Association of exposure to hydrocarbon air pollution with the incidence of atopic dermatitis in children

Atopic dermatitis (AD) is a common chronic relapsing inflammatory skin disease associated with intense itching and recurrent eczematous lesions [1]. Hanifin-Rajka major diagnostic criteria including pruritus, typical morphology, chronic or chronically relapsing dermatitis, and personal or family history of atopy have been used most frequently to diagnose AD in Taiwan [2]. In a process referred to as the “atopic march,” food allergy and AD are usually an early sign of other subsequent allergic disorders [3, 4]. Up to 80% of the children with AD eventually develop allergic rhinitis or asthma later in their childhood [5]. AD begins most commonly in the early childhood. Approximately 15–30% of the children and 10% of the adults are affected worldwide [6, 7]. In approximately 80% of the cases, childhood AD did not persist beyond 8 years of age and in less than 5% of the cases, it persisted into adulthood. Particularly, prolonged persistence of AD (more than 10 years) was associated with greater severity of the disease [8]. AD obviously influences patients’ quality of life and has financial implications. Itching and scratching are the two main symptoms that affect the quality of life in childhood AD. These symptoms affect the quality of sleep, thus requiring a treatment regime, affect the ability to participate in sporting activities, and result in social embarrassment [9]. The 2006 report from the American Academy of Dermatology, the most comprehensive contemporary research on the economic impact of AD, revealed that the total annual burden of AD was $4.228 billion. AD was associated with the fifth-highest overall treatment cost among all skin diseases in the US, placing a tremendous financial burden on the society [10]. Hence, it is critical to identify and control the risk factors in susceptible subjects for successful treatment and prevention of childhood AD.

Over the past 30 years, the worldwide prevalence of AD has increased considerably, particularly in industrialized countries [6]. Although both genetic and environmental factors are involved in the etiology of AD, the recent increase in the prevalence of is mainly attributed to environmental factors [11]. There is growing evidence suggesting that air pollution may act as an important environmental risk factor for the development and aggravation of childhood AD [12‐15]. A variety of air pollutants such as particulate matter (PM); nitrogen oxide compounds (NO_x); environmental tobacco smoke (ETS); traffic-related air pollution (TRAP) caused by pollutants such as PM, NO, NO₂, SO_2, CO, CO₂, O₃; and volatile organic compounds (VOCs) have been mentioned as risk factors for the development or aggravation of AD [11]. Skin barrier dysfunction is considered the initial step in the development of AD. The skin barrier plays pivotal roles in immune surveillance and homeostasis and in preventing the penetration of irritants and allergens [6, 16, 17]. Air pollutants may induce oxidative stress in the skin, leading to skin barrier dysfunction or immune dysregulation [18, 19]. TRAP, especially O₃, has been observed to alter the resident skin flora and cause predisposition to S. aureus colonization [18]. Other dust particles and diesel exhaust particulates have also been demonstrated to exert toxicological effects on human skin [19]. Further research is needed to determine the mechanism behind the role of air pollutants in AD.

Although several studies support the development or aggravation of childhood AD due to air pollutants, current evidence regarding the skin aspects of air pollution remains relatively scarce in contrast to that regarding airway diseases such as asthma [20]. Moreover, previous studies have limitations such as inaccurate study design and assessment and the presence of confounding variables such as obesity, genetics, and comorbidities. For example, several studies have considered a mixture of substances including ETS, VOCs, and NO_x, representing a combined impact on human health. Selection bias was also observed due to potential misclassification in some cross-sectional studies, since the diagnosis of AD was not confirmed by a physician and was based simply on reports from the patients or their parents [11].

In the present study, we focused on the association between hydrocarbons and the development of childhood AD. Total hydrocarbons (THCs), which are organic chemical compounds consisting of non-methane hydrocarbons (NMHCs) and methane (CH₄), are responsible for approximately 85% of the global energy consumption due to rapid industrialization and urbanization. It is unclear whether air pollutants released during combustion of hydrocarbons, particularly CH₄, affect the body’s largest organ, the skin. Hence, we conducted this nationwide retrospective study using real-world data in Taiwan to evaluate the effect of exposure to these air pollutants on the risk of AD in children.

