Wide variations in the prevalence of childhood asthma have been documented worldwide with more prevalent asthma symptoms in more affluent countries.1 ‘Western lifestyle’ and urbanisation have been suggested to explain the worldwide geographic variation in asthma prevalence.2 In support of this, urban–rural differences in asthma prevalence have been observed, with most comparative studies in adults and children having reported lower asthma prevalence in rural compared to urban areas,3–5 although some studies have not found such differences.6,7 Establishing the reasons for the protective role of rural residence on asthma prevalence is very important for aetiologic understanding leading to future prevention and identification of treatment strategies, as the global asthma burden continues to rise.8

A number of reasons could explain the urban–rural differences in asthma prevalence, including differences in diagnosing patterns, environmental exposures, and behaviours. While microbial exposures from animals or unpasteurised milk in rural areas have been highlighted as potential protective factors,9,10 the aforementioned reasons should be considered as part of the Westernisation and urbanisation package.

Compared to worldwide prevalence rates of asthma, the Republic of Macedonia appears to have a moderately low prevalence of current wheeze1 and a low prevalence of ever-diagnosed asthma.2 Given this fact, the paucity of information on asthma in adolescents, and the need to investigate the underlying reasons for the apparent association between urban–rural status and asthma, the objective of this study was to determine if there was an association between wheeze and asthma with rural dwelling among a national sample of Macedonian adolescents and, if so, to investigate the characteristics that may explain this association. As part of this process, we sought to profile and compare urban and rural dwelling Macedonian adolescents.

In total, 5507 adolescents took part in this study (90.3% participation rate). Of these, 577 (10.5%) resided in rural areas. The study population was evenly distributed by sex (50.5% female) with most adolescents residing in North and Western Macedonia (81.4%) and being of Macedonian ethnic background (68.4%). With regard to personal characteristics, compared to urban areas, a higher proportion of adolescents from rural areas were non-Macedonian, from Eastern Macedonia, and had used Paracetamol at least once per month in the past year but a lower proportion had physical activity three or more times per week, had 5h or more per day of screen time, and had a mother with university education (Table 1). With regard to environmental exposures, those from rural areas were less likely to have a mother or father who smoked, use electricity for cooking or home heating but had a higher proportion of adolescents reporting a cat or dog ownership, using fire for cooking or wood for home heating compared to urban dwellers (Table 2). Finally, there were differences between urban and rural dwellers regarding dietary characteristics where rural dwellers ate higher amounts of meat, fish, and rice but lower amounts of fruits, vegetables, pasta, margarine, and milk (Table 3).

The prevalence of current wheeze was lower in rural dwellers compared to urban dwellers (4.9% vs. 7.2%, p=0.03) and this was also true for the prevalence of asthma (1.2% vs. 1.9%, p=0.26). After adjustment for potential confounders, the associations remained protective but were weaker and no longer statistically significant for current wheeze (Table 4).

When considering current wheeze as the outcome (Table 4), inverse associations were seen with being non-Macedonian, eating fruit three or more times per week and living in Eastern Macedonia. Watching television or playing PC games more than 5h per day, Paracetamol use and having a dog in the home increased the risk of having current wheeze. Dose–response relationships were observed with fruit consumption, screen time and Paracetamol use. There were also trends (p<0.10) of an increased risk of current wheeze associated with a higher frequency of truck passing and current paternal smoking.

When considering asthma as the outcome (Table 4), in adjusted analyses there was an increased risk of asthma associated with being male and higher Paracetamol use and inverse associations with rice when it was consumed 1–2 times per week and living in Eastern Macedonia. A dose–response relationship was observed for Paracetamol use. Again, there was a trend (p<0.10) towards an increased risk of asthma associated with a higher frequency of truck passing.

Table 5 presents the results of our mediation analysis approach. The association between urban–rural status and current wheeze increased (i.e. became weaker as it approached the null value) by 5% or greater when region or all three dietary variables were included. Similarly, the association between urban–rural status and asthma changed by more than 5% when region, rice, or all three dietary variables were added to the model. The addition of having a dog resulted in a strengthening of the association between urban–rural status and current wheeze by 11.9%. For both current wheeze and asthma, the largest change towards the null came with the addition of region (9% and 19%, respectively).

