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Corneal Sensitivity and Inflammatory Biomarkers in Contact Lens Discomfort

López–de la Rosa, Alberto; Martín-Montañez, Vicente; López-Miguel, Alberto; Calonge, Margarita; Enríquez–de-Salamanca, Amalia; González-García, María Jesús

doi: 10.1097/OPX.0000000000000784
Original Articles
Press Release

Purpose The aim of this study was to analyze whether symptoms of discomfort in hydrogel contact lens (HCL) wearers were associated with changes in corneal sensitivity or levels of tear inflammatory mediators.

Methods Sixty-six subjects were included: 47 HCL wearers, further divided into 24 symptomatic and 23 asymptomatic wearers by the Contact Lens Dry Eye Questionnaire short form and 19 non–contact lens wearers. At least 24 h after HCL removal, we obtained scores from the Ocular Surface Disease Index and mechanical, hot, and cold corneal thresholds using a Belmonte esthesiometer. We collected 4 μl of tears with a capillary micropipette and measured levels of 12 inflammatory markers using a bead-based array: epidermal growth factor, fractalkine, interleukin-10 (IL-10), IL-1β, IL-1 receptor antagonist, IL-2, IL-4, IL-6, IL-8, monocyte chemoattractant protein 1, tumor necrosis factor-α, and matrix metalloproteinase 9.

Results There were no significant differences between groups in corneal sensitivity thresholds and levels of tear molecules. The following significant correlations were found in the total sample pooled: Ocular Surface Disease Index correlated with mechanical threshold (p < 0.01; rho = −0.324) and epidermal growth factor (p < 0.01, rho = −0.330), and mechanical threshold correlated with heat threshold (p < 0.01, rho = −0.321).

Conclusions Twenty-four hours after HCL removal, symptoms of discomfort in HCL wearers are not related to changes in corneal sensitivity or tear inflammatory mediator levels. This might indicate either that HCL wear has no effect on these parameters or that ocular surfaces recover from HCL-caused effects during the first hours after HCL removal. However, there were correlations for associations between symptoms, corneal sensitivity, and some molecules in tears.




Ocular Surface Group, IOBA-University of Valladolid, Campus Universitario Miguel Delibes, Valladolid, Spain (ALdlR, VM-M, AL-M, MC, AE-d-S, MJG-G); Networking Research Center on Bioengineering Biomaterials and Nanomedicine (CIBER-BBN), Valladolid, Spain (VM-M, MC, AE-d-S, MJG-G); and VISION I+D, SL, Edificio IOBA, Campus Universitario Miguel Delibes, Valladolid, Spain (AL-M).

María Jesús González-García IOBA-University of Valladolid Campus Miguel Delibes Paseo de Belén 17 E-47011 Valladolid Spain e-mail:

Contact lenses (CLs) are a common method for correcting refractive errors. It has been estimated that there are about 140 million CL wearers (CLWs) worldwide.1 However, 35 to 60% of these users suffer symptoms of discomfort such as foreign body sensation, burning, itching, or dryness while wearing their CLs.2–4 These complaints are the principal cause of discontinuing CL wear4,5; therefore, CL discomfort is of significant concern for clinicians and the industry.5,6 Unfortunately, the cause of this intolerance is still unknown, and the relationship between symptoms and clinical signs remains unclear.7

Use of CLs can reduce corneal sensitivity, as has been reported in polymethyl methacrylate,8,9 rigid permeable,9,10 and hydrogel10–12 CL (HCL) wearers; however, the etiology is not completely understood yet. Corneal sensitivity reduction was initially attributed to hypoxia produced by CL wear.13 Recent studies using high-oxygen-transmission CLs suggest that corneal sensitivity reduction may be caused by a combination of several factors apart from hypoxia, such as mechanical stimulation or presence of inflammatory mediators induced by CL wear.11–14 In addition, corneal sensitivity reduction may interfere with blinking rate and tear production, which can lead to increased symptoms of dryness and discomfort.15,16

Inflammatory mediators have a role in pain initiation and maintenance, as well as hyperalgesia.17,18 Although several tear inflammatory mediators are present in tears of healthy subjects,19,20 an upregulation of these molecules has been related to some conditions, including dry eye syndrome21–24 or CL wear.25–28 Dry eye syndrome is widely recognized as an inflammatory condition.21–24 In CLWs, despite the fact that some inflammatory markers have been found upregulated,25–28 this process is not clear yet. Specifically, epidermal growth factor (EGF),25,26 interleukin-6 (IL-6),27,28 and IL-825,27 are altered with CL wear. Because of their role in pain and hyperalgesia,17,18 inflammatory molecules in tears may be partially responsible for the symptoms of discomfort during CL wear. This is an important issue that should be addressed.

