Introduction

The prevalence of cigarette smoking in the United States among adults was 17.8% as recently as 2013, with significantly high tobacco use rates (21.9%) among young men aged 18–24 [1]. High rates of tobacco use in American households over the last decade has translated to the exposure to tobacco smoke of 88 million non-smoking children and adults ≥3 years of age between 2007–2008, and of 40% of children ages 3–11 between 2011–2012, resulting in a number of adverse health effects including middle ear disease and eustachian tube dysfunction (ETD) [2–4]. It has been hypothesized that environmental tobacco smoke may lead to ETD as a result of disruption in mucociliary clearance mechanisms of the eustachian tube, chemical irritation, allergic inflammation of the mucosa in response to chemicals contained in the tobacco smoke, and overall immunosuppressive effects secondary to tobacco smoke exposure that could lead to greater susceptibility to bacterial infections of the middle ear [5]. However, a survey of the literature conducted in 1995 did not find sufficient support in prior studies for the association of passive smoking with ETD; they cited the inadequate inclusion of other risk factors, potentially biased inclusion and exclusion criteria, and inappropriate use of statistical tests as potential shortcomings of the reviewed literature [6]. Eustachian tube dysfunction often manifests as acute otitis media with effusion (OME), recurrent acute otitis media with effusion (RAOME), or chronic otitis media with effusion (COME) [7].

Early studies examining the risk factors in children for developing eustachian tube dysfunction and need for tympanostomy tube placement for the treatment of RAOME observed that children who lived in households with at least one parent who smoked were more likely to require surgical management of OME [8,9]. Several subsequent case control studies found significantly increased odds of environmental tobacco smoke exposure in children with RAOME and OME [10–14]. Large birth-cohort studies conducted in the United Kingdom and Norway corroborated findings that children with mothers who smoked had a higher risk of developing middle ear disease [15,16]. Results of recent meta-analyses also support an association between middle ear disease and environmental tobacco smoke exposure [17,18]. Indeed, it has been shown that there are elevated serum cotinine levels and impaired mucociliary clearance mechanisms in the adenoid tissue of young children with OME [19,20].

Of importance is the reconciliation of conflicting findings regarding the link between passive smoking and ETD, particularly in light of the great physical and financial costs associated with treatment of recurrent middle ear disease in children. While one study shows that a decline in clinic visits for OME from 1993–2006 may reflect a decline in environmental tobacco smoke exposure of children during those years [21], the prevalence of children exposed to tobacco smoke currently remains high [2]. Nevertheless, there have been studies that have not found an elevated prevalence of passive smoking in those with COME or surgically treated RAOME [22,23].

To resolve these conflicting findings in the literature, we utilized results of a nationally representative sample of adult and pediatric patients in the NHANES 2005–2010 cycle to examine the association between passive or active smoking and ETD.

Materials & Methods

Results

A total of 2,977 children and adolescents aged 12–19 years of age participated in tympanometry measurements in NHANES 2005–2006, 2007–2008, and 2009–2010 cycles. Baseline characteristics are listed in Table 1. Children and adolescents with ETD were more frequently male, obese, and had a higher prevalence of sinus problems, cold or earache within 24 hours prior to tympanometry.

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Table 1. ^aDemographic Characteristics of children and adolescent participants by ETD, National Health and Nutritional Examination Surveys, 2005–2010 (N = 2977).

https://doi.org/10.1371/journal.pone.0163926.t001

Median (IQR) for serum cotinine levels were 0.06 ng/mL (0.02–0.76). In total, 1,559 children and adolescents were exposed to environmental tobacco smoke based on serum cotinine levels. Using NHANES standardized population weights, 5.5% of those exposed to ETS had ETD [median (IQR) middle ear pressures -114 (-156; -36)]

Compared to unexposed adolescents, the odds ratios (95% confidence interval) of ETD for those exposed to ETS in ages 12–15 in the first, second and third tertile of cotinine concentrations were, respectively, 1.38 (0.53–3.60), 0.99 (0.42–2.30) and 2.67 (1.12–6.34); p-value for linear trend = 0.45, and in ages 16–19 were 1.28 (0.48–3.41), 0.99 (0.40–2.48), and 2.86 (1.19–6.88); p-value for the linear trend = 0.10 (Table 2).

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Table 2. Multiple logistic regression examining the association of serum cotinine levels and eustachian tube dysfunction in children and adolescents exposed to environmental tobacco smoke from the National Health and Nutrition Examination Survey 2005–2010 Cohorts.

https://doi.org/10.1371/journal.pone.0163926.t002

Discussion

We report that exposure to environmental tobacco smoke increases ETD as defined by tympanometry measurements in those with elevated serum cotinine levels in a nationally representative sample of children and adolescents in the United States.

