developed by the participants of the EU Summit on chronic respiratory diseases under the leadership of Euforea. CONCLUSION: The Vilnius Declaration represents an important step for the fight against air pollution in chronic respiratory diseases globally and has a clear strategic relevance with regard to the EU Health Strategy as it will bring added value to the existing public health knowledge.

Cytokine responses to allergens during the first 2 years of life in Estonian and Swedish children.

BACKGROUND: The prevalence of atopic disease among children in the formerly socialist countries in Europe, with a life style similar to that prevailing in Western Europe 30-40 years ago, is low, whereas there has been a pronounced increase in industrialized countries over the last decades. The environment during infancy influences the risk of developing allergy for many years, perhaps even for life. OBJECTIVE: To investigate the development of allergen-specific cytokine responses during the first 2 years of life in two geographically adjacent countries with marked differences in living conditions and incidence of atopic diseases, i.e. Estonia and Sweden. METHODS: The development of immune responses to food (beta-lactoglobulin (BLG) and ovalbumin (OVA)) and inhalant (cat and birch) allergens was studied from birth up to the age of 2 years in 30 Estonian and 76 Swedish infants. Clinical investigation and skin prick tests were performed and blood samples were obtained at birth and at 3, 6, 12 and 24 months. RESULTS: The levels of IL-5, IL-10 and IL-13 secreted by peripheral blood mononuclear cells stimulated with BLG, OVA and cat allergen in Estonian and Swedish infants declined during the first 3 months of life. All cytokines then progressively increased in the Swedish infants, indicating the replacement of non-specifically responding immature cord blood T cells with specific T memory cells, which are primed postnatally. The resurgence of allergen-specific responses in the Estonian infants was less marked. These differences were particularly notable for birch-specific T cell responses, which correlated with development of atopic disease in the Swedish children. CONCLUSIONS: The development of specific T cell memory to food and inhalant allergens during the first 2 years of life differs between infants living in Sweden and Estonia, and mirrors the disparate patterns of expression of allergic disease which subsequently develops in the respective populations.

Intestinal microbiota and immunoglobulin E responses in 5-year-old Estonian children.

BACKGROUND: Over the last few decades, several studies from different parts of the world have indicated an increasing prevalence of allergic diseases. This has been related to environmental factors, like changes of microbial pressure. Our previous studies have demonstrated differences in the intestinal microbiota between allergic and non-allergic children. AIM: To test the hypothesis that the intestinal microbiota and IgE response are related, both in allergic and non-allergic 5-year-old Estonian children. METHODS: The study group comprised 19 allergic and 19 non-allergic 5-year-old children, selected from a larger group who had been followed from birth. The diagnosis of allergy was based on clinical examination of the children and on data obtained from the questionnaires. The faecal microbiota were quantified by seeding serial dilutions on nine different media for incubation in different environment. The composition of the gut microbiota was expressed both as absolute counts of the various species and their relative share among the total counts of identified microbiota. RESULTS: Bifidobacteria were less commonly detected in children with allergic diseases than in healthy children and clostridia comprised a higher proportion among their gut microbes. Children with specific IgE antibodies to defined allergens had higher counts of clostridia and the counts of clostridia correlated with the level of serum IgE, but only so in allergic children. In non-allergic children, the serum IgE levels showed a positive correlation with the counts of bacteroides. CONCLUSION: The development of allergic diseases seems to be associated with the composition of the gut microbial ecosystem. High counts of potential pathogens, such as clostridia, are associated with clinical manifestations of allergy and IgE antibody formation.

Atopic sensitization and atopic dermatitis in Estonian and Swedish infants.

