Association of Long-Term Exposure to Ambient Air Pollution With the Risk of Acute Primary Angle Closure

Abstract

Purpose: The purpose of this study was to investigate the association between long-term exposure to ambient air pollutants and the risk of acute primary angle closure (APAC).

Methods: Two hundred eighty-one (281) patients with APAC and 730 age- and sex-matched controls hospitalized between January 2017 and December 2019 were enrolled in this retrospective case-control study. Residential exposure to ambient air pollutants, including fine particulate matter (PM_2.5), inhalable particulate (PM₁₀), nitrogen dioxide (NO₂), sulfur dioxide (SO₂), and ozone were estimated by satellite-models or ground measurement. Multivariate regression analyses explored the association between annual air pollutants exposure and the risk of APAC.

Results: Of the 1011 participants (31.1% were male subjects), the average age was 64.0 years. Long-term exposure to PM_2.5, PM₁₀, and SO₂ were significantly associated with an increased risk of APAC. The adjusted odds ratios (aORs) for each interquartile range (IQR) increment of PM_2.5, PM₁₀, and SO₂ were 1.28 (95% confidence interval [CI] = 1.06–1.57), 1.26 (95% CI = 1.06–1.50), and 1.30 (95% CI = 1.04–1.62) separately, after controlling for confounders. Robust associations were observed for a longer lag 2-year exposure.

Conclusions: Long-term exposure to PM_2.5, PM₁₀, and SO₂ was associated with an increased risk of APAC in a Chinese population. Our findings provide epidemiological implications on the adverse effects of air pollution on ocular diseases.

Translational Relevance: Long-term exposure to ambient air pollutants increased the risk of APAC.

Introduction

Glaucoma is a leading cause of irreversible blindness worldwide with increasing prevalence. It is estimated that the number of people aged 40 to 80 years with glaucoma will grow rapidly from 76 million in 2020 to 111.8 million in 2040.¹ The incidence rates and subtypes of glaucoma vary among ethnic groups and geographic regions.¹ Primary angle closure glaucoma (PACG) is the predominant subtype in Asian populations as opposed to primary open angle glaucoma (POAG) in the Western world.^1,2 PACG is more visually damaging and at a higher risk for blindness than POAG.³ Acute, symptomatic phase of PACG (acute primary angle closure [APAC]) is characterized as a sudden onset with obvious eye discomfort, visual impairment, and usually systemic symptoms, which has been reported with highest prevalence in the Chinese population compared with other ethnic individuals.⁴ 

Air pollution is a major public health concern accounting for an estimated 1.24 million deaths in 2017 in China.⁵ Air pollution exposure has been suggested to increase the risk of multiple adverse health outcomes, such as respiratory diseases,^6–8 cardiovascular diseases,^8,9 and cancer.^8,10 The potential biological mechanisms of air pollution include oxidative stress,¹¹ inflammation activation,¹² and endothelial dysfunction.¹³ Eyes are in direct contact with the environment, and biological evidence has illustrated that air pollution can induce intraocular inflammation, corneal cell apoptosis, and oxidative stress on eyes.¹⁴ Several eye diseases, such as conjunctivitis and dry eyes, have well-documented association with air pollution.^15–17 However, the studies on the impact of long-term exposure to ambient air pollution on glaucoma remain insufficient.^18–23 Even though these studies demonstrated that long-term exposure to fine particulate matters (PMs; including PM_2.5 and PM₁₀) increased the risk of glaucoma, the association of other air pollutants, such as nitrogen dioxide (NO₂), sulfur dioxide (SO₂), and ozone (O₃) with the risk of glaucoma still unclear. Meanwhile, the diagnosis of glaucoma was reported by the participants^18,22 or based on disease code^19,20,23 in most of these studies. Additionally, only a few studies explored the effects of air pollutants on the specific clinical subtype of glaucoma.^21,24 To the best of our knowledge, no studies have investigated the association of long-term exposure to ambient air pollutants with the risk of APAC. Understanding their relationship may have great importance to public health policy planning in China and other countries with big challenges of air pollution and the aging population. 

The aim of the current study was to investigate the associations of long-term exposure to ambient air pollutants with the risk of APAC. Given the increasing number of individuals with glaucoma globally,¹ we aimed to provide informative insights into understanding the potential mechanisms and the early prevention of glaucoma. 

