GENDER-SPECIFIC DIFFERENCES OF BRONCHIAL ASTHMA PHENOTYPES IN CHILDREN DEPENDING ON PUBERTY STATUS

E-mail: nbohutska@ukr.net Оbjective of the study was to evaluate if sex-based differences exist in clinical and epidemiologic characteristics of bronchial asthma (BA) in children before and after puberty. Material and methods. 120 school-age children with persistent BA (80 of whom – males and 49 – pre-puberty individuals), have been examined in observational study with cross-section design. Inclusion criteria: age from 6 to 18 years old; a diagnosis of BA for at least one year; informed consent of parents and children. Exclusion criteria: orphans; the presence of any other chronic lung disease. The first group included 49 patients before puberty, the second clinical group was formed of 71 patients after puberty onset. The clinical anamnestic, allergologic, spirometric and statistical methods of research were used. Results. Early onset BA non significantly associated with male gender before puberty and late onset BA phenotype slightly predominated in post-pubertal females (RR=1,3; 95%CI:0,6-3,0). Regardless of gender non-severe BA predominated in pre-puberty period and post-puberty period associated with non significantly increased risk of severe BA phenotype (RR=1,6; 95%CI:0,5-5,1 and RR=1,4; 95%CI:0,8-2,5 in females and males respectively). Atopic BA predominated in males and non-atopic phenotype associated with female gender both in preand postpuberty. Phenotype of BA with exercise induced bronchoconstriction was equally distributed among both sexes regardless of puberty status. After puberty risk of hospitalization to emergency department due to BA exacerbation in males significantly decreased (RR=0,6; 95% CI:0,4-0,8), while in females such risk slightly increased (RR=1,4; 95% CI:0,7-2,7). Conclusion. Male gender slightly associated with atopic phenotype, early onset BA before puberty and significantly reduced risk of hospitalization due to exacerbation after puberty. Female gender slightly associated with non-atopic BA phenotype and elevated risk of hospitalization due to BA exacerbation after puberty


Original research
Introduction. The prevalence of bronchial asthma (BA) has increased and asthma currently affects approximately 1-18% of children worldwide [1]. BA has sex-specific differences in prevalence, in particular BA is far more common in boys than girls during early childhood, but the prevalence equalizes between the genders during adolescence and then switches to a female predominance in adulthood [2,3]. BA comprised of highly heterogeneous clinical phenotypes resulting from complex interplay between genetic and environmental stimuli. The factors related to BA prevalence may differ depending on sex in preschool and school-aged children [4,5]. The sex difference in the prevalence of BA is reflected in the sex difference in the hospitalization rate and BA severity [3]. While much focus has been placed on extrinsic environmental stimuli, intrinsic environment such as sex can interact with genes to influence BA risk [6,7]. The impact of a BA may be different according to gender in terms of different BA clinical phenotypes manifestations in children and adolescents [8][9][10]. However, only few studies have examined sexspecific effects, especially in childhood [5,6].
Objective of the study was to evaluate if sexbased differences exist in clinical and epidemiologic characteristics of BA in children before and after puberty.
Material and methods. The research assignments were to study the peculiarities of clinical phenotypes of BA in children depending on gender in and to investigate the detailed data of BA manifestations in males and females before and after puberty onset. 120 children of 6-18 years old of both sexes with at least one year duration of persistent BA were examined. The first (I) group included 49 patients with persistent BA before puberty, the second (II) clinical group was formed of 71 patients with diagnosis of persistent BA after puberty onset. No significant differences by sex, age, and place of residence have been shown due to correctly formed clinical groups of comparison. Methods: questionnaire answers (Alexithymia Questionnaire for Children; the Toronto Alexithymia Scale; The Spielberger State-Trait Anxi-ety Inventory), familial anamnesis, Tanner scale score, birth weight and body mass index (BMI), allergic skin tests results, total serum IgE, index of bronchial lability, PC 20 H (bronchial non specific hyperresponsiveness test to histamine inhalations which caused 20% fall of FEV 1 ). The clinico-anamnestic, allergologic, spirometric and statistical methods of research were used.
Results and their discussion. In the examined cohort late onset BA phenotype (debut after 6 years old) predominated regardless of gender and puberty status, first of all in post-pubertal females as compared to pre-puberty period (RR=1,3; 95%CI:0,6-3,0). Such association may be explained by tendency of increasing BA prevalence in girls with aging as well as with BA under diagnosing (Yentl syndrome). Early onset BA (up to 3 years old) non significantly associated with male gender before puberty. Nonsevere BA diagnosing predominated in pre-puberty period both in girls and boys, but post-puberty period regardless of sex associated with non significantly increased risk of severe BA phenotype as compared to alternative asthma variant (RR=1,6; 95%CI:0,5-5,1 and RR=1,4; 95%CI:0,8-2,5 respectively). Atopic (allergic) BA predominated in males regardless of puberty status, as well as non-atopic phenotype associated with female gender both in pre-and postpuberty. Exercise induced asthma (phenotype with exercise induced bronchoconstriction) was almost equally distributed among both sexes regardless of puberty status. Futhermore, such atopic manifestations as max skin papula to one of the epidermal allergens and genealogic index of positive allergic familial anamnesis significantly predominated in males as compared to females in pre -and postpuberty respectively. No any significant differences of the spirometric indices were revealed in groups of children depending on gender and puberty status (see table).
Females tended to have lower birth weight as compared to males regardless of puberty status and no differences of actual BMI in groups of comparison were revealed. Alexithymia significantly associ-ated with pre-puberty period regardless of gender (p<0,04) and no any sex differences of state or trait anxiety levels were revealed in groups of comparison, but transition from pre-to post-puberty in females was accompanied by significant rise of state anxiety (34,0±13,6 versus 44,6±10,2 points, p<0,04). After puberty risk of hospitalization to emergency department due to BA exacerbation significantly decreased as compared to pre-puberty period in males (RR=0,6; 95%CI:0,4-0,8) and such risk slightly increased in post-puberty in females (RR=1,4; 95%CI:0,7-2,7).

Conclusions
1. Late onset BA phenotype with debut after 6 years old non significantly predominated in children regardless of gender and puberty status, first of all in post-pubertal females, while early onset BA (up to 3 years old) associated with male gender before puberty.
2. Non-severe BA diagnosing predominated in pre-puberty period both in girls and boys, but postpuberty period associated with slightly increased risk of severe BA phenotype regardless of gender. After puberty risk of hospitalization to emergency department due to BA exacerbation in boys significantly decreased and in girls such risk slightly increased.
3. Non-atopic a BA phenotype associated with female gender both in pre-and post-puberty, while atopic (allergic) BA predominated in males regardless of puberty status, as well as skin papula to the epidermal allergens and genealogic index of positive allergic familial anamnesis significantly predominated in males as compared to females in pre -and post-puberty respectively. Gender-stratified analyses identified associations with significantly lower birth weight in females as compared to males regardless of puberty status and no differences of actual BMI in groups of comparison were revealed.
Prospects for further research. Further investigations are needed to examine the effect of genderspecific differences in changes of asthma prevalence and phenotypes in pre-and post puberty taking into account Tanner stages.