Sulfur dioxide and exacerbation of allergic respiratory diseases: A time-stratified case-crossover study

Abstract

Background:

Strong epidemiological evidence suggests that air pollution plays a significant role in the exacerbation of allergic respiratory diseases. This study aimed to assess the potential relationship between daily levels of sulfur dioxide (SO₂) and emergency department (ED) visits for allergic diseases.

Materials and Methods:

Data regarding ED visits for allergic respiratory diseases were routinely collected from the EDs in the Zlatibor district, and the General Hospital, Užice. The daily average concentrations of SO₂ were obtained from the regional automatic air quality monitoring stations. All data were collected from June 2012 to July 2014. A time-stratified case-crossover design was used. Crude odds ratios (ORs) and ORs adjusted for weather conditions were calculated using conditional logistic regression.

Results:

Statistically significant associations were seen between 0-day lagged exposure to SO₂ and ED visits for all allergic diseases (OR = 1.62; 95% confidence interval [CI]: 1.05–2.48; P = 0.028) and between 2-day lagged exposure to SO₂ and ED visits for asthma with allergic rhinitis (OR = 2.00; 95% CI: 1.03–3.88; P = 0.042). These results were adjusted for temperature, temperature², and humidity.

Conclusion:

Our results suggest that short-term exposure to SO₂ conferred an increased risk of ED visits for allergic respiratory diseases, particularly for asthma with concomitant allergic rhinitis.

INTRODUCTION

The prevalence of allergic diseases is increasing worldwide.[1,2,3] It is estimated that more than 100 million workdays and school days are lost in Europe every year.[4]

Strong epidemiological evidence suggests that air pollution has an important role in the development of asthma and other allergic respiratory diseases, as well as in their exacerbation.[5,6,7] Numerous studies have demonstrated that short-term exposure to high concentrations of the principal air pollutants (ozone, nitrogen oxides, carbon monoxide, sulfur oxides, and particulate matter [PM] - PM10 and PM2.5) may contribute to and exacerbate asthma.[8,9,10,11]

Sulfur dioxide (SO₂) is an important air pollutant that can be a threat to human health, animal health, and plant life. Exposure to high concentrations of SO₂ may result in irritation and dysfunction of the respiratory tract. The most common clinical findings associated with SO₂ exposure are bronchospasm, pulmonary edema, pneumonitis, and acute airway obstruction.[12]

The recently published report “Air Pollution and Human Health: The Case of the Western Balkans” has shown that the population of the Western Balkans region to which Serbia belongs, is exposed to several times higher concentrations of air pollution in comparison to the national and EU guideline levels.[13] To the best of our knowledge, the relationship between outdoor air pollution and population health has not been explored sufficiently in the Western Balkans region.

Short-term exposure to SO₂ is largely related to the type and nature of local sources.[13] The emission of this pollutant is mostly related to the fossil fuel consumption, industrial processes, and volcanic activities.[12] In the Western Balkans region, the largest source of SO₂ in the air is the combustion of fossil fuels in thermal power plants, mostly in lignite power plants.[13] This region is characterized by energy poverty and a lack of awareness of the need to move to more sustainable and more environmentally friendly heating systems.[14]

It is well known that short-term exposure to elevated concentrations of SO₂ has effects on human health. For the first time in Serbia, we conducted a time-stratified case-crossover study to assess the relationship between the gaseous SO₂ pollutant and visits to emergency departments (EDs) due to worsening of allergic asthma and allergic rhinitis.

MATERIALS AND METHODS

Study design

A time-stratified case-crossover study was conducted in the Zlatibor district, western Serbia. The city of Užice is an administrative, economic, social, and cultural center of this part of Serbia, located in the valley of the river Đetinja, surrounded by three mountains: Zlatibor, Tara, and Zlatar. Sevojno, as one of two municipalities of Užice, is an industrial center with copper and aluminum mills, construction companies, and metal recycling facilities.