BACKGROUND: Early life events seem to have a major impact on the development of tolerance or sensitization. OBJECTIVE: The aim of the study was to compare the prevalence of sensitization and atopic dermatitis (AD) during the first 2 years of life in Estonia and in Sweden. METHODS: Two groups comprising 110 Estonian and 123 Swedish infants were followed from birth up to 2 years of age. Data about symptoms of allergy, infections and use of antibiotics were obtained by questionnaires. Clinical examinations, skin prick tests (SPTs) with food and inhalant allergens, and blood sampling for IgE analyses were carried out at 3, 6, 12 and 24 months. RESULTS: The cumulative incidence of AD and positive SPTs were lower in the Estonian than the Swedish infants (14% vs. 24%; P = 0.06 and 13% vs. 24%; P = 0.03), while circulating IgE antibodies were more common (39% vs. 27%; P = 0.06) and often present without any clinical significance in Estonian children. Estonian infants had respiratory illnesses more often and they had received antibiotics more frequently. Use of antibiotics increased the risk for positive SPT in the Estonian (odds ratio = 1.7, 95% confidence interval = 1.1-2.5), but not in the Swedish infants. This may be explained by the use of broad-spectrum antibiotics in Estonia, while in Sweden mostly penicillin was prescribed. CONCLUSIONS: The prevalence of AD and positive SPTs was lower in the Estonian than the Swedish infants, while circulating IgE antibodies were more common and often present without any clinical significance. These differences cannot simply be explained by infections, or use of broad-spectrum antibiotics in the two countries, although more the natural lifestyle in Estonia may be contributing factor.

Development of atopic sensitization and allergic diseases in early childhood.

UNLABELLED: Atopic diseases and atopic sensitization were studied from birth up to 2 y in a population-based prospective study. Physical examinations were done at 6, 12 and 24 mo, including skin-prick tests and blood samples, for the determination of serum IgE level and circulating IgE antibodies to food and inhalant allergens. In addition, questionnaire surveys were done about clinical symptoms of allergy, infections and the home environment. At 2 y the prevalences of definite and probable atopic diseases were 17% and 13%, respectively. The cumulative incidence of allergy was 25%. Atopic dermatitis was the main manifestation of atopy, with a peak prevalence of 15% at 2 y. The prevalence of positive skin-prick tests was constant at all ages, i.e. 7% at 6, 12 and 24 mo. Positive skin-prick tests against inhaled allergens were more than twice as common at 24 than at 12 mo, while sensitivity to food decreased. In contrast, circulating IgE antibodies to egg became more common with age, reaching 20% at 2 y. CONCLUSIONS: The present study indicates that manifestations of allergic diseases and incidence of sensitization to foods and inhalants are equally common in Estonian and Scandinavian children during the first 2 y of life, despite a much lower prevalence among older children and adults in Estonia.

The development of atopic sensitization in Estonian infants.

In a prospective study, 251 infants were followed from birth up to 12 months of age, recording manifestations of allergy by questionnaires at 3, 6, 9 and 12 months and by clinical examinations at 6 and/or 12 months. Blood samples were obtained at birth and at 6 and 12 months and analysed for serum IgE levels. The children were skin-prick tested with foods at 6 and 12 months of age and with inhalant allergens at 12 months. Blood samples from SPT-positive individuals and controls were analysed for the presence of IgE antibodies to common inhalant allergens and their cord sera for the presence of IgE antibodies to cow's milk and egg. Twelve infants (7%) were sensitized against foods [3 to cow's milk (CM) and 9 to egg white (EW)] at 6 months and 11 (5%) (2 to CM and 9 to EW) at 12 months. Seventeen infants (7%) had IgE antibodies against inhalant allergens at 6 and/or 12 months, as determined by either SPT and/or the demonstration of circulating IgE antibodies. Out of 30 children with positive SPT and/or circulating IgE antibodies against foods and inhalant allergens at any age, 6 had atopic dermatitis, 4 gastrointestinal food allergy, 1 urticaria and 4 probable allergy, while 15 had no clinical manifestation of allergy. Immunoglobulin E antibodies against Ascaris were detected in 17% of the infants with S-IgE levels > 20 kU/l. The study indicates that the incidence of sensitization and manifestations of allergic disease is similar among Estonian and Scandinavian infants during the first year of life. Given earlier findings indicating a significantly higher prevalence of atopic disease in Scandinavian school-children relative to their counterparts in Eastern Europe, the present study suggests that the key events which determine disease expression do not occur exclusively during the first year of life.