The purpose of this study was to analyze symptoms of discomfort, corneal sensitivity thresholds, and tear levels of inflammatory molecules in symptomatic and asymptomatic HCL wearers and compare them with non-CLWs. We also studied the correlations between symptoms of discomfort, corneal sensitivity, and inflammatory mediators in tears in the total sample pooled.

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This study was approved by the University of Valladolid Ethics Committee and complied with the tenets of the Declaration of Helsinki. The nature of the research and the protocols were explained to each subject before written consent was obtained.

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The HCL wearers included in the study were divided into symptomatic (SCLWs) and asymptomatic (ACLWs) wearers based on the Contact Lens Dry Eye Questionnaire (CLDEQ) short form.29 Non–contact lens wearers (NCLWs) were also included as control subjects. Inclusion criteria were age between 18 and 45 years to avoid possible affectation related to aging (i.e., presbyopia visual symptoms and ocular surface changes), subjective spherical refraction between −0.75 and −5.00D, astigmatism ≤−0.75D, and distance visual acuity ≤0.0 LogMAR. In addition, CL users had to have worn HCLs for at least 6 months before being included in the study, whereas those included in the ACLW group had to wear their CLs at least 5 days per week and 6 hours per day. The SCLW group did not have any frequency of wear requirements to not exclude subjects who do not use CL frequently because of discomfort. Moreover, the Ocular Surface Disease Index30 (OSDI) score had to be less than 13 in the NCLWs, with the aim of avoiding the presence of dry eye disease.31 Exclusion criteria included extended or continuous CL wear (overnight use), any active ocular disease, anterior ocular surgery, systemic disease that contraindicates CL wear, and use of any topical medication other than artificial tears.

The study protocol consisted of one visit in which all subjects had been awake for at least 2 h before their assessment, and the CLWs had not worn their lenses for at least 24 h. The temperature of the examination room was always at 16 to 17°C, and its relative humidity was between 50 and 60%.

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Symptom Assessment

Symptoms of discomfort were quantified by administering the OSDI questionnaire.30 The OSDI consists of 12 questions evaluating symptoms of ocular discomfort and dryness suffered during the previous week; its total score can range from 0 (no symptoms) to 100 (most severe). This questionnaire was given to every volunteer; however, CLWs were instructed to answer the questionnaire regarding the symptoms that they had suffered while wearing their CLs.

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Tear Collection

Four microliters of tears were collected nontraumatically from the right eye of every subject using glass capillary micropipettes (Drummond Scientific Co., Broomall, PA), as previously described.21 They were collected from the lacrimal meniscus in the temporal canthus of the eye, avoiding reflex tearing as much as possible. Each sample was then diluted in a sterile collection tube containing 16 μl of ice-cold Milliplex Cytokine Assay Buffer (Millipore Iberica, Madrid, Spain), and it was immediately stored at −80°C until assayed.

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Corneal Sensitivity Measurements

Corneal sensitivity thresholds were measured using a Belmonte esthesiometer.32,33 This device consists of a tip, where an air jet is expulsed, and a central unit, where the clinician selects the characteristics of the air jet. The tip of the esthesiometer was fixed to a slitlamp table, and the subjects were seated opposite the tip, which was placed 5 mm from the corneal apex to perform the measurements. Airflow was applied to the central cornea for 3 s. Subjects could freely blink except during the 3-s airflow.

Mechanical and thermal (heat and cold) thresholds were assessed in the right eye of every subject using the method of levels, allowing 1- to 2-min intervals between stimuli.32–34 Mechanical threshold was always evaluated first to fix a mechanical subthreshold to be used when measuring thermal thresholds. Mechanical threshold was measured using an airflow ranging between 0 and 200 ml/min.32,34 Airflow temperature during this stage was calculated to match that of the corneal surface, 34°C,32,35 so as not to stimulate thermal receptors. Thermal thresholds were then evaluated using airflows at different temperatures and flows 10 ml/min below mechanical threshold to avoid mechanical stimulation.33,34 The order of heat and cold threshold measurement was randomized. Temperature range of airflow over the cornea was from −4 to +3.6°C from the basal value (34°C).

