1. Renata Melnikova, MD, PhD student IS ESTONIA ENDANGERED BY EPIDEMIC OF ALLERGY?

2. Epidemiology Epidemiology is the study of the distribution and determinants of health-related states or events (including disease), and the application of this study to the control of diseases and other health problems Various methods can be used to carry out epidemiological investigations: surveillance and descriptive studies can be used to study distribution analytical studies are used to study determinants http://www.who.int/topics/epidemiology/en/

3. Bousquet et al., Allergy 2011 The epidemics of allergy

4. Studies, study areas, study population The name of the study Study period Age (y.o.)Nr of participants Study area ECRHS1993 - 201425 – 652460Tartu FinEsS1995 - 200015 - 1617525Narva, Tallinn, Saaremaa ISAAC1993 – 20026 - 1413548Tallinn Riikjärv et al., 19951992 – 9310 - 121519Tallinn, Tartu Vasar et al., 2011200310 – 201561Elva, Narva, Pärnu, Võru Eriksson et al., 20041997 - 20001 - ?156Tallinn, Tartu Voor T, PhD thesis1997-2003 0 - 5 115 Tartu Julge et al., 20011993 - 99273 Budarova Master’s thesis, 2009 2007 - 8158Tallinn

5. Main fields of study Sensitization Bronchial asthma Rhinitis/ rhinoconjunctivitis/ rhinitis and/or conjunctivitis Atopic Dermatitis Urticaria Gastroenteritis Food hypersensitivity Risk factors Heredity Gender Environment and lifestyle Microflora

6. Prevalence of sensitization in Estonia Riikjärv et al., 1995 Riikjärv et al., 2000 Raukas-Kivioja et al., 2007 Jõgi et al., 1995 Study areaTartuTallinn SaaremaaTallinnTartu Study period1992199719991997-981994 - 95 Age (y.o.)10 - 121015 - 6420 - 44 D.pteronyssinus2.9 %6.1% *4.4%6.1%6.6%15.0% D. farinae--------- 4.0%5.2%6.0%--------- Timothy3.5 %4.8% 1.8% *5.8%8.3%8.3% Birch2.2%2.6%4.1%2.5% *6.6%6.0% Cat3.8%6.1% *7.2%3.4% *7.4%12.3% Dog1.4%2.0%4.7% *3.8% *8.9%11.7% Cockroach--------- 9.7% *15.5% mono- allergy 3% --------- * p<0.001

7. Prevalence of sensitization in Estonia SPT vs RAST (adult studies) Jõgi et al., 1995Jõgi et al., 1998 MethodsSPTsIgE D. pteronyssinus15.0%9.7% Cat12.3%4.8% Dog11.7%--------- Timothy8.3%8.3%9.2%9.2% Birch6.0%6.6% Mugwort10.0%--------- Cladospoorum4.3%1.2% Alternaria5.3%---------

8. Prevalence of sensitization in Estonia SPT vs RAST (school children studies) 1992 – 93 correlation between the two methods was not good Riikjärv et al., 1995 2003 – 4 correlation between SPT and RAST is better positive SPT 18.2% positive sIgE 20% Julge et al., 2009 SPT posSPT neg sIgE pos3239 (55%) sIgEneg7 (18%)702

9. Sensitization to inhalant allergens, birth cohort studies Julge et.al, 2001 (children born in 1993/94) Voor PhD thesis (children born in 1997/98) Julge et.al, 2001 (children born in 1993/94) Voor PhD thesis (children born in 1997/98) SPT sIgE cat0.5 y.o.---------1.6% 1 y.o.1.4%1.0%4.2%6% 2 y.o.4.1%3.8%11.8%7% 5 y.o.1.4%1%13.6%5% birch0.5 y.o.--------- 0%--------- 1 y.o.--------- 3.5%4% 2 y.o.0.5%0%3.5%3% 5 y.o.1.0%1%13.5%7% house dust mite 1 y.o.1.8%---------2.1%--------- 2 y.o.2.3%---------7.6%--------- 5 y.o.1.4%---------19.4%--------- Swedish --------- 1% 2.3% 8% --------- 5.4% 16% --------- Swedish --------- 0% 2% 7% --------- 1% 3% 14% ---------

