Contact lens–related inflammation can range from discomfort to corneal infiltrative events. Even though contact lens discomfort is a very mild form of inflammation, 1 it can be a major problem for the wearer because it can limit length of wear and is a primary reason for discontinuing contact lens wear. 2,3 Refitting contact lens wearers who report discomfort with daily disposable lenses, regardless of material, is often used to try to improve comfort. 4,5 However, the mechanism of improved comfort with daily disposable contact lenses is not fully understood.
Cytokines are biomarkers of inflammation and can be released into tears by ocular surface cells during contact lens wear and contact lens–related complications. 6–9 Apart from the possible mechanism of neurobiology in contact lens discomfort, 10,11 the pathology of the discomfort may also have an inflammatory component. 8 The absolute concentration of cytokines in tears does not appear to change dramatically during short-term daily disposable contact lens wear. 8 The ratio of proinflammatory to anti-inflammatory cytokine concentrations has been associated with infectious diseases, including keratitis, 12 and may also be associated with the immune response to contact lens wear. 13 However, the association between symptoms and the ratio of proinflammatory to anti-inflammatory cytokines has not been investigated previously.
Contact lens wearers with discomfort have also been shown to have an altered conjunctival morphology including reduced goblet cell density, higher conjunctival epithelial metaplasia, and greater dendritic cell density. 14–17 Adverse changes in conjunctival cell morphology are associated with metabolic dysfunction or physical trauma, 18,19 and such changes are commonly associated with induction of the inflammatory cascade, including production of cytokines and other chemotactic substances. 20 The effects of contact lens replacement schedule on conjunctival cell morphology and tear cytokines concentrations have not been investigated to date.
This pilot study aimed to explore certain ocular inflammatory responses and clinical outcomes, including conjunctival cell morphology, by contact lens replacement schedule. In this study, we compared the concentrations and ratios of tear cytokines and changes to conjunctival cell morphology in healthy habitual daily disposable and reusable soft contact lens wearers.
This was a cross-sectional, single-visit study conducted at the State University of New York College of Optometry between May 2015 and July 2016. The study followed the tenets of the Declaration of Helsinki, and the local institutional review board approved the research before recruitment began. Written informed consent was obtained from all participants prior to their participation. Because of the nature of a pilot study, a convenience sample of 36 healthy full-time soft contact lens wearers (>6 h/d, >5 d/wk) was recruited from the State University of New York College of Optometry and the metropolitan community by way of e-mail and flyers. In order to control for potential age effects, all subjects were between the ages of 18 and 30 years. All patients were established daily wear contact lens wearers with at least 3 and no more than 15 years of lens wear experience and had a documented medical record of wearing the same type of soft contact lenses (modality and material) for at least 1 year. All subjects were also required to work primarily indoors to avoid potential confounding effects of excessive UV light or wind exposure.
Exclusion criteria of this study included overnight wear, active ocular infection/inflammation (e.g., clinically active allergy indicated as chemosis or papillary reaction, blepharitis, or meibomian gland disease was confirmed by the slit-lamp examination after consent), systemic disease likely to affect the ocular surface (e.g., thyroid disease, diabetes), treatment with anti-inflammatory medications or eye drops during the 3 months prior to the study visit, a prior history of eye surgery or rigid contact lens wear, or smoking or pregnancy during the study period. No eye drops or eye wash was allowed for at least 3 days before the study visit.
All study visits were carried out between 10 AM and 4 PM. Subjects were also required to report after a minimum of 3 hours after waking and with at least 1 hour of contact lens wear prior to the visit, in order to minimize diurnal variations in tear cytokine levels. 21 After informed consent was obtained, general health information and contact lens history, including lens care solution used over the last 3 months, were obtained. Dry eye symptoms were assessed using the Ocular Comfort Index 22 and Contact Lens Dry Eye Questionnaire 8. 23 For both questionnaires, a higher score indicates more discomfort.