The study participants were adults aged 18 years and older who lived in Užice, Sevojno, Čajetina, and Kosjerić, and who visited an ED or were hospitalized with a diagnosis of asthma or allergic rhinitis during the time period from July 01, 2012, to June 30, 2014. According to the 2011 Serbian Census, estimates of the number of adult residents were 78,040, 14,745, and 12,090 for Užice (including Sevojno), Čajetina, and Kosjerić, respectively.[15]

Health data

Data on allergic respiratory diseases were obtained retrospectively from ED visits in Užice, Sevojno, and Kosjerić and from the General Hospital in Užice. Patients' age, sex, diagnosis, and date of the visit were recorded. Criteria for inclusion in the study were adults 18 years of age and over, diagnosed with allergic rhinitis (International Classification of Diseases [ICD], 10^th revision, code J.30.4), allergic asthma (ICD, 10^th revision, code J.45.0), or asthma with allergic rhinitis. We excluded all ED visits due to nonallergic asthma, as well as visits due to exacerbation of allergic respiratory diseases caused by infection.

Environmental data

The concentrations of SO₂ (μg/m³) were obtained on a daily basis from the regional automatic ambient air quality monitoring stations placed in Užice, Sevojno, and Kosjerić. The daily values of concentration were calculated by averaging over all these stations. The SO₂ concentration was measured by a simple and sensitive spectrophotometric method.

The weather data such as temperature (°C), relative humidity (%), and air pressure (mbar) were obtained from the automatic weather station at Zlatibor.[16]

The study was approved by the Ethics Committee of the Health Center Užice (no.: 0303/8785).

Statistical analysis

A time-stratified case-crossover analysis as an alternative to the Poisson time series regression model was applied to analyze the potential risk of ED visits for respiratory allergic diseases related to short-term exposure to SO₂. This design represents a special type of matching in which cases serve as their own controls. We compared the time just preceding the acute event (”case” time) with every 7^th day before and after the event day (”control” time). The advantage of case-crossover design is that characteristics such as gender and age that might confound the association are controlled for.[17]

Categorical variables were presented by absolute numbers and percentages, while mean and interquartile range (IQR) were used for continuous variables. Age was presented as mean and also as categorical variable (<65 and ≥65 years).

The association between SO₂ and weather characteristics, such as temperature, humidity, and air pressure was assessed by Spearman's rank correlation, applicable for nonnormal data. For the assessment of normality, the Kolmogorov–Smirnov test was used. Three models of conditional logistic regression analyses (one unadjusted and two adjusted for the potentially confounding influences of the meteorological conditions) were applied for all allergic respiratory diseases, and each allergic disease separately (dependent variables) by including the SO₂ exposure estimates as an independent variable. We included different lag periods (lag 0, 1, 2, and 3) to detect the event day (lag 0) and events in the previous 3 days of exposure (lag 1, 2, and 3, respectively). The cumulative effect of exposure was also calculated. The confounders for the first adjusted model were temperature, humidity, and air pressure on the same day as SO₂ exposure estimates, while temperature, temperature², and humidity on the previous day were confounders in the second adjusted model.

The results of the analyses were presented as the odds ratios (ORs) and their 95% confidence intervals (CIs). We calculated the ORs for the daily mean level of SO₂ concentration presented by the IQR.

A P < 0.05 was considered statistically significant. All statistical analyses were performed using Statistical Package for the Social Sciences (SPSS) version 21.0 (SPSS Inc., Chicago, IL, USA).

RESULTS

During the study period, we observed 523 ED visits for allergic respiratory diseases. There were more women than men (62.5% vs. 37.5%). The mean age of the patients was 45.95 ± 17.24 years (mean ± standard deviation), and most of them (84.1%) had <65 years of age. More than three-thirds of all ED visits (76.3%) occurred during the heating season. The distribution of 245 asthmatic patients with allergic rhinitis who visited ED in the same period, according to sex, age, and the heating season was similar [Table 1]. Thirty-two (6.1%) of all patients were hospitalized.

Table 1.

