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Mucin Balls Influence Corneal Infiltrative Events

Szczotka-Flynn, Loretta B.; Jiang, Ying; Stiegemeier, Mary Jo; Mutti, Donald O.; Walline, Jeffrey; Wilson, Tawnya; Debanne, Sarathe Mucin Ball Study Group

doi: 10.1097/OPX.0000000000001045
Feature Article — Public Access

Purpose To determine whether mucin ball (MB) formation is protective against corneal infiltrative events (CIEs) as previously reported.

Methods Two hundred eighty-two eligible participants were enrolled at three sites in the USA. Participants began a 1-month continuous wear run-in period with high modulus lotrafilcon A lenses to assess their ability to form MBs (phase 1). Subsequently, they were stratified by this characteristic and randomized to balafilcon A or comfilcon A lenses for 7-day extended wear and followed for 1 year (phase 2). MB formation in each phase was defined as repeated presence of any MBs on a person level. Multivariable Cox proportional hazards regression was used to model the probability of a CIE as a function of MB formation in each phase and other covariates.

Results Of the 282 participants who entered phase 1, 218 of them entered the phase 2 randomized trial during which 33 CIEs occurred. Overall, 74%, 61%, and 79% of participants repeatedly produced MBs in lotrafilcon A, balafilcon A, and comfilcon A lenses, respectively. Early repeated MB presence in phase 1 with lotrafilcon A lenses significantly increased the rate of CIEs in phase 2 (12-month follow-up) by 466% (HR 4.66, 95% confidence interval 1.10–19.79, P = .0372). Repeated, longer-term MB presence during wear of balafilcon A or comfilcon A in phase 2 did not significantly reduce the incidence of CIEs; however, it significantly decreased the rate of CIEs by 62% (hazard ratio (HR) 0.380, 95% confidence interval 0.145–0.998, P = .0494).

Conclusions The overarching hypothesis that MB formation is protective against CIEs throughout extended wear was not supported. Although a protective effect of longer-term MB presence on rate of CIEs was detected, early-onset MB formation substantially increased the hazard for CIE in subsequent wear with different lens types.

*OD, PhD, FAAO

MD, MS

OD, FAAO

§PhD

University Hospitals Eye Institute, University Hospitals Case Medical Center, Cleveland, Ohio (LS-F); Departments of Ophthalmology & Visual Sciences (LS-F) and Epidemiology & Biostatistics (SD, YJ), Case Western Reserve University, Cleveland, Ohio; Western Reserve Vision Care, Beachwood, Ohio (MJS); The Ohio State University College of Optometry, Columbus, Ohio (DOM, JJW); and Johnson & Johnson Vision Care, Inc., Jacksonville, Florida (TW).

Loretta B. Szczotka-Flynn, University Hospitals Eye Institute, 11100 Euclid Ave., Lakeside 4126C, Cleveland, OH 44106, e-mail: loretta.szczotka@uhhospitals.org

A recent survey of contact lens prescribing practices in the Unites States from 2002 to 2014 revealed that silicone hydrogel lenses replaced traditional low Dk hydrogels as the soft lens material of choice.1 Although silicone hydrogel materials provide more oxygen transmissibility, especially during extended wear, the risk of microbial keratitis is unchanged and the incidence of inflammatory complications is increased with silicone hydrogel lenses compared to their lower oxygen permeable hydrogel counterparts.2–4

During extended wear with silicone hydrogel lenses, the incidence of symptomatic corneal infiltrative events is 2.5 to ~6% per year.5–8 When asymptomatic corneal infiltrative events are included, the rates range from ~6 to 26% per year, though these events are often only observed with frequent follow-up.4,9,10 Contact lens–related corneal infiltrative events have been attributed to responses to bacteria or their toxins, preservatives and preservative toxicity, post-lens debris, hypoxia, and acute or self-limiting microbial infections.11,12 It has been well documented that extended wear13–16 and bacterial adhesion to lenses,10,17–23 especially silicone hydrogel lenses,24–26 significantly increases the risk of corneal infiltrative events. The general hypothesis is that during extended wear, corneal infiltrative events are acute inflammatory reactions to the presence of bacteria, bacterial products, toxins, enzymes, or by-products adhered to the contact lens, which provoke an infiltrative response.27

Clinically evident changes in the ocular defense mechanisms from contact lens wear may be additional factors associated with corneal infiltrative event risk. The mucus layer contains mucins, inorganic salts, and water; it covers the corneal and conjunctival epithelial apical surfaces, acts as a barrier to pathogen penetrance,28 and inhibits bacterial multiplication.29,30 During extended contact lens wear in some patients, clinically visible mucin balls develop as spherical, translucent, insoluble tear film–derived bodies composed of ocular surface mucins shed from the epithelial surface.31–33 The Longitudinal Analysis of Silicone Hydrogel (LASH) Contact Lens Study assessed the association between presence of mucin balls and corneal infiltrative events in a secondary analysis of the dataset.34 The LASH study followed 205 participants over 12 months of lotrafilcon A continuous wear for factors associated with time to development of corneal infiltrative events. Unexpectedly, mucin ball presence was found to decrease the risk of corneal infiltrative events, and the effect was greatest when they were repeatedly present over time.34 It was proposed that mucin ball presence represented either a viscous mucus layer or a physical barrier between the lens and corneal surface, which prevented upregulation of the immune response when lens-adhered bacterial antigens were simultaneously present.

