Significant disparities in allergy prevalence and microbiota between the young people in Finnish and Russian Karelia.

BACKGROUND: Atopic allergy has been more common among schoolchildren in Finland, as compared to Russian Karelia. These adjacent regions show one of the most contrasting socio-economical differences in the world. OBJECTIVE: We explored changes in allergy from school age to young adulthood from 2003 to 2010/2012 in these two areas. The skin and nasal microbiota were also compared. METHODS: Randomly selected children from Finnish (n = 98) and Russian Karelia (n = 82) were examined in 2003, when the children were 7-11 years of age, and again in 2010 (Finnish Karelia) and 2012 (Russian Karelia). We analysed self-reported allergy symptoms and sensitization to common allergens by serum sIgE values. The skin (volar forearm) and nasal mucosa microbiota, collected in 2012 (aged 15-20 years), identified from DNA samples, were compared with multivariate methods. RESULTS: Asthma, hay fever, atopic eczema, self-reported rhinitis, as well as atopic sensitization, were threefold to 10-fold more common in Finland, as compared to Russian Karelia. Hay fever and peanut sensitization were almost non-existent in Russia. These patterns remained throughout the 10-year follow-up. Skin microbiota, as well as bacterial and fungal communities in nasal mucosa, was contrastingly different between the populations, best characterized by the diversity and abundance of genus Acinetobacter; more abundant and diverse in Russia. Overall, diversity was significantly higher among Russian subjects (Pskin < 0.0001, Pnasal-bacteria < 0.0001 and Pnasal-fungi < 0.01). Allergic diseases were not associated with microbial diversity in Finnish subjects. CONCLUSIONS AND CLINICAL RELEVANCE: Differences in allergic phenotype, developed in early life, remain between populations. A parallel difference in the composition of skin and nasal microbiota suggests a potential underlying mechanism. Our results also suggest that high abundance and diversity of Acinetobacter might contribute to the low allergy prevalence in Russia. Implications of early-life exposure to Acinetobacter should be further investigated.

Hunt for the origin of allergy - comparing the Finnish and Russian Karelia.

The Finnish and Russian Karelia are adjacent areas in northern Europe, socio-economically distinct but geoclimatically similar. The Karelia Allergy Study was commenced in 1998 to characterize the allergy profiles in the two areas. Allergy prevalence had increased in Finland since the early 1960s, but the situation in Russia was unknown. The key finding was that allergic symptoms and diseases were systematically more common in Finnish children and adults than in their Russian counterparts. For example, in the early 2000s, hay fever in school children was almost non-existent in Russian Karelia, and only 2% were sensitized to birch pollen compared with 27% in Finnish Karelia. Adult birth cohorts showed that among those born in the 1940s, the sensitization to pollens and pets was at the same low level in both countries, but among younger generation born in the late 1970s, the difference was already manifold. Seropositivity to some pathogens, microbial content in house dust and drinking water seemed to confer allergy protection in Russia. In subsequent studies, it became apparent that on the Finnish side, healthy children had a more biodiverse living environment as well as greater diversity of certain bacterial classes on their skin than atopic children. Abundance of skin commensals, especially Acinetobacter (gammaproteobacteria), associated with anti-inflammatory gene expression in blood leucocytes. In vivo experiments with the mouse model demonstrated that intradermally applied Acinetobacter protected against atopic sensitization and lung inflammation. These observations support the notion that the epidemic of allergy and asthma results from reduced exposure to natural environments with rich microbiota, changed diet and sedentary lifestyle. Genetic studies have confirmed strong influence of lifestyle and environment. With our results from the Karelia study, a 10-year National Allergy Programme was started in 2008 to combat the epidemic in Finland.

Green areas around homes reduce atopic sensitization in children.