Characteristics of emergency department visits for allergic respiratory diseases in the Zlatibor district, Serbia

Variables	Allergic respiratory diseases (n=523), n (%)*	Asthma with allergic rhinitis (n=245), n (%)
Sex
Males	196 (37.5)	87 (35.5)
Females	327 (62.5)	158 (64.5)
Age (years±SD)	45.95±17.24	44.71±16.03
<65	440 (84.1)	216 (88.2)
≥65	83 (15.9)	29 (11.8)
Heating season†	404 (76.3)	187 (76.3)
Nonheating season	119 (22.8)	58 (23.7)

*Allergic rhinitis, asthma, and asthma with allergic rhinitis; ^†15^th October to 15^th April. SD=Standard deviation

Daily concentrations of SO₂ and weather characteristics during the study period are presented in Table 2.

Table 2.

Sulfur dioxide concentrations and weather variables in the Zlatibor district, Serbia

Variable	Mean±SD	Minimum	25%	50%	75%	Maximum	IQR
SO2 24 h (mg/m3)	17.95±9.08	11.51	13.05	15.00	17.54	80.78	4.49
Temperature (°C)	15.41±9.24	−6.67	7.57	16.20	22.80	36.23	15.03
Humidity (%)	57.91±19.91	11.53	40.10	58.30	74.53	98.80	34.43
Air pressure (mbar)	962.21±6.67	936.33	958.27	962.90	966.73	982.33	8.47
Heating season*
SO2 24 h (mg/m3)	18.37±9.35	11.51	13.08	15.00	18.42	77.77	5.35
Temperature (°C)	14.77±9.24	−6.67	7.00	15.20	22.33	36.23	15.33
Humidity (%)	58.68±19.92	11.53	41.02	59.14	74.68	98.80	33.66
Air pressure (mbar)	961.19±6.85	936.33	958.03	962.73	966.93	982.33	8.90
Nonheating season
SO2 24 h (mg/m3)	16.54±7.97	11.86	12.99	14.93	15.07	80.78	2.07
Temperature (°C)	17.60±8.93	−2.10	11.27	18.90	24.23	35.90	13.08
Humidity (%)	55.33±19.67	11.53	38.83	50.93	74.27	96.80	35.43
Air pressure (mbar)	962.26±6.03	941.33	958.75	963.07	966.03	979.80	7.28

*6-month period in the year, from 15^th October to 15^th April. SO₂=Sulfur dioxide; SD=Standard deviation; IQR=Interquartile range

Mean daily concentrations of SO₂ did not exceed permitted limit values for the EU (125 μg/m³ for 24 h) and were higher during the winter season so-called “heating season” with a comparison to the summer season so-called “nonheating season” (18.37 ± 9.35 vs. 16.54 ± 7.97).

The seasonal trend of monthly mean concentrations of SO₂ during the 2-year study period is presented in Figure 1.

Figure 1.

Seasonal trend of monthly mean concentrations of sulfur dioxide in the Zlatibor district, Serbia (2012 - 2014)

The levels of SO₂ were elevated during the heating season although did not exceed the limit values and low during the nonheating season.

Statistically significant negative correlation in the present study was found between temperature and SO₂ (y = 22.9 − 0.43x; coefficient correlation ρ = −0.44), while statistically significant positive correlation was seen between humidity and SO₂ (y = 49.18 + 0.51×; ρ =0.29). Higher concentration of SO₂ during winter months might be associated with reduced dilution efficiency by diffusion of air flow, increased combustion of fuel from biomass for heating, as well as with inversion of temperature resulting in smog occasions.

Crude and adjusted ORs with their 95% CI for ED visits due to worsening of respiratory allergic diseases in relation to short exposure of SO₂ are shown in Table 3.

Table 3.