In order to better understand the differences between regions within Macedonia as a mediating factor in the association between urban–rural status and current wheeze and asthma, we completed a comparison of personal, health behaviour, dietary, and environmental characteristics between regions (Table 6). We found that there were significant differences between regions that suggest lower education levels, screen time, air pollution, and overweight/obesity and more dog and cat ownership in Eastern Macedonia compared to the north and west region. We also found differences in the dietary habits between regions. Finally, when considering a ratio of current wheeze-diagnosed asthma, we found that the ratio was lower in the north and west region (3.7:1) compared to the eastern region (5.1:1) which may suggest differences in diagnosing patterns.

A lower prevalence of wheeze and asthma in rural dwelling Macedonian young adolescents compared to urban ones was observed with consistent results between analyses using the two outcomes. Statistical significance was occasionally lost due to differences in the strength of association between asthma or wheeze or to the lack of statistical power when asthma was the outcome. Given the higher overall prevalence of current wheeze compared to that of ever-diagnosed asthma and the general consistency in the related results under-diagnosis of asthma in early adolescence in our country can be inferred. For epidemiological research, asthma symptoms seem to be more reliable as the diagnosis of asthma in population-based studies is challenging, especially in developing countries where under-diagnosis of asthma is present.1

Our findings concur with previous research worldwide, demonstrating a protective effect of rural dwelling on asthma and wheeze. Sole et al.,16 analysing ISAAC Phase 3 data in 13–14 year-old Brazilian adolescents, reported higher prevalence rates of asthma-related symptoms and asthma diagnosis among adolescents living in urban compared to those living in rural areas. In a Canadian study involving young adolescents, a lower risk of current asthma was associated with rural and non-metro-adjacent dwelling in comparison to metro region dwelling.17 The compared results from two cross-sectional studies conducted in 7–8-year-old children living in urban and rural areas of Cyprus18 have shown lower prevalence rates of current wheeze and lifetime asthma in rural dwellers in 2000 and non-significantly different related prevalence rates between the both groups of children in 2008. Rises in current wheeze and asthma prevalence rates have been generally observed in both the urban and rural areas, but these consistently appeared more pronounced in the rural areas, indicating possible recent environmental and lifestyle changes there.

In contrast, Pesek et al.19 found a similar prevalence of diagnosed asthma in urban and rural children in Arkansas, with higher asthma morbidity in the previous two years in the rural group. In a Greek study that enrolled children aged 8–10 years, reported asthma and wheeze did not differ between urban and rural areas, whereas cough was more prevalent in the urban area. However, long-term exposure to an urban environment was found to be associated with sub-clinical airway narrowing.20

The results of the mediation analysis in the present study suggested that the region of Macedonia mediated, at least to some degree, the association between urban–rural status and current wheeze or asthma and that diet might be part of the reason for this mediating effect.

The comparison of personal, health behaviour, dietary, and environmental characteristics between regions within Macedonia pointed out many differences between Eastern Macedonia and North/Western Macedonia with similar differences seen between urban and rural areas. As a higher proportion of adolescents from rural areas were from Eastern Macedonia, the same factors may contribute to the lower prevalence of wheeze and asthma in rural areas. Also, under-diagnosis of asthma was more prevalent in the eastern region and it could not be completely ruled out as a possible reason for the lower asthma prevalence in this region and in rural dwelling adolescents; however current wheeze was also considered as an outcome showing lower prevalence by region and urban–rural status.

