Abstract
Purpose:
To examine the impact of hydroxypropyl guar–hyaluronic acid (HPG-HA) dual-polymer eye drops on inflammatory cytokines in the tears of individuals experiencing computer vision syndrome.
Methods:
A randomized, double-masked, multi-center interventional study was conducted. One hundred and sixteen computer users with symptoms (using computers over 3 h daily for at least 1 year) were randomized into two groups; 56 patients received HPG-HA eye drops, and 60 patients received preserved saline drops, both twice daily for a duration of 3 months. The primary outcome was the reduction of inflammatory cytokines (interleukin-1 beta [IL-1β], IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, interferon-γ, and tumor necrosis factor-α) in conjunctiva and tears of computer users. The secondary outcomes encompassed alterations in dry eye symptom scores, Schirmer test results, tear breakup time (TBUT) values, and Nelson grade at the 3-month mark.
Results:
At baseline, tear inflammatory cytokines and tear film parameters were similar in both the supplement and placebo groups. Tear inflammatory cytokine levels showed no significant changes from baseline at 3 months postintervention in the tear supplement group, despite numerical reduction. However, the tear supplement group demonstrated a notable improvement in dry eye symptoms (P < 0.001), Schirmer test scores (P < 0.001), and TBUT scores (P < 0.001); however, there was no significant alteration in goblet cell counts or morphology of conjunctival epithelial cells.
Conclusions:
Treatment with HPG-HA dual-polymer eye drops for 3 months does alleviate dry eye symptoms and decrease tear evaporation rate in patients with computer vision syndrome. However, it does not alter tear inflammatory cytokines nor increase conjunctival goblet cell density.
Keywords: Computer vision syndrome, Dry eye, Goblet cell density, Tear cytokines
INTRODUCTION
Several factors can affect ocular surface health, such as contact lens wear, refractive surgical procedures, and extended computer use. Post coronavirus disease 2019, personal computer use has skyrocketed in schools, offices, and homes. People of all ages – children, students, professionals, and seniors – spent 2–12 h daily on computers, with mobile phone usage adding to this load. Individuals with computer vision syndrome may exhibit symptoms such as eye strain, fatigue, headache, dryness of eyes, redness, foreign body sensation, blurred vision, and occasionally backache and neck pain. Computer vision syndrome is a public health issue that adversely impacts the quality of life related to vision.1
A study by Hagan and Lory2 found that the prevalence of dry eye symptoms in men and women using computers ranged from 68% to 73%. Prolonged use of computers and the resulting tear film instability can lead to tear hyperosmolarity, damage to the ocular surface epithelium, and an increase in inflammatory mediators such as interleukins (ILs) and cytokines.3,4,5
Significantly elevated IL-6 levels in their tears of patients with ocular surface disorders as compared to controls were revealed in a recent meta-analysis.6
Eye drops containing lubricants do offer temporary relief from dry eye symptoms caused by computer vision syndrome.7 It remains unclear whether there is any change in inflammatory tear cytokines/chemokines or alterations in conjunctival goblet cell density (GCD) after treatment with these supplements.
The aim of this randomized double-masked study was to assess whether tear supplements containing hydroxypropyl guar–hyaluronic acid (HPG-HA) dual-polymer reduce inflammatory cytokines/chemokines in tears and enhance limbal cytology and morphology (via impression cytology) in symptomatic computer users compared to a placebo (preserved saline drops).
METHODS
At three eye centers in the subcontinent, a multi-center, randomized, double-masked study was conducted. The trial received approval from the Ethics Boards of the GS Medical College and Hospital, Pilkhuwa, and all patients provided written informed consent as per the tenets of the Declaration of Helsinki. The trial was registered with the clinical trial registry (UMIN), trial ID UMIN0000360042.