BACKGROUND: Western lifestyle is associated with high prevalence of allergy, asthma and other chronic inflammatory disorders. To explain this association, we tested the 'biodiversity hypothesis', which posits that reduced contact of children with environmental biodiversity, including environmental microbiota in natural habitats, has adverse consequences on the assembly of human commensal microbiota and its contribution to immune tolerance. METHODS: We analysed four study cohorts from Finland and Estonia (n = 1044) comprising children and adolescents aged 0.5-20 years. The prevalence of atopic sensitization was assessed by measuring serum IgE specific to inhalant allergens. We calculated the proportion of five land-use types--forest, agricultural land, built areas, wetlands and water bodies--in the landscape around the homes using the CORINE2006 classification. RESULTS: The cover of forest and agricultural land within 2-5 km from the home was inversely and significantly associated with atopic sensitization. This relationship was observed for children 6 years of age and older. Land-use pattern explained 20% of the variation in the relative abundance of Proteobacteria on the skin of healthy individuals, supporting the hypothesis of a strong environmental effect on the commensal microbiota. CONCLUSIONS: The amount of green environment (forest and agricultural land) around homes was inversely associated with the risk of atopic sensitization in children. The results indicate that early-life exposure to green environments is especially important. The environmental effect may be mediated via the effect of environmental microbiota on the commensal microbiota influencing immunotolerance.

Allergy gap between Finnish and Russian Karelia on increase.

BACKGROUND: Multinational time-trend analyses of atopic disease have shown that the East-West gradients in prevalence are shrinking. We set out to clarify whether the disparities in the occurrence of atopy and atopic diseases in Finnish and Russian Karelia during the past 10 years have diminished and how the prevalence of atopy has evolved with successive years of birth. METHODS: Two surveys with identical methodology were performed in 1997/1998 and 2007. The study population comprised randomly selected adults, aged 25-54 years, from Finnish and Russian Karelia. Serum samples were collected for total and specific IgE measurements. Clinical data were obtained by questionnaires. RESULTS: Sensitization rates to birch pollen increased from 7.8% to 14.8% (P < 0.001) and to cat from 6.1% to 10.8% (P < 0.001) in Finland. In Russia, no significant increase was found. Contrary to this, total IgE remained stable in Finland but decreased significantly (P < 0.001) in Russia. Analyses based on years of birth revealed that the prevalence of sensitization to allergens increased with successive birth years in Finland, but remained stable in Russia. Over the 10 years, self-reported physician-diagnosed asthma increased from 5.5% to 8.1% (P = 0.05) and hay fever from 8.1% to 13.2% (P < 0.001) in Finland. CONCLUSIONS: Disparities in the prevalence of atopy and atopic disease between Finnish and Russian Karelia have further grown. The 'allergy epidemic' continues in Finland and is mainly attributable to the years of birth effect shown in atopy prevalence. In Russia, no signs of the epidemic are discernible, although the decrease in total IgE may indicate a change in environmental exposure.

Scientific rationale for the Finnish Allergy Programme 2008-2018: emphasis on prevention and endorsing tolerance.

In similarity to many other western countries, the burden of allergic diseases in Finland is high. Studies worldwide have shown that an environment rich in microbes in early life reduces the subsequent risk of developing allergic diseases. Along with urbanization, such exposure has dramatically reduced, both in terms of diversity and quantity. Continuous stimulation of the immune system by environmental saprophytes via the skin, respiratory tract and gut appears to be necessary for activation of the regulatory network including regulatory T-cells and dendritic cells. Substantial evidence now shows that the balance between allergy and tolerance is dependent on regulatory T-cells. Tolerance induced by allergen-specific regulatory T-cells appears to be the normal immunological response to allergens in non atopic healthy individuals. Healthy subjects have an intact functional allergen-specific regulatory T-cell response, which in allergic subjects is impaired. Evidence on this exists with respect to atopic dermatitis, contact dermatitis, allergic rhinitis and asthma. Restoration of impaired allergen-specific regulatory T-cell response and tolerance induction has furthermore been demonstrated during allergen-specific subcutaneous and sublingual immunotherapy and is crucial for good therapeutic outcome. However, tolerance can also be strengthened unspecifically by simple means, e.g. by consuming farm milk and spending time in nature. Results so far obtained from animal models indicate that it is possible to restore tolerance by administering the allergen in certain circumstances both locally and systemically. It has become increasingly clear that continuous exposure to microbial antigens as well as allergens in foodstuffs and the environment is decisive, and excessive antigen avoidance can be harmful and weaken or even prevent the development of regulatory mechanisms. Success in the Finnish Asthma Programme was an encouraging example of how it is possible to reduce both the costs and morbidity of asthma. The time, in the wake of the Asthma Programme, is now opportune for a national allergy programme, particularly as in the past few years, fundamentally more essential data on tolerance and its mechanisms have been published. In this review, the scientific rationale for the Finnish Allergy Programme 2008-2018 is outlined. The focus is on tolerance and how to endorse tolerance at the population level.

