SPIROMETRIC CHANGES IN CHILDREN WITH ASTHMA EXPOSED TO ENVIRONMENTAL TOBACCO SMOKE AND TREATED WITH INHALED CORTICOSTEROIDS

Introduction/Objective: Corticosteroids are the most frequently prescribed antiinflammatory treatment in asthma. Purpose of this study was to compare spirometric parameters as a response to inhaled fluticasone propionate (FP) treatment in children with asthma, exposed and non-exposed to environmental tobacco smoke (ETS). Methods: The study included 527 children aged between 1 and 16 years with persistent asthma divided into the groups of ETS exposed (ETSE, N=337) and ETS free (ETSF, N=190) children. Spirometry was performed before (1 st set of results) and after 6 months of FP (2 st set of results). “Good lung function” (GLF) was defined as FEV1≥85%, and “poor lung function” (PLF) as FEV1<85%. Results: Among ETSE children, 208 had one smoking parent, 129 had two, 228 had smoking mothers and 238 smoking fathers. ETSE children received a higher FP dose (p<0.0001) which was increased with the increase of the number of smokers in the family. ETSE children had significantly lower lung function both in the 1 st and in the 2 nd sets of tests compared to ETSF children (p<0.05). After FP treatment, both groups improved all spirometric parameters (p<0.001). In the 2 nd set of spirometric tests, children of smoking mothers had lower spirometry values compared to smoking fathers ́ children (p<0.05). The proportion of children improving from PLF to GLF after 6 months of FP was much higher among ETSF than ETSE children (p<0.05). Conclusions: Children ETSE had lower spirometric values before FP. After 6-months of FP treatment children in both groups improved spirometric values, but improvement was better in ETSF children.


INTRODUCTION:
Asthma, as the most frequent chronic disease in children, could be triggered by infection, allergens, psychological and hormonal factors, physical exercise, as well as by environmental irritants and contaminants such as tobacco.A retrospective analysis of data from 192 countries, done by Oberg at al., showed that as many as 40% of children were regularly exposed to second-hand smoke.[1] The WHO, California Environmental Protection Agency, and US Surgeon General Report have presented evidence of a higher incidence of acute lower respiratory infections and acute otitis media, more hospital admissions, and earlier onset of asthma in environmental tobacco smoke (ETS) exposed children.[2][3][4] Many studies have provided evidence that fetal exposure to chemical mediators secondarily released in response to tobacco, and postnatal passive smoking present a risk factor of reduced lung function.[5][6][7][8][9][10] The prenatal and postnatal effects of secondhand smoke may vary among individuals depending on individual genetic susceptibilities and gene-environment interactions.
Corticosteroids are the most effective anti-inflammatory therapy for asthma.Several studies in adult asthmatics and COPD patients provide evidence that chronic inflammation in the airways of smokers may be resistant to the anti-inflammatory effects of corticosteroids.[11][12][13][14] Studying children Cohen et al. found that ETS exposure may attenuate the beneficial effect of inhaled corticosteroids (IC) among children with asthma.[16] Therefore, we conducted a study in order to 1) assess whether children with persistent asthma exposed to ETS had lower values of lung function tests compared to the nonexposed ones, 2) examine if there is a difference between exposure to smoking mother or smoking father or to both smoking parents and 3) compare the effect of inhaled corticosteroid treatment with FP on lung function parameters in ETS exposed and nonexposed children with asthma.

