ORIGINAL ARTICLE. Risk Factors for Dry Eye Syndrome: A Retrospective Case-Control Study. Optometry and Vision Science, Vol. 92, No.

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1 /15/ /0 VOL. 92, NO. 00, PP. 00Y00 OPTOMETRY AND VISION SCIENCE Copyright * 2015 American Academy of Optometry ORIGINAL ARTICLE Risk Factors for Dry Eye Syndrome: A Retrospective Case-Control Study Wan-Ju Yang*, Yan-Ning Yang*, Jin Cao, Zi-Hui Man, Jing Yuan*, Xuan Xiao, and Yi-Qiao Xing* ABSTRACT Purpose. To investigate the independent risk factors of dry eye syndrome (DES) in Chinese. Methods. A hospital-based age- and sex-matched population was enrolled with a case-control ratio of 1:2, with 789 DES case patients and 1119 healthy family members. Both groups underwent standard ophthalmologic examinations, including slit-lamp evaluation of the anterior segment, measurement of tear film breakup time, Schirmer test, and corneal fluorescein staining. Data on demographic characteristics and lifestyle habits were collected using a questionnaire. Dry eye syndrome risk factors were identified by univariate and multivariate logistic regression analyses. Results. The following independent risk factors showed significant association with DES: diabetes (odds ratio [OR], 1.408; 95% confidence interval [CI], to 1.924), hepatitis C (OR, 3.326; 95% CI, to 6.776); connective tissue disease (OR, 2.157; 95% CI, to 2.771), benign prostatic hyperplasia (OR, 3.892; 95% CI, to 6.116), rosacea (OR, 3.747; 95% CI, to 7.120), posttraumatic stress disorder (OR, 1.449; 95% CI, to 2.013), hematopoietic stem cell transplantation (OR, 7.269; 95% CI, to ), head and neck radiotherapy (OR, 8.776; 95% CI, to ), postmenopausal estrogen therapy (OR, 1.912; 95% CI, to 3.151), antihistamines (OR, 2.040; 95% CI, to 2.746), antidepressants (OR, 1.982; 95% CI, to 3.647), contact lenses (OR, 2.366; 95% CI, to 4.423), and video display terminal exposure for more than 6 h/d (OR, 2.275; 95% CI, to 3.568). Potentially protective factors against DES were vitamin supplements (OR, 0.716; 95% CI, to 0.972) and 6-3 fatty acidyrich diet (OR, 0.514; 95% CI, to 0.796). Conclusion. Several known risk factors of DES are applicable to Chinese, and some distinctive dietary factors may be protective in this population. (Optom Vis Sci 2015;92:00Y00) Key Words: dry eye syndrome, risk factors, case-control study Dry eye syndrome (DES) is a disorder of the tear film and ocular surface, which presents with eye discomfort, visual disturbance, tear film instability, destruction and inflammation of the ocular surface, and high tear osmolarity. 1 Epidemiologic studies have indicated that the prevalence of DES ranges from 7.8 to 33.78% of the general population, 2Y12 depending on the diagnostic criteria and investigative methods used in the studies. *MD PhD MS Eye Center, Renmin Hospital of Wuhan University, Wuhan, China (all authors); and Department of Ophthalmology, Central Hospital of Wuhan, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China (W-JY). This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. Various population-based studies have sought to measure the prevalence of DES and the associated risk factors. However, the risk factors for DES vary with the genetic factors, cultures, living environment, and lifestyles prevalent in different regions. 6,8,13Y15 Studies reported hitherto have focused on the cross-sectional epidemiology of DES worldwide, whereas retrospective case-control studies on the risk factors for DES are limited. In particular, most of the studies reported from Southeast Asian countries such as China, Japan, and Korea 2,16Y21 have been cross-sectional investigations, and the prevalence and risk factors of DES assessed in these studies have been restricted to specific age groups or populations. Because these are cross-sectional studies, they are based on simple association and do not allow for a distinction between cause and effect or an assessment of the outcome. 22 Therefore, this study was aimed at identifying the risk factors for DES in a population of Wuhan city, Hubei province, China, through a retrospective case-control study, with a view to obtaining data that could serve as a basis for further prospective studies and facilitate the development of effective strategies for the prevention and treatment of DES.