Opposite gene by environment interactions in Karelia for CD14 and CC16 single nucleotide polymorphisms and allergy.

BACKGROUND: Finnish Karelians have a higher prevalence of allergic disease than Russian Karelians. As both populations are generally from the same ethnic group, the Karelian population offers a unique opportunity to analyse genetic and allergic disease interactions between 'Western' and 'Eastern' environments. OBJECTIVES: We investigated associations between allergic diseases and CD14 and CC16 polymorphisms in Finnish vs Russian Karelian women. METHODS: Adult female Karelians (330 Finnish and 274 Russian) were recruited, examined for a range of symptoms and conditions including rhinitis, itchy rash, asthma and atopy and genotyped for CD14 C-159T and CC16 A38G. RESULTS: For both CD14 C-159T and CC16 A38G, the risk allele for atopic phenotypes in Finnish Karelia was the protective allele in Russian Karelia. For CD14 C-159T, an interactive effect on ever itchy rash (P(interaction) = 0.004), itchy rash <12 mo (P(interaction) = 0.001) and dry cough at night in the past 12 months (<12 months) (P(interaction) = 0.011) was found; the risk allele was C in Russians and T in Finns. For CC16 A38G, an interaction was significant for ever rhinitis (P(interaction) = 0.006), rhinitis <12 mo (P(interaction) = 0.004), and marginally significant for ever hayfever (P(interaction) = 0.07), allergic eye symptoms <12 mo (P(interaction) = 0.09); their risk allele was G in Russians and A in Finns. CONCLUSION: An Eastern vs Western environment appears to exert an effect via opposite alleles on risk of allergic diseases in adult women.

Finnish Allergy Programme 2008-2018--time to act and change the course.

BACKGROUND: The prevalence of allergic diseases has grown in Finland, similarly to many other western countries. Although the origin of allergy remains unresolved, increasing body of evidence indicates that the modern man living in urban built environment is deprived from environmental protective factors (e.g. soil microorganisms) that are fundamental for normal tolerance development. The current dogma of allergen avoidance has not proved effective in halting the 'epidemic', and it is the Finnish consensus that restoring and strengthening tolerance should more be in focus. AIM: The national 10-year programme is aimed to reduce burden of allergies. The main goals are to (i) prevent the development of allergic symptoms; (ii) increase tolerance against allergens; (iii) improve the diagnostics; (iv) decrease work-related allergies; (v) allocate resources to manage and prevent exacerbations of severe allergies and (vi) decrease costs caused by allergic diseases. METHODS: For each goal, specific tasks, tools and evaluation methods are defined. Nationwide implementation acts through the network of local co-ordinators (primary care physicians, nurses, pharmacists). In addition, three nongovernmental organizations (NGOs) take care of the programme implementation. The 21 central hospital districts carry out a three step educational process: (i) healthcare personnel; (ii) representatives and educators of NGOs and (iii) patients and the general population. For outcome evaluation, repeated surveys are performed and healthcare registers employed at the beginning, at 5 years, and at the end of the programme. The process will be evaluated by an independent external body. CONCLUSION: The Finnish initiative is a comprehensive plan to reduce burden of allergies. The aim is to increase immunological tolerance and change attitudes to support health instead of medicalizing common and mild allergy symptoms. It is time to act, when allergic individuals are becoming a majority of western populations and their numbers are in rapid increase worldwide. The Programme is associated with the Global Alliance of Chronic Respiratory Diseases (GARD), WHO.