Odds ratios for the relationship between exposure to sulfur dioxide and emergency department visits for allergic rhinitis and asthma in the Zlatibor district, Serbia

ED visits	Lags	OR* (95% CI)	OR† (95% CI)	OR‡ (95% CI)
Allergic respiratory diseases	Lag (0)	1.53 (1.01–2.31), P=0.044	1.53 (1.00–2.34), P=0.049	1.62 (1.05–2.48), P=0.028
Asthma with allergic rhinitis	Lag (−2)	1.97 (1.03–3.77), P=0.041	1.97 (1.02–3.80), P=0.044	2.00 (1.03–3.88), P=0.042

*Crude; ^†Adjusted for temperature, humidity and air pressure on the same day; ^‡Adjusted for temperature, temperature² and humidity on the previous day. ED=Emergency department; OR=Odds ratio; CI=Confidence interval

We observed statistically significant associations between 0-day lagged exposure to SO₂ and ED visits for all allergic diseases ([crude OR = 1.53; 95% CI: 1.01–2.31; P = 0.044]; OR adjusted for temperature, temperature², and humidity [OR = 1.62; 95% CI: 1.05–2.48; P = 0.028]). Statistically significant associations were also found between 2-day lagged exposure to SO₂ and ED visits for asthma with allergic rhinitis ([crude OR = 1.97; 95% CI: 1.03–3.77; P = 0.041]; OR adjusted for temperature, temperature², and humidity [OR = 2.00; 95% CI: 1.03–3.88; P = 0.042]).

DISCUSSION

It is well known that short-term SO₂ exposure depends on the prevailing meteorological conditions. According to our results, the levels of SO₂ in the Zlatibor district were elevated during the heating season although did not exceed the limit values and low during the nonheating season. Similar results were reported in other studies.[18,19]

Like Polish authors, we observed seasonal variation of SO₂ concentration as a consequence of different atmospheric conditions in summer and winter months, changing weather on a particular day, and human-induced activity.[19]

Our results that statistically significant associations were found between exposure to SO₂ and ED visits for allergic diseases are in agreement with previously published studies in adults[18,20,21] and children.[22,23,24,25,26,27,28] However, several authors failed to detect any association between SO₂ and asthma ED visits/hospitalizations.[29,30]

Zheng et al. in a large meta-analysis of 65 available studies showed that SO₂ was associated with significantly increased risks of ED visits and hospitalizations due to asthma: relative risk (95% CI); 1.011 (1.007, 1.015); I² test = 77.1%; population attributable fractions (95% CI): 1.1 (0.7, 1.5).[8] In a recently published time-stratified case-crossover study in Chengdu, China, Chen et al. found that after adjustment for weather conditions, IQR increase in SO₂ of 13 μg/m³ was associated with an increase of 18.8% in emergency ambulance dispatches for asthma.[18] The observed effect of the SO₂ on asthma ED visits/hospitalization is biologically plausible. It has been observed that SO₂ stimulates airway inflammation and eosinophilia and induces bronchospasm and airway fibrosis in asthma.[31] It has been shown that SO₂ and its derivatives could increase epidermal growth factor (EGF), EGF receptor, intercellular adhesion molecule-1, and cyclooxygenase-2 expression in human bronchial epithelial cells (BEP2D), through transcription and translation processes that may explain inflammation and overproduction of mucus in asthma exacerbation.[32]

The main strengths of the present study are a novel population reviewed, applied time-stratified case-crossover design as an appropriate method for the assessment of brief changes in risk related to short-term exposure of SO₂, and risk adjustments for the potential confounding influence of weather condition.

However, we are aware of some limitations of this study. First, the exposure to SO₂ pollutant for each individual was estimated on the basis of regional measurements of SO₂ pollution from fixed-site monitoring stations. Second, the possible confounding influence of other air pollutants and aeroallergens on the risk estimation was not taken into account. Third, our study results may not be generalizable to the entire Serbian population. Further studies with data on larger populations from different settings would be necessary to confirm our findings.

CONCLUSION

Our results confirm a significant association between short-term exposure to SO₂ and increased risk of ED visits for allergic respiratory diseases, particularly for individuals with asthma with coexisting allergic rhinitis, in the Zlatibor district. Further studies considering the possible confounding influence of other air pollutants and aeroallergens on the risk estimation are needed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.