Study design
This cohort study was conducted at the Children's Hospital for Respiratory Diseases and Tuberculosis, Belgrade, Serbia, from June 2011 to June 2012.We screened 726 children (6-16 years old) with persistent asthma, with one or more asthma exacerbations treated in the emergency unit in the preceding 12 months, not receiving systemic or IC for at least two months.The diagnosis of asthma was established according to the Global Initiative for Asthma (GINA) recommendations.[17] Lung function testing was performed by means of spirometry (Pneumoscreen, Jaeger), according to the protocol of the European Respiratory Society.[18] The subjects were suspended from the use of short-acting β2 adrenergic agents at least 6 hours before the test.The following parameters were measured: VC, FVC, FEV 1 , FEV 1 /VC, PEF, MEF 75 , MEF 50 , MEF 25 and FEF 25-75 .[19] Spirometry was performed at the beginning of the study (1 st set of results) and after 6 months of IC treatment (2 st set of results).We classified the asthma severity according to the baseline value of lung function parameters rather than according to the intensity and frequency of asthma symptoms.[20] According to the FEV 1 < 85% or ≥ 85% of predicted values by age, sex, height and weight, we divided children into groups with "poor lung function" (PLF) and with "good lung function" (GLF).This cutoff point was chosen in order to define the group of asthmatic children with the lowest 5% lung function.[5] Smoke free families and families with smoking parents (mother or/and father) were included into the study.Children who were active smokers themselves or had additional chronic illness such as nephritic syndrome, diabetes, epilepsy, etc. were not included in the study.
Fluticasone propionate (FP) metered dose inhaler (MDI) was used in the daily dosage ranging from 50 to 1000 mcg for 6 months.The clinicians prescribed the initial FP dose according to the asthma symptoms, lung function parameters and patients' age.They were blinded to the child's ETS exposure.The dose was maintained through the 6 months of the study.Children below the age of 12 were instructed to use FP MDI through the volumatic chamber.No one was treated with long-acting β2 adrenergic agents or anti-leukotriene agents.An allergy and asthma history was obtained at the first visit.According to the responses and parental personal statements, we divided children into two groups: children exposed to ETS at home (exposed cohort -ETSE) and ETS free children (control cohort -ETSF), and scheduled for regular check-ups every 2 months.Skin prick test (SPT) was performed and total serum IgE was taken to all children.[21] The study was approved by the institutional review board of the Children's Hospital for the Respiratory Diseases and Tuberculosis, Belgrade, Serbia and informed consents were obtained from the patients and parents/caregivers.

Participants
Out of 726 children we excluded 129 for not meeting the entry criteria.The remaining 597 children were divided into ETSE, N=382 (64%) and ETSF, N=215 (36%) groups.