A disparity in the association of asthma, rhinitis, and eczema with allergen-specific IgE between Finnish and Russian Karelia.

BACKGROUND: A substantial variation in the association of asthma, rhinitis and eczema with elevated serum allergen-specific immunoglobulin E (sIgE) levels between different populations has been reported. Here, we wanted to clarify whether these proportions are different in Finnish and Russian Karelia, and compared the ability of questionnaires, skin prick tests (SPT) and sIgE measurements to detect atopic conditions in these adjacent areas with different living conditions. METHODS: Randomly selected schoolchildren, aged 6-16 years, and their mothers from Finland (n = 344 children, 344 mothers) and Russia (427 and 284 respectively) participated. SPTs and sIgE measurements to common inhalant and food allergens were performed. The occurrence of asthma, rhinitis, eczema and related symptoms was assessed with an International Study of Asthma and Allergies in Childhood-based questionnaire. Correlation between SPT and sIgE was estimated using the Spearman correlation coefficient. RESULTS: The rate of positive sIgE results was significantly higher in Finland among both mothers and children. Seventy-seven per cent of Finnish children and 43% of Russian children with asthma were sIgE positive. The respective figures for hay fever were 94% and 67%, and for eczema 68% and 41%. This discrepancy was similar but of lower magnitude among mothers. The overall occurrence of asthma, rhinitis and eczema was very low in Russian Karelia. The correlation between SPT and sIgE results was generally good. CONCLUSION: Asthma, rhinitis and eczema in Russian Karelia are not only rare but also, to a large extent, have no sIgE component. Therefore, the ability of questionnaires to detect sIgE-mediated atopic conditions in this area of Russia is poor.

Microbial content of drinking water in Finnish and Russian Karelia - implications for atopy prevalence.

BACKGROUND AND AIM: The influence of microbial quality of drinking water from different sources on the occurrence of atopy has been poorly examined. This study was undertaken to clarify the association between the overall microbial content in drinking water and the occurrence of atopy among schoolchildren from two neighbouring areas with profound differences in living conditions and lifestyles. METHODS: Drinking water samples were obtained from kitchens of nine schools in North Karelia, Finland and of nine schools from Pitkäranta, the Republic of Karelia, Russia. The pupils of these schools were participants of the Karelian Allergy Study. Occurrence of atopy, determined by skin prick test positivity (one or more) to 14 common airborne and food allergens, was measured in all 563 children, aged 7-16 years, from these 18 schools. Water samples were analysed using standard methods for drinking water analyses including viable counts for Escherichia coli, intestinal enterococci, coliform bacteria and heterotrophic bacteria. In addition, total cell counts including both viable and nonviable bacteria, algae and protozoans were assessed using epifluorescence microscope with 4'-6-diamidino-2-phenylindole (DAPI) staining. RESULTS: In Finland, 29% of the children were sensitized to birch when compared with 2% of the Russian children (P < 0.0001). Overall, sensitization rates for any of the pollens were 39% and 8% (P < 0.0001), and for any of the allergens 48% and 16%, respectively (P < 0.0001). Because of substantial differences in raw water sources and treatment practices, the total numbers of microbial cells in drinking water were many-fold higher in Russia than in Finland. A dose-response relationship was found for occurrence of atopy and the DAPI value indicative of microbial cell content in the water (P < 0.0001). Further, multivariate logistic regression analysis revealed that high (>10(6) cells/ml) and intermediate (10(5)-10(6) cells/ml) DAPI values were associated with reduced risk of atopy (odds ratio 0.34, 95% confidence interval 0.20-0.57 and 0.39, 0.23-0.69, respectively), independently from other factors. CONCLUSION: High overall content of micro-organisms in drinking water may be associated with reduced risk of atopy, independently from other determinants.

Signs of reversing trends in prevalence of asthma.