Subjects were asked to remove their contact lenses, and clinical assessments were conducted in the order of least to most invasive, as listed below. A slit-lamp examination was conducted to assess the anterior segment of the eye, including eyelid, ocular surface, and tear film integrity, as well as bulbar and limbal redness in both eyes, using the Corneal and Contact Lens Research Unit grading scale. 24 Basal tears were collected from the temporal lower tear meniscus of both eyes with a clean disposable glass micropipette (Blaubrand intraMARK, Wertheim, Germany). The same investigator (CC) collected all tears and maintained an estimated tear flow not more than 3 μL/min to reduce reflex tears. 25 A break was given after 5 minutes of tear collection or if reflex tears were observed. Tears from both eyes were pooled to obtain a total of approximately 15 to 20 μL. Tears were centrifuged to remove cells and debris within 1 hour of collection and then stored at −80°C. Tear cytokine concentrations were batch analyzed using customized multiplex assays (X-plex format, human cytokine group 1, six factors: interleukin 1β [IL-1β], IL-6, IL-10. IL-12[p70], IL-17A, and tumor necrosis factor α; Bio-Rad Laboratories, Minneapolis, MN) as previously described. 26 These cytokines were selected because they have been shown to be associated with contact lens wear and with changes to conjunctival cell morphology. 6–9,27
Following tear collections, fluorescein and lissamine green dyes were instilled, and corneal and conjunctival staining was graded using the modified Oxford Scale. 28,29 Two conjunctival impression cytology samples were then collected. One of the conjunctival impressions was collected from a temporal conjunctival area approximately 6 to 18 mm away from the limbus of one randomly selected eye. This region of the conjunctiva, which is not covered by standard contact lenses, was defined as the contact lens–uncovered region. A second sample was taken from the fellow eye at a temporal conjunctival area approximately 0 to 6 mm away from the limbus, a region partially covered by standard contact lenses. This region was defined as the contact lens–covered region. Topical anesthetic (0.5% proparacaine hydrochloride; Alcon, Tokyo, Japan) was instilled at the inferior fornix prior to collection of samples, and a Millicell cell culture insert (model PICM01250; Merck Millipore, Ireland) was used to collect each sample. The insert was placed on the conjunctiva for 2 to 5 seconds and removed carefully. The procedure for staining the samples has been described previously. 30 Briefly, impression cytology samples were immersed immediately in 95% ethanol and stored at 4°C until analysis. The samples were placed in a 12-well plate and stained with periodic acid–Schiff stain. Images of five nonoverlapping regions per sample were captured using a microscope (Olympus BX51WI; Olympus, Japan). The density of goblet cell per image (20×) was manually counted using PhotoShop element 10 (Adobe, United Kingdom); cells crossing the bottom and right borders of images were not counted. Goblet cell density was reported as cells per millimeter squared. Conjunctival epithelial cell metaplasia was evaluated (40×) using the modified Nelson and Wright grading scheme 31 (grades 0 to 3). Goblet cell density and conjunctival metaplasia grade for five nonoverlapping images were averaged for analysis.
Data were analyzed using SPSS version 21 (SPSS for Mac, Chicago, IL). Data were tested for normality using the Shapiro-Wilk test (P > .05). Independent t tests or Mann-Whitney U tests, as appropriate, were carried out to examine the differences between replacement schedules (reusable vs. daily disposable) for symptoms, ocular surface integrity, tear cytokines, and conjunctival cell morphology. Because sex has been identified as a possible confounder of tear cytokine concentrations, 32 generalized linear models controlling the variance of sex in the outcome variables were performed. Differences in conjunctival cell morphology between contact lens–covered and contact lens–uncovered conjunctival areas were assessed using paired t tests or Wilcoxon signed rank tests, as appropriate. The ratios of the concentration of proinflammatory and anti-inflammatory cytokines 33–35 were calculated, and associations were determined with symptoms, slit-lamp findings, and conjunctival cell morphology. Pearson or Spearman correlations, as appropriate, were used to assess the relationships between outcome variables and the effects of duration of contact lens wear. Partial correlations were used to control for the effect of replacement schedule. Significance was determined at P < .05.
Twenty-one females and 15 males, with a mean age of 23.8 ± 1.8 years, were included in this study. Generalized linear models indicated that sex was not associated with any clinical evaluations, conjunctival cell morphology, or tear cytokine concentrations, and so sex was not included in the statistical models. Twenty-two subjects used reusable and 14 subjects used daily disposable contact lenses full time (>6 h/d, >5 d/wk) for at least 1 year based on patient report and medical records (Table 1). All reusable-wear subjects used multipurpose solution. The average duration of contact lens wear for all subjects was 8.8 ± 3.4 years, and the study visit time was 1:15 PM ± 2 hours. Age, duration of contact lens wear, and time of study visit were not significantly different between replacement schedule groups (Table 1).