Development of allergy and IgE antibodies during the first five years of life in Estonian children.

BACKGROUND: Epidemiological studies have demonstrated a low prevalence of allergic diseases and atopic sensitization among schoolchildren and young adults in the formerly socialist countries of Central and Eastern Europe as compared to Western Europe. OBJECTIVE: The aim of our study was to prospectively investigate IgE responses to food and inhalant allergens and the development of allergy during early childhood in a population with a low prevalence of atopic disorders. METHODS: In a population-based prospective study, 273 children were followed from birth through the first 5 years of life, recording manifestations of allergy by questionnaires and clinical examinations at 0.5, 1, 2 and 5 years (n = 213). Skin prick tests (SPT) were performed using natural foods (cow's milk, egg white) and commercial extracts of inhaled allergens (cat, dog, D. pteronyssinus, birch, timothy). In addition, serum IgE levels and circulating IgE antibodies against the seven allergens were determined. RESULTS: The prevalence of allergic diseases at 5 years of life was 19%. Atopic dermatitis was the most common allergic disease at all ages. The point prevalence of positive skin prick tests was 7% at 0.5, 1 and 2 years of age, and 3% at 5 years. Circulating IgE antibodies against food allergens were common at all ages, i.e. 13, 23, 36 and 36%, respectively, at 0.5, 1, 2 and 5 years. The prevalence of circulating IgE antibodies to inhalant allergens increased from 1.5% at 0.5 years to 11% at 1, 19% at 2 and 47% at 5 years. The antibody levels were generally low, however. The value of positive SPT and the presence of IgE antibodies in the diagnosis of clinical allergy were low. CONCLUSION: The results of this prospective study carried out in a previously socialist country with a low allergy prevalence among schoolchildren and young adults indicate that transient sensitization in early childhood is followed by a down-regulation of skin reactivity.

Indoor allergen levels and other environmental risk factors for sensitization in Estonian homes.

The prevalence of allergic disease is low in Eastern Europe for reasons that are poorly understood. Our study aimed to investigate the levels of exposure to indoor allergens and living conditions among Estonian infants in relation to sensitization. Dust samples were collected during four winter months in 1993/94 from the homes of 197 infants participating in a prospective study of sensitization. Information about living conditions was collected through a home visit and interviewing the mothers when the children were 6 weeks old. Three dust samples were collected from each home; i.e., from the infant's mattress, bedroom floor, and living-room carpet. The levels of allergens were determined by ELISA with monoclonal antibodies. The highest allergen level in a home was regarded as the peak value. The peak geometric mean values (+/-SD) of Der p 1 and Der f 1 were 0.3 (0.07-1.4) microg/g dust, of Can f 1, 0.86 (0.23-3.12) microg/g dust, and of Fel d 1, 0.1 (0.01-0.9) microg/g dust. In 12 homes (9%), the peak value of house-dust mite (HDM) allergens exceeded 2 microg/g dust, with Der p 1 as the dominating allergen. Multivariate analyses indicated that high levels of HDM allergens were more common in apartments that were on the ground floor or first floor, that were heated with stoves, and/or that had a dampness problem. The mean allergen levels at home were similar in children sensitized to HDM (n=17, 0.29 vs 0.3 microg/ g dust), dog (n=5, 0.55 vs 1.06 microg/g dust, and cat (n=18, 0.21 vs 0.09 microg/g dust) and in children who were not sensitized to these allergens. Most of the sensitized children were exposed to relatively low allergen levels at home; i.e., below 1 microg/g dust. This level was exceeded in the homes of 4/17 mite-, 5/18 cat-, and 0/5 dog-sensitized children. The similar levels of the major indoor allergens in Estonia and in Scandinavia indicate that the large differences in atopy prevalence among children and young adults in the two regions are not due to differences in allergen exposure. No allergen threshold level for sensitization was identified.