2 2 Risk Factors for Dry Eye SyndromeVYang et al. METHODS Study Design The study was designed as a retrospective case-control investigation, with a case-control ratio of 1:2. Data regarding the demographic and clinical characteristics of the patients and relevant lifestyle habits were collected using a questionnaire and clinical examination. The study protocol was approved by the Human Research Ethics Committee, Renmin Hospital of Wuhan University, and in accordance with the Declaration of Helsinki. Written informed consent was obtained from all the participants before the start of the study. Subject Recruitment We recruited 789 patients who received treatment of DES at the Department of Ophthalmology, Renmin Hospital of Wuhan University, China, between December 2009 and December The diagnosis of the syndrome was made on the basis of the criteria defined by the International Dry Eye WorkShop. 1 Healthy control subjects (n = 1119) of age similar to the patients (T2years) but without eye diseases were recruited from among the family members of the enrolled patients. The case-control ratio was 1:2, and the groups were matched for both age and sex. Dry eye syndrome was diagnosed on the basis of the responses to a questionnaire. All patients completed the Ocular Surface Disease Index (OSDI) questionnaire during the interview and before the ophthalmic examination. 23 The questionnaire collected data for a weeklong recall period about the frequency of DES (sensitivity to light; gritty, painful, or sore sensation; and blurred or poor vision), limitations of daily activities (reading, watching television, working on computers, or night driving), and the effects of environmental triggers (wind, low humidity, or air conditioning). Responses to each item were graded in severity by using a five-point scale ranging from 0 (no problem) to 5 (major problem). The composite OSDI score ranged from 0 to 100, with higher scores indicating more severe symptoms. Clinically significant DES was defined by the presence of DES symptoms, positive result of the Schirmer test, or ocular surface staining in either eye. For all the enrolled patients, the onset of DES symptoms was less than 6 months before enrollment. Patients were excluded if they had active ocular lesions such as trichiasis, pterygium, infectious conjunctivitis, keratitis, uveitis, and glaucoma within the last 3 months before enrollment or if they had undergone intraocular or extraocular surgeries within the last 6 months before enrollment. Data Collection The OSDI questionnaire was filled out by an investigator during a face-to-face interview with each participant. To eliminate the inappropriate answers and reduce the margin of error, the questionnaire was completed a second time by the same investigator within a week of the first interview. The responses were regarded as accurate only when the same responses were obtained for a given item in both the interviews. The investigators were graduate students majoring in ophthalmology with a certain level of background knowledge of epidemiology. The questionnaire included items pertaining to demographic characteristics, clinical data, medical and surgical history, and individual lifestyle habits. Data were collected for the following demographic characteristics from the participants of both groups: name, age, sex, and body mass index. Further, the medical history of the patients was also recorded in detail, including history of hypertension, thyroid disease, diabetes mellitus, hepatitis, stress disorder, depression, and posttraumatic obstructive sleep apnea hypopnea syndrome (OSAHS). Data regarding the medications received were also recorded, including history of receiving antihypertensives, antidepressants, anxiolytics, antihistamines, postmenopausal estrogen therapy, radiation therapy for the head and neck, vitamin supplements, and other drugs. Details of personal habits were noted, including history of contact lens use (more than 6 h/d within the past month), exposure to visual display terminal (VDT) for more than 6 h/d via a computer or other electronic display devices, and frequency of the consumption of food rich in 6-3 fatty acids such as flaxseed and fish oil. In addition, all the enrolled subjects in both groups underwent standard ophthalmologic examinations, including evaluation of the anterior segment by using a slit lamp, measurement of tear film breakup time, Schirmer test, and corneal fluorescein staining. Dry eye syndrome was diagnosed if any of the following criteria were met: (1) presence of any of the subjective symptoms including dryness, foreign body sensation, burning, fatigue, discomfort, or vision fluctuations, as well as tear film breakup time of less than or equal to 5 seconds or Schirmer I test results (no surface anesthesia) of less than or equal to 5 mm/5 min; (2) presence of any of the subjective symptoms including dryness, foreign body sensation, burning, fatigue, discomfort, or vision fluctuations, as well as tear film breakup time of more than 5 seconds and less than or equal to 10 seconds or Schirmer I test results (no surface anesthesia) of less than 5 mm/5 min and less than or equal to 10 mm/5 min, along with positive conjunctival and corneal fluorescein staining. Statistical Analysis Statistical analysis was performed using the independent sample t test and W 2 test by IBM SPSS Statistics, Version 19.0 (IBM Corp, Armonk, NY). All data were expressed as mean T SE. Univariate and multivariate logistic regression analyses of each factor were performed to calculate the Wald W 2 value, p value, odds ratio, and 95% confidence interval. A p value less than 0.05 was considered significant. RESULTS Patient Characteristics The study used baseline data of 789 patients who were diagnosed as having DES on the basis of the criteria specified by the International Dry Eye WorkShop. 1 Age- and sex-matched control subjects without any eye diseases were enrolled in the control group, with the case-control ratio being 1:2. Among the 1908 subjects included in this study, 789 were male (41.4%) and 1119 were female (58.6%). Table 1 shows the age distribution of participants in both groups (56.32 T vs T 17.66, p ).