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Inflammatory Marker Analysis

Inflammatory marker levels in tear samples were determined by X-MAP technology using commercial assays and were analyzed using a Luminex IS-100 (Luminex Corporation, Austin, TX), as previously described.21 The following molecules were analyzed: EGF, fractalkine, IL-1β, IL-1 receptor antagonist (Ra), IL-2, IL-4, IL-6, IL-8, IL-10, monocyte chemoattractant protein 1 (MCP-1), and tumor necrosis factor-α (TNF-α) with the Milliplex Human Cytokine/Chemokine Magnetic Bead Panel, 11-plex HCYTOMAG-60 K kit (Millipore). Matrix metalloproteinase 9 (MMP-9) concentration was measured in a separate assay with an MMP-9 single-plex assay (HMMP2-55 K magnetic bead Panel 2; Milliplex), which recognized the MMP-9 inactive zymogen and MMP-9 active forms.

Ten microliters of the 1:10 buffer-diluted sample was incubated with antibody-coated capture beads overnight under agitation at 4°C. After washing, beads were further incubated with biotin-labeled human anticytokine or anti–MMP-9 antibodies, depending on the case, for 1 h, followed by streptavidin-phycoerythrin incubation for 30 min. Standard curves of known concentrations of recombinant human cytokines and MMP-9 were used to convert fluorescence units to molecule concentration (in picograms per milliliter). Minimum detectable concentrations (in picograms per milliliter), based on manufacturer specifications, were EGF, 2.8; fractalkine, 22.7; IL-1β, 0.8; IL-1Ra, 8.3; IL-2, 1.0; IL-4, 4.5; IL-6, 0.9; IL-8, 0.4; IL-10, 1.1; MCP-1, 1.9; TNF-α, 0.7; and MMP-9, 2.0. When the concentration was below the assay detection limit, the minimum detectable value was accepted as the concentration level.36 However, molecules whose detection percentage was less than 70% were excluded from the statistical analysis.37,38

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Statistical Analysis

The sample size was calculated with the online freeware “Power Analysis for ANOVA Designs” (available at It was taking into account that three groups were compared, level of signification was determined as 0.05, effect size as 1.0, and statistical power as 80%. Based on these parameters, total sample size calculated was 20 subjects for each group. Data were analyzed using SPSS 20.0 for Windows (Chicago, IL). Sample distributions for sex and time of day in which the visit occurred (morning, 9 a.m. to 1 p.m., or afternoon, 4 to 8 p.m.) were analyzed using the χ2 test, whereas percentage data were compared using the z test for column proportions. Main variables assessed and sample distribution for age were tested for normality and equality of variances using the Shapiro-Wilk test and Levene test, respectively. Detection percentages of the inflammatory molecules among groups were analyzed using the χ2 test. To avoid the influence of the time of collection (morning/afternoon), data standardization was applied for inflammatory molecule level comparisons; standardization was applied, subtracting the mean and dividing by the standard deviation (SD) of each group. One-way analysis of variance (ANOVA) was used to compare data if normality was assumed or the Kruskal-Wallis H test was used if normality could not be assumed. When a significant p value was obtained, a Student ’s t-test (normality), Mann-Whitney U (non-normality, equal variances), or Kolmogorov-Smirnov Z (non-normality, unequal variances), applying the Bonferroni correction, was used to compare groups. Correlations between variables were analyzed in the total sample (CLWs + NCLWs) using the Spearman correlation coefficient, rho, after applying data standardization (as explained above) to avoid the influence of each group on the measured parameters. Data are presented as mean ± SD.

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A total of 66 subjects were included in the study, 27 men and 39 women, with a mean age of 26.9 ± 6.7 years (range, 18 to 45 years). Demographic characteristics of the sample are shown in Table 1.



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OSDI Questionnaire

Significant differences were found in OSDI values between the SCLW and ACLW groups (p < 0.001, Mann-Whitney U) and also between the SCLW and NCLW groups (p < 0.001, Kolmogorov-Smirnov Z). Fig. 1 shows the OSDI score for each study group.



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Corneal Sensitivity

Mechanical and thermal (hot and cold) thresholds for all study groups are shown in Fig. 2. No significant differences were found among groups in mechanical (p > 0.05, Kruskal-Wallis H), hot (p > 0.05, Kruskal-Wallis H), or cold (p > 0.05, ANOVA) thresholds.



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Inflammatory Marker Tear Levels

All molecules were analyzed in all samples with the exception of MMP-9, which could not be analyzed in tears from nine subjects because of a limitation in sample collection (only 1 μl could be collected in these subjects). The percentage detection of each marker is summarized in Table 2. There were no significant differences in the detection percentages among groups for each marker (p > 0.05, χ2). Molecules detected in less than 70% of the cases (IL-2, TNF-α, IL-1β, and IL-4) were not included in the statistical analysis. Mean levels of the molecules detected higher than 70% are shown in Fig. 3. There were no significant differences in the concentration levels of the inflammatory markers measured among groups (p > 0.05, Kruskal-Wallis H).