Daily disposable and reusable wearers generally showed only mild clinical symptoms and signs (Table 2). There was a greater degree of conjunctival staining in reusable contact lens wearers (P = .025; Table 2). Reusable contact lens wearers also showed higher concentrations of all tear cytokines (P < .01; Table 2) and greater conjunctival metaplasia in the region covered by contact lenses (P = .01; Table 3). There was no difference between lens replacement groups in conjunctival epithelial metaplasia in the region not covered by contact lenses or in goblet cell density in either region of the conjunctiva (Table 3).
For all participants, goblet cell density in the non–contact lens–covered conjunctival region was significantly higher than that in the region covered by contact lenses (regional differences, P < .001; Table 3). Contact lens replacement schedule did not affect this regional difference. There was also a higher grade of conjunctival metaplasia in the region of the conjunctiva covered by contact lenses compared with the region not covered by lenses (regional differences, P < .001; Table 3).
There were no associations between symptoms during contact lens wear and the concentration of individual cytokines in tears or conjunctival cell morphology. Although symptoms were generally mild, higher symptoms were associated with a higher ratio of IL-1β to IL-10 (Contact Lens Dry Eye Questionnaire 8: ρ = 0.38, P = .02; Ocular Comfort Index: ρ = 0.42, P = .01) and IL-12(p70) to IL-10 (Ocular Comfort Index only: ρ = 0.33, P = .049). A higher ratio of IL-1β to IL-10 was also associated with greater goblet cell density (ρ = 0.33, P = .046) and lower conjunctival epithelial metaplasia in the region of the conjunctiva not covered by lenses (ρ = −0.41, P = .01). A higher ratio of IL-12(p70) to IL-10 was associated with greater goblet cell density only in the region of the conjunctiva covered by contact lenses (ρ = 0.33, P = .04). Also, the associations between tear cytokine concentrations and conjunctival cell morphology in both regions could not been found.
This study found that reusable soft contact lens wear was associated with higher concentrations of tear cytokines, more conjunctival staining, and greater conjunctival epithelial metaplasia compared with daily disposable contact lens wear. In addition, conjunctival goblet cell density was numerically lower in reusable lens wearers in the region covered by the contact lens. Higher ratios of proinflammatory to anti-inflammatory cytokines were associated with greater symptoms during lens wear and higher goblet cell density. This pilot study provides evidence that replacement schedule can affect measureable anterior segment inflammation and conjunctival cell morphology.
This is the first study to compare tear cytokine concentrations between daily-reusable and daily-disposable-soft-contact-lens wearers. There were significantly higher tear cytokine concentrations in daily-reusable than in daily-disposable-soft-contact-lens wearers. Higher concentrations of cytokines in reusable contact lens wearers could be due to the regular use of contact lens care solutions, particularly multipurpose solutions in this study, and the accumulation of deposits/cellular debris on lenses. The use of certain multipurpose contact lens–disinfecting solutions has been shown to increase the concentration of tear cytokines (IL-6, IL-8, IL-17A, and tumor necrosis factor α), 27 which is consistent with the findings in the current study. The effects of deposits/cellular debris on tear cytokine concentrations would require further investigation.
A clinical trial that compared the use of one contact lens material, senofilcon A, reported a significant improvement in end-of-day comfort and dryness when used as a daily disposable rather than a reusable contact lens with either multipurpose or hydrogen peroxide solution. 5 The finding that concentrations of individual cytokines were different between the groups in this study but comfort was not supports previous findings that contact lens discomfort may not be related to the absolute concentration of cytokines in tears. 8 This study demonstrated a positive association between symptoms and ratios of proinflammatory to anti-inflammatory cytokines, IL-1β to IL-10 or IL-12(p70) to IL-10. The balance between cytokines may be critical in maintaining the homeostasis and hence comfort of the ocular surface during lens wear.
