Ocular Surface, Intraocular Pressure, and Lens Condition in Bronchodilator and Steroid-Treated Patients with Chronic Pulmonary Disease

Asthma and chronic obstructive pulmonary disease (COPD) are frequent diseases in older adults that are linked to an increased risk of morbidity and mortality [1]. For the majority of asthma patients, the first-line maintenance therapy is an inhaled corticosteroid (ICS), which works by reducing inflammation and thereby preventing symptoms [2]. ICSs are not recommended as first-line therapy and are required for patients with severe to very severe COPD who experience frequent exacerbations and are given in combination with a long-acting β₂-agonist [3].

Systemic inflammation, hypoxia, and multiple drug use in COPD and asthma also affect the eyes, which are well-perfused organs. Caused by the opacification of the lens, cataract is the most common visual impairment worldwide [4]. Systemic corticosteroid use and long-term administration of high-dose ICSs are risk factors for cataract formation [5]. Dry eye disease (DED), which increases in frequency with increased life expectancy, use of technological devices, air pollution, and drug use, is a public health problem [6]. Dry eye disease was found to be more prevalent in people with asthma, particularly females, and was linked with comorbidities such as urticaria and the use of leukotriene receptor antagonists, antihistamines, and ICS [7].

Although population-based studies have found conflicting findings regarding the link between inhaled CS and glaucoma, it is reported that prolonged administration of high doses of ICS increased the risk of composite ocular hypertension (OH) or open-angle glaucoma [8]. Bronchodilator therapy can be administered via a nebulizer or an inhaler. Though widely used in patients with these conditions, it can have systemic and local effects even in its inhaled form. There is a paucity of studies on the effects of inhaled and nebulized bronchodilator therapies on the eye. In this study, we aimed to evaluate DED, intraocular pressure (IOP), and cataract incidence in bronchodilator- and steroid-treated chronic pulmonary disease patients.

We evaluated 202 eyes of 101 patients with chronic pulmonary disease treated with an inhaler and/or nebulized therapy in Boyabat State Hospital in Sinop, Turkey, in this observational study conducted between March 2019 and December 2019, in accordance with the Declaration of Helsinki. The study enrolled patients with chronic respiratory disease (asthma and COPD) who had been receiving bronchodilator therapy for at least 1 year. The study excluded patients with diabetes, collagen vascular disease, glaucoma, a history of contact lens use, and retinal and refractive surgery. The study protocol is summarized in Figure 1. Bronchodilator therapy was administered with a nebulizer or an inhaler device. Doses taken were based on prescribing instructions for monthly use.

Intraocular pressure was measured with a Goldman applanation tonometer in the mornings (9:00 a.m.) and the evenings (5:00 p.m.), and then averaged. OH was defined as an average IOP of more than 21 mm Hg. Cataract type was examined by slit-lamp biomicroscopy. To evaluate DED, the tear fluid breakup time (TBUT) and Schirmer I tests were performed. The tear fluid breakup time (TBUT) was determined using the following procedures: 5 µL fluorescein was placed in each eye, three measurements were taken in each eye, and the average was calculated, and Schirmer I tests were determined using the following procedures: 10 µL of propacain was placed in the inferior fornix of each eye, followed by Schirmer’s strips left in place for 5 min. Patients were classified as DED if their Schirmer I test scores were less than 15 mm or their TBUT test scores were less than 10 s.

IBM SPSS Statistics for Windows, Version 22.0, was used to conduct the statistical analysis (IBM Corp., Armonk, NY, USA). The Kolmogorov-Smirnov/Shapiro-Wilks test was used to assess the distribution of variables. When continuous variables are normally distributed, they are expressed as mean and standard deviation; when they are not normally distributed, they are presented as median (min-max). Categorical parameters are represented by numerical values (%). We used the two-sample t test for normally distributed data and the Mann-Whitney U test for non-normally distributed data when comparing continuous outcome variables between groups. To compare categorical variables, the Pearson χ² test was performed. To explore potential risk factors and establish independent predictors of patients’ clinical outcomes, logistic regression analysis was utilized. To measure model fit, Hosmer-Lemeshow goodness-of-fit statistics were used. To determine statistical significance, an overall 5% type-1 error level was applied.

A total of 202 eyes of 101 patients with chronic pulmonary disease were included in this study. Patients had a mean age of 66.4 ± 11.9 years, and 46.5% (n = 47) were female. Of the patients, 48 (47.5%) had COPD, and 53 (52.5%) had asthma. The population characteristics, treatment options, and ocular findings in patients are summarized in Table 1. With regard to intraocular pressure and DED, there were no statistically significant differences between asthma and COPD cases (Table 1). Cataract and presence of pseudophakia were more frequently detected in COPD than in asthma cases (p = 0.006) (Table 1). Nuclear cataract was the most common type witnessed among the cases (n = 36, 80%).