Materials and Methods

Study Participants and Study Design

This retrospective, case-control study was conducted at Eye and ENT Hospital, Fudan University. A total of 701 patients with APAC hospitalized between January 2017 and December 2019 were initially included. Among them, 292 participants were excluded because their residential addresses were not in Shanghai, and another 128 patients were excluded to match with the controls in age and sex according to the ratio of 1 to 3. The study finally included 281 patients with APAC. Eyes meeting the following criteria are diagnosed as APAC: (1) intraocular pressure (IOP) of more than 30 mm Hg; (2) typical ocular and/or systemic symptoms include intense ocular or periocular pain, blurred vision, seeing halos around lights, severe headache above the attacked eye, nausea and/or vomiting; and (3) typical ocular signs, such as conjunctival injection, corneal epithelial edema, an unreactive mid-dilated pupil, and shallow anterior chamber.^25,26 An occluded angle in the attacked eye examined by gonioscopy or ultrasound biomicroscope (UBM) was essential for the diagnosis of APAC. Patients with APAC as well as with other severe ocular disorders, such as macular degeneration and diabetic retinopathy, were excluded from the study. Glaucoma caused by secondary angle closure, such as neovascularization and uveitis, were excluded as well. 

Age- and sex-matched inpatients without glaucoma diagnosis during the same inclusion time as APAC constituted the control group. Both the cases and controls were permanent residents in Shanghai and only individuals aged over 50 years were enrolled in the study. This study adhered to the tenets of the Declaration of Helsinki and was approved by the Ethics Committee of the Eye and ENT Hospital, Fudan University. Informed consent was waived by the Institutional Review Board of Eye and ENT Hospital, Fudan University. 

Ambient Air Pollutants Exposure

Ambient annual levels of PM_2.5 and PM₁₀ were obtained from the China High Air Pollutants (CHAP) datasets. The detailed methodology has been reported previously.^27,28 In brief, it is generated using a combination of satellite-derived MODIS/Terra+Aqua MAIAC aerosol optical depth (AOD), ground-based monitoring and model stimulation. Ambient PM_2.5 and PM₁₀ at approximately 1.0 × 1.0 km resolution were estimated by using the randomized tree approach, with 10-fold cross-validation R² of 0.87 and 0.73, respectively. In our study, geocoding was conducted at each residential location of participants to estimate the annual average exposure concentration of PM_2.5 and PM₁₀. Ambient daily average concentrations of NO₂, SO₂, and O₃ maximum for 8 hours were obtained from the nearest air monitoring station of each residential address. The distance from each participant's residence was mainly within 5.0 km of the nearest air monitoring station. These air monitoring stations released real-time concentratioins of air pollutants, in strict accordance with normative documents to ensure the accuracy and integrity of monitoring data. The annual average concentrations of air pollutants were calculated to estimate the exposure for each participant. 

Covariates

Information including age, sex, height, weight, marital status, residential addresses, chronic disease (i.e. hypertension and diabetes), and the onset date of the first acute attack was collected from the hospital medical records. Body mass index (BMI) was calculated by dividing weight (kg) by the square of height (m²). The behavior factors of alcohol intake and smoking were collected as well. Household environmental data on cooking fuels were also recorded. Solid fuels were defined as a primary usage of coal or wood, whereas marsh gas or electricity was classified as clean fuels. Additionally, monthly ambient temperature and relative humidity were derived from China Meteorological Data Service Center and averaged for annual exposure for participants. 

Statistical Analyses

Descriptive analysis was applied to describe the characteristics of the participants. The Student's t-test or Chi-square test was used to compare the difference. Multiple logistic regression model was performed to explore the association of 1-year average ambient air pollutants exposure with the risk of APAC. The selection of the covariates was based on two criteria: (1) the well-known or possible risk factors of APAC based on the current knowledge; and (2) variables changed the main effect by 10% or more after included in the regression model.^29,30 In the main analysis, we fitted 3 models: model 1 (crude model); model 2 adjusted for sex, age, BMI, marital status, cigarette smoking, alcohol consumption, and type of household cooking fuels; and model 3 further adjusted for hypertension, diabetes, ambient annual temperature, and relative humidity based on model 2. The adjusted odds ratios (aORs) with 95% confidence intervals (CIs) were used for the estimation of each interquartile range (IQR) increment in ambient air pollutants with APAC. 