3 Risk Factors for Dry Eye SyndromeVYang et al. 3 TABLE 1. Age distribution of all participants Age Male (n = 789) Female (n = 1119) Total (N = 1908) range, y DES (n = 263) Control (n = 526) DES (n = 373) Control (n = 746) DES (n = 636) Control (n = 1272) 20Y T T T T T T Y T T T T T T Y T T T T T T Y T T T T T T Y T T T T T T Y T T T T T T T T T T T T 3.12 Total T T T T T T Data are expressed as mean T SD (in years). The independent samples t test of two groups showed that there was no significant difference in age (t = 0.137; p = 0.891). Univariate Analysis for Factors Related to the DES We analyzed all the considered factors with the conditional logistic regression model (> = 0.05) and identified the following 20 risk factors associated with DES: history of hypertension, diabetes, hepatitis C, OSAHS, thyroid disease, connective tissue disease, gout, benign prostatic hyperplasia, rosacea, stress disorder, depression, posttraumatic stress disorder (PTSD), and hematopoietic stem cell transplantation; history of receiving head and neck radiation therapy, postmenopausal estrogen therapy, antihistamines, antidepressants, anxiolytics, and drugs for prostatic hypertrophy; and use of VDT for more than 6 h/d and corneal contact lenses (p G 0.05). Additionally, the regular consumption of vitamin supplements and foods rich in 6-3 fatty acids was found to be protective factors against DES (Table 2). Multivariate Analysis for Factors Related to the DES Using the 22 factors identified to be significantly associated with DES in univariate analysis, we performed multivariate logistic regression analysis (forward stepwise selection: likelihood ratio, > into = 0.05, > out = 0.10) to exclude the influence of confounding factors and their interaction with the relevant factors. The results showed that the independent risk factors associated with DES were followed: history of diabetes, hepatitis C, connective tissue disease, benign prostatic hyperplasia, rosacea, PTSD, and hematopoietic stem cell transplantation; history of receiving head and neck radiation therapy, postmenopausal estrogen therapy, antihistamines, and antidepressants; and use of contact lenses and exposure to VDT for more than 6 h/d. Additionally, the use of vitamin supplements and regular consumption of food rich in 6-3 fatty acids were found to be protective against DES (Table 3). DISCUSSION Dry eye syndrome is an important disorder in the light of the current lifestyle practices that cause considerable eyestrain. Age and sex have been reported as important factors associated with the occurrence of DES, whereas other risk factors are often ignored. 2,6,8 In this study, we sought to identify risk factors of DES other than age and sex. Therefore, we conducted this ageand sex-matched case-control (1:2 ratio) study in the Wuhan area of China and identified some independent risk factors for DES. Diabetes is one of the leading causes of blindness in older people. Although epidemiologic evidence obtained on the prevalence of DES among diabetic patients is limited, some studies have shown a correlation between diabetes mellitus and DES. 13,14,24 Furthermore, a negative correlation between diabetes mellitus and DES was recorded in a Japanese study. 16 This may be attributed to the peripheral neuropathy and decreased corneal sensitivity in diabetic patients resulting in an underestimation of dry eye symptoms or lifestyle changes made by the patients after being diagnosed with diabetes, which may reduce the odds ratio for DES. Elderly diabetic patients are at a high risk of developing DES, because of the diabetes-induced decrease in corneal sensation, which leads to a decrease in tear production and, therefore, dry eyes. This mechanism is similar to that observed in subjects using corneal contact lenses. The mechanical stimulation of the cornea by the long-term use of contact lenses leads to decreased corneal sensitivity, corneal relative hypoxia, damage to nerve endings, and toxicity owing to the lens care solution and the lens surface sediment. All these factors affect the quality of the tear film, its integrity, and its metabolic function, eventually leading to decreased basal tear secretion and inducing superficial punctate staining of the corneal epithelium. 