Altogether, 7304 children (2.96%) were diagnosed with AD within the cohort of 246,844 children (between January 1, 2001 and December 31, 2012). The demographic data of the patients are presented in Table 1. The mean age of the patients was 6.50 years (SD: 3.39 years). The proportion of boys and girls was similar (51.6% vs. 48.4%). Most of the participants were from families belonging to the lowest monthly income category (83.4%) and resided in the most urbanized areas (33.2%).

We collected the data of participants under conditions of THC, NMHC, and CH₄ exposure based on the location of the Taiwan Air Quality Monitoring station. Concentrations of each air pollutant were categorized by quartiles, ranging from Q1 (the lowest concentration) to Q4 (the highest concentration). Tables 2, 3 and 4 show the baseline characteristics of children exposed to four levels of THC, NMHC, and CH₄ concentrations. Children with the highest THC, NMHC, and CH₄ exposure concentrations lived in areas with higher urbanization.

Table 5 shows the increase in incidence rate of AD from 0.69 to 6.45, from 1.72 to 4.37, and from 0.73 to 7.74 per 1000 person-years with an increase in the THC, NMHC, and CH₄ exposure concentrations, respectively. In the multivariable Cox proportional hazard regression, the adjusted HR for AD increased with an increase in the THC, NMHC, and CH₄ exposure concentrations from 1.65 (95% CI: 1.47–1.84) to 10.6 (95% CI: 5.85–7.07), from 1.14 (95% CI: 1.06–1.24) to 2.47 (95% CI: 2.29–2.66), and from 1.70 (95% CI: 1.52–1.89) to 11.9 (95% CI: 10.8–13.1), respectively when compared with the corresponding exposure concentrations in the Q1 quartile (1.00) (Table 5).

Figure 1 shows the Kaplan–Meier curves for the cumulative incidence separated by pollutant concentrations in each quartile (Q1, Q2, Q3, and Q4). During a follow-up of 12 years, the cumulative incidence rates of AD were lower among children living in areas with lower quartile concentrations of THCs, NMHCs, and CH₄ than among those living in areas with higher quartile concentrations.

In the present population-based longitudinal study, we demonstrated that Taiwanese children exposed to higher concentrations of THCs, NMHCs, and CH₄ were at an increased risk of developing AD regardless of adjustment for potential confounding factors such as age, sex, monthly income, and urbanization level. Our cohort study also revealed a clear dose-response relationship between air pollution and AD. The present study is distinctive in several respects. We assessed the real-world data from the Children’s File. Children are more susceptible than adults to the effects of air pollution, as their lungs and immune systems are still developing, they breathe faster than adults, and their respiratory tracts are more permeable [25]. AD diagnosis in our study was confirmed by a physician, minimizing the potential for selection bias. Our study might be one of the first to investigate the relationship between AD and CH₄, an active greenhouse gas, to identify the dermatological effect of a single component.

Taiwan is located in East Asia, the most polluted region in the world. Currently, it is facing severe air pollution, especially in major urban areas, due to rapid increase in population and industrial development as well as transportation demands. While the number of children with AD continues to increase in both developed and developing countries, the prevalence of AD in Taiwan appears to have grown dramatically over recent decades [26]. According to the Taiwan National Study 2000 to 2007, the overall 8-year prevalence of AD is approximately 6.7% [27]. Due to such rapid growth in the number of AD cases with increased urbanization and industrialization, the role of environmental factors, especially airborne pollutants, has garnered increasing attention. Over the past 10 years, a number of studies have shown that TRAP and air pollutants such as PM, VOCs, and ETS are associated with the development and exacerbation of AD. Multiple comprehensive studies have been conducted in pediatric age group with a large dataset. In a French study that enrolled 4907 children who had resided at their current addresses for 3 years or longer, lifetime AD was significantly associated with 3-year averaged concentrations of PM₁₀, NO₂, NO_x, and CO (adjusted odds ratios [ORs]: 1.13, 1.23, 1.06, and 1.08, respectively) [28]. In a prospective birth cohort study from Munich that included 2860 children aged 4 years, NO₂ exposure (per 6.4 mg/m³) was associated with both physician-diagnosed AD and parental reports of AD symptoms (ORs: 1.18 and 1.11, respectively) [29]. In a cross-sectional study from Shanghai during 2011–2012 that enrolled 3358 preschool children, a positive correlation was observed between increased gestational and lifetime exposure to a mixture of SO₂, NO₂, and PM₁₀ and childhood AD (ORs: 1.78 and 1.87, respectively) [30]. In 91,642 children from the US National Survey of Children’s Health, moderate to severe eczema was associated with elevated levels of NO₃ and PM_2.5 (ORs: 1.249 and 1.070, respectively) [31]. A few studies also revealed that prenatal exposure to VOCs and ETS are likely to induce a Th2-dominant immune status or the development of AD after birth [32‐34]. In the present study, we observed that the adjusted HRs for AD increased with an increase in the exposure concentration of THCs (from 1.65 to 10.6), NMHCs (from 1.14 to 2.47), and CH₄ (from 1.70 to 11.9) when compared with exposure to the corresponding concentrations in the Q1 quartile.