Computer users with symptoms (using computers for over 3 h a day for at least 1 year) were selected for the trial. Enrollment was based on the Indian dry eye questionnaire (dry eye scoring system [DESS©]).8
Patients suffering from ocular infections, prior LASIK surgery, allergic conjunctivitis, contact lens use, herpetic eye disease, diabetes, or liver diseases were excluded. Patients having fluorescein allergy were also excluded. Drugs (tetracyclines, corticosteroids, and omega-3 fatty acids) and topical treatments affecting tear film profile were stopped before the intervention. Patients also avoided rehydrating eye drops for 12 h before testing.
Patients were assessed initially and again 3 months after beginning treatment. The main outcome measured was the decrease in inflammatory markers in the tears and conjunctiva of computer users after 3 months compared to baseline levels. The cytokines/chemokines measured included IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, interferon-γ (IF-γ), and tumor necrosis factor-α (TNF-α).
The secondary outcomes at 3 months included changes in dry eye symptom scores, production of tears (Schirmer test), stability of tear film (tear breakup time [TBUT]), and conjunctival epithelial cell morphology and goblet cell counts.
Dry eye symptoms were scored from 0 to 3 for ocular fatigue, vision blurring, itching or burning, sandy or gritty sensation, and redness (DESS©). Scores: absent (0), sometimes present (1), frequently present (2), and always present (3). Dry eye severity: mild (0–6), moderate (6.1–12), and severe (12.1–18) [Figure 1].
Figure 1.
The Indian dry eye questionnaire. DESS: Dry eye scoring system
Participants visited the dry eye clinic between 10 AM and 12 PM. One eye per patient was selected randomly for examination. Participants were assessed at 22°C ± 1.4°C with 48% ± 10% relative humidity.
An independent investigator thoroughly examined the eyes, noting visual acuity and inspecting the lid margins, eyelashes, and meibomian gland openings for blockages.
Tear film evaluations were conducted before tear collection, and patients completed the Indian dry eye questionnaire (DESS). The investigator conducting all clinical evaluations was masked to the treatment group of participants. The TBUT was measured initially to avoid the influence of eyelid manipulation on the results. A fluorescein strip wetted with saline was placed over the lower conjunctiva. Patients were instructed to blink to evenly distribute the fluorescein, and the tear film was subsequently examined using a cobalt blue filter on a slit-lamp. The time between the last blink and the first dry spot on the cornea was recorded, averaging three readings. A TBUT under 10 s suggests dry eye syndrome.
After a 30-min interval, a Schirmer test was conducted using 0.4% oxybuprocaine with the eyes closed. A result of <6 mm wetting also confirmed a diagnosis of dry eye syndrome.
A tear sample (nonstimulated) was collected using a 5-mL microcapillary from the lower lid’s marginal tear strip near the lateral canthus, ensuring avoidance of contact with neighboring structures (conjunctiva, cornea, or lid margin). Tears (20 μL) were collected from one eye and stored at −70°C in microtubes.
The samples were diluted tenfold using the assay diluent for the experiment. A volume of 100 μL per sample was utilized to measure IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IF-γ, and TNF-α.
Tear cytokine levels were quantified utilizing a Quansys Biosciences 10-plex assay kit, capable of detecting IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IFN-γ, and TNF-α. Following the manufacturer’s guidelines, tear samples were thawed, centrifuged, and analyzed. Cytokine levels in 100 μL samples were measured using ELISA-based chemiluminescence. Absorbance was measured using Q-View Imager and QView™ Software.
The ranges for detecting cytokines were IL-1β (29–218 pg/mL), IL-2 (2.13–5000 pg/mL), IL-4 (1.37–4500 pg/mL), IL-5 (1.55–4500 pg/mL), IL-6 (0.02–3000 pg/mL), IL-8 (0.16–2800 pg/mL), IL-10 (0.25–3300 pg/mL), IF-γ (1.8–3800 pg/mL), and TNF-α (1.02–4000 pg/mL).
An examiner conducted conjunctival impression cytology (CIC) using a standard technique as described previously.9,10 Slides were viewed first under a light microscope at ×100 magnification and then at ×400 magnification to analyze cells.