Regarding intraocular pressure, there was no difference between the groups in terms of demographic characteristics, respiratory disease type, and treatment strategies (Table 2). Dry eye disease was more common in patients on both inhaled and nebulized therapy compared with those taking inhalers only (37 [49.3%] versus 21 [80.8%], p = 0.005) (Table 3). All of the cases were taking ICSs and long-acting β₂ agonists in combination (ICS-LABA). We found statistically significant differences between formaterol beclomethasone, formaterol budesonide, and salmeterol fluticasone in terms of the rate of dry eyes in patients receiving the ICS-LABA combination (3 [27.3%], 23 [53.5%], 32 [68.1%], p = 0.038, respectively) (Table 3). Patients taking nebulized corticosteroid had a higher rate of dry eyes than those who did not (p = 0.001).

Increased age (p < 0.001), male sex (p < 0.001), and smoking history (p = 0.003) were found to be associated with an increased risk of cataracts (pseudophakic and cataract cases) (Table 4). The higher incidence of cataracts in COPD in comparison to asthma cases was statistically significant (p = 0.005). Cataracts were also more common in patients receiving bronchodilator therapy via a nebulizer (p = 0.031) as opposed to an inhaler device, as well as being more prevalent in patients using systemic corticosteroids due to exacerbation during the past year (p = 0.044). There were more cataracts in patients using nebulized short-acting β₂-agonists (SABA) and muscarinic antagonists (SAMA) in combination (SABA-SAMA) (p = 0.013) and those taking corticosteroids via a nebulizer (p = 0.005). A statistically significant association was observed between prolonged use of the LABA-ICS combination and an increased incidence of cataracts (72 [12–144] vs. 48 [12–120]; p = 0.041).

Multivariate analyses evaluated independent factors contributing to an increased risk of DED and cataracts. A unit increase in ICS-LABA use was associated with a 1.02-fold increase in cataract risk (OR: 1.02, CI: 1.01–1.04, p = 0.016), and ex-smokers had 7.1 times as many cataracts as non-smokers (OR: 7.10, CI: 1.63–30.88, p = 0.009), while current smokers had 10.8 times as many cataracts (OR: 10.79, CI: 1.70–68.30, p = 0.011) (Table 5). Patients who used a nebulized corticosteroid had a 9.15 times higher risk of developing dry eyes than those who did not (OR: 9.15, CI: 2.34–35.75, p = 0.001). In patients using ICS-LABA, in comparison to formoterol beclomethasone, salmeterol fluticasone was found to increase the risk by 7.49-fold for DED (OR: 7.49, CI: 1.48–35.75, p = 0.015) (Table 6).

Bronchodilators and ICSs are widely used in the treatment of asthma and COPD, but they can have systemic and local effects even when used in inhaled form. Inhaled anticholinergics are generally well tolerated, but pupil dilation, blurred vision, and acute glaucoma may occur, which may result from droplets escaping from loose-fitting nebulizer masks. ICSs are one of the therapeutic options for COPD and the main treatment option for asthma. The corticosteroid is inhaled directly into the airways and effectively treats respiratory tract inflammation. ICS has fewer systemic effects than oral corticosteroids as the dose is significantly lower and only a small fraction of the dose is absorbed systemically. Ocular complications such as cataract, glaucoma, corneal stromal calcification, conjunctival necrosis, retinal/choroidal embolism, and central serous chorioretinopathy can all occur after corticosteroid use. In this study, we evaluated risk factors for dry eye disease, intraocular pressure, and cataract in patients with chronic pulmonary disease treated with bronchodilator therapy.

In our study, the risk of developing dry eye was found to be nine times higher in patients using nebulized corticosteroids than in those who did not, whereas salmeterol fluticasone increased the risk of DED seven times compared to formoterol beclomethasone in patients using ICS-LABA combination. Sangwan et al. [9] examined the “inhaled” dose and the percentage of the nominal dose deposited on the face and in the eyes using a pediatric face model, three nebulizers, and seven mask types. The facial deposition ranged between 0.44 and 2.34%, whereas the ocular deposition ranged between 0.09 and 1.78% of the nebulizer charge. Some bronchodilator medications may accidentally enter the eyes when used with an inhaler. Still, when administered as nebules via a mask that covers the nose, more of these medications may be directly deposited into and penetrate the eyes. In this study, the inhaler forms of these drugs caused DED, possibly resulting from increased tear evaporation due to airflow rather than their pharmacological effects on the cornea and conjunctiva. Demodex is an important pathogen responsible for blepharitis. It is possible that nebulized steroids increase the incidence of blepharitis by disrupting the ocular surface flora and causing DED. Nebulized SABA-SAMA may reduce tear production with its antimuscarinic effect and shorten tear breakup time due to the airflow that occurs when the drugs are taken in the form of nebules via a mask.

