DISCUSSION
In this cross-sectional epidemiological study on atopic eczema in Kosovo, within the GAN collaboration, we have found very low prevalence of any of the three atopic eczema markers as compared with other GAN centres. In fact, only three centres, two in India (Lucknow, 1.9% and Mysuru, 1.4%) and the one in Sri-Lanka (Anuradhapura, 1.1%) had lower prevalence of symptoms of current eczema than Ferizaj (2.2%); and this centre had the lowest prevalence of severe eczema symptoms, with only five cases in the whole population surveyed (<0.5%). With respect to eczema ever, only nine into sixteen Mexican centres and one Indian (Mysuru) had a prevalence lower than 3.0%, the one found in Ferizaj. The centre with the highest prevalence of those markers in Kosovo is Gjakova with 5.5%, 0.7% and 6.8% respectively for current eczema symptoms, severe eczema symptoms, and eczema ever. Those figures are also quite low as compared to the rest of GAN centres3.
Although there has not been any other previous study on the epidemiology of atopic eczema in Kosovo, there have been some in the Balkan region. In the ISAAC phase III survey5, carried out around 2002, Tiranë (Albania) reported the prevalence of eczema markers defined as in the present study as follows: current eczema symptoms, 2.0%; severe eczema symptoms, 0.2%; and eczema ever, 2.9%, respectively. Furthermore, the corresponding figures for Rijeka (Croatia) and Skope (Republic of Macedonia) were 2.9%, 0.2% and 8.5%; and 2.7%, 0.3% and 3.7%, respectively. There were also data from five centres in Serbia and Montenegro, which ranged 2.8%-8.0%, 0.5%-1.3%, and 8.2-17.9%, respectively. The report by Zivković et al.7 on Serbia and Montenegro expands further the data included in the ISAAC phase III report and showed low prevalence rates of other eczema markers.
Apart from offering the first epidemiological data on atopic eczema in Kosovo it is also interesting to study epidemiological factors which might be associated to this condition in a geographical area with very low prevalence where, to the best of our knowledge, those factors have not been yet studied among adolescents. Of those studied factors in the meta-analyses of the six centres, male sex is independently associated to both a significant lower prevalence of current eczema symptoms and of eczema ever (if Prizren is excluded in the latter case) (figure 1). The prevalence of severe eczema symptoms is too low to allow any multivariate statistics. The influence of sex in atopic eczema has been previously studied in adolescents in the Balkan area: Stipic-Markovic et al. 9 found no association between eczema markers and sex in Zagreb among adolescents included in the ISAAC phase III survey. However, other studies have found that different eczema markers are significantly more prevalent in female sex in this age group, like that by Mercer et al. carried out in Cape Town (South Africa)16. In the EPI-CARE study, a recent international cross-sectional study in children (6 months to <12 years old) and adolescents (12 to <18 years old) using ISAAC methods and defining atopic dermatitis with the same criteria as in the present study found that prevalence differences by sex, in one or the other direction, existed in some countries but not in others17. However, the authors did not report those differences separately in the two age groups studied. In the BAMSE study, a longitudinal population-based cohort study, carried out in Stockholm, the follow-up visit at age 11-14 years did show a significantly higher prevalence among females when using an eczema questionnaire specifically designed for the study18. The same was found in a large international cross-sectional study among adults 18–65 years old19, and previously in a Swedish study on individuals 17-75 years of age which used the GA2LEN questionnaire to assess eczema symptoms20. These findings are shared by other studies21,22. A recent BAMSE report after the visit at 24 years of age of the individuals in the cohort, further extends the finding of male sex is associated to lower prevalence of eczema markers23. Sex hormones seem to play a role in this difference after puberty24.Current eczema symptoms and eczema ever were also associated to exercise in an apparently not dose-response fashion. Making regular exercise was significantly associated with the increase of prevalence of both atopic eczema markers overall, although this was not the case in some of the centres (figure 2).
As found in the present study, exercise has been associated to eczema previously, although the information is quite limited. In a systematic review and metanalysis by Kim et al. 25 in 2016 only seven manuscripts were included after searching all relevant literature databases since their existence. Three studies found some association between exercise an eczema; three showed an inverse relationship and one did not find any association. Only five of them had enough data to be included in metanalysis which yield non-significant summary effects, but interestingly, the only study in adolescents26 showed a significant positive association. Both the two other studies (not included in the metanalysis) which found positive associations were also performed in in children or adolescents27,28. Only one of the studies showing no association was in adolescents. It should be noted that this one only included 481 individuals29. All those studies in adolescents and children used the ISAAC methodology, which requires a sample size of 3000. More recent studies offer additional information. For instance, Jago et al.30, using accelerometers in a ALSPAC population of 6473 adolescents, concluded that the number of minutes of vigorous exercise is not related either to asthma or to eczema, but it is inversely associated to obesity. The nature of the ISAAC studies (cross-sectional) vs. de ALSPAC (longitudinal) and the different ways of measuring exercise (simple questionnaire vs. accelerometer) can explain the discrepancy. However, it cannot be ruled out that low to moderate exercise is associated to higher prevalence of eczema, while moderate to vigorous is not. It well might be that low intensity exercise with skin exposure to environment and climate aggression and sweat could facilitate mild eczema flares in not highly predisposed individuals; and, in contrast, those highly predisposed avoid vigorous exercise to escape from severe flares. In fact, higher disease severity is associated with decreased levels of physical activity secondary to itch, in adults, has been previously shown31. The curve of the association between the amount of exercise and the severity of eczema (and thus, awareness in self-reported surveys) might have an inverted U shape.
On the other hand, Honjo et al. 32 found a positive independent association of exercise induced wheeze with eczema in a group of 12,405 asthmatic children 6 to 18 years of age following ISAAC definitions. This is probably in keeping with our findings that the association of exercise with eczema is higher in those adolescents who also reported current wheeze (table 2). We cannot say whether the proportion of atopy was higher in the individuals who wheeze than in those who did not wheeze, but this possibility cannot also be ruled out.
The third variable that was consistently associated to eczema markers was taking paracetamol, both at least once last year and at least once last month (figure 3). This was more consistent for current eczema symptoms than for eczema ever and was probably driven by those individuals who have both eczema and wheeze (table 2). There have been several reports linking the use of paracetamol with eczema, even showing that this association is higher when several allergic diseases coexist33-36. Thus, it cannot be said whether the association between paracetamol and eczema might be driven by asthma and/or rhino-conjunctivitis and/or allergy. The present study shows that the association with frequent use (at least one last month) holds even among those adolescents without current wheeze, but only for current symptoms of the condition. The effect of early paracetamol intake on eczema in children 6-7 years of age with neither asthma nor rhino-conjunctivitis symptoms, has been previously shown37. This probably indicates that the drug impairs the antioxidant system which is crucial to maintain skin integrity after aggression38.
The present study has a main weakness which is its cross-sectional nature, precluding to obtain any causal relationship. On the other hand, the study was conducted using validated methods, on a quite large sample with high participation rate, which is representative of the whole country of Kosovo. It has the additional interest of being an area with quite low prevalence of atopic eczema.
In summary, this study shows that, in an area of low prevalence of atopic eczema, both sex, exercise and paracetamol intake are associated to the number of eczema cases, also in those adolescents without current asthma symptoms. Male sex is associated to lower prevalence while mild to moderate exercise and frequent use of paracetamol are associated to higher prevalence of the condition.