Several recent reports have provided evidence that the burden of asthma may have levelled off, after increasing for decades. Implementation of the national and global asthma prevention and management guidelines that have led to earlier detection and improved treatment of asthmatics, is considered to be involved in this apparent change for the better. In addition, environmental influences associated with the modern life may have reached the maximum in inducing symptoms and disease in genetically susceptible individuals in some areas. Available data obtained from Canada and non-English-speaking countries in Europe show that the peak in asthma prevalence has been reached at the level of 8-12%. This review outlines the most recent literature on time trends in asthma prevalence and considers the possible causes of the current trends. Problems and pitfalls in appraising studies on time trends are also discussed.

Highly elevated serum phyto-oestrogen concentrations in patients with diabetic nephropathy.

BACKGROUND AND OBJECTIVES: Phyto-oestrogens, naturally occurring phenolic, hormone-like compounds, have raised considerable interest due to their anticarcinogenic, antiatherogenic and antioxidative potential. Oxidative stress may be one of the key factors in the development of vascular complications in patients with type 1 diabetes. Here, we tested the hypothesis that high concentrations of phyto-oestrogens in serum may be associated with lower occurrence of vascular complications in these patients. SUBJECTS: A total of 400 patients, recruited consecutively from the participant register of the nationwide FinnDiane study of type 1 diabetes and divided into four parallel groups according to the severity of their renal disease with 100 patients to each group: (i) normoalbuminuric patients, (ii) microalbuminuric patients, (iii) macroalbuminuric patients, and (iv) patients with end-stage renal disease (ESRD). MAIN OUTCOME MEASURES: Phyto-oestrogen concentrations in serum (enterolactone, daidzein, genistein and equol) and urine (enterolactone), assessed by time-resolved fluoroimmunoassay. RESULTS: Highly elevated serum concentrations of phyto-oestrogens were measured amongst patients with diabetic nephropathy, and low concentrations amongst patients without diabetic complications. The pattern was similar for all phyto-oestrogens measured, although the increase in mean serum concentrations along with the increasing severity of renal disease was steepest for enterolactone, ranging from 13 nmol L(-1) amongst women and 18 nmol L(-1) amongst men in normoalbuminuric patients to 181 and 206 nmol L(-1) in women and men, respectively, in patients with ESRD (P < 0.001 for both genders between the groups). A strong correlation between serum enterolactone and creatinine concentration was found (r = 0.60, P < 0.001). CONCLUSIONS: The serum concentration of phyto-oestrogens and the severity of diabetic renal disease showed a close positive association, suggesting that phyto-oestrogens are unable to provide any major protective effect, through antioxidative or other mechanisms, on the development of diabetic renal and cardiovascular complications.

Asthma and atopy - the price of affluence?

Irrespective of improved knowledge of many aspects of atopic diseases, the unfavorable trends in their prevalence particularly among children could not have been reversed. A growing body of evidence suggests that something may lack from our societal affluence that has the capacity to provide protection against the development of atopic diseases. Much attention during the last years has been devoted to the hygiene hypothesis. This review outlines the impact of environment and lifestyle, particularly from the perspective of the East-West gradient, on the development of atopic diseases, with a special emphasis on the hygiene hypothesis in its broadest sense.

Smoking and atopy as determinants of sputum eosinophilia and bronchial hyper-responsiveness in adults with normal lung function.