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Some significant correlations were found in the total sample pooled: OSDI score correlated inversely with mechanical threshold (p < 0.01; rho = −0.324) and with EGF tear levels (p < 0.01, rho = −0.330). We also found that mechanical threshold correlated inversely with heat threshold (p < 0.01, rho = −0.321). These correlations are shown in Fig. 4.



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This study examined corneal sensitivity and tear inflammatory molecules in tears in symptomatic and asymptomatic CLWs and NCLWs. The results reveal that there are no differences in these parameters between the study groups at least 24 h after CL removal. In addition, we found some relationships between these clinical and biochemical variables and the symptoms of discomfort.

The CLWs were divided into symptomatic and asymptomatic by administering the CLDEQ, an instrument designed for this purpose.29 In addition, symptoms of ocular discomfort were quantified by means of the OSDI questionnaire to obtain a quantitative score because the CLDEQ does not provide information regarding the severity of the symptoms. In our study, we found that OSDI values were significantly higher for the SCLW group in comparison with the ACLW and NCLW groups, indicating that SCLW subjects suffer more symptoms, as expected. However, it must be taken into account that NCLWs were only eligible for the study if they had an OSDI value lower than 13.31

Mechanical sensitivity measurements showed that there were no significant differences in mechanical thresholds among the SCLW, ACLW, and NCLW groups. This indicated that mechanical threshold was not affected by CL wear, independently of whether wearers were symptomatic or asymptomatic. Controversially, there are some studies with soft daily HCL wearers that report an increase in mechanical threshold.10–12 However, it is notable that all of these studies took the CL wear measurements without taking a CL-free rest period longer than 10 min, considerably different from our methodology. On the other hand, Velasco et al.,39 despite finding an increase in mechanical threshold after 8 h of HCL use, showed that the threshold is fully recovered within the first 4 h after CL removal. Moreover, authors who instructed CLWs to remove their CLs the night before the assessment did not find any differences in mechanical threshold between NCLWs and CLWs40 or between symptomatic and asymptomatic CLWs.41 Considering these studies, and despite the fact that we did not analyze this effect, an alternative to the suggestion that HCL use does not affect mechanical threshold is the possibility that HCL use does indeed affect mechanical threshold in some way but that the thresholds recover once the CLs are removed. This assumption could mean that the possible mechanical adaptation because of CL wear disappears within just 24 h of remaining without CL wear.

Both (hot and cold) thermal corneal thresholds were measured in our study. The outcomes showed that there were no significant differences in thermal thresholds among the SCLW, ACLW, and NCLW groups. Our study is the first one to report thermal thresholds in HCL users; however, Tanelian and Beuerman42 reported an increase in heat threshold after 8 h of polymethyl methacrylate CL use that completely disappeared within 24 h after CL removal. Our findings may indicate that HCL use does not affect thermal thresholds. On the other hand, taking into consideration the findings of Tanelian and Beuerman,42 thermal thresholds might be affected by HCL use but recover normal states after removing the CLs, and it would be independent of the symptoms of discomfort. Therefore, in case CL wear provokes an alteration in the function of corneal nerves, this effect seems to disappear 24 h after CL removal.

Tear concentrations of 12 inflammatory markers were analyzed; the markers were chosen because they had either appeared altered in previous studies on CLWs25–28 and on dry eye disease21–24 or had been shown to be pain related.18,21,22 The analysis of these inflammatory markers showed no significant differences of tear concentration among any of the groups. This lack of differences may indicate that these molecules in tears are unaffected by HCL wear. Conversely, some of these tear markers (EGF, IL-6, and IL-8) have previously been found altered in CLWs.25–28 However, it is remarkable that these authors (except for Dogru et al.28) did not establish a CL-free period before taking measurements, as we did. Dogru et al.28 instructed their subjects to remove their CLs the night before the morning of the assessments; in any case, this was less time than the 24 h our volunteers remained without CLs, besides other differences in methodology, such as time from awakening when samples were taken, type of CL users (neophytes vs. experienced), or type of CL used, that may also explain the different results obtained.