15 The development of DES in subjects with exposure to VDT for more than 6 h/d is attributed to the change in the blink response. 25 When a person views a VDT, the blink response decreases from 20 to 25 times per minute to 5 to 10 times per minute. This decrease results in the failure of the uniform distribution of tears on the corneal surface and, possibly, increased tear evaporation. The prolonged use of computers, video games, and other display devices has become one of the main reasons for the increase in the prevalence of DES among the population. 16 Nagao et al. 26 found that patients with hepatitis C are more susceptible to DES than those with hepatitis B. In addition, the risk of developing DES has been reported to gradually increase with the development of liver cirrhosis. 27 These findings are consistent with those of the present study. There may be a couple of reasons for the increased risk of DES in hepatitis C patients. First, hepatitis C virus can be detected in tears of hepatitis C patients 28 ; this suggests that the virus can cause lymphocytic infiltration of the lacrimal gland, 29 resulting in DES. Second, the

4 4 Risk Factors for Dry Eye SyndromeVYang et al. TABLE 2. Univariate logistic regression analysis of risk factors for DES Variable DES, n Control, n Coefficients p OR value 95% CI BMI Y e Y2.096 Q Y1.471 Hypertension No Yes Y1.641 Diabetes No Yes Y2.017 History of hepatitis No Hepatitis B j Y1.366 Hepatitis C Y4.350 Cerebrovascular disease No Yes Y2.002 OSAHS history No Yes Y2.471 Thyroid disorder No Yes Y2.127 Connective tissue disease No Yes Y2.627 Gout No Yes Y3.457 Benign prostatic hyperplasia No Yes Y5.463 Acne rosacea No Yes Y4.111 PTSD No Yes Y2.102 Depression No Yes Y3.869 History of treatment Hematopoietic stem cell transplantation No Yes Y Head and neck radiation therapy No Yes Y Postmenopausal estrogen therapy No Yes Y2.827 Use of antihistamines No Yes Y2.311 (continued next page)

5 TABLE 2. (Continued) Risk Factors for Dry Eye SyndromeVYang et al. 5 Variable DES, n Control, n Coefficients p OR value 95% CI Use of antidepressants No Yes Y4.402 Use of anxiolytics No Yes Y2.723 Treatment of enlarged prostate No Yes Y4.018 Use of vitamin supplements No Yes j Y0.896 Consumption of food rich in 6-3 fatty acids No Occasional j Y0.993 Often j Y0.689 Corneal contact lens No Yes Y3.560 VDT exposure for 96 h/d No Yes Y2.845 OR, odds ratio; CI, confidence interval; BMI, body mass index. medications used for the management of chronic hepatitis C, such as >-interferon and ribavirin, can impair the ocular surface tear dynamics and cause squamous metaplasia in patients with DES. The effects of these medications can persist even 6 months after their discontinuation. 30 Clinically, it is recommended that patients with liver diseases, particularly those with hepatitis C, should be closely monitored for signs of DES. Our study identified that history of connective tissue disease was one of the risk factors for DES. In patients with connective tissue disorders, the abnormal immune system fails to clearly distinguish between foreign antigens and self-antigens, thereby leading to the production of antibodies against self-antigens and an abnormal immune response to self-antigens. Eye tissue becomes the target of autoantibodies, leading to the ocular manifestations of DES. 31 Connective tissue diseases that are associated with DES are as follows: Sjögren syndrome, systemic lupus erythematosus, rheumatoid arthritis, ocular pemphigoid, and other types of immune diseases involving scar formation. Further, head and neck radiation therapy has also been shown to be associated with the development of DES in our study; radiation therapy can TABLE 3. Multivariate logistic regression analysis of risk factors for DES Variable Coefficients SE Wald W 2 df p OR value 95% CI Diabetes Y1.924 History of hepatitis C Y6.776 Rheumatoid arthritis Y2.771 Benign prostatic hyperplasia Y6.116 Acne rosacea Y7.120 PTSD Y2.013 Stem cell transplantation Y Radiation therapy Y Postmenopausal estrogen therapy Y3.151 Use of antihistamines Y2.746 Use of antidepressants Y3.647 Use of vitamin supplements j Y0.972 Consumption of food rich in 6-3 fatty acids j Y0.796 Use of corneal contact lens Y4.423 VDT exposure for 96 h/d Y3.568 OR, odds ratio; CI, confidence interval.