A minimum of 10 high-power fields (HPFs) were analyzed to assess the presence of goblet and epithelial cells. The number of goblet cells per HPF was counted, and the GCD was estimated by dividing the goblet cells per HPF by the sampling area in square millimeters. Using Nelson’s criteria, grades 0 and 1 were considered normal, and grades 2 and 3 were deemed abnormal.
Both the computer user groups (n = 5 each) were examined for IL-1β, IL-6, IL-8, and TNF-α mRNA expression in impression cytology specimens using QuantiTect SYBR Green real-time polymerase chain reaction (Qiagen) to determine the inflammatory cytokine source.
In order to determine the sample size required for comparing the mean difference in IL-6 levels between the two groups, an initial pilot study was conducted with 10 subjects. The mean decrease in IL-6 score in the tear supplement group (Group 1) was 0.83 and in the placebo group (Group 2) 0.69, respectively. The standard deviation was 0.47. With 1:1 randomization, 90% power (alpha = 0.05), and a precision error of 5% to detect a difference of 20% or more in IL-6 between the groups, the estimated sample size for each group was calculated to be 46. A total of 116 eligible participants were recruited, surpassing the minimum sample size needed to attain the intended study power.
Allocation codes were generated through software within our community medicine department. Stratification was conducted based on clinical center, employing a permuted-block method with variable block sizes. Patients were randomly assigned to two groups using parallel assignment. Healthcare personnel not involved in patient care opened sealed RED envelopes containing the allocation codes.
Group 1 was administered an artificial tear solution comprising HPG-HA dual-polymer (Systane hydration, Alcon Singapore Pvt. Ltd., South Avenue, Singapore 637313) eye drops twice daily over a period of 3 months. Conversely, the placebo group received preserved saline drops (Rinsol, Gaymed Labs Pvt. Ltd., Delhi, India) with identical frequency. Both participants and investigators were blinded to the treatment allocations. The bottles for both types of eye drops were designed to appear similar. Noncare health staff evaluated patient compliance. At each monthly visit, subjects returned bottles, measured remaining eye drops, and received new packs. Subjects were told to keep a standard diet and avoid extra supplements.
Statistical analysis
The IBM SPSS Statistics version 29 (IBM Inc., Armonk, NY, USA) was used for data analysis. Independent t-tests verified baseline group similarities. Chi-square tests were applied to proportions. Normally distributed data were reported as mean ± standard deviation. The data that were not normally distributed underwent a Box-Cox transformation. Linear regression with a robust variance estimator compared mean changes in continuous variables between the groups. A one-way repeated-measures analysis of variance (ANOVA) assessed mean test value differences over 3 months (tear supplement vs. placebo). Mauchly’s test indicated sphericity violation, χ2 (2) = 6.27, P = 0.043, requiring a Greenhouse–Geisser correction (ε = 0.648). A post hoc Tukey’s test with Bonferroni correction identified differences. P < 0.05 adjusted for multiple comparisons (to reduce false positive results) was considered to indicate statistical significance.
RESULTS
Out of 134 patients, 18 were lost to follow-up. Group 1 (tear supplement group) had 56 subjects, and Group 2 (placebo) had 60 subjects. One hundred and four patients completed the 3-month follow-up, with cost constraints causing 12 dropouts. The study included 46 males and 58 females.
Table 1 indicates that the baseline test values for IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IF-γ, and TNF-α, as well as tear film parameters such as Schirmer, TBUT, Nelson grade, and GCD, were comparable between the groups receiving the tear substitute and those receiving the placebo.
Table 1.