Some of the inflammatory markers analyzed in these studies have also been found unaltered in CLWs. González-Pérez et al.26 found no differences in the concentrations of IL-6, IL-8, and MMP-9 in tears after 12 months of silicone hydrogel CL use on a continuous-wear basis compared with nonusers. Dogru et al.28 found no altered levels of IL-8 and IL-10 in tears of HCL wearers after 2 weeks of CL use compared with their baseline. Markoulli et al.43 reported no significant differences in MMP-9 tear concentrations after wearing HCL for 1 month. Thus, the possible release of inflammatory mediators in CLWs seems to be debatable. Moreover, Schultz and Kunert44 reported that, although IL-6 levels were higher during CL use, these levels became similar to those of non-CL users 6 days after CL removal. Consequently, another possible explanation of our results (although we did not analyze the effect) may be that inflammatory mediators might only be present during CL wear and that any increase might revert to normal concentration values after CL removal, independently of whether CLWs suffer symptoms of discomfort during CL wear or not. This supposition involves that the possible inflammatory response to CL wear weakens after CL removal, and it is not detectable at all within 24 h without CL wear.

We also found some significant correlations among the study variables in the total sample pooled. First, the OSDI score correlated inversely with the mechanical threshold. This correlation has been described several times in a population of healthy subjects and dry eye patients, altogether.45,46 In addition, our research group had previously found that the presence of grittiness symptoms was associated with a decrease in mechanical threshold,34 which might agree with this study finding. It seems reasonable that subjects with lower mechanical thresholds (higher sensitivity) might be more sensitive to any stimulus, and as a result, they might report more symptoms of ocular discomfort.

We also found that the OSDI score was inversely correlated with EGF levels. Epidermal growth factor in tears has been reported to be involved in epithelial wound healing and has been associated with proper functioning of the lacrimal gland.47,48 This fact may explain this correlation, if discomfort (based on the OSDI score) was partially caused by abnormal lacrimal gland function; nonetheless, inadequate lacrimal gland function may not be the only cause of ocular discomfort.

Finally, we found that mechanical threshold correlated inversely with heat threshold. Mechanical threshold is determined by mechanosensory and polymodal fibers, whereas heat threshold is determined by polymodal fibers.35,49 Feng and Simpson50 reported an interaction in healthy subjects between mechanical and chemical thresholds (the latter determined by polymodal fibers), in which chemical threshold decreases as flow rate increases and mechanical threshold diminishes as chemical stimulation rises. Therefore, our results might be explained because stimuli processed by polymodal fibers are not processed separately as different thresholds. This theory would also explain the lack of significant correlations with cold threshold because it is determined by stimulation of cold receptors, so there would be no interaction with other stimuli. Moreover, Feng and Simpson50 found no effect of temperature reductions on mechanical and chemical thresholds. Contrary to these findings, Bourcier et al.51 reported a direct correlation between mechanical and thermal (both heat and cold) thresholds in healthy subjects. Consequently, further studies are needed to clarify the exact relationships among the different types of corneal sensitivity.

The present study has some limitations. The first is caused by the diversity of CL materials, solutions, and wearing schedules that the CLWs had, as we did not control these variables initially. However, to minimize possible bias, CLWs always remained at least 24 h without wearing their CLs. This CL-free time was relevant in our outcomes because of the possible changes that the different variables could have suffered during this time. Second, the uneven distribution of males and females within the SCLW group could have introduced a bias in the study outcomes; nonetheless, this distribution reflects daily clinical practice because there is a larger percentage of women reporting symptoms of CL discomfort than men.3

In conclusion, our study showed that corneal sensitivity assessed after at least 24 h of CL nonuse is not affected by HCL wear, regardless of whether wearers are symptomatic or asymptomatic. Likewise, this finding also applies to the concentration of tear markers associated with ocular surface inflammation, which was unchanged at assessment time. This might indicate either that HCL wear has no meaningful effect on these parameters or that the ocular surface recovers from the effect caused by HCL wear during the first hours after CL removal. However, the significant correlations found also suggest that there is some kind of association between symptoms, corneal sensitivity, and the levels of some tear markers. Future studies with diverse intervals of CL-free time should be carried out to confirm our findings.

María Jesús González-García

IOBA-University of Valladolid

Campus Miguel Delibes

Paseo de Belén 17

E-47011 Valladolid



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Amalia Enríquez-de-Salamanca and María Jesús González-García have contributed equally to this article.

We thank Carmen García-Vázquez for technical assistance and Itziar Fernández, PhD, for statistical advice.

Presented, in part, at the Association for Research in Vision and Ophthalmology Annual Meeting, Orlando, Florida, on May 4–8, 2014.

Received March 18, 2015; accepted August 7, 2015.

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contact lens; discomfort; corneal sensitivity; cytokines; chemokines

© 2016 American Academy of Optometry