Association of short-term exposure to sulfur dioxide and hospitalization for ischemic and hemorrhagic stroke in Guangzhou, China

Stroke is the second leading cause of death in the world [1]. According to Global Burden of Disease (GBD) Study 2016, the highest age-standardized incidences of stroke were observed in east Asia, especially China (354 [95% UI 331–378] per 100,000 person-years) [2]. Ischemic stroke and hemorrhagic stroke account for approximately 70 and 28% of all stroke cases, respectively [3]. Moreover, the incidence of stroke continues to rise in China in recent years [3]. Therefore, identification of modifiable risk factors for stroke has significant public health implications.

Hypertension, diabetes mellitus and dyslipidemia are major risk factors for cardiovascular diseases including stroke [4, 5]. The high prevalence of these risk factors is a major burden to most economies around the world. Ambient air pollution is also a well-known risk factor for stroke morbidity [6], but the majority of evidence are focused on particulate matter (PM) [7, 8]. Sulfur dioxide (SO₂) is a non-flammable, colorless gas with a strong pungent odor at room temperature, which is primarily released from the combustion of sulfur containing fossil fuels at power plants (73%) and other industry facilities (20%) [9]. As a strong respiratory irritant and bronchoconstrictor, SO₂ could induce systemic inflammation and oxidative stress [10], which might take a role in stroke. Short-term exposure to ambient SO₂ was associated with increased risk of stroke morbidity in a meta-analysis mainly based on developed countries [6]. However, in developing countries like China, the evidence is limited and very few studies [11] distinguished between ischemic and hemorrhagic stroke. Most studies only focused on ischemic stroke but the results have not been conclusive yet, with some finding evidence of a positive association [12] but not in other studies [13‐16].

Guangzhou is one of the most densely populated cities in China. The industrial production and traffic burden make SO₂ one of the main atmospheric pollution sources in Guangzhou [16], which is severer than those in developed countries [17]. Moreover, the stroke mortality in Guangzhou was relatively higher compared to other cities of China [18].

Therefore, we conducted a time-series study to examine the short-term association between ambient SO₂ and hospital admissions of ischemic and hemorrhage stroke in Guangzhou, respectively.

Table 1 presented the stroke, meteorological and air pollution data in Guangzhou during January 1, 2009 to December 31, 2014. Overall, 58,473 ischemic stroke and 9167 hemorrhagic stroke hospital admissions were recorded, the distribution of age is presented in Supplementary Table 1. The daily average temperature was 21.99 °C while daily relative humidity was 76.30%. The average concentrations of air pollutants including SO₂, PM₁₀, PM_2.5, NO₂ and O₃ were 27.82 μg/m³, 72.93 μg/m³, 46.07 μg/m³, 54.33 μg/m³ and 68.69 μg/m³, respectively.

The correlation coefficients between SO₂ and other pollutants varied from 0.31 to 0.48. And SO₂ is negatively correlated with humidity, which is opposite to temperature. (Supplementary Table 2).

For ischemic stroke, we observed the maximum effect of SO₂ at lag0 day (Table 2). Every 10 μg/m³ increase of SO₂ was associated with 1.27% (95%CI, 0.42–2.12%) increase of ischemic stroke (Table 2). In all the two-pollutant models, the effects of SO₂ remained in line with that of single pollutant model (Table 4). When looking into the different age groups, a 10 μg/m³ increase of SO₂ concentrations on lag 0 day represented 1.39% (95%CI, 0.35–2.45%) and 1.21% (95%CI, 0.02–2.42%) increment for ischemic stroke hospital admissions in < 65 and ≥ 65 years old group, respectively (Table 3). And we found SO₂ still increased the risk of hemorrhagic stroke hospital admission with the adjustment of NO₂ and O₃ for < 65 years (Table 4). But null association existed in two pollutant model for ≥65 years (Table 4).

For hemorrhagic stroke, the effect of SO₂ reached the maximum value on lag1 day (Table 2), with percentage change of 1.55% (95%CI, 0.02–3.11%) per 10 μg/m³. But neither of the effect is significant in < 65 and ≥ 65 years old group (Table 3). The effect of SO₂ lost statistical significance after including NO₂, PM₁₀ and PM_2.5 but it’s still significant when O₃ was included (Table 4).

Sensitivity analyses were performed to check the robustness of results in terms of the degrees of freedom in the smooth function of time trend, which was similar to that in the main model (Supplementary Table 3).

This is one of the few studies specified not only association between SO₂ and ischemic stroke but also hemorrhagic stroke hospital admissions in developing countries so far.

Our study suggested that ambient SO₂ was significantly associated with increased hospital admissions for ischemic stroke. A 10 μg/m³ increase of the same day/lag 1 day SO₂ was associated with increments of 1.27% (0.42–2.12%) and 0.93% (0.09–1.78%) ischemic stroke hospital admissions risk, respectively. The associations were robust to the adjustment of all the other air pollutants. For example, the most informative pollutant of traffic emissions NO₂. The association were comparable to previously studies [6, 11, 12, 16].

