Article Text
Abstract
Background Environmental tobacco smoke (ETS) exposure in children is linked with the development of allergic asthma. However, its influence on allergic sensitisation in children has not been conclusively determined.
Objective To systematically review existing evidence of ETS exposure's impact on markers of allergic sensitisation in children.
Methods CENTRAL, MEDLINE and EMBASE databases were searched. Included studies assessed following markers of atopic sensitisation: total immunoglobulin E (tIgE) concentrations, at least one specific IgE (sIgE+), and positive skin-prick tests (SPTs+) in ETS-exposed and non-exposed children.
Results 8 studies on the influence of ETS on tIgE concentration (2603 patients), 6 studies on ETS and sIgE+ (9230 participants) and 14 papers on ETS and SPT (14 150 patients) met our inclusion criteria. ETS was shown to raise tIgE concentrations by 27.7 IU/mL (95% CI 7.8 to 47.7; I2=58%; results based on 3 studies) and to increase the risk of atopic sensitisation, as assessed by sIgE+ (OR=1.12, 95%CI 1.00 to 1.25; I2=54%; results based on 4 studies) and SPT+ (OR=1.15; 95% CI 1.04 to 1.28; I2=0%; results based on 10 studies). In a subgroup analysis, this effect was most pronounced in children <7 years (preschoolers) by OR=1.20; (95% CI 1.05 to 1.38) and OR=1.30 (95% CI 1.05 to 1.61), (for sIgE+ and SPT+, respectively).
Conclusions Current analysis supports an association between ETS exposure in early childhood and the increased risk of allergic sensitisation. Subgroup meta-analyses demonstrate that younger children suffer the most from detrimental immunomodulating effects of ETS exposure. This study underscores ETS as an important but avoidable risk factor for the development of allergic disease in children.
- Allergy
- Immunology
- Respiratory
- Systematic Review
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What is already known on this topic
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Environmental tobacco smoke exposure increases the incidence of asthma in children, however, the mechanisms of this are unclear.
What this study adds
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Data combined from nineteen population-based cohort studies (24,000 children) suggests household smoke exposure influences postnatal immunoregulation.
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Tobacco smoke exposure has been demonstrated to increase sensitivity to allergens in children, measured by serum IgE and skin testing.
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Immunoregulatory mechanisms are suspected to play a role in the increased frequency of allergy, seen in children exposed to household tobacco smoke.
Introduction
Environmental tobacco smoke (ETS) in children is believed to be related to impaired lung function and an increased risk to allergy and asthma.1 According to a recent systematic review by Burke et al,2 ETS exposure increases the incidence of asthma in children by at least 20%. The development of asthma in those exposed to ETS during pregnancy and early childhood is attributed to increased sensitivity to allergens.3 However, the precise immune pathways driving this phenomenon are still under debate and available data from large cross-sectional and cohort studies are conflicting.4–7 The existing evidence on smoking and allergic sensitisation was summarised by Strachan and Cook in 1998 in a systematic review, however, their results suggest no conclusive association.8
Over the last 15 years, evidence has been surfacing which demonstrates the effect of tobacco smoke on immune function in a variety of in vitro and animal models.9 The limited existing data on passive smoking and its direct effects on immune responses and respiratory health in children seem to confirm these observations.10–12 Therefore, our aim was to systematically review and update data from cross-sectional and cohort studies regarding the effect of ETS on serum total immunoglobulin E (tIgE) and specific IgE (sIgE) and skin-prick tests (SPTs), since they are easily assessable and objective markers of allergic sensitisation in children.13
Methods
The study used standard methods for systematic reviews and was reported in accordance with MOOSE (Meta-analysis of observational studies in epidemiology).
Search and selection
The Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library), MEDLINE (1966–2012), and EMBASE (1980–2012) databases were systematically and independently searched by three researchers (WF, MR, BMZ) in April 2013. Disagreements were resolved through discussion (further details online supplementary file).