RESULTS
In our sample of 527 children, the sex distribution was 263 (49.9%) boys versus 264 (50.1%) girls.There were 190 (36.1%) children with asthma living in smoke free families, 208 (39.5%) living in families with one smoking parent, and 129 (24.5%) living with two.228 (43.3%) children were living with actively smoking mothers (before the pregnancy 51% of mothers were smokers, during the pregnancy 41% continued to smoke) and 238 (45.2%) with actively smoking fathers.
The arithmetic mean of the FP dose prescribed to all children was 225.1±120.0mcg per child per day.ETSE received a significantly higher FP dose (Figure 2) than ETSF children (F=31.2,p<0.001).There was no difference in the FP dose between subgroups of ETSE children.
According to the FEV 1 ≥ 85% of predicted values and FEV 1 < 85% of predicted in the first spirometry and exposure to ETS, we divided children into subgroups: in the GLF group there were 251 ETSE and 153 ETSF children, in the PLF group there were 86 ETSE and 37 ETSF children.In the GLF group, ETSE children had more exacerbations 12 months before the study, a higher value of total IgE, received a higher dose of FP per day, and had a higher percentage of at least one positive skin prick test compared to the ETSF children.
In the PLF group, ETSE children had the higher value of total IgE and received a higher dose of FP compared to the ETSF children.(Table 1) All subgroups of ETSE children had significantly lower baseline values of all lung function test parameters than the ETSF children (Table 2).
In the final spirometry the mean FEV 1 was 109.9±14.2%.All ETSF and ETSE children significantly improved all lung function parameters 6 months after the introduction of FP, except for the FEV 1 /FVC values in children of smoking mothers (p=0.18).Analysis of the 2 nd set of spirometry results in Table 2 showed: (1) values of FEV 1, FEF 50 and FEF 75 were still lower in all subgroups of ETSE children compared to ETSF children; (2) the value of FEV 1 /FVC was lower in children of smoking mothers and both smoking parents compared to the ETSF children, while there was no difference between the children of smoking fathers and ETSF children;  3) The comparison of FEV 1 according to ETS exposure in GLF and PLF children before and after the FP treatment estimated the risk of having "poor lung function" (Table 4).The percentage of children improving from PLF to GLF after 6 months of FP was much higher in ETSF than in ETSE children.In the ETSE group, 51% of children passed from PLF to GLF group.In the ETSF group, 82% of children passed from PLF to GLF.DISCUSSION In this study a high percentage of smoking families (63.9%) was found, which is common in developing countries.[22,23,24,25] Baseline characteristics of ETSE showed that they had lower FEV 1 , higher total IgE, more positive SPT and more previous asthma exacerbations compared to ETSF children.ETSE received a significantly higher FP dose per day.We assume that clinicians prescribed higher doses of IC to the patients with more intensive symptoms and lower spirometry parameters, regardless of the child's tobacco exposure.
In this study, children with FEV 1 < 85% had more smoking parents.[6] In the GLF group, ETSE children had more exacerbations 12 months before the study, had higher serum IgE values, received higher doses of FP per day, and had a higher percentage of at least one positive SPT compared to the ETSF children.In the PLF group, ETSE group of children had higher total IgE level and received a higher dose of FP per day compared to the ETSF children.Further analysis is required to determine whether the increased rate of exacerbations was linked with IgE status and not ETS status.Another question is whether ETSE children additionally suffered from another respiratory problem ("COPD type").
Many studies confirmed that children exposed to tobacco smoke had more exacerbations which are red flags of poor control [1][2][3][4]9,10,26].Some studies have documented an association between maternal smoking during pregnancy and elevated cord blood total IgE, as well as an increased risk for the development of allergic disease.[27,28] Other studies, however, have not replicated these findings.The updated meta-analysis of the evidence relating parental smoking to allergic sensitization in children as measured by a skin-prick test, IgE levels, and presence of allergic rhinitis and eczema did not show any significant association of maternal smoking with total serum IgE, allergic rhinitis, or eczema, and had no effect on secondhand smoke on skin-prick positivity.[29,30] Farooqi and Hopkin suggested that there was no significant association between maternal smoking and atopy, and maternal atopy constitutes the main risk for the development of atopy in children.[31] This study was conducted in children with asthma, and significant difference was shown in total serum IgE and positive SPT between ETSE and ETSF children.
As we expected, the lung function test parameters in ETSE and ETSF children significantly improved on IC.However, lung function parameters in ETSE children have never reached the values of those in ETSF children.What we found interesting was that the children of smoking mothers had lower values of all lung function test parameters in the final spirometry compared to the children of smoking fathers.This was probably due to the amount of the time smoking mothers spend at home with children, and consequently higher ETS exposure.Our findings confirmed the findings of many other studies that have reported differences in the lung function between children with asthma exposed and nonexposed to ETS. [1,6,8] An international study of parental smoking and lung function in more than 20,000 primary school children showed the lasting effect of smoking during pregnancy on the lung function, while the effects of past and current ETS exposure were smaller.[5] Other studies exploring the effects of ETS on asthma severity showed that ETS exposed individuals had worse lung function, more exacerbations, more health care resource utilization, and greater level of bronchial hyperreactivity in comparison to those not exposed.[6][7][8][9][10] The comparison the 1 st and the 2 nd set of spirometric results in ETSF and ETSE children showed that some lung function parameters improved more in ETSF and some in ETSE children.Practically, the improvement was similar in both groups, although ETSE children took higher doses of FP.This finding is in contrast with studies providing evidence that ETS exposure may attenuate the beneficial effect of IC among children with asthma.[16] The proportion of children improving from PLF to GLF after 6 months of FP was much higher among ETSF compared to ETSE children.This is in accordance with the work of Cohen RT et al. who found that fetal exposure to chemical mediators secondarily released in response to tobacco impaired the response to inhaled corticosteroid in children with asthma.[16] It is very important to educate children with asthma and their parents about the negative effects of ETS.[32,33] The education may decrease the future ETS exposure of a child.In addition, the smoking habits of parents represent a risk factor associated with the initiation of smoking during adolescence among children.[34][35][36] Many governments have conducted tobacco control campaigns, however, the adequate implementation of these measures is essential.[37] The limitation of this study was investigators' inability to check real ETS exposure of the children in their home environment.Another limitation was our inability to check parents' active or passive smoking status and passive smoking status of children by measuring carbon monoxide (CO) in the exhaled air with Smokerlyzer.Moreover, we did not perform a bronchodilator test with short acting β 2 -agonists (BDT) after the 1 st spirometry to asses reversibility of bronchoconstriction in the airways of ETSF and ETSE children.We though it would be helpful to asses the lack of reversibility in ETSE children and would suggest a "COPD-like" component of their illness, but the majority of the children (82%) had FEV1≥85% of predicted and in most of them positive BDT could not be obtained.Finally, we were not able to assess direct compliance with the IC therapy.