Key characteristics (baseline)
| Measure** | Group 1 (tear supplement) | Group 2 (placebo) | P* |
|---|---|---|---|
| Age (years) | 23.1±1.7 | 23.8±1.9 | 0.057 |
| IL-1β | 523±47.5 | 522.3±47 | 0.943 |
| IL-2 | 131.6±5.1 | 134±5.5 | 0.056 |
| IL-4 | 364.6±7.3 | 366.4±18 | 0.064 |
| IL-5 | 264.8±13 | 266.3±14 | 0.083 |
| IL-6 | 1404±4.6 | 1400±4.8 | 0.078 |
| IL-8 | 473±30 | 474.8±34 | 0.069 |
| IL-10 | 452±13.5 | 458±44 | 0.146 |
| IF-γ | 320±16.8 | 322±16 | 0.666 |
| TNF-α | 344±32 | 346±44 | 0.234 |
| DESS score | 7.6±1.6 | 7.4±1.5 | 0.539 |
| Schirmer | 17.3±1.8 | 17.5±1.9 | 0.548 |
| TBUT | 11.8±2 | 12.1±2.3 | 0.467 |
| Nelson grade | 1.2±0.28 | 1.25±0.29 | 0.303 |
| GCD (cells/mm2) | 780±21 | 783±20.5 | 0.344 |
*Independent t-test, **The data are presented as mean±standard deviation, tear film breakup time, and goblet cell density, cells/mm2. IL: Interleukin, IF-γ: Interferon-γ, TNF-α: Tumor necrosis factor-α, DESS: Dry eye scoring system, TBUT: Tear breakup time, GCD: Goblet cell density
On impression cytology, the mRNA expression levels of IL-1β, IL-6, IL-8, and TNF-α exhibited an increase ranging from 1.4- to 2-fold at baseline.
At baseline, 36% of patients in the tear substitute group showed abnormal Schirmer tests, compared to 34% in the placebo group. Abnormal TBUT was seen in 58% of the tear substitute group versus 56% in the placebo group. Thirty-six percent of the tear substitute group had abnormal cytology, compared to 34% in the placebo group.
Repeated-measures ANOVA showed no significant difference in mean cytokine levels or GCD from baseline at 3 months after intervention in Group 1. A Bonferroni-adjusted post hoc analysis confirmed that tear cytokines and GCD did not significantly change from baseline to 1 month or from baseline to 3 months after intervention [Table 2]. Notably, there was a significant improvement in dry eye symptoms, Schirmer’s test scores, and TBUT after 3 months.
Table 2.
Group 1 mean test values at 6 months postintervention
| Measure** | Baseline | 6 months postintervention | P* |
|---|---|---|---|
| IL-1β | 523±47.5 | 518±51.2 | 0.632 |
| IL-2 | 131.6±5.1 | 129±5.9 | 0.093 |
| IL-4 | 364.6±7.3 | 361±11.1 | 0.173 |
| IL-5 | 264.8±4 | 262±9.6 | 0.105 |
| IL-6 | 1404±4.6 | 1401±9.7 | 0.125 |
| IL-8 | 473±3.0 | 470±9.7 | 0.116 |
| IL-10 | 452±13.5 | 450±18 | 0.437 |
| IF-γ | 320±16.8 | 316±16.7 | 0.266 |
| TNFα | 344±8.7 | 342±8.6 | 0.175 |
| DESS score | 7.6±1.6 | 1.2±1 | 0.001 |
| Schirmer | 17.3±1.8 | 19.9±1.4 | 0.001 |
| TBUT | 11.8±2 | 15.4±2.1 | 0.001 |
| Nelson grade | 1.2±0.28 | 1.16±0.3 | 0.503 |
| GCD (cells/mm2) | 780±21 | 774±26.6 | 0.281 |
*Independent t-test, **The data are presented as mean±standard deviation, tear film breakup time, and goblet cell density, cells/mm2. IL: Interleukin, IF-γ: Interferon-γ, TNF-α: Tumor necrosis factor-α, DESS: Dry eye scoring system, TBUT: Tear breakup time, GCD: Goblet cell density
In the placebo group, repeated-measures ANOVA showed no significant change in mean cytokine levels or GCD from baseline at 3 months postintervention. Bonferroni-adjusted post hoc analysis also indicated no significant changes in tear cytokines and GCD from baseline to 1 month or 3 months after intervention [Table 3]. Dry eye symptoms improved significantly, whereas TBUT showed only a borderline change.
Table 3.
Mean test values at 3 months after intervention (Group 2)
| Measure** | Baseline | 3 months postintervention | P* |
|---|---|---|---|
| IL-1β | 522.3±47 | 524±45.7 | 0.836 |
| IL-2 | 134±5.5 | 135±5.3 | 0.362 |
| IL-4 | 366.4±18 | 365±5.2 | 0.526 |
| IL-5 | 266±4.7 | 264±4.4 | 0.072 |
| IL-6 | 1400±4.8 | 1399±6.4 | 0.058 |
| IL-8 | 474.8±34 | 473.5±3.7 | 0.101 |
| IL-10 | 458±4.4 | 456±4.7 | 0.839 |
| IF-γ | 322±16 | 319±14.2 | 0.789 |
| TNF-α | 346±4.4 | 344±4.3 | 0.654 |
| DESS score | 7.4±1.5 | 5.2±1.5 | 0.001 |
| Schirmer | 17.5±1.9 | 17.8±1.8 | 0.357 |
| TBUT | 12.1±2.3 | 13.8±2.4 | 0.049 |
| Nelson grade | 1.25±0.29 | 1.2±0.27 | 0.282 |
| GCD (cells/mm2) | 783±20.5 | 780±21.8 | 0.469 |
*Independent t-test, **The data are presented as mean±standard deviation, tear film breakup time, and goblet cell density, cells/mm2. IL: Interleukin, IF-γ: Interferon-γ, TNF-α: Tumor necrosis factor-α, DESS: Dry eye scoring system, TBUT: Tear breakup time, GCD: Goblet cell density
Table 4 compares the mean test values between Group 1 and Group 2 after 3 months of intervention. No significant differences were observed in tear cytokines and GCD. However, Group 1 showed significant improvements in dry eye symptoms, Schirmer test score, and TBUT (P < 0.001). The placebo group also experienced better dry eye symptoms.
Table 4.
Mean test values at 3 months postintervention
| Measure** | Group 1 (tear supplement) | Group 2 (placebo) | P* |
|---|---|---|---|
| IL-1β | 518±51.2 | 524±45.7 | 0.533 |
| IL-2 | 129±5.9 | 135±5.3 | 0.131 |
| IL-4 | 361±11.1 | 365±5.2 | 0.261 |
| IL-5 | 262±9.6 | 264±4.4 | 0.057 |
| IL-6 | 1401±9.7 | 1399±6.4 | 0.238 |
| IL-8 | 470±9.7 | 473.5±3.7 | 0.068 |
| IL-10 | 450±18 | 456±4.7 | 0.090 |
| IF-γ | 316±16.7 | 319±14.2 | 0.268 |
| TNF-α | 342±8.6 | 344±6.3 | 0.136 |
| DESS score | 3.8±0.52 | 5.2±1.5 | 0.001 |
| Schirmer | 19.9±1.4 | 17.8±1.8 | 0.001 |
| TBUT | 15.4±2.1 | 13.8±2.4 | 0.001 |
| Nelson grade | 1.16±0.3 | 1.2±0.27 | 0.242 |
| GCD (cells/mm2) | 774±26.6 | 780±21.8 | 0.099 |
*Independent t-test, **The data are presented as mean±standard deviation, tear film breakup time, and goblet cell density, cells/mm2. IL: Interleukin, IF-γ: Interferon-γ, TNF-α: Tumor necrosis factor-α, DESS: Dry eye scoring system, TBUT: Tear breakup time, GCD: Goblet cell density
After 3 months, Group 1 showed no significant increase in GCD or nuclear–cytoplasmic ratio of conjunctival epithelial cells [Figure 2a and b]. The placebo group also showed no significant changes in these two parameters.
Figure 2.
(a) Baseline photomicrograph of impression cytology specimen stained with periodic acid-Schiff and H and E, ×400 showing squamous metaplasia (SM). Red arrow indicates a normal cell, and black arrow indicates reduced nuclear–cytoplasmic ratio (SM), (b) Photomicrographs of impression cytology specimens, stained with periodic acid-Schiff and H and E, ×400 magnification, showing persistent squamous metaplasia and decreased goblet cell density 3 months postintervention
Group 1 experienced transient blurred vision following administration of high-viscosity eye drops, whereas Group 2 reported temporary discomfort or burning sensations. These adverse effects were mild and did not necessitate discontinuation of treatment for any patient. No other clinically significant adverse events were observed in either group.