10. Sensitization to food, birth cohort studies Julge et.al, 2001 (children born in 1993/94) Voor PhD thesis (children born in 1997/98) Julge et.al, 2001 (children born in 1993/94) Voor PhD thesis (children born in 1997/98) milkSPT sIgE 3 month old---------0% ---------9% 6 month old1.7%0%12%9%/ 1 year old0.9%1%20.7%6% 2 year old0% 25.8%10% 5 year oldno data0%23.26% egg white 3 month old---------4,5%---------11% 6 month old5.2%6%4.2%15% 1 year old4.1%6.4%5.6%10% 2 year old1.8%3.8%20.6%18% 5 year old0%1%23.2%13% Swedish 3% 6.8% 3.8% 2.3% 1% 9% 16.4% 19.3% 11.6% 8% Swedish 8% 13% 7% 5% 9% 12% 13% 17% 14% 8%

11. Sensitization to food school children study (ISAAC) IgE antibodies against a panel of common food allergens (egg white, milk, soya bean, fish, wheat and peanut) Positive 8%, i.e. 13 out of 163 children 2 of 12 patients having positive IgE to tested food and answered food questionnaire reported hypersensitivity to food Sandin et al., 2005

12. Sensitisation Summary Prevalence in different areas was unequal Prevalence of the sensitization in Estonia in 90 th was lower than in countries with western type of life In small children prevalence of sensitization to foods with age decrease and vs to inhalation allergens increase Sensitization to food allergens About ¼ of small children have antigens milk or egg white Children could have sensitization to some other foods as well (soya, nuts, fish, flour) Prevalence of sensitisation had an upward trend sIgE and SPT are not the same

13. Prevalence (%) of asthma symptoms wheezing/ or whistling StudyprevalenceStudy period Age (y.o.) Study centres Jõgi et al., 199626.5%1993/9420 - 44Tartu Meren et al., 200121.7%1995/9615 - 64Narva, Saaremaa, Tallinn Vasar et al., 20112.9%200310 - 20Elva, Narva, Pärnu, Võru Annus et al., 20058.5%1993/9413– 14Tallinn 9.2%2001/2002 Riikjärv et al., 19957.0%1992/9310 - 12Tallinn, Tartu Annus et al., 20018.4%1996/97Tallinn Annus et al., 20059.3%1993/946 – 7Tallinn 9.7%2001/2002

14. Prevalence (%) of asthma symptoms and self- reported asthma, ECRHS study (20 – 44 y) Burney et al., Eur Respir J, 1996 in Estonia Summarized data of different international centres across the World Min 25 th centile Median 75 th centileMax Wheeze 26,84,114,920,725,232,0 Wheeze with breathlessness 7,81,47,79,813,916,3 Wheeze without a cold 12,82,09,312,716,221,6 Waking with tightness in the chest 13,96,29,713,517,520,5 Waking with breathlessness 8,11,54,77,38,911,4 Waking with cough 42,66,025,627,929,542,6 Attack of asthma 1,81,32,63,14,59,7 Treatment for asthma 0,6 2,43,55,09,8

15. The proportion of asthma and chronic bronchitis diagnosed among subjects with wheeze Pallasaho et al., European Journal of Epidemiology, 2005

16. Prevalence of asthma in childred StudyAge (y.o.)PrevalenceStudy period Julge et.al, 2001, Voor PhD thesis 0,5 0%1994, 1997/98 Julge et.al, 2001 1 0,5%1994/95 Voor PhD thesis3%1998/99 Julge et.al, 2001 2 2%1995/96 Voor PhD thesis6%1999/2000 Julge et.al, 2001 5 6,5%1999 Voor PhD thesis7%7%2002/2003 Annus et al., 2005 6 - 7 1.4%1993/94 4.1%2001/2002 Riikjärv et al., 1995 10 - 12 2.9%1992/93 Annus et al., 20012.5%1996/97 Annus et al., 2005 13 - 14 3.3%1993/94 4.7%2001/2002

17. Prevalence of asthma in adults StudyprevalenceStudy period Age (y.o.) Study centres Jõgi et al., 19962%1993/9420 - 44Tartu Meren et al., 20012%1995/9615 - 64Narva, Saaremaa, Tallinn 5 – 8% # # asthma diagnosed after additional study

18. Asthma/ asthmatic symptoms and atopy Children studies: ≥1 SPT positive 26% among wheezers (49 – 58% in Sweden) 9% among nonwheezers (16-22% in Sweden) Annus et al., 2001 Adult studies: The prevalence of atopy among asthmatic 15% (in Barcelona 78%, an average for countries participated in ECRHS 56%) Sunyer et al., 2004

19. Bronchial asthma Summary Prevalence of wheezing in Estonia is high, but prevalence of more specific symptoms was near median when compared to other European data Jõgi et al., 1996, Burney et al., 1996 Prevalence of asthma in Estonia 2 – 5% Jõgi et al., 1996 Meren et al., 2001 Asthma could be underdiagnosed Meren et al., 2005 Prevalence of sensitisation among asthmatics is lower than in western Europe Annus et al., 2001, Sunyer et al., 2004 Prevalence of asthma has an upward trend Annus et al., 2005

20. Rhinitis StudyStudy periodDefinitionAgePrevalence Rhinitis (referred to the 12-month prevalence) Jõgi et al., 19961993-94Do you have any nasal allergies including hay fever? 20 - 4417.8% Annus et al., 20051993/94Has your child had a problem with sneezing, or a runny, or blocked nose when he/she did not have a cold or flu? 6 – 711.6% 2001/200213.1% Annus et al., 20011996/9710 - 126.2% Annus et al., 20051993/94 13 -14 23.3% 2001/200224.5% Rhinoconjunctivitis Annus et al., 20051993/94In the past 12 month, has this nose problem been accompanied by itchy- watery eyes? 6 – 73.9% 2001/20024.7% Annus et al., 20011996/9710 - 126.2% Annus et al., 20051993/94 13 -14 5.3% 2001/20027.3% * Vasar et al., 20112003Diagnosed by a doctor10 – 204.9% * p<0.001

21. Rhinitis or rhinoconjunctivitis diagnosed after clinical evaluation Age1993/94 born Tartu children (Julge et.al, 2001) 1997/98 born Tartu children (Voor PhD thesis) Relevant study conducted in Sweden, 1996/2000 born children (Voor PhD thesis) 3 month---------0% 6 month0% 1 year0% 2 years1% 0% 5 years old5.5%6%14% * * p<0.001

22. Time trends Jõgi et al, Allergy 1996 1970-751960-651950-55 Reported nasal allergies Reported asthma related symptoms

23. Annus et al., Pediatr Allergy Immunol 2005 Time trends

24. Atopic dermatitis StudyPrevalenceStudy periodAgeDefinition Annus et al., 2005 12%1993 – 946 – 7Flexural rush = Has your child had an itchy rash, that coming and going for at least 6 month, at any time in the past 12 month, affected any of the following places: the folds of the elbows, behind the knees, in front of the ankles, under the buttocks, or around the neck, ears or eyes? 13.5% *2001 – 2002 Annus et al., 2001 6.2%1996 - 9710 - 12 Annus et al., 2005 7.7%1993 -/94 13 -14 9.4% *2001 – 2002 Julge et.al, 2001 4 – 15%1993 – 1999 0 - 5 Diagnosed after clinical examination Voor PhD thesis 2 – 8%1997 - 2003 Vasar et al., 2011 8.3%200310 - 20 * p<0.001

25. Atopic dermatitis Age1993/94 born Tartu children (Julge et.al, 2001) 1997/98 born Tartu children (Voor PhD thesis) 2007/2008 born Tallinn children (Budarova Master’s thesis, 2009) 3 month4% 6 month4 %5% 1 year10.5 %7%30% 2 years15%12% 5 years old10%8%

26. Risk factors of allergic diseases heredity gender environment and the way of life: – hygiene hypothesis (intestinal microflora, antibiotics, infections, number of siblings, pet ownering) – diet (breastfeeding, fish intake), obesity – pollution (air pollution, smoking and environmental tobacco exposure) Annus T., PhD thesis, 2005 Bousquet et al., Allergy 2011

27. Risk factors Heredity a significant factor for asthma and sensibilization (but not to mite and symptoms associated with it) Jõgi et al., 1998 family history of asthma was a risk factor for asthma (OR 4.3) Meren et al., Respir Med 2001 a risk factor for allergic disorders in the offspring in particular for the same condition the greatest risk with maternal asthma influence on asthma in girls (OR 9.9, 95% CI 4.1 – 23.8) Annus PhD thesis

28. Sensitization and gender was not associated with sensitization at 2 y Vasar et. al., 2000 sensitization was more common in boys ( 20% vs 10% ) Braback et al., 1995 male sex was an independent risk factor for atopy ( OR for positive IgE to cat 2.9, CI95% 1.1 – 7.5 ) Jõgi et al., 1998 men were significantly more sensitized to the storage mites compared with women (for Acarus siro 10.3% vs 5.0%, and Lepidoglyphus destructor 10.3% vs 5.3%) Raukas-Kivioja et al. 2003

29. Asthma/asthmatic symptoms and gender was not associated with atopic symptoms at 2 y Vasar et. al., 2000 Female sex was a risk factor for symptoms common in asthma, but not for diagnosed asthma Meren et al., 2001 Female sex was a risk factor for nocturnal cough both in Tartu and Uppsala and for nocturnal chest tightness and nocturnal breathlessness in Tartu Jõgi et al., 1996 the risk of wheezing (lifetime and last year wheezing), if atopic higher in girls (OR 3.5, 95% CI 1.4±9.1) than in boys (OR 1.6, 95% CI 0.6±3.9) Annus PhD thesis

30. Atopy and infections NonatopicAtopicp value Janson et al., 2007 (ECRHS, Reykjavik, Tartu, Uppsala) 36.6%24.8%<0.001 Julge et al., 201043%46%0,05 H. pylory respiratory infection the number of severe respiratory infection before 5 years of age was not associated with BHR in adult Jõgi et. al., 2004 in the birth cohort study was shown no correlation between the numbers of episodes of infections and allergy Voor et al., 2005

31. Allergy development and intestinal microflora Björkstén et al., JACI 2001

32. The intestinal microflora in allergic Estonian and Swedish 2-year-old children Allergic Non-allergic Estonian children Swedish children Björkstén et al., Clinical and Experimental Allergy 1999

33. Allergy and microflora changers in Estonia within the first ears of independence Estoniian children born 1993/94 vs 1996/97 the counts of gram-positive anaerobic cocci and bacteroides were decreased the pattern of microbiota became the same as that was in Sweden E. Sepp et al., Clinical and Experimental Allergy 2005

34. Allergy and antibiotics The use of antibiotics during the first year of life increased the risk for positive SPT (OR=1.7, 95%CI 1.12 - 5) in Estonian, but not in the Swedish infants There was no correlation between the use of antibiotics during the second year of life and SPT and AD Voor et al., Clin Exp Allergy 2005 In 6-7 old children allergic rhinitis, current asthma, and wheezing were related to the use of antibiotics in the first year of life Annus PhD thesis

35. Risk factors for sensitization domestic location before the age of 5 years SPT positiveUrban areaSuburban areaRuralTest for trend, p-value At least 1/15 tested allergens 39,2%36,0%28,3%p = 0.02 Pollen19,4%17,0%8,7%p = 0.003 Cat9,9%9,0%3,3%p = 0.01 Dog12,1%9,0%4,9%p = 0.01 Raukas-Kivioja et al., Clin Exp Allergy 2003

36. Pet at home Exposure to pets during childhood was significant for mite asthma in adults (OR 6.5, CI95% 1.33 – 31.7) Jõgi et al., 1998 Having animals at home before the age of five was a risk factor for a positive SPT against cat dander (OR 2.4) but not to any other allergen in adults Raukas-Kivioja et al., 2003 Pet ownership was not associated with either atopic symptoms or sensitization at 2 y Vasar et. al., 2000