Previous studies reported that conjunctival epithelial metaplasia at the region approximately 1 to 4 mm away from the limbus worsened with contact lens wear and may be associated with duration of wear. 17,36,37 The current study found a higher metaplasia grade with reusable versus daily disposable soft contact lens wear but only in the region partially covered by the contact lens (samples collected next to limbus). This suggests that interaction with the lens edge design or modulus may have a direct effect on the conjunctival cells in this area. 38,39 Further research with larger sample populations should be conducted to better understand the effects of various lens designs on conjunctival cell morphology and cytokines.
The regional differences found in thus study were consistent with earlier findings of goblet cell density increasing from near zero at the limbus to more than 300 cells/mm2 in the peripheral bulbar conjunctiva. 40 However, this is the first study to demonstrate a regional difference in the amount of conjunctival metaplasia.
Cytokines expressed on the ocular surface can promote or inhibit mucin secretion and proliferation or apoptosis of goblet cells. 41,42 The concentration of tear IL-6 has been associated with lower goblet cell density in subjects experiencing dry eye. 43 A relationship between absolute tear cytokine concentrations and goblet cell density or conjunctival epithelial metaplasia was not found in the current study. This may be due to the fact that our subjects were only mildly symptomatic with lens wear. 44 However, higher ratios of proinflammatory to anti-inflammatory cytokines IL-1β to IL-10 and IL-12(p70) to IL-10 were associated with lower metaplasia and higher goblet cell density. There are no previous reports on the role of IL-1β, IL-12(p70), and IL-10 on goblet cell function, but IL-1 may affect the glycosylation of mucins 45 and thus goblet cell secretion. Animal studies would be helpful to explore potential relationships between cytokines and conjunctival morphology.
Higher conjunctival staining was found in the reusable contact lens replacement group. This could be a response to accumulating deposits on the lenses or leaching of multipurpose solutions used with reusable lenses. Alternatively, higher conjunctival staining could be due to mechanical damage from lens edge designs or higher modulus materials. 46 Only nine subjects in this study wore hydrogel soft contact lenses materials so the study was not adequately powered to examine the potential effects of contact lens materials or designs.
All study visits were conducted at least 3 hours after waking and between 10:00 AM and 4:00 PM in order to minimize any overnight swelling or diurnal variation of anterior segment findings and tear cytokine concentrations. Redness, temperature, and blood flow of bulbar conjunctiva have been shown to increase upon waking and return to baseline levels 3 to 4 hours after waking. 47 Willcox et al. 8 and Benito et al. 21 showed diurnal variation of IL-8 and tumor necrosis factor α concentration between morning and late evening (before sleep) and IL-10 and IL-1β between midday and evening. Even though the specific number of awake hours at the time of study visit was not collected, the mean study visit time was in the midday in both groups; therefore, any differences between groups are not likely attributable to diurnal variation.
A limitation of this pilot study is the cross-sectional study design, which allowed the inclusion of subjects wearing their habitual contact lenses. However, because more than 10 different types of lenses were included in this study, it is unlikely to see a specific bias due to a particular design or material. Future prospective crossover studies could randomly assign neophyte lens wearers to different replacement schedules, materials, or designs to explore the direct effects on ocular inflammatory responses and symptoms. In addition, this pilot study did not collect the number of days of wear for the reusable lenses and the wearing time before the study visit. Therefore, we were unable to examine the effects of estimated accumulated deposits/cell debris and the wearing time on inflammatory biomarkers. Future studies should also consider the use of other symptoms questionnaires such as the Ocular Surface Disease Index 48 or a visual analog scale. 49
In conclusion, this study demonstrated higher tear cytokine concentration and conjunctival cell metaplasia in habitual reusable soft contact lens wear with use of multipurpose solution compared with daily disposable contact lens wear. Also, the results suggest that the region covered by soft contact lenses may be a more appropriate area to study differences in conjunctival cell morphology for contact lens–related studies. The balance of proinflammatory and anti-inflammatory cytokines may be helpful to assess inflammatory status of the eye and relationships with other biomarkers and symptoms of discomfort. Based on the findings of this pilot study, future prospective studies can be planned to quantify the potential effects of lens material, design, and replacement schedule on the ocular surface.
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