In our study, advanced age, smoking, and use time of the inhaler ICS-LABA combination were found to be independent predictors of the development of cataracts. Of the 45 patients with cataracts, 80% had the nuclear type. Cataracts were found more frequently in patients with COPD than those with asthma, which may be due to the COPD patient population being older than asthma patients. Chronic hypoxia and inflammation due to COPD may also affect the lens and cause cataracts [10]. Cataract, which develops due to aging, is caused by the lifetime accumulation of oxidative damage that leads to cortical and nuclear cataracts, quite late in life [11, 12]. Corticosteroids may work by blocking sodium-potassium pump in the lens epithelium, resulting in water accumulation in the lens fibers and protein agglutination, resulting in the formation of posterior subcapsular cataracts [13]. Oral, parenteral, and ICSs cause cataracts more frequently than nasal, auricular, and dermal use [14, 15]. ICSs were found to be related to the development of posterior subcapsular and nuclear cataracts in a population-based cross-sectional investigation [16]. A large prospective, placebo-controlled study of 7,000 patients from 32 countries looked at budesonide therapy and the development of cataracts over 3 years and found that patients did not have a cataract risk after budesonide therapy [17]. However, a meta-analysis by Weatherall et al. [18] reported that the risk of cataracts increases by approximately 25% for every 1,000 µg/day increase in beclomethasone dipropionate or equivalent dose.

We observed a 10-fold increase in the risk of cataracts in current smokers. Cigarette-related oxidative stress and free radicals can denature lens proteins and trigger cataract formation. One study found a relationship between smoking and pure nuclear opacity in their study and showed that the density of the opacity increased as the dose of smoking increased [19]. In smokers, all cataract types were reported to have a significantly higher prevalence and that the risk increases with the number of cigarettes smoked [20].

In the present study, inhaled or nebulized corticosteroids had no effect on intraocular pressure. Prolonged administration of high doses of ICS was observed to increase the risk of composite OH or open-angle glaucoma [8]; short-term administration of ICS was reported to have no significant effect on IOP or central corneal thickness in asthmatic children with no familial history of glaucoma [21]. Mitchell et al. [22] proposed a link between the use of ICSs and the presence of increased IOP or glaucoma in patients who had a family history of glaucoma. In a meta-analysis including 18 studies and 31,665 individuals, glaucoma risk and IOP results were evaluated in patients using ICS, and the results did not support a positive association between ICS and glaucoma or between ICS and IOP [23].

There were several limitations to the present study. This study did not collect data on the duration of cataract surgery, the severity of cataracts, the thickness of retinal nerve fibers, the visual field, pachymetry, or the proportion of patients with visual impairment. Second, our study’s average age was higher than that of comparable COPD clinical studies. Increasing age has consistently been associated with nuclear and cortical opacities; therefore, the age factor should be kept in mind when evaluating the results of this study. We evaluated patients who had been using prescribed bronchodilators for longer than a year; however, the duration of use of each drug type was evaluated on a monthly basis, while the amount used was not calculated as an average daily dose. Environmental factors, such as exposure to various pollutants, may be significant risk factors for both asthma and DED, however they were not evaluated in this study. Finally, because this study was conducted cross-sectionally, the present findings may have limited generalizability.

This study found that administering bronchodilators or corticosteroids via nebulizer but not inhaler is related to greater rates of dry eye. Smoking, aging, and long-term inhaler steroid use were all linked to an increased risk of cataracts. Longitudinal and larger sample size studies are needed to evaluate the cause-effect relationship.

The study received approval from the Sinop University Local Ethics Committee (approval number: 2020/12), as well as informed consent from all participants.

The authors declare that there is no conflict of interest.

The authors received no financial support for this research.

Ozge Aydin Guclu designed the study and conducted the data analysis. Ayna Sariyeva Ismayılov and Ozge Aydin Guclu performed the research and contributed to important reagents, data collection, writing of the manuscript, and the critical review of the manuscript. All authors approved the final version of the manuscript.

Data supporting this study are included within the article.