6 6 Risk Factors for Dry Eye SyndromeVYang et al. damage the targeted organs, causing diffuse degenerative atrophy of the meibomian gland and ultrastructure damage of lacrimal gland tissue. 32 The use of certain medications can also lead to DES. Consider antihistamines for example. Antihistamines are H1 receptor antagonists and can reach the lacrimal gland through the blood circulation; thus, they can influence the muscarinic activity and subsequently reduce the secretion of the lacrimal gland and goblet cells. 33 Previous studies have indicated that postmenopausal women receiving estrogen therapy show reduced incidence of DES. 34 However, more recent studies have shown that estrogen replacement therapy may lead to the degeneration of the lacrimal gland and reduction in tear secretion, thereby increasing the risk of DES. 35 In this study, both antihistamine treatment and estrogen replacement therapy were found to be risk factors for DES. The long-term use of these drugs may increase the prevalence of DES. Posttraumatic stress disorder refers to a class of clinical symptoms occurring after exposure to a serious traumatic event, which greatly damage mental health. Galor et al. 36 investigated American veterans and found a connection between PTSD and the prevalence of DES. This finding was confirmed in our study, which showed that PTSD was one of the risk factors for DES. A possible explanation for this finding is the use of medications used to relieve the symptoms of PTSD. In this study, univariate analysis showed that depression, use of antidepressants, and use of anxiolytics were risk factors for DES; however, the relationship between DES and the mental states other than PTSD did not hold true in the multivariate analysis. Our findings indicate that the presence of benign prostatic hyperplasia, rosacea, and hematopoietic stem cell transplantation was correlated with a risk of developing DES. This correlation may be attributed to the medications used for treating these diseases. Although the potential effects of these drugs on the ocular surface still remain largely unknown, it is possible that they may cause adverse effects eventually leading to the development of DES. 37,38 In addition, our study showed that the regular consumption of vitamin supplements and food rich in 6-3 fatty acids is protective against DES, which is consistent with the findings of previous studies. 39 This is because supplementation with vitamins and food rich in 6-3 fatty acids can reduce the expression of some inflammation markers on the conjunctiva and thereby improve the symptoms of DES. 40 The oral vitamin supplements considered in this study include vitamin A, beta-carotene, vitamin B 6, vitamin B 12, vitamin C, vitamin E, and multivitamins. The main purpose of administering oral vitamin supplements to these subjects who responded to the questionnaire is the prevention of cardiovascular disease. Some of the subjects were recommended the vitamin supplements for relief of neurological or skin diseases. It is well known that the lack of vitamin A is an important risk factor for DES; recent evidence has also shown that high level of vitamin D consumption is associated with decreased incidence of DES, which is consistent with our conclusion. 41 Most of the similar studies reported thus far have focused on a cross-sectional analysis of the epidemiology of DES. Generally, the investigations have been focused on specific population groups and show simple association rather than a cause-and-effect relationship; additionally, such investigations do not account for exposure and outcome. To overcome this, we designed a retrospective, case-control study to identify and reclassify these risk factors. We believe that this approach would provide a fresh insight into the clinical features of DES and that our findings provide a basis for further prospective, multicenter studies aimed at developing strategies for the management of DES and some pointers for educating the general public, especially in China, regarding measures to avoid the occurrence of DES. In summary, the present study confirmed the applicability of some of the previously known risk factors for DES in a Chinese population and also identified two protective factors, namely, use of vitamin supplements and regular consumption of food rich in 6-3 fatty acids. ACKNOWLEDGMENTS We thank Prof. Xiao-Dong Tan for outstanding administrative support in this work. Grant support was provided by the National Natural Science Foundation of China (No ). The authors have no potential conflicts of interest to declare. Received May 2, 2014; accepted October 23, REFERENCES 1. 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