Atopic allergy and delayed type hypersensitivity in Estonian children.

BACKGROUND: A shift in the balance ofT helper (Th) cell subsets towards a polarized Th2 population is generally accepted to occur in atopic disease, however, both Th1 and Th2 disorders have increased over the past decades in Western communities. OBJECTIVE: The aim of our study was to investigate delayed type hypersensitivity (DTH) response in atopic and non-atopic children in a population with a low prevalence of allergic disorders. METHODS: Skin prick tests (SPT) were performed with fresh egg white and extracts of five inhalant allergens, i.e. cat, dog, house dust mite (Dermatophagoides pteronyssinus), birch and timothy, and DTH response was evaluated by Multitest CMI in 72 Estonian 4- to 6-year-old children. RESULTS: The frequency of response to diphtheria was significantly increased in SPT-positive children (55% vs. 26%, chi2 = 5.5; P = 0.038). The induration to diphtheria (2.4 +/- 0.5 vs. 0.9 +/- 0.2 mm; P = 0.004), and tetanus (3.5 +/- 0.6 vs. 2.1 +/- 0.3 mm; P = 0.025) was significantly greater in the SPT-positive children. The cumulative size of induration in the positive DTH tests was significantly greater in the SPT-positive children (9.0 +/- 1.2 vs. 5.2 +/- 0.6 mm, P = 0.01). CONCLUSION: In this group of children our findings do not support the hypothesis of an immune deviation with decreased Th1 and increased Th2 responses leading to atopic disease, but rather a process of immune modulation whereby both Th1 and Th2 responses are increased in atopic subjects.

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.

Intestinal microflora of Estonian and Swedish infants.

The intestinal microflora of 1-y-old healthy Estonian (n = 27) and Swedish infants (n = 29) was studied by quantitative culture of faecal samples. The major differences were high counts of lactobacilli and eubacteria in the former and increased numbers of clostridia in the latter babies. Bifidobacteria and anaerobic cocci prevailed equally in both groups, while eubacteria and enterococci were the major microorganisms in many Estonian infants and bacteroides and clostridia in many Swedish infants. The microflora of the Estonian infants was in many aspects similar to the flora prevailing in infants of western Europe in the 1960s. The results suggest a shift in the intestinal microflora among infants in western industrialized countries.

Allergy development and the intestinal microflora during the first year of life.

BACKGROUND: The intestinal microflora is a likely source for the induction of immune deviation in infancy. OBJECTIVE: The purpose of this study was to prospectively relate the intestinal microflora to allergy development in 2 countries differing with respect to the prevalence of atopic diseases. METHODS: Newborn infants were followed prospectively through the first 2 years of life in Estonia (n = 24) and Sweden (n = 20). By that age, 9 Estonian and 9 Swedish infants had developed atopic dermatitis and/or positive skin prick test results. Stool samples were obtained at 5 to 6 days and at 1, 3, 6, and 12 months, and 13 groups of aerobic and anaerobic microorganisms were cultivated through use of standard methods. RESULTS: In comparison with healthy infants, babies who developed allergy were less often colonized with enterococci during the first month of life (72% vs 96%; P <.05) and with bifidobacteria during the first year of life (17% to 39% vs 42% to 69%; P <.05). Furthermore, allergic infants had higher counts of clostridia at 3 months (median value, 10.3 vs 7.2 log(10); P <.05). The prevalence of colonization with Staphylococcus aureus was also higher at 6 months (61% vs 23%; P <.05), whereas the counts of Bacteroides were lower at 12 months (9.9 vs 10.6 log(10); P <.05). CONCLUSION: Differences in the composition of the gut flora between infants who will and infants who will not develop allergy are demonstrable before the development of any clinical manifestations of atopy. Because the observations were made in 2 countries with different standards of living, we believe that our findings could indicate a role for the intestinal microflora in the development of and protection from 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.

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.