In addition, sensitivity analysis was performed to test the robustness of the association by repeating the analysis using 2-year average exposure levels of air pollutants. 

All statistical analyses were conducted using R (version 4.0.3; R Foundation for Statistical Computing, Vienna, Austria) and SPSS version 20.0 (IBM, Armonk, NY, USA). The 2-side P < 0.05 was considered as statistical significance. 

Results

We first compared if there were any significant differences in the baseline characteristics of patients with APAC who were included and excluded from the study. As shown in Supplementary Table S1, no significant differences were found in sex, age, BMI, marital status, chronic conditions, and axial length between the 2 groups. Table 1 shows the characteristics of the enrolled participants, including 281 patients with APAC and 730 healthy controls. No significant differences were found in sex, age, smoking exposure, alcohol consumption, chronic conditions, type of household cooking fuels, ambient average temperature, and relative humidity between the study participants. The body height and body weight were statistically significantly lower in the patients with APAC group compared to those in the healthy controls group (both P < 0.0001), but BMI showed no significant difference between these two groups (P = 0.113). A slightly higher number of patients with APAC were unmarried when compared with the controls (P = 0.048). 

Table 1.

 

Characteristics of the Participants Included in the Study, Mean ± SD/N (%)

 

The ambient annual average exposure concentrations of air pollutants among the participants are shown in Supplementary Table S2. The annual average concentrations of PM_2.5, PM₁₀, and NO₂ in our study were 37.25 µg/m³, 51.91 µg/m³, and 39.44 µg/m³, respectively, which were remarkably above the World Health Organization (WHO) Air Quality Guideline of 5 µg/m³, 15 µg/m³, and 10 µg/m³, respectively.³¹ In addition, the comparison results of the exposure concentrations of the five pollutants between patients with APAC and the controls are shown in Table 2. There were statistically significantly higher exposure levels of PM_2.5 (P < 0.001), PM₁₀ (P = 0.012), and SO₂ (P = 0.002) in patients with APAC compared to those in the healthy controls. 

Table 2.

 

Comparison of the Exposure Concentrations of the Five Air Pollutants Between Patients With and Without APAC

 

Table 3 shows the multivariable regression analysis between annual ambient air pollution and the risk of APAC. Higher exposure concentrations of PM_2.5, PM₁₀, and SO₂ were positively associated with a higher risk of APAC in the crude and adjusted models, with the aOR of 1.28 (95% CI = 1.06–1.57) for PM_2.5, 1.26 (95% CI = 1.06–1.50) for PM₁₀, and 1.30 (95% CI = 1.04–1.62) for SO₂ in the fully adjusted model (model 3). The odds ratios along with their corresponding 95% CIs for all covariates in models 1 to 3 are shown in Supplementary Table S3. 

Table 3.

 

The Association Between Ambient Annual Air Pollutants Exposure and the Risk of APAC

 

In addition, the sensitivity analysis showed very similar associations of 2-year lag time exposure to PM_2.5, PM₁₀, and SO₂ with the APAC risk (Supplementary Table S4). 

Discussion

Our study contributed to the current understanding that long-term exposure to ambient PM_2.5, PM₁₀, and SO₂ was associated with the risk of APAC in a Chinese population. To the best of our knowledge, this is the first study to report the association between long-term air pollution exposure and APAC diagnosis. 

Even though not large in number, the studies about the association between air pollution and glaucoma have been reported in recent years. It has been suggested that high levels of PM_2.5 is associated with self-reported glaucoma.^18,22 Similar to our findings, results from the rural Chinese regions²¹ and the UK Biobank data²² observed that long-term exposure to ambient PM_2.5 is related to an increased risk of glaucoma. The annual average concentration of PM_2.5 in Shanghai in our study was 37.25 µg/m³, which was higher than that in the UK Biobank data (9.9 µg/m³)²² and lower than that in rural Chinese regions (62.4 µg/m³).²¹ The disease outcomes in many of the previous studies were based on self-reported glaucoma^18,22 or disease code,^20,23 and the specific types of glaucoma were not classified.^18,20,22 A multicenter study conducted in mainland China showed that long-term exposure to PM_2.5 was associated with glaucoma and PACG rather than with POAG.²¹ Another nested case-control study performed in Taiwan showed that greater PM_2.5 exposure was related to increased risk of POAG in individuals aged 65 years or older.²³ The differences in study designs, exposure measurements, and individual characteristics may account for the inconsistent results between these two studies.²¹ 