DISCUSSION
This placebo-controlled, randomized, double-masked study examined whether treatment with HPG-HA tear supplements for 3 months alters inflammatory cytokines/chemokines in patients suffering from computer vision syndrome.
This is among the first controlled studies to evaluate cytokine expression specifically after intervention in computer vision syndrome patients. In addition, using HPG-HA tear supplements did not significantly change inflammatory cytokine or chemokine levels in their tears. After 3 months, dry eye symptoms, tear production, and tear film stability improved, but conjunctival cell morphology and goblet cell counts remained unchanged. In the placebo group (saline with polyhexanide [PHMB]: 0.0001%), dry eye symptoms and tear film breakup time also improved unexpectedly. Purite is an oxidative preservative that breaks down into natural tear components – sodium, chloride, oxygen, and water – and is generally well-tolerated by the eye.11 The unexpected improvement in symptoms and TBUT may result from increased ocular surface hydration.
Prolonged computer use is known to cause ocular surface inflammation; this is evidenced by the presence of mediators such as prostaglandins, interleukins (IL-1), and leukotrienes in tears.12 In addition, chronic inflammation of the ocular surface may lead to alteration of epithelial cell morphology and reduction of conjunctival goblet cell count.13,14
Numerous artificial tear formulations, differing in composition and viscosity, are available in various forms, including gels, ointments, and drops. They help maintain the tear film by supplementing its layers, reducing evaporation, stabilizing it, and lubricating the eyes to prevent complications.15,16 However, they do not modify tear cytokines, increase nuclear–cytoplasmic ratio (reverse metaplastic changes) in conjunctival epithelial cells, or increase goblet cell counts.17,18
A study conducted by Duan et al.18 observed decreased mRNA expression of MUC1, MUC16, and MUC20 in the CIC specimens of symptomatic video display terminal (VDT) users, compared to VDT users who did not meet the criteria for DED.3 Changes in inflammatory cytokines after topical and dietary interventions have not been studied in the tears of symptomatic computer users.
Research have shown that the presence of elevated levels of IL-1, IL-6, IL-8, IFN-γ, and TNF-α in the conjunctival epithelium is linked to dry eye. These studies have primarily concentrated on Sjogren syndrome with aqueous-deficient dry eye.19,20
Only a few studies have documented alteration in cytokines in the tears of people suffering from computer vision syndrome.
A study conducted by Ribelles et al. found that older women who work on computers for extended hours exhibit significantly higher levels of IL-1β and IL-6 compared to those who do not engage in computer work.21 This indicated an appropriate inflammatory response in the tears of these patients who frequently use computers. Women taking antioxidants and omega-3 fatty acids showed significantly lower levels of inflammatory cytokines.
A study by Bhargava et al. reported that oral administration of anti-inflammatory omega-3 fatty acids can reduce dry eye symptoms, lower tear evaporation rate, and improve Nelson grade in young individuals who use computers for more than 3 h per day for at least 1 year.22 The study suggested that ocular surface inflammation might be a key factor in computer vision syndrome-related dry eye but did not evaluate tear cytokines and chemokines due to cost constraints.
Our study had limitations and strengths. The patients were not evaluated in controlled conditions; the impact of environmental confounding variables could not be excluded. A randomized controlled study design was our strength. This study is the first to evaluate in inflammatory cytokine expression in computer vision syndrome patients following intervention (Medline Search). Due to cost constraints, not all inflammatory cytokines/chemokines could be analyzed.
In conclusion, treatment with HPG-HA dual-polymer eye drops for 3 months did not change tear inflammatory cytokines or increase conjunctival GCD in patients suffering from computer vision syndrome.
Conflicts of interest
There are no conflicts of interest.
Acknowledgment
We thank <www.indianmedicalstats.com> for statistical analysis.
Funding Statement
Nil.
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