The shear and tension forces caused by mechanical interactions between contact lenses and the ocular surface contribute to mucin ball formation.32,35,36 Although mucin balls have been noted with all types of contact lens materials, extended wear with silicone hydrogel lens materials is known to produce the most because of high material modulus,37 minimal protein deposition,38 and depletion of aqueous tears beneath lenses during overnight wear,39,40 resulting in a mucin-rich post-lens tear film. The protective effect noted in the LASH Study was hypothesized to be secondary to mucins entrapping foreign objects or microbes, mucin balls functioning as “ball bearings” to separate the lens physically from the corneal epithelium, and/or simply that clinical detection of mucin balls represented a biomarker for a more concentrated or viscous mucus layer improving ocular surface defense against pathogens. Because the LASH Study was not designed to assess this question specifically, and the findings are relevant to the clinical community fitting contact lenses for extended wear, the current study was designed to definitively determine whether mucin balls are protective against corneal infiltrative events. We also sought to determine whether the ability to form mucin balls (possibly representing a generous mucin profile) and/or the physical presence of mucin balls during overnight wear offered protection against corneal infiltrative events while controlling for in vivo microbial colonization of contact lens surfaces and ocular adnexa during extended wear of silicone hydrogel contact lenses. Our two aims were as follows:

  1. To determine whether the ability to form mucin balls was a biomarker for some unknown (protective) mucin characteristic against corneal infiltrative events.
  2. To determine whether the mucin balls themselves play a protective role against corneal infiltrative events.
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METHODS

This was a multicenter study with three sites participating: University Hospitals Eye Institute (Cleveland, OH), The Ohio State University College of Optometry (Columbus, OH), and Western Reserve Vision Care (Beachwood, OH). A randomized clinical trial was nested within a cohort study. The cohort study addressed the question of whether the ability to form mucin balls offers protection against corneal infiltrative events, and the randomized trial was designed to answer the question of whether the physical presence of mucin balls during extended wear offers protection against corneal infiltrative events.

All participants signed a written informed consent before participation. The study was approved by the University Hospitals Case Medical Center and The Ohio State University Institutional Review Boards for coverage of their respective sites and followed all the Tenets of the Declaration of Helsinki. Participants were enrolled beginning in September 2011, and the last participant was followed through February 2014. Eligible subjects were >18 years of age, free of any active anterior segment disorders or history of corneal surgery, with otherwise normal corneas and refractive errors suitable for spherical extended soft contact lens wear. Potential participants were excluded if they were pregnant or lactating, had an immunocompromising disease, or were taking chronic systemic corticosteroids (with the exception of corticosteroid inhalers) or any ocular medications. Smokers were excluded because there is a potential confounding association between smoking, corneal infiltrative event risk, and decreased mucin ball formation (data on file from LASH Study).

Study visits included three scheduled visits in phase 1, five scheduled visits in phase 2, and unscheduled visits as needed. Phase 1 included a baseline/enrollment visit where all eligible participants were fit to lotrafilcon A lenses for continuous wear, a 10-day continuous wear visit, and 25-day continuous wear visit. At the 25-day continuous wear visit, participants were randomized into either balafilcon A or comfilcon A lenses for extended wear and entered phase 2, which included visits after 7 days of extended wear, and 1, 4, 8, and 12 months of extended wear. Further details of each phase are listed below. Lenses were removed at all visits except the 10-day visit. Whenever lenses were removed, detailed slit-lamp examinations were performed with fluorescein and lissamine green disclosure dyes, noninvasive tear break-up time was assessed, and mucin balls were graded using fluorescein-pooling mucin ball depression scales developed and used in the LASH Study.34 These scales included an assessment of mucin ball surface area and density in each of five corneal zones as well as a 4-point overall grading system across the entire cornea. Additionally, the following scales were used for assessments at each protocol visit: Efron Grading Scales41,42 were used for grading limbal and bulbar redness, blepharitis, meibomian gland dysfunction, corneal neovascularization, epithelial microcysts, corneal edema, papillary conjunctivitis, and overall corneal staining. A modified version of the Institute for Eye Research (IER) grading scale was used for corneal staining to account for staining density in each of five corneal zones, as was done in the LASH Study.10 Lissamine green conjunctival staining was graded using an adaptation of the Oxford Scale in four conjunctival quadrants. All investigators were certified on use of these scales before enrolling participants.

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Cohort Study

The hypothesis pursued in the cohort study was that a person’s ability to form mucin balls represented a particular mucin profile that offered protection against corneal infiltrative events during subsequent extended wear with silicone hydrogel lenses. Phase 1 of the cohort study was a run-in period to determine if participants would naturally form mucin balls if provoked by wearing a lens made of the highest silicone hydrogel material modulus commercially available for 1 month of continuous wear. Enrolled participants were classified as repeated mucin ball formers, or not, after a run-in phase that comprised up to 30 days of continuous wear with the lotrafilcon A lens (Air Optix Night & Day Aqua; Alcon Laboratories, Ft. Worth, TX), which has a modulus of 1.4 MPa. Mucin ball formation was assessed from white light slit-lamp examination with lenses on eye (10-day visit) and by mucin ball–induced impressions detected by fluorescein administration after lens removal (25-day visit).

If wear was disrupted or repeated mucin ball status could not be determined, phase 1 was repeated until mucin ball status could be properly recorded at least twice during 1 month of uninterrupted continuous wear. Participants then entered the randomized trial and were followed over 12 months of extended wear in one of two different lens types for the development of a corneal infiltrative event in phase 2. The ability to repeatedly form mucin balls in phase 1 was the main covariate of interest on the risk of corneal infiltrative event development in phase 2, the 12-month follow-up period that compromised this cohort study.

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Randomized Clinical Trial, Phase 2

The hypothesis pursued in this phase was that physical presence of mucin balls during extended wear with silicone hydrogel lenses offered protection against corneal infiltrative events. In phase 2, the randomized trial, two lenses of different modulus were used assuming the higher modulus lens would create more mucin balls than the lower modulus lens. The comfilcon A and balafilcon A lenses were selected a priori, based on material modulus (0.8 and 1.1 MPa, respