Active or Passive Exposure to Tobacco Smoking and Allergic Rhinitis, Allergic Dermatitis, and Food Allergy in Adults and Children: A Systematic Review and Meta-Analysis

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Background:
Allergic rhinitis, allergic dermatitis, and food allergy are extremely common diseases, especially among children, and are frequently associated to each other and to asthma. Smoking is a potential risk factor for these conditions, but so far, results from individual studies have been conflicting. The objective of this study was to examine the evidence for an association between active smoking (AS) or passive exposure to secondhand smoke and allergic conditions.

Methods and Findings:
We retrieved studies published in any language up to June 30th, 2013 by systematically searching Medline, Embase, the five regional bibliographic databases of the World Health Organization, and ISI-Proceedings databases, by manually examining the references of the original articles and reviews retrieved, and by establishing personal contact with clinical researchers. We included cohort, case-control, and cross-sectional studies reporting odds ratio (OR) or relative risk (RR) estimates and confidence intervals of smoking and allergic conditions, first among the general population and then among children.

We retrieved 97 studies on allergic rhinitis, 91 on allergic dermatitis, and eight on food allergy published in 139 different articles. When all studies were analyzed together (showing random effects model results and pooled ORs expressed as RR), allergic rhinitis was not associated with active smoking (pooled RR, 1.02 [95% CI 0.92–1.15]), but was associated with passive smoking (pooled RR 1.10 [95% CI 1.06–1.15]). Allergic dermatitis was associated with both active (pooled RR, 1.21 [95% CI 1.14–1.29]) and passive smoking (pooled RR, 1.07 [95% CI 1.03–1.12]). In children and adolescent, allergic rhinitis was associated with active (pooled RR, 1.40 (95% CI 1.24–1.59) and passive smoking (pooled RR, 1.09 [95% CI 1.04–1.14]). Allergic dermatitis was associated with active (pooled RR, 1.36 [95% CI 1.17–1.46]) and passive smoking (pooled RR, 1.06 [95% CI 1.01–1.11]). Food allergy was associated with SHS (1.43 [1.12–1.83]) when cohort studies only were examined, but not when all studies were combined.

The findings are limited by the potential for confounding and bias given that most of the individual studies used a cross-sectional design. Furthermore, the studies showed a high degree of heterogeneity and the exposure and outcome measures were assessed by self-report, which may increase the potential for misclassification.

Conclusions:
We observed very modest associations between smoking and some allergic diseases among adults. Among children and adolescents, both active and passive exposure to SHS were associated with a modest increased risk for allergic diseases, and passive smoking was associated with an increased risk for food allergy. Additional studies with detailed measurement of exposure and better case definition are needed to further explore the role of smoking in allergic diseases.

Please see later in the article for the Editors' Summary

Published in the journal: Active or Passive Exposure to Tobacco Smoking and Allergic Rhinitis, Allergic Dermatitis, and Food Allergy in Adults and Children: A Systematic Review and Meta-Analysis. PLoS Med 11(3): e32767. doi:10.1371/journal.pmed.1001611
Category: Research Article
doi: https://doi.org/10.1371/journal.pmed.1001611

Summary

Introduction

Allergic rhinitis, allergic dermatitis, and food allergy, in addition to asthma, are extremely common diseases worldwide. Indeed, allergic rhinitis affects 10% to 20% of the general population in Europe and the US [1],[2] and up to 40% of children [3]. The prevalence of allergy to any food varies between 3% and 35% [4], while that of allergic dermatitis reaches 20% in many countries [5]. These diseases have profound consequences on the patient's quality of life and imply a high cost both to the patient and insurance providers [6],[7]. Among infants, these costs reach more than US$4,000 per year per case of food allergy [8].

Recent studies have suggested that these diseases are but one unique set of immunoglobulin-E (IgE)-mediated allergic conditions, linked by the common thread of “atopic march” [9]. This concept postulates that those conditions are a continuous state that starts with dermatitis and food allergy and eventually progresses to asthma and allergic rhinitis. Indeed, these diseases often co-exist in the same patient and can predict the occurrence of each other [10].

Worldwide, the prevalence of allergic diseases has increased substantially in the last few decades [11],[12], which may have two explanations. On the one hand, increased clinician awareness, as well as patient and parental awareness, may have led to improved identification and increased case presentation to physicians [12]. On the other hand, it is possible that this increase is due to changing exposure to known and unknown risk factors [13], and among these factors, smoking may play a role. An increased risk of allergic diseases among individuals exposed to tobacco smoke is biologically plausible as smoking is known to facilitate sensitization to perennial indoor allergens, such as those caused by furry animals, as well as to some outdoor allergens such as pollen [14].

Increased risk of food allergy among infants exposed to tobacco smoke is also plausible. Food allergens are likely to be found in house dust. Swallowed foods are also inhaled or aspirated by infants, and thus, may cause sensitization that could be facilitated by exposure to tobacco smoke. The early and simultaneous exposure to tobacco smoke and food allergens may interfere with the normal development of immunologic tolerance and thus, facilitate sensitization to food [14].

Furthermore, smoking augments nasal responses to allergen in atopic subjects and increases IgE, immunoglobulin G4 (IgG4), and postallergen histamine levels in nasal lavage fluid [15],[16].

Allergic conditions are, in general, more prevalent in children. A potential effect of smoking would have a considerable impact on public health due to the frequency of exposure worldwide. Indeed, children and adolescents are exposed to secondhand smoke in a proportion that varies between 27.6% in Africa and 77.8% in Europe [17] and approximately 14% of all children were exposed to maternal smoking during pregnancy [18].

Several studies have assessed the association between smoking exposure and allergic diseases. In each of the allergic conditions, results were conflicting and alternated between the harmful effects of smoking [14],[19],[20] and protection [21]–[23], while some studies could not find evidence of any effect [24]–[26].

Except for a systematic review and meta-analysis examining the relationship between smoking and asthma in children [27], to our knowledge, there is no comprehensive meta-analysis that examines the evidence for a relationship between smoking and allergic conditions. We, therefore, summarized the scientific evidence and carried out a meta-analysis on exposure to active and passive smoking and the risk of allergic rhinitis, allergic dermatitis, and food allergy among adults and children/adolescents.

Methods

Data Sources and Searches

We searched databases from 1966 to June 30th, 2013, to identify all potentially eligible studies. For Medline, we applied the following algorithm both in medical subject heading and in free text words: (“SEASONAL ALLERGIC RHINITIS” OR “POLLEN ALLERG*” OR “POLLINOSIS” OR “POLLINOSES” OR “HAY FEVER” OR “RHINITIS, ALLERGIC, NONSEASONAL” OR “RHINITIS, ALLERGIC, PERENNIAL” OR “DERMATITIS, ATOPIC” OR ECZEMA OR “FOOD ALLERGIES” OR “HYPERSENSITIVITY, FOOD”) AND (SMOKING OR TOBACCO OR CIGARETT*). We used similar strategies to search Embase and the five regional bibliographic databases of the World Health Organization (AIM, LILACS, IMEMR, IMSEAR, WPRIM). We searched meeting abstracts using the ISI Proceedings database from its inception in 1990 to 2013. We also examined the references of every article retrieved and those of recent reviews of allergic rhinitis and smoking [16],[28]–[33] and established personal contact with clinical researchers to trace further publications or reports. We considered including any relevant article, independently of the language of publication.

Study Selection

Studies were included if: (1) they presented original data from cohort, case-control, or cross-sectional studies (ecologic studies were not included); (2) the outcome of interest was clearly defined as allergic rhinitis, allergic dermatitis, or food allergy; (3) one of the exposure factors was smoking, either by the subjects themselves or their relatives; (4) they provided estimates of odds ratio (OR), relative risk (RR), or prevalence odds ratio and their confidence intervals, or enough data to calculate them. If data on the same population were duplicated in more than one study, the most recent study was included in the analysis. When data for different types or levels of exposure were available in the same study, such as passive smoking, active smoking, or maternal smoking during pregnancy, we considered each type of exposure separately. We developed a standard data-recording form in which we recorded authors, year of publication, study location, sample size, outcome, outcome measurement details, effect estimator (OR, RR, other), effect estimate, 95% CIs, adjustment factors used, and study design including if the International Study of Asthma and Allergies in Childhood (ISAAC) methodology was followed. ISAAC is a large international epidemiologic study on risk factors of allergic diseases, the methods of which are widely used. When further clarification was necessary, we attempted to contact the authors. Abstracts were reviewed independently by two authors (BT and JS).

Quality Assessment

Study quality was assessed using a five-point binary scale specifically developed for this study. The scale is based on the Newcastle-Ottawa scale [34] with modifications in view of standard guidelines and our own judgment. The Newcastle-Ottawa scale is a scoring system that assesses every aspect of an observational epidemiologic study from a methodological point of view. For this meta-analysis, we tried to use those elements that were common to all epidemiologic designs and thus shortened the scale considerably. We used the following criteria labelled as “yes” or “no”: (1) whether assessment of the smoking habit included duration and/or quantity (yes) or not (no); (2) whether rhinitis diagnosis included clinical features and IgE or skin prick test (SPT) measurements (yes) or was based on clinical examination or questionnaire only (no), whether dermatitis diagnosis included clinically assessed diagnosis (yes) or was based on questionnaire information only (no), whether the diagnosis of food allergy was based on clinical diagnosis with SPT, IgE, or open-challenge test (yes) or was based on questionnaire information only (no); (3) whether results were adjusted for age, sex, and at least one other potential confounder (yes) or not (no); (4) whether participation exceeded 80% of the people initially approached (yes) or not (no); and, finally (5) whether the target population was clearly defined (yes) or, on the contrary, based on convenience sampling of subjects such as patients of a single consultation (no). Throughout this assessment, when the information on a specific item was not provided by the authors, we graded this item as “no.” We carried out a pooled analysis on those studies that fulfilled at least three criteria and compared with those that scored fewer than three. As a secondary analysis, we stratified our results on criterion 1 and present the pooled relative risks in Table S2.

Data extraction and quality scoring were performed independently by two reviewers (BT and JS) and the results were merged by consensus. The complete protocol and results for quality scoring are available in Table S1.

Data Synthesis and Analysis

We weighted the study-specific log odds ratios for case control and cross-sectional studies, and log relative risks for cohort studies by the inverse of their variance to compute a pooled relative risk and its 95% confidence interval. For each study, we used the estimate of the effect measure that was adjusted for the largest number of confounders. We present both fixed-effects and random effects pooled estimates but use the latter when heterogeneity was present. Odds ratios from case-control studies were assumed to be unbiased estimates of the relative risk [35].

We used a version adapted to small samples of the DerSimonian and Laird Q test to check for heterogeneity [36]. The null hypothesis of this test is the absence of heterogeneity. To quantify this heterogeneity we calculated the proportion of the total variance due to between-study variance (Ri statistic) [36]. Furthermore, we explored the origin of heterogeneity by restricting the analysis to subgroups of studies defined by study characteristics such as study design, type of exposure (active or passive smoking), and age of the participants (children/adolescents or adults).

To check whether the pooled estimates were significantly different between subgroups we carried out a meta-regression with the global effect as dependent variable and the subgroup variable as moderator.

We assessed publication bias, first visually, using funnel plots and then, more formally, using the test proposed by Egger and colleagues [37]. We also used the trim-and-fill method to correct for potential publication bias. All analyses were performed with the software HEpiMA version 2.1.3 [38] and STATA version 12 with its macros metabias, metareg, and metatrim.

The secondary analyses (children and adolescents/adults, ISAAC/other, cohort and case-control studies combined/cross-sectional studies, high quality/low quality) were planned a priori.

Results

We identified 196 studies, published in 139 different articles and carried out in 51 countries, on active or passive smoking and allergic diseases that met our inclusion criteria (Figure 1). The data from one study were obtained from the authors [39]. We found 97 studies on allergic rhinitis [19],[21],[24],[39]–[118], [91] on allergic dermatitis [19],[20],[22],[24]–[26],[44]–[46],[48],[53],[60]–[65],[67],[73],[75],[76],[78],[83]–[87],[91],[93],[96],[97],[99],[101]–[103],[105]–[107],[110],[111],[116]–[165], and eight on food allergies [14],[23],[26],[73],[126],[136],[166]–[168].

**Fig. 1. Flow diagram for study selection.**

A large majority of the articles retrieved initially were excluded either because they did not provide any effect measure or the outcome was allergy at large. More specifically, of the studies that could have been relevant to our meta-analysis but were finally excluded, eight were discarded because they were an early version of cohort studies updated in subsequent publications [169]–[176]. Other studies published their results several times [175]–[181] in which case we chose to include the most complete report. Some studies were excluded because the outcome was not allergic rhinitis, dermatitis, or food allergy but rather SPT or IgE concentrations [182]–[192]. We also excluded nine studies that used either unspecific outcomes such as nasal symptoms [193],[194], or a mixture of allergic diseases as a single outcome [195]–[201]. Eight studies [138],[202]–[208] were excluded as they did not present any effect measure. Finally, one ecologic study was not considered further [209].

Globally, heterogeneity was substantial overall and similarly high after stratification by design, quality features (including adjustment for confounders), and study population. Given the substantial heterogeneity, we focused on the random effects analyses; however, the fixed effects analyses are presented for comparison and only discussed where they differ.

Allergic Rhinitis

Thirty-four studies on active smoking and 63 studies on passive smoking were available (Figures 2 and 3; Tables 1 and 2). The overwhelming majority of the studies assessed diagnosis through questionnaire and only seven studies used SPT or IgE measurements for the case definition [39],[42],[46],[52],[57],[101],[113]. The study by Wright and colleagues [42] measured SPT reactivity but used a definition of physician diagnosed allergic rhinitis that included both SPT-positive and SPT-negative children. More than half of the studies used ISAAC criteria for the definition of allergic rhinitis. Finally, 11 studies assessed maternal smoking during pregnancy [44],[45],[47]–[49],[60],[70],[81],[93],[99],[114].

**Fig. 3. Study-specific and random effects pooled relative risks of passive smoking and allergic rhinitis.**

**Tab. 1. Relative risks and 95% confidence intervals of allergic rhinitis by smoking exposure in case-control and cohort studies.**

**Tab. 2. Relative risks and 95% confidence intervals of allergic rhinitis by smoking exposure in cross-sectional studies.**

Table 3 shows the results for associations between smoking and allergic rhinitis.

**Tab. 3. Pooled relative risks and 95% confidence intervals of allergic rhinitis and smoking.**

Active Smoking

Using random effects analysis, there was no significant association between active smoking and the risk of allergic rhinitis when all studies are considered (RR = 1.02; 95% CI 0.92–1.15). Using fixed effect analysis for all studies, there was a significant association between active smoking and risk of rhinitis (RR = 1.06, 95% CI 1.03–1.08); however, this may be explained by the considerable amount of heterogeneity due to differences in designs, case, and exposure definitions and adjustment for confounders. It is remarkable that, under the fixed effects model, the result of the cross-sectional subgroup (RR = 1.09; 95% CI 1.06–1.12) is statistically significant and opposed to the result of the cohort studies subgroup (RR = 0.87; 95% CI 0.82–0.93).

When restricting the analysis to the ten studies carried out on children and adolescents, active smoking was associated with an increased pooled relative risk of 1.40 (95% CI 1.24–1.59). In further sub-group analyses, the association was significant in the studies that used the standardized ISAAC protocol (RR = 1.50, 95% CI 1.35–1.66), but not those that used their own protocol (RR = 0.96, 95% CI 0.88–1.08). A reverse association between active smoking and allergic rhinitis was observed in adults only (RR = 0.90, 95% CI 0.82–0.99)

Passive Smoking

Using random effects analysis, there was a significant association passive smoking and allergic rhinitis (RR = 1.10, 95% CI 1.06–1.15). Similar findings were observed in subgroup analyses by adjustment for confounding variables (RR = 1.07; 95% CI 1.03–1.12 for full adjustment, RR = 1.15; 95% CI 1.04–1.27 for incomplete adjustment), quality scores (RR = 1.10; 95% CI 1.04–1.15 for high quality, RR = 1.10; 95% CI 1.02–1.19 for low quality), and for cross-sectional studies (RR = 1.09; 95% CI 1.05–1.14); however, there was no significant association between passive smoking and allergic rhinitis when restricting the analysis to cohort studies (RR = 1.14; 95% CI 0.96–1.34) or case-control studies (RR = 1.14; 95% CI 0.46–2.82).

In subgroup analyses based on age group, a significant association between passive smoking and allergic rhinitis was observed in adults only (RR = 1.17; 95% CI 1.03–1.32) and in children and adolescents (RR = 1.09; 95% CI 1.04–1.14). For maternal pregnancy smoking, there was no evidence for a a significant increase in the risk of allergic rhinitis in the offspring (RR = 1.07; 95% CI 0.92–1.28).

Publication Bias

The funnel plot of active smoking seems to be slightly skewed to the left, which indicates a potential lack of studies that favor a positive association of the disease with smoking (Figure 4). However, the Egger's test of asymmetry yielded a nonsignificant p-value of 0.27 and no hypothetical study was suggested as missing in the trim-and-fill procedure. The funnel plot for passive smoking (Figure 5) and the corresponding results of the Egger's test did not show any evidence of publication bias (p = 0.53), but two new studies were imputed in the trim-and-fill procedure yielding a modified pooled relative risk of 1.10 (95% CI 1.05–1.14).

**Fig. 4. Funnel plot of relative risk versus standard error of relative risk: allergic rhinitis, active smoking.**

**Fig. 5. Funnel plots of relative risk versus standard error of relative risk: allergic rhinitis, passive smoking.**

Allergic Dermatitis

We retrieved 33 studies on active smoking and 58 studies on passive smoking (Figures 6 and 7; Tables 4 and 5). About one-third of the studies used ISAAC criteria for case definition. Nineteen studies assessed maternal smoking during pregnancy [44],[45],[48],[83],[93],[99],[121],[127],[128],[130],[133]–[136],[140], [153], [158], [160], [164].

**Fig. 7. Study-specific and random effects pooled relative risks of passive smoking and allergic dermatitis.**

**Tab. 4. Relative risks and 95% confidence intervals of dermatitis by smoking exposure in case-control and cohort studies.**

**Tab. 5. Relative risks and 95% confidence intervals of allergic dermatitis by smoking exposure in cross-sectional studies.**

**Tab. 6. Pooled relative risks and 95% confidence intervals of allergic dermatitis and smoking.**

Active Smoking

Using random effects analysis, active smoking was significantly associated with an increased risk of allergic dermatitis overall (RR = 1.21; 95% CI 1.14–1.29) and in both adults (RR = 1.14; 95% CI 1.07–1.22) and in children and adolescents (RR = 1.36; 95% CI 1.17–1.46)

In sub-group analyses, the association between active smoking and allergic dermatitis was similar based on age, adjustment for confounding, quality scores, and for cohort studies and cross-sectional studies, although there was no significant association between active smoking and allergic dermatitis observed in the four case-control studies (RR = 1.47; 95% CI 0.92–2.32).

Passive Smoking

Using random effects analysis, passive smoking was associated with an increased risk of allergic dermatitis in the general population (RR = 1.07; 95% CI 1.03–1.12).

In sub-group analyses, the association between passive smoking and allergic dermatitis was significant when restricted to cross-sectional studies (RR = 1.07; 95% CI 1.02–1.12), but not for cohort (RR = 1.09; 95% CI 0.96–1.23) or case-control studies (RR = 1.10; 95% CI 0.88–1.38). A significant association between passive smoking and allergic dermatitis was observed for those studies with adjustment for confounding variables (RR = 1.08; 95% CI 1.03–1.13) and higher quality scores (RR = 1.11; 95% CI 1.05–1.18), but not those without adjustment (RR = 1.06; 95% CI 0.98–1.14) or low quality scores (RR = 1.03; 95% CI 0.96–1.11).

A significant association was observed in those studies including adults only (RR = 1.26; 95% CI 1.02–1.55) and in those including children and adolescents only (RR = 1.06; 95% CI 1.01–1.11). No significant association was observed between maternal smoking and allergic dermatitis (RR = 1.07; 95% CI 0.96–1.19).

Publication Bias

The Egger's test for asymmetry of the funnel plot of active smoking (Figure 8) yielded a p-value of 0.28 and no study was added in the trim-and-fill procedure. No asymmetry was detected for passive smoking (Figure 9) through the Egger's test (p = 0.33) but the trim-and-fill procedure suggested that ten potential studies were missing. The modified random effects pooled relative risk was 1.04 (95% CI 1.00–1.08).

**Fig. 8. Funnel plots of relative risk versus standard error of relative risk: allergic dermatitis, active smoking.**

**Fig. 9. Funnel plot of relative risk versus standard error of relative risk: allergic dermatitis, passive smoking.**

Food Allergies

We retrieved only one study for active smoking and six studies for passive smoking, while three studies assessed maternal smoking during pregnancy (Figure 10; Table 7). All were carried out in children or infants populations.