37. Breastfeeding 4/5 children with positive SPT to cow‘s milk at 6 or 12 months of age had been exclusively breastfed for < 1 month Julge et al., Acta Paediatr 1997 Infants who had been exclusively breast fed for at least two months had lower values of IgE at 6 months Julge et al., 1997 at 2 years Vasar et al., 2000 Protective effect of breastfeeding for at least 3 month was visible only in boys and only for bronchial asthma and rhinoconjunctivitis Annus PhD Thesis 2005 until 6 months of age might be beneficial breast milk feeding till 12 month of age associates with AD development (74% of children had AD) Budarova Master’s thesis, 2009

38. RHINE childhood fish intake and adult asthma Laerum et al., Clinical and Experimental Allergy 2007 anytime

39. Obesity and onset of asthma/ respiratory symptoms Gunnbjornsdottir et al, Eur Respir J 2004 61

40. Traffic/air pollution a high level of exhaust particles outside home was not a risk factor respiratory symptoms specific to allergic disease Orru et al., 2009 Influence of frequent truck traffic was – not a risk factor for wheezing or current asthma – was a risk factor of allergic rhinitis Annus PhD thesis, 2005 Living in the polluted area (Narva/Tallinn vs Saaremaa) was associated with higher risk for: – mainly bronchitic symptoms Meren et al., 2001 – for sensitization Raukas-Kivioja et al., 2007

41. Smoking and asthma respiratory symptoms (wheezing, sputum production, and chronic productive cough) and smoking were strongly correlated most symptoms increased significantly with the numbers of cigarettes smoked per day Meren et al., 2001, Pallasaho et al., 2005 Current smoking associated with wheezing and all nocturnal symptoms (but not nocturnal chest tightness) J6gi et al., 1996 Smoking was significantly associated with BHR Jõgi et al., 2004 Subjects who quit smoking during follow-up had an increased remission rate of bronchial asthma Holm et al., 2007

42. Smoking and asthma a strong dose-response relationship between ETS exposure and respiratory symptoms in adults outside the home more serious effects than ETS exposures at home Larsson et al., Eur Respir J 2003 maternal (but not paternal) smoking was a risk factor for coughing attacks a highly significant dose-response relationship was seen between maternal smoking and coughing attacks (in Poland and Estonia, but not in Sweden) Braback et al., 1995

43. Smoking/ exposure to tobacco smoke and sensitization Exposure to tobacco smoke at home during infancy was associated with an increased risk for atopic sensitisation to animal dander in 10 – 12 y.o. children Current (when a child is 10-12y) parental smoking was not related to atopic sensitisation Braback et al. 1995 Parental smoking were not associated with either atopic symptoms or sensitization at 2 y Vasar et al., 2000 Maternal smoking during childhood was associated with a doubled risk for sensitization to mite Jõgi et al., 1998

44. Summary I Field of studynumber of participants age (y.o.) area of study sensitization inhalant allergenes38180.25–67Narva, Saaremaa, Tallinn, Tartu food allergenes5511 - ?Tallinn, Tartu bronchial asthma questionnaires370010.25–64Elva,Pärnu,Saaremaa,Tallinn,Tartu,Võru clinical examination19490.25–20Elva, Pärnu,Tallinn,Tartu,Võru rhinitis questionnaires370010.25–64Elva,Pärnu,Saaremaa,Tallinn,Tartu,Võru clinical examination19490.25 - 20Elva, Pärnu, Tallinn, Tartu, Võru atopic dermatitis questionnaires155550.25–20Elva, Pärnu, Tallinn,Tartu,Võru clinical examination20070.25 - 20Elva,Pärnu,Tallinn,Tartu,Võru food hypersensitivity4961 - ?Tallinn, Tartu

45. Summary II The prevalence of asthma in Estonia could be underestimated The prevalence of allergic diseases and sensitization has growing trends Risk factors that shown significance in Estonian studies heredity gender environment and life style hygiene hypothesis (intestinal microbiota, antibiotics, infections, number of siblings) dietary (breastfeeding, fish intake) obesity smoking and environmental tobacco exposure allergen exposure