Studies of prolonged tobacco smoke exposure in rats have shown a loss of cilia, squamous metaplasia, and goblet cell aplasia followed by hyperplasia in the eustachian tube mucosa over the course of months [24,25]. Smoke exposure may produce mucosal inflammation in the middle ear as evidenced by increased production of tumor necrosis factor-α in murine middle ear epithelial cells [26]. Long-term passive smoking may result in increased mucous secretion into the eustachian tube, as demonstrated in rats over a 6-month period of exposure; when combined with smoke-induced impaired mucociliary clearance of the eustachian tube, obstruction may occur resulting in middle ear disease and OME [5,20,24]. Indeed, further studies in rats have found that tobacco smoke exposure results in prolonged mucociliary clearance times and an inability to equilibrate negative middle ear pressure with increasing smoke exposure [27].

This study supports the findings of recent meta-analyses evaluating the association between middle ear disease and environmental tobacco smoke exposure, which reported an odds ratio of 1.37–1.62 of developing middle ear disease and an odds of 1.83–1.86 of undergoing surgery for middle ear disease in children who lived with a smoker [17,18]. Indeed, it has been shown that elevated serum cotinine levels are associated with a 38% higher rate of new episodes of OME in children ≤3 years of age in one study, and histopathologic analysis of adenoid tissue in passive smokers with OME has demonstrated significantly impaired mucociliary transport relative to non-smokers with OME [19,20].

Because middle ear effusion typically occurs in the setting of negative middle ear pressure caused by ETD, tympanometry is a useful tool to assess eustachian tube function [28–30]. Two separate studies of approximately 800 six-to-seven-year-old children found that passive smokers had increasingly negative middle ear pressures by tympanogram and a higher frequency of middle ear effusion in a dose-dependent manner [28,29]. The first study conducted in 1989 found a trend toward greater middle ear negative pressure by tympanometry with increasing serum cotinine concentration, with an adjusted odds ratio of 1.13 for every two fold increase in cotinine concentration [29]. The second study conducted in 1990 reported a significant trend of growing prevalence of Type B tympanograms with increasing numbers of smokers in the home (χ² = 4.15, p<0.05) [28]. Our cohort demonstrated similar findings in support of the association among passive smoke exposure and increased ETD as defined by negative middle ear pressure. A primary difference between our study and the aforementioned studies is the stratification of those with ETD. We defined ETD as middle ear pressures below 100 mm H₂O, an objective and easily reproducible measurement indicative of ETD. In contrast, prior studies have only examined the association between tympanogram type and the number of smokers in the household [28,29], which is less specific and more subjective, especially in regard to classifying tympanogram type.

Previous studies have also found a positive association between serum cotinine concentration and increasingly negative middle ear pressure [29]. Our results indicate that a serum cotinine above 0.414 ng/mL may be useful to indicate a threshold for and subsequent correlate for the presence middle ear disease for at risk children. Moreover, we demonstrate that in children exposed to ETS at high concentrations, there is a significantly higher odds of ETD. It may be that children have variable susceptibilities to the effects of environmental tobacco smoke and mucociliary clearance of the eustachian tube resulting in unpredictable degrees of ETD. Moreover, because the half-life of cotinine is up to 20 hours, children who had been exposed just prior to being tested may have higher levels of cotinine regardless of the number of smokers in the household, resulting in serum cotinine levels that are not representative of the degree of chronic tobacco smoke exposure. The metabolism of nicotine to cotinine may also vary with age, sex, diet, and inhibitors of the liver enzymes CYP2A6 responsible for nicotine metabolism [31]. The aforementioned factors may affect serum cotinine concentration and confound the relationship between ETD and cotinine levels, possibly accounting for the non-linearity of that relationship within this study.

The strengths of this study include analysis of tympanometric and smoke exposure information available in a large, nationally representative cohort of pediatric patients that allows for adjustment of a number of possible confounders. Nevertheless, inherent limitations of this study include tympanometric measurements and cotinine levels as secondary measurements of ETD and tobacco smoke exposure, respectively. Moreover, this study is cross-sectional, and therefore causality with respect to exposure variables cannot be determined. While this study attempts to estimate the prevalence of eustachian tube dysfunction in the general population, it must be recognized that the analysis is vulnerable to the limitations of selection bias, imperfect response rate, and individuals with missing data.

In all, our results suggest an association between passive smoking and ETD in children. Further investigation of longitudinal cohorts would provide greater insight into the long-term consequences of prolonged smoke exposure on eustachian tube function, especially as passive smokers age into adolescence and adulthood. Opportunities for future study include establishing a more defined relationship between environmental tobacco smoke exposure and ETD. Presently, it is unknown what cumulative dose of tobacco smoke exposure is required to produce negative middle ear pressures and subsequently ETD. Moreover, given recent insights into the possible underlying mechanism of ETD caused by smoke exposure, it may be clinically relevant to identify children that may be at a greater risk for developing ETD at lower dosages of smoke exposure, such as those predisposed to allergies and atopic disease.

Acknowledgments

This work was presented at the 2015 American Academy of Otolaryngology Annual Meeting in Dallas Texas on September 28^th 2015.