**Tab. 7. Study-specific and 95% confidence intervals of food allergies and smoking.**

Active Smoking

The only available study on active smoking and food allergies did not show any significant association (RR = 0.58; 95% CI 0.21–1.55).

Passive Smoking

Using random effect analysis, including the six studies investigating exposure to secondhand smoke, showed that passive smoking was associated with a nonsignificant increase of the risk of food allergy (RR = 1.16; 95% CI 0.85–1.59). When the only cross-sectional study was excluded and the analysis was based on five cohort studies, passive smoking was significantly associated with an increased risk of food allergy (RR = 1.43; 95% CI 1.12–1.83) (Table 8). As with allergic rhinitis and allergic dermatitis, we could not detect any association with maternal smoking during pregnancy with food allergies (RR = 1.01; 95% CI 0.56–1.82) (Table 8).

**Tab. 8. Pooled relative risks and 95% confidence intervals of food allergies and smoking.**

Publication Bias

The funnel plot (Figure 11), although not a valuable way to assess publication bias in this case due to the small sample size, did not provide evidence of asymmetry (p = 0.09).

**Fig. 11. Funnel plot of relative risk versus standard error of relative risk: food allergy, passive smoking.**

Meta-regression

The meta-regression with the pooled log relative risk as a dependent variable and the population variable as a moderator, introduced in the model as a dichotomous variable (adults/pediatric population), yielded the following results for the children and adolescents when compared to the adults: allergic rhinitis and active smoking: RR = 1.55, 95% CI 1.30–1.84; allergic rhinitis and passive smoking: RR = 0.93, 95% CI 0.81–1.06; allergic dermatitis and active smoking: RR = 1.18, 95% CI 1.01–1.39; and allergic dermatitis and passive smoking: RR = 0.83, 95% CI 0.65–1.06. These results suggest that the associations between allergic rhinitis and allergic dermatitis with active smoking are significantly greater among children and adolescents than among adults. Although these meta-regression RRs were not statistically significant at a 95% level for passive smoking, in Tables 3 and 6 we present the results of children and adolescent populations as a subgroup both for active and passive smoking.

Sub-group Analyses in Children and Adolescents

We calculated the random effects pooled relative risks for children cohort studies, then for children cohort studies and case-control studies combined. For cohort studies, passive smoking was not significantly associated with allergic rhinitis (RR = 1.14; 95% CI 0.96–1.34, nine studies), or allergic dermatitis (RR = 1.09; 95% CI 0.96–1.23, 14 studies), but was significantly associated with an increased risk of food allergy (RR = 1.43; 95% CI 1.11–0.83, five studies). For cohort and case-control studies combined, passive smoking was significantly associated with an increased risk for allergic rhinitis: RR = 1.17 (95% CI 1.00–1.38, ten studies), but not for allergic dermatitis: RR = 1.07 (95% CI 0.96–1.19, 18 studies).

Sensitivity Analysis

To further evaluate the possibility that the results obtained for children/adolescents were due to publication bias, we assumed that cross-sectional studies are the kind of studies that are most probably rejected by journals in case of null results and recalculated our pooled estimates under the following extreme assumptions: (1) published cross-sectional studies are only half of the studies of smoking and allergic rhinitis ever conducted among children, (2) all unpublished studies found an RR of 1, (3) the unpublished studies found the same prevalence of allergic diseases as the average of the published studies. Under these extreme assumptions, the random effects pooled estimates for active smoking still show a significant increase in risk: RR = 1.16 (95% CI 1.08–1.25) for allergic rhinitis and RR = 1.13 (95% CI 1.05–1.21) for allergic dermatitis.

Discussion

The results of our systematic review and meta-analysis suggest that active and passive smoking are associated with a modest increase in risk for some allergic diseases. In the overall population, active smoking was associated with a modest increase in the risk for allergic dermatitis but not allergic rhinitis, while passive smoking was associated with modest increases in the risks for both allergic dermatitis and allergic rhinitis. Among children and adolescents, we observed significant associations between both active and passive smoking and allergic rhinitis and allergic dermatitis, and passive smoking was associated with an increased risk for food allergy

In children and adolescents, while the observed increase in risk for allergic diseases associated with smoking was small, the findings are important given that to the prevalence of active and passive smoking in this population can be high. Worldwide, 14% of adolescents aged 13 to 15 are active smokers with some countries reaching a prevalence of 40%, and nearly 25% of the children who smoke have smoked their first cigarette before the age of 10 years [210]. Furthermore, in the US, more than one-third of children live with at least one adult smoker [211]. In other parts of the world, passive exposure to tobacco among children is even higher as nearly half of children were exposed to tobacco smoke at home [212]. On the basis of the figures above, in countries with high smoking prevalence we estimate that 14% of allergic rhinitis and 13% of allergic dermatitis are attributable to active smoking [213]. Eliminating active smoking in children and adolescents would then prevent one in every seven cases of allergic rhinitis and one in every eight cases of allergic dermatitis.