CONCLUSION
Children ETSE had lower values of lung function tests both before and after treatment.This study did not provide enough evidence that ETS exposure may attenuate the beneficial effect of IC in children with asthma, suggesting that timely protection of children with asthma from adverse effect of ETS makes sense, since there is no proof that their airways respond less to IC, which is the case in adult smokers with COPD and asthma.
Additional 45 children were excluded from the ETSE group due to acute asthma exacerbation, lost contact, etc., leaving a sample of 337 children.We divided ETSE children into three subgroups: children of smoking mothers (N=228), children of smoking fathers (N=238) and children of both smoking parents (N=129).From the ETSF group 25 children were lost for reasons similar to ETSE group, leaving the sample of 190 children.(Figure 1: Patients enrolment flow chart).SNEZANA DA DODA RECENICU, da li potpisuju roditelji?Statistical analysisAll data was statistically analyzed using the software SPSS 17 for Windows.The ordinal data was analyzed with Pearson chi square test and Fisher exact test if needed.Odds ratio (OR) with 95% confidence interval (CI) were calculated from 2*2 tables.Continuous variables are expressed as means ± SDs.Numerical data (after verification of normal distribution with Kolmogorov Smirnov test) in two groups were compared with Student t test for related samples (since we had only 2 time points), and Fisher parametric ANOVA (Analysis of variance) for comparing more than two groups or more than two measures.Homogeneity of variance was checked for all variables and in all cases p values exceeded 0.05.The Fishers Least Significant Difference (LSD) test was used for multiple comparisons.The results were controlled with the Tukey test that provided identical pvalues in all instances.A probability value of p < 0.05 was considered statistically significant.

( 3 )
the value of FEF 25 was lower in children of smoking mothers compared to the ETSF children, however, there was no difference in children of smoking fathers and both smoking parents compared to the ETSF children; (4) the children of smoking mothers had lower values of all lung function test parameters compared to the children of smoking fathers; (5) there was no difference in PEF between ETSE and ETSF children.There was no difference in FVC between the ETSF and ETSE children both in the 1 st and 2 nd sets of tests.The improvement in IC was quite similar between ETS exposed and not exposed children except in a few points.In children of non-smoking mothers, improvement of MEF 25 was significantly higher (p<0.05)compared to children of smoking mothers.Children of smoking fathers had significantly better improvement in MEF 75 , MEF 50 and MEF 25 (p<0.05)compared to children of non-smoking fathers.Children of both smoking parents had significantly better improvement in PEF and MEF 75 (p<0.05)compared to children of both non-smoking parents.(Table ETSE children were treated with higher doses of FP than the ETSF children.After 6 months of IC treatment, both ETSE and ETSF children significantly improved all lung function test parameters.However, ETSE children did not reach the spirometric values of ETSF children, despite receiving the higher IC doses.The improvement of lung function test parameters under IC treatment was practically the same in ETSF and ETSE children, but the improvement in children of smoking mothers was significantly lower than in children of smoking fathers.The proportion of children improving from PLF to GLF after 6 months of FP was much higher in ETSF than in ETSE children.