Apart from PM_2.5, we also observed that PM₁₀ and SO₂ exposure were significantly associated with the increased risk of APAC. These pollutants also have been reported to have detrimental effects on human health^32,33 but gain less attention in glaucoma. In a time-stratified case-crossover study conducted in Shanghai, Li et al. found that acute exposure to PM_2.5, PM₁₀, NO₂, and CO was associated with increased outpatient visits of patients with acute glaucoma.²⁴ Our findings as well as Li et al.’s study indicated that both very short and long-term exposure to PM_2.5 and PM₁₀ were related to increased risk of acute glaucoma attack. However, acute glaucoma was composed of APAC and glaucomatocyclitic crisis in Li et al.’s study,²⁴ which belonged to two different types of glaucoma with quite different pathogenic mechanisms. In addition, their study used each patient as his or her own referent and only evaluated the air pollution levels on the outpatient visit day of acute attack. Differences in study populations, study designs, and sensitivities of glaucoma subtypes to pollutants exposure may explain the discrepancy in the types of air pollutants associated with glaucoma attack between our and their studies. 

To date, the biological mechanisms underlying the adverse effects of ambient air pollution exposure on glaucoma remain unclear. Animal experiments in mice showed that PM_2.5 exposure resulted in IOP increase.³⁴ Moreover, it has been demonstrated that air pollution is related to increased levels of oxidative stress and pro-inflammatory factors.^13,35 Oxidative stress markers and inflammatory cytokines have been reported to be elevated in the aqueous humor and serum of patients with glaucoma.^36,37 Increased oxidative stress and the subsequent activation of NLRP3 inflammasome mediated pyroptosis were observed in the trabecular meshwork cells after PM_2.5 exposure, finally affecting the functions of trabecular meshwork cells.³⁴ Additionally, the specific constituent of PM_2.5, black carbon, is reported to be a risk factor for increased IOP in male individuals with high oxidative stress allelic score.³⁸ However, the acute obstruction of anterior chamber angle is the main mechanism of APAC. Whether and how anterior segment anatomy is influenced by air pollution remains unknown. Forward rotation of ciliary processes and increased thickness of the choroid are common contributors of angle closure.²⁵ We speculate that long-term exposure to air pollution may cause the edema of ciliary body and choroid through the mechanisms of oxidative stress and inflammation, finally leading to a more crowded or even closed angle. More animal and clinical studies are needed to verify this hypothesis in the future. 

The strengths of our study include that it was the first study performed in the developing country to investigate the association of long-term exposure to multiple air pollutants with the risk of APAC. In addition, the APAC outcome was recorded according to the clinical diagnosis by ophthalmologists. Most of the previous studies used the international classification of disease (ICD) code or self-reported glaucoma as disease outcomes, which might lead to misclassification. 

There are some limitations in our study. First, the cross-sectional design made the study impossible to establish a casual relationship. Longitudinal studies are warranted to establish the temporality of exposure to ambient air pollution and the presence of APAC. Second, we only estimated the exposure to ambient air pollutants using residential addresses as a proxy for individual exposure. The sources of air pollutants in different locations, such as work places, were not available in the present study. This was likely to cause exposure misclassification and introduce bias. Future investigations with high-resolution details of personal exposure with recorded time-activity patterns are merited. Third, the study only enrolled hospitalized subjects from a single tertiary hospital in Shanghai, which limited the generalizability of the findings. Last, the residual or uncontrolled confounders like psychiatry stress and dietary factors were not adjusted in the model due to lack of information. Further multicenter longitudinal studies with larger sample size are warranted to substantiate our findings. 

In conclusion, the current study provides epidemiological implications of long-term exposure to ambient air pollutants, especially to PM_2.5, PM₁₀, and SO₂, is associated with the risk of APAC in a Chinese population. It is promising to develop environmental interventions and public health policies aimed at addressing air pollution to help reduce the risk of APAC. 

Acknowledgments

Supported by funds from the key project of the National Natural Science Foundation of China (82030027); and the Clinical Research Plan of SHDC (2020CR6029). The funders had no role in the study design, data collection, the analysis and interpretation of data, preparation of the manuscript, or the decision to publish. 

Disclosure: N. Wu, None; W. Shi, None; X. Sun, None