Inclusion criteria
The studies were eligible if they met our predefined inclusion criteria: (1) full-text cross-sectional, case-control or prospective cohort studies; (2) study participants aged 0–18 years from non-selected, random populations; (3) studies reporting the effects of postnatal ETS exposure, at longest follow-up for studies with multiple time points. We included only papers reporting: (1) tIgE concentrations, (2) detection of at least one positive result of sIgE antibodies to any common food or inhalant allergen (when IgE ≥0.35 kU/L) at any point (sIgE+) or (3) presence of any positive SPT to any common food or inhalant allergen (transverse wheal diameter ≥3 mm) (SPT+). No further restrictions (eg, regarding the methodological quality of individual studies, language, geographical setting) were imposed.
Exclusion criteria
We excluded studies performed on children in preselected a priori risk factor cohorts (ie, born to parents with history of atopy, diagnosed with any allergic disorder or attending outpatient allergy clinics), studies focusing on prenatal ETS exposure, and studies assessing cord-blood IgE level.
Data extraction
All data were independently extracted by pairs of investigators and underwent triple cross-reference procedure by using a standardised protocol and data extraction form.
Risk of bias assessment
The risk of bias (study quality) was assessed by considering measure exposure and outcomes, methods used to control for confounding factors, and the appropriateness of the statistical analysis, based on elements of the STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) guidelines,14 the AHRQ (Agency for Healthcare Research and Quality's) checklist for observational studies,15 and the Newcastle-Ottawa Scale 16 quality (see online supplementary tables A1 and A2). As recommended by the Center for Reviews and Dissemination, 17 we did not use a scale with a summary score.
Statistical methods
Pooled weighted mean differences between tIgE concentrations in ETS exposed and control (non-exposed) groups were estimated using a random effects meta-analysis.
Positive sIgE and SPT results were pooled using a generic inverse variance fixed-effect (FE) meta-analysis model18 of OR between the exposed and unexposed groups, as studies were conducted in similar populations regarding the participant's age, health status, time of exposition to ETS, and exposure to other risk factors and no significant between-study heterogeneity was noted.
We also performed a subgroup analysis to evaluate for differences between children under the age of 7 years (hereafter called preschoolers) and school age children (≥7 years), as well as between prospective and cross-sectional studies. A vast majority of children in our dichotomy belong to one group (preschoolers) or the other (children of whom the vast majority attends compulsory educational facility) with little overlap, although regional variations mean the terms may not precisely reflect their educational status. Statistical heterogeneity was addressed using the I2 index (p<0.05 considered statistically significant) as well as through visual inspection of L'Abbé plots. All statistical analyses were done using Review Manager (RevMan) software (V.5.1 Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2011).
Results
Studies included
Our initial search strategy yielded 1655 citations; 181 abstracts were identified for further evaluation. Of these, we retrieved 70 full articles and finally included 24 reports of 19 study cohorts on 24 172 children (figure 1). Altogether there were 11 cross-sectional studies, 5 ,7 ,19–30 4 prospective cohort studies4 ,6 ,31–34 and 4 case-control studies. 10 ,35–37 The studies were conducted in various regions of the world. The included subjects were aged 0–17 years.
Outcomes reported
Eight studies (n=2603) reported tIgE as an outcome (see online supplementary table SI), 6 publications (5 studies) (n=9230) assessed sIgE (see online supplementary table SII), and 14 publications/11 studies (n=14 150) reported positive SPTs (see online supplementary table SIII).
Exposures measured
The definition of smoking varied across the studies and only few reports used cotinine urine measurements to verify tobacco smoke exposure.5 ,30 ,36 Each study included in this review was investigated for possible confounding factors and the data used in meta-analysis were statistically adjusted for these factors when possible (see online supplementary table SI, SII, SIII and table A3).
Excluded studies and the reasons for exclusion are summarised in online supplementary table IV.
Environmental tobacco smoke and total IgE
Only four studies, 10 ,24 ,26 ,35 comprising a total of 434 participants (262 ETS-exposed, and 172 non-exposed subjects) were included in this meta-analysis. The summary effect size as assessed by a random-effects model, revealed a strong and significant tendency towards increased tIgE levels in ETS-exposed individuals at the level of 89.9 IU/mL (95% CI 30.9 to 148.9 IU/mL) (p=0.003). However, the comparison of included studies revealed considerable heterogeneity among examined populations (p<0.00 001, I²=95%). This effect was mainly attributed to the study conducted by El-Nawawy et al10 on Egyptian children, whose results reported an overall, extremely high concentration of tIgE. Therefore the results should be treated cautiously (figure 2A).
After the exclusion of the questioned study, a statistically significant trend towards increased tIgE concentrations was still present with an acceptable level of homogeneity (I²=58%, p=0.07). All the studies consistently demonstrate the elevated tendency and the mean difference in tIgE level between ETS-exposed and non-exposed children was 27.7 IU/mL (95% CI 7.8 to 47.7; p=0.006; figure 2B).
Due to the limited number of studies with high level of heterogeneity, a subgroup analysis was not performed.
Environmental tobacco smoke and specific IgE
The four studies eligible for meta-analysis involved 6629 participants (2161 ETS-exposed and 4468 non-exposed) with moderate heterogeneity calculated at I2=54% (p=0.09).5 ,6 ,21 ,33 The FE estimate demonstrated that ETS exposure increased the risk of allergic sensitisation (OR=1.12; 95% CI 1.00 to 1.25), and the effect was on the border of statistical significance (p=0.06). Subsequent subgroup analyses performed with the use of the FE model indicated that in children aged <7 years ETS exposure was associated with the increased risk of atopic sensitisation with an OR=1.20 (95% CI 1.05 to 1.38; figure 3). The observed effect was even stronger in the identified prospective studies with an OR=1.35 (95% CI 1.10 to 1.66; figure 4).
Environmental tobacco smoke ETS and skin-prick tests
Eight studies (9033 participants) 4 ,5 ,19 ,22 ,27 ,29 ,33 ,36 were eligible for dichotomous meta-analysis. In two other reports (4080 children) analysis was based on OR only, we therefore applied generic inverse variance analysis in order to estimate an overall effect. There was no statistical heterogeneity among the included studies (I²=0%). ETS exposure increased the risk of a positive SPT result with OR=1.15 (95% CI 1.04 to 1.28, p=0.007). This effect was more pronounced in children under the age of 7 years (preschoolers and those who have just entered primary school) with the subgroup effect size at OR=1.30 (95% CI 1.05 to 1.61, p=0.02), but not apparent in the older group (OR=1.11, 95% CI 0.99 to 1.25; figure 5). Yet again, the effect was stronger in prospective as compared with cross-sectional studies, (OR=1.43 and OR=1.13, respectively; figure 6).
Discussion
Principal findings
In this systematic review and meta-analysis we have demonstrated that ETS exposure in children increases the risk of atopic sensitisation. Parental smoking is associated with: (1) significantly higher tIgE concentrations, (2) the presence of sIgE to any common allergens (>0.35 kU/L); and (3) positive SPT against common allergens in children. The observed effect was moderate and mostly expressed in preschoolers (<7 years).
Methodology
In this systematic review and meta-analysis we included only studies focusing on children from non-selected, random populations. Therefore, all studies conducted in children with an a priori increased risk of allergic sensitisation (eg, positive family history of allergy, atopic children from the outpatient allergy clinics) were excluded. In contrast to the recent meta-analysis by Burke et al,2 this methodology allowed us to avoid a systematic bias, resulting from baseline differences in the selected populations. However, it can be considered a strength (considerable homogeneity) and a weakness (limited number of studies included) of the presented meta-analysis.
The effect of ETS on tIgE concentrations was analysed in eight studies, but only four studies comprising 434 participants were eligible for meta-analysis (figure 2A, B). The high level of heterogeneity of the studies was attributed to the higher IgE concentrations observed in rural Egyptian children (mean tIgE in controls was 189 IU/mL) as compared with Italian and Polish children.10 The most probable explanation for this discrepancy was a high incidence of parasitic diseases in this group. It is well-known that parasitic infections can produce very intense levels of IgE with the concentrations reaching 3000 kU/L.38 Although our data were too limited to ultimately determine the impact of ETS exposure on serum tIgE, this effect has already been postulated by others and confirmed in adults in the European Community Respiratory Health Survey, a cross sectional analysis of 13 000 participants.39
Strong points and limitations of the study
Since smoking is a well-known factor of morbidity in the course of pre-existing allergic disease, the strong point of this study was an attempt to assess the effects of tobacco smoke exposure on the general population. This enabled us to reliably evaluate the phenomenon of atopy induction by cigarette smoke in children with and without previously known increased risk of allergy and renders these results generalisable. This aspect distinguishes our study from other former analyses.2 ,7 ,8 ,40 Studies encompassing only children with allergic disease are at risk of systematic error, since selective avoidance of smoking by parents of atopic children is likely to bias the results. At the same time, the conclusions from our study directly concern healthy children and those who may be predisposed to allergic sensitisation and those already diagnosed with allergic disease.
Another strong point of our work was the assessment of an age-related effect of tobacco smoke exposure. Previous observations suggested that the period of exposure may be important, especially regarding exposure during pregnancy and infancy.8 ,12 Although the role of prenatal exposure to tobacco smoke is crucial for the development of allergic sensitisation,8 we decided to limit our search only to the studies reporting postnatal ETS exposure, since it is extremely difficult to disentangle prenatal from postnatal effects. Studies assessing cord-blood IgE were also excluded, as its level is considered rather a risk factor for the development of atopy and not a reliable marker of current allergic sensitisation.
Our findings indicate however, that the detrimental influence of ETS exposure is significant to children in the preschool era, with an age-related decline in the strength of the effect during the school years.40 The observations reflect the time of contact as older children spend less amount of time at home. It has been suggested that critical time in this context is the first 3–4 years of life, since this period is crucial for the development of an individual profile of the respiratory immune response.40 ,41 However, in the view of our results as well as the recent data by Mitchell et al42 this time window should be extended to 6–7 years.
The presented systematic review with meta-analysis has several limitations. Our rigorous inclusion criteria significantly limited the number of analysed studies (from 1606 identified articles only 16 were included in the meta-analysis) restricting the possibility of a more comprehensive analysis. Even though the search strategy was very comprehensive (several databases, triple checked at each stage, unrestricted language limitations, correspondence contact with the authors of selected studies), some studies may not have been identified, especially if they have never been published or were published in less indexed languages.43 Moreover, in many of the identified studies the influence of parental smoking on the allergic sensitisation was not the primary outcome. Thus, it is possible that the studies with relevant data were not identified with our search strategy (ETS and allergic markers not mentioned in the title/abstract), and, ‘publication bias’ and ‘selective reporting’ bias cannot be excluded.
Furthermore, the majority of data included in this review were drawn from well-planned cross-sectional studies, and therefore the cause-effect relationship of the observed phenomena may be questioned. The inclusion of randomised control trials would have certainly increased the value of our review,44 but such studies were not identified and will probably not be carried out due to the obvious ethical reasons.
Another potential limitation of this systematic review regards a variety of methods used to assess the exposure of children to ETS. These included: cotinine urine measurements, number of cigarettes smoked daily by family members (YES/NO or 1–10 vs 10 or more), smoking by any of the parents (none, smoking mother or father, both smoking). Due to this heterogeneity, the conclusions drawn from the present meta-analysis seem encouraging, but not definite.
Potential confounders
Since confounding factors can influence the strength of the results of observational studies,43 each study included in this review was investigated for possible confounding factors (see online supplementary table A3) and data used in meta-analysis were statistically adjusted for these factors whenever possible (see online supplemenetary tables SI, SII, SIII). It is an important argument in the evaluation of the presented study, since analyses that adjust for confounding variables were often proved not to reach statistical significance.43 ,45
Comparison with other studies
This systematic review with meta-analysis is currently the most recent and reliable review of the topic reported to date. Our results are consistent with earlier observations from several large prospective cohorts and cross-sectional studies demonstrating higher risks of atopic asthma, eczema and rhinitis in children exposed to ETS,1 ,6 ,19 ,33 ,42 ,46 as well as with the latest reports confirming its detrimental effect on the incidence of asthma in children. 2 ,40 ,42 ,47 However, in this report we included only studies assessing the influence of ETS exposure on objective markers of allergic sensitisation, and not the studies assessing particular allergic disease (asthma, atopic eczema, hay fever, wheezing) as an outcome. This approach had permitted us to objectively assess the actual influence of tobacco smoke on the immune system, with particular respect to the early mechanisms of allergic immune response. Assessing particular allergic disease as an outcome would not allow for such objectivity, since the majority of diagnostic criteria have changed over time. Moreover, in numerous epidemiological studies, the diagnosis is based only on data from parental questionnaires, which invariably leads to a recall bias. The former studies aiming at similar review are not free from these inaccuracies.2 ,7 ,8 ,40
The most thoroughly conducted previous analysis is a study carried out in 1997 and published by Strachan and Cook in 1998.8 Despite the significant number of identified studies (36 articles), it is not free from methodological and formal errors.43 ,48 The major include the lack of information on: language limitations, multiple-referencing and cross-referencing, and verification of identified studies, as well as adopting inappropriate markers of atopic disease (umbilical IgE and SPT results defined positive when ≥0 mm), and others.
There are three other reports published recently, demonstrating that ETS exposure in children increases the incidence of asthma and wheezing by at least 20%: two systematic reviews by Burke et al2 and Tinuoye et al,47 as well as International Study of Asthma and Allergies in Childhood (Phase 3) report by Mitchell et al.42 These results correspond to our data, suggesting that ETS exposure increases the risk of atopic disease by 12–15% (and up to 20–30% in preschool children).
Conclusions and future research
In summary, the presented systematic review of observational studies with meta-analysis showed that household exposure to tobacco smoke after birth promotes the expression of immunological markers of allergic sensitisation and increases the risk of atopic disease in children. However, the majority of data was drawn from cross-sectional and cohort studies, and therefore the results should be treated with caution.
In future studies, efforts should be made to precisely and uniformly define the exposure to tobacco smoke (the number of cigarettes, hours of exposure, a period of exposure). Clear measures of controlling for important confounders are also required.
Acknowledgments
The authors thank Dr Sean C Kearney, Medical University of Warsaw, for his contributions towards the completion of this publication and Dr E Słotwińska-Rosłanowska from the Warsaw School of Economics for advice in statistical analysis and for reviewing the manuscript. The study was supported by the Medical University of Warsaw. The authors declare no conflict of interests.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Files in this Data Supplement:
- Data supplement 1 - Online supplement
- Data supplement 2 - Online table 1
- Data supplement 3 - Online table 2
- Data supplement 4 - Online table 3
- Data supplement 5 - Online table 4
Footnotes
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Contributors Conception and design, or analysis and interpretation of data (WF, MR, JJ, AS, BMZ, MK); drafting the article or revising it critically for important intellectual content (WF, MR, AS, BMZ); final approval of the version to be published (WF, MR, JJ, AS, BMZ, MK).
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Competing interests None.
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Provenance and peer review Not commissioned; externally peer reviewed.