Diet showed different patterns in rural and urban dwellers with some associations seen with asthma and wheeze. “Pro-Mediterranean” foods rich in antioxidants, cis-monounsaturated fatty acids, and dietary fibre (fruit, vegetables, rice, fish, pulses, cereals, potatoes) have been postulated to act protectively while other food types (meat, fast food, trans-fatty acids in dairy products and margarine) to have an aggravating effect on asthma.21–23 In an earlier Canadian study, in contrast to our results, the association between asthma and an urban–rural gradient was not mediated by diet.17

The mediation analysis approach in the present study also suggested that current dog ownership strengthened the association between urban–rural status and current wheeze. The relation between exposure to cats and dogs and childhood asthma is complicated and the reported exposure–response relationships can be contradictory. Exposure to pets may increase the risk of developing allergic diseases in sensitised children through allergen production. Asthma symptoms may also be related to non-allergic mechanisms such as inflammation caused by endotoxin when encountered as part of a pathogen. However, development of tolerance to early-life pet allergen exposure or immune system modulation by endotoxin can explain the reported protective role of pet exposure on asthma.24 In the airways endotoxin may induce the production of inflammatory cytokines in the non-allergic Th1 immune pathway.25 There are inconsistent reports from epidemiological studies examining the role of endotoxin, linked to the presence of animals in home and farm living, and wheeze and asthma in childhood.25–27 While endotoxin exposure in early life and in farm residents appears to have a protective effect on asthma, there is evidence supporting its association with asthma severity and wheeze in schoolchildren.25

In addition, several modifiable health behaviours (screen time, Paracetamol use, current dog ownership and fruit consumption) were associated with current wheeze or asthma or both, irrespective of the location of residence and after adjustment for potential confounders. Asthma was documented to be inversely associated also with rice consumption 1–2 times per week, but not with more frequent consumption. This might be due to a poor diet where rice is consumed in great amounts instead of other healthy food. In general, lack of exercise and sedentary behaviours are associated with obesity and the latter with asthma, although there are complex relationships between each of them and asthma.28 In the last decade prenatal and postnatal Paracetamol exposure has been consistently reported as a risk factor for development and/or maintenance of asthma, with oxidant-induced airways inflammation and enhanced Th2 allergic immune responses as the main proposed underlying mechanisms.29,30

In the present study sex showed opposite associations with male respondents at increased risk for ever-diagnosed asthma and female respondents at increased risk for current wheeze. It is well known that in children asthma has a higher prevalence in boys before puberty and a higher prevalence in women in adulthood. Generally, around puberty girls will have a higher incidence of asthma31 and this can be supported by wheeze being more common in our females.

Our results relied on self-reported information and could have been affected by information bias. However, the ISAAC phase 3 questionnaires are standardised and have been broadly used internationally. A further possible limitation is that urban–rural status was defined on the basis of current residency. We did not know if the urban respondents had previous rural dwelling experience, as migration of rural persons into cities is common in our country. As child's early life exposures are of great importance in asthma development, this might affect our results. Most respondents were residing in urban areas and in North/Western Macedonia where the asthma prevalence was higher. However, it is likely that the urban–rural differences in asthma would be more prominent without rural migrants in urban areas. There were no data on the farming background of the rural respondents; however, most of them would be expected to be farming according to the rural lifestyle in our country. Another limitation was that the question about pet ownership included both the close contact with pets at home and also pets outdoors. Finally, related to diet as a mediating factor in the urban–rural associations with current wheeze and asthma, there was a lack of data on consumption of specific types of fruit, vegetables, fish, and milk and the way of their storage and processing before consumption.

In summary, a lower prevalence of asthma was found in rural compared to urban dwelling Macedonian adolescents although the association was not statistically significant after adjustment for other factors, suggesting that the effect is mediated by at least one of these other factors, explaining the association. The association between urban–rural status and current wheeze or asthma was mediated by the region of the country, with diet likely as a part of the reason for this mediating effect. Having a dog resulted in a strengthening of the association between urban–rural status and current wheeze. This supports the hypothesis that the environment can explain the differences in asthma between urban and rural areas. Further studies are needed to investigate in greater detail the environmental and lifestyle factors, especially diet, in different regions of the country and their impact on urban–rural differences in asthma prevalence. Irrespective of where adolescents live, under-diagnosis of asthma should be considered as an important problem in the Republic of Macedonia and managed adequately.

The authors have no conflict of interest to declare.