However, the associations of SO₂ and hemorrhagic stroke were more variable and imprecise. We observed significant associations between lag 1/lag 2 days SO₂ exposures and hemorrhagic stroke hospitalization risk, with percentage change of 1.55% (0.02–3.11%) and 1.52% (0.02–3.04%), respectively. But when adjusted for other air pollutants in our models (except O₃), the magnitude of risk due to SO₂ exposure turned out to be statistically insignificant. Previous evidences on SO₂-hemorrhagic stroke association are scarce and inconsistent [11, 29]. The discrepant results on hemorrhagic stroke may be explained by differences in average pollutant levels, meteorological patterns and population characteristics between studies [30]. For example, in the study of Liu et al. [11], SO₂ concentration level was 39.6 ± 41.2 μg/m³ with remarkably higher variation than that in Guangzhou (21.99 ± 6.37 μg/m³) in our study. The exposure levels and exposure patterns might partly explain the difference.

The identification of potentially vulnerable subpopulation has significant implications for public health [12], therefore we stratified the stroke cases into < 65 and ≥ 65 years groups. For ischemic stroke, we found that the effect estimates of SO₂ were higher for the < 65 than that in the ≥65 age group, which is the opposite of Tian et al. [12]. This may be due to the varied activity patterns for different age groups in different cities. The elderly in Guangzhou tend to stay in door or in the park nearby, while people under 65 years old usually take vehicles or public transportation to work and have more exposure on SO₂, because the vehicle exhaust emission is one of the main sources of SO₂. But for hemorrhagic stroke hospitalization, there was no evidence of effect in neither age subgroup in any lag structure. It might be related to the smaller number of daily hospital admissions of hemorrhagic stroke (4 ± 3 cases/day) in this study. The lower incidence of hemorrhagic stroke may lead to larger imprecision in the estimates [6]. In addition, we noted that 70.14% hemorrhagic stroke cases were < 65 years old, while 59.75% ischemic stroke cases were ≥ 65 years old, which was similar to previous observations [11]. But the different age distribution of ischemic and hemorrhagic stroke should not be ignored. It might also contribute to the different relationship between SO₂ and ischemic and hemorrhagic stroke.

The mechanism behind the adverse stroke effects associated with SO₂ is biological plausible. The inhalation of SO₂ could alter heart rate variability, elevate oxidative and enhanced blood coagulation and thrombosis formation [31]. Animal study also showed that SO₂ elevated the levels of cyclooxygenase-2, interleukin-1b, tumor necrosis factor-a, intercellular adhesion molecule-1 mRNA and protein, which might also play a role in the development of stroke [32]. These pathophysiologic changes may be related to the development and progression of stroke. Nevertheless, the exact biological pathways underlying the health impact of SO₂ need further investigations.

Although this study found that the magnitude of elevated risk of stroke due to SO₂ exposures in Guangzhou was relatively small, it should not be ignored. Coal related air pollution, characterized by high level of SO₂, remains to be an important environmental problem in China, including Guangzhou [10]. The increased risk of ischemic stroke and hemorrhagic stroke due to the exposures of SO₂ estimated in this work highlights the need for continued vehicle emission control, desulfurization, and promotion of hydropower and nuclear power from the government [33] and vigilance for the health risks of air pollution. There are several limitations of this study. First, averaging air pollution exposures over Guangzhou may introduce exposure measurement error. Secondly, as a retrospective ecological study, personal exposure confounders could not be excluded in the model, and we have no access to individual air pollution exposure data. Further studies based on personal measurements or modeled residential concentrations are warranted to evaluate the health effects of SO₂, especially at low levels or in the real world. Moreover, the potential misclassifications for the stroke diagnosis should also be taken into consideration. However, all the hospitals included in this study are top-ranked public hospitals with high quality of electronic diseases diagnosis records in Guangzhou. Another limitation of the present study is the lack of consideration of more age groups, as the distribution of ischemic and hemorrhagic stroke might vary across the age (e.g. 65–74, and ≥ 75 years), we recommend future studies to examine the association in subgroups as 65–74, and ≥ 75 years. Due to the limited number of hemorrhagic stroke hospitalizations, studies based on enlarged sample size or in multi-cites should be performed to examine the association in the future. In addition, hypertension, diabetes mellitus and dyslipidemia are important risk factors for stroke [4]. Further studies taking the comorbidity of stroke and hypertension, diabetes mellitus and dyslipidemia into consideration could be helpful to identify effective ways to prevent stroke.

In summary, we found short-term exposure to ambient SO₂ may significantly increase the risks of hospitalization for ischemic stroke. The findings may contribute to a better understanding of the health effects of SO₂.