That age is an important effect modifier for the relation between tobacco exposure and risk of allergic diseases is biologically plausible. The US Surgeon General has suggested that the immaturity of the respiratory, nervous, and immune systems in children may make them vulnerable to health effects of smoking [214]. Furthermore, unlike adults, children have limited options for avoiding exposure to secondhand smoke and are unable to reduce the quantity of products inhaled [214].

Our finding that maternal exposure is not associated with the risk of allergic diseases in the offspring confirms the results from a previous meta-analysis that focused on the risk of allergic sensitization measured through skin prick positivity or IgE concentrations [30]. It is possible that the lack of observed association is due to the existence of bias given that parents of children at high risk of allergy may selectively avoid smoking during pregnancy.

The findings from our meta-analysis are subject to several limitations. The majority of studies were cross-sectional, a design that does not allow for causal inference and can overestimate relative risks given its reliance on prevalence ratios. When restricted to cohort studies our analyses showed that many of the results were no longer significant, especially for the subgroup analysis in children and adolescents. There is then some evidence that the findings may be impacted by study design.

Residual confounding (confounding remaining after adjustment) may explain some of our findings. For some of our analyses, we were unable to detect meaningful differences in the results between studies that had incomplete adjustment for confounders and those with more complete adjustment for confounders and our findings were broadly similar when restricting the analyses to studies with higher quality scores. However, there are likely to be other factors, such as genetic factors that were not controlled for and may play a role in the relationship between smoking and allergic diseases. Although publication bias cannot be ruled out, its magnitude is likely to be low as shown by the robustness of our sensitivity analysis.

Several studies assessed allergic diseases through self-report only, which can lead to misclassification of allergic and non-allergic conditions. Similarly, the findings are limited by measurement error in the smoking exposure given that a majority of studies assessed exposure to smoking in a qualitative fashion and often on a yes/no basis instead of using a quantitative assessment. Misclassification and measurement error in SHS assessment may result from a respondent's lack of knowledge about current or past exposure, biased recall, whether intentional or unintentional, and the difficulty in characterizing an exposure in complex indoor environments [215]. A standard set of items to identify passive smoking in distinct settings is needed [216]. If misclassification exists, it is probable that the outcome misclassification is not differential in regard to smoking and, similarly, measurement error in smoking assessment is not differential in regard to diagnosis. In this case, the results would be biased towards the null value, which means that the association with smoking observed in our meta-analysis is underestimated.

In our subgroup analyses, we were unable to identify any factors that accounted for study heterogeneity. Given the high heterogeneity estimates, we focused our interpretation on the random effects estimates. The random effects model gives increased weights to the effect of small studies, which may introduce bias in the estimation. It is worth noting that for some of the analyses, the fixed effects and random effects estimates differ substantially; this may be due to differences in case or exposure definition and in adjustment for potential confounders. AU: ok to delete>it appears that you have said this in the previous sentence.

Our subgroup analyses found stronger evidence for associations between smoking and allergic diseases in children and adolescents than adults. Furthermore, our meta-regression suggested that the association between active smoking and allergic disorders is larger in children and adolescents than in adults, which advocates for a transient effect through life. This finding is in accordance with the “atopic march” concept that suggests that the sequence of sensitization that starts in childhood may show a tendency to spontaneous remission later in life [217]. It is then plausible that sensitization to tobacco is mitigated by increasing age. Further research is needed to verify whether the association between smoking and risk of allergy in adults is similar for those who started smoking as an adult and those who started smoking during childhood or adolescents.

Future studies should minimize measurement error in the exposure and misclassification bias in the outcome. These studies should avoid cross-sectional designs, use extensive validated questionnaires in order to assess smoking in a quantitative fashion, and should be based on an optimal diagnosis of allergic diseases.

Supporting Information

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