Data concerning the determinants of sputum eosinophilia and bronchial hyper-responsiveness (BHR) in large cohorts of individuals with normal lung function are limited. Here, we assessed the occurrence of sputum eosinophilia and BHR and identified the risk factors for these variables in two populations living in North Karelia, Finland, and in Pitkäranta, the Republic of Karelia, Russia. These areas are geographically adjacent, but differ, however, fundamentally in major cultural, socioeconomical and lifestyle aspects. The study population comprised 790 Finns and 387 Russian, aged 25-54 years, who were randomly enrolled from the population registers. A methacholine challenge test to measure BHR was successfully performed in 581 (74%) Finns and 307 (79%) Russians with virtually normal lung function (FEV1 > 70% of predicted). Of these, induced sputum samples were obtained from 41% of the Finns and from 67% of the Russians. The proportion of current smokers was 27% among the former and 42% among the latter. Sputum eosinophilia was assessed using a semi-quantitative method, and total concentrations of sputum eosinophilic cationic protein (ECP) and myeloperoxidase (MPO) were measured using an immunoassay. Risk factors for BHR and sputum eosinophilia were identified with a regression analysis. The prevalence of sputum eosinophilia was 22% among the Finns and 19% among the Russians, and the respective figures for BHR were 14% and 13%. The median ECP concentration in sputum was significantly higher among the Russians as compared with the Finns (P<0.001), whereas for MPO, the difference did not achieve significance. Current smoking was significantly associated with both sputum eosinophilia and BHR in Russia (OR 3.1, 95% CI 1.2-7.6 for sputum eosinophilia, 2.8, 1.3-6.1 for BHR) and with BHR in Finland (2.1, 1.3-3.7). Atopy showed a tendency to be another risk factor for BHR in Finland (1.6, 0.98-2.6). In conclusion, sputum eosinophilia and BHR occurred commonly among the Finns and the Russians with normal lung function. Current smoking was significantly associated with BHR in both countries and additionally with sputum eosinophilia in Russia. Atopy was identified as a risk factor, albeit of borderline significance, for BHR in Finland only, suggesting that there may be differences in the aetiology and nature of BHR between the two countries.

Role of persistent infection in the control and severity of asthma: focus on Chlamydia pneumoniae.

Conventional risk factors have been unable to explain most of the substantial increase in the prevalence of asthma observed in many countries during the last few decades. Much attention has been directed at the "hygiene hypothesis", the apparent inverse relationship between intense systemic childhood infections and the subsequent development of asthma and atopy. However, it is not only the absence or scarcity of infections, but the prolonged presence of certain microorganisms in the lungs that may be involved in the development of asthma. Accumulating evidence suggests that Chlamydia pneumoniae, an intracellular ubiquitous pathogen with an innate propensity to persist and cause chronic infections, may be associated with asthma. This microorganism can achieve a state of "latency" in which it is viable but dormant and does not multiply. During this state, however, chlamydia continues to synthesize the "stress" protein, a 60-kDa heat shock protein (hsp60). This protein is able to elicit a strong host inflammatory response at sites of its production and appears to be involved in tissue injury and scarring processes. As inflammation has been found to be present in almost all asthmatics, whatever the severity and aetiology of the disease, inhaled glucocorticoids now have an established position in the treatment of early stages. However, corticosteroids negatively affect many aspects of cell-mediated immunity and favour the shift from a T-helper-1-type response towards a T-helper-2-type response. Corticosteroids may thus severely deteriorate the host's ability to eradicate an intracellular pathogen, such as Chlamydia pneumoniae, which requires a properly functioning cell-mediated (T-helper-1-type) immune response to be cleared. These drugs are also able to reactivate persistent Chlamydia to an active growth phase, which, by increasing the production of pro-inflammatory cytokines at the site of infection, can further amplify inflammation in the airways of patients with asthma.

Puzzling associations between childhood infections and the later occurrence of asthma and atopy.

The current unfavourable trends in asthma and atopy prevalences have raised great concern and have challenged investigators to accelerate search for new risk factors for atopic diseases. The lack or scarcity of intense, systemic infections in early life has been postulated to increase susceptibility of becoming sensitized to otherwise harmless allergens in later life. This hygiene hypothesis is considered one of the most plausible explanations for the current trends in atopic diseases to date. There are data to suggest that measles, hepatitis A, and Mycobacterium tuberculosis infection in early life may prevent the subsequent development of atopic diseases. The hypothesis is based on the concept that certain viral and bacterial infections, which induce a strongly polarized T helper (Th)-1 type response and a long-lasting memory immunity, are in early life able to reverse or prevent the biased Th1/Th2 balance in individuals prone to atopy and asthma. Evidence for the ability of mycobacterial infections to alter the Th1/Th2 balance has also been obtained from murine models. In humans, the critical time period during which immunomodulation with long-lasting effects is considered most successful is within the first two years of life. Possibly also nonpathogenic residents of the intestinal mucosa are involved in the proper maturation of the immune system. The use of antibiotics has been shown to be positively associated with the development of asthma and atopy. The mechanisms underlying these associations remain largely unknown.