Rapid industrialization coupled with urbanization has led to accumulated global waste production due to the continuously increasing demand for energy. Hydrocarbons, which are organic chemical compounds consisting of hydrogen and carbon, form the basis of the majority of global energy production via fossil fuel combustion and evaporation of gasoline. Both NMHCs and CH₄ are composed of THCs. Most of the hydrocarbons on earth are naturally derived from decomposition of organic matter in petroleum and are generated by human activity. NMHCs, often referred to as VOCs, are unstable forms of substances such as benzene and their derivatives.

A great number of animal and epidemiological studies have reported negative effects of VOCs on skin barrier function. A prospective study in Korea revealed that an increase of 1 ppb in outdoor benzene and total VOC concentrations was associated with a 27.38 and 25.86% increase in AD symptoms, respectively [14]. Kim et al. observed that exposure to airborne formaldehyde leads to an increase in transepidermal water loss and stratum corneum pH in healthy subjects as well as in AD patients [15]. In a rat AD model, Han et al. showed that formaldehyde exposure aggravated pruritus and skin inflammation. These results suggest that formaldehyde penetrated the injured skin barrier and exacerbated Th1 responses and serum IgE levels in AD rats [35]. In several previous studies, certain VOCs and polycyclic aromatic hydrocarbons have been proposed to activate the ligand-activated transcription factor AhR, leading to downstream activation of inflammation and itch mediators such as artemin [36, 37]. Adverse health effects of direct exposure to CH₄, a nontoxic greenhouse gas, have been scarcely reported except suffocation due to high concentrations. The present study is the first one to suggest that CH₄ exposure contributes to an increased risk of AD development. Rapid industrialization and urbanization contribute to increased CH₄ production. Increasing urbanization has been accompanied by a rise in larger cities with increasing population densities. Densely populated areas aggravate the spread of contagious infectious diseases. Emerging infectious diseases may worse skin inflammation caused by AD [38]. Further studies are needed to confirm this hypothesis.

Although our study was a large-scale population-based cohort study, it has several limitations. Although AD is a complex and multifactorial disorder, we did not consider other environmental factors such as temperature, humidity, and ultraviolet light that might interact with airborne pollutants [39]. Other potential risk factors for AD such as atopic family history, dietary factors, pet and prenatal exposure, and even the severity of AD could not be estimated in the present study due to the lack of information in the Children’s File. The reported prevalence of AD was 7.2% in a previous study wherein 11,874 students from 14 schools in central Taiwan completed the International Study of Asthma and Allergies in Childhood questionnaire [40]. However, the present study revealed a prevalence of 2.96% during the study period. This finding implies that AD might have been underdiagnosed in the present study, particularly in those with mild or infrequent symptoms. This disparity in findings might be explained by the following factors. We defined AD as at least three medical records of ICD-9-CM codes 691 or 691.8 due to the chronic and relapsing nature of AD and to avoid overdiagnosis. Thus, although this approach reduced the risk of false positives, it might have led to a low prevalence of AD diagnosis during the study period. Patients with mild AD may not seek medical services or be coded for the clinical diagnosis of AD by a physician. Moreover, the selection of another ICD-9-CM code for the diagnosis of AD by a physician may also lead to underestimation of AD prevalence. Furthermore, due to the inclusion characteristics of our database, children enrolled during the study period who became older than 18 years of age in 2012 were also taken into account. Thus, the exposure measurement might have been calculated partially after the age of 18. Exposure to indoor air pollution was not investigated in our study. Hence, our results might not represent the overall effect of air pollution on AD [41].

Our findings indicated that exposure to higher concentrations of THCs, NMHCs, and CH₄ might lead to an increased risk of AD development. Further studies are needed to gain a better understanding of the role of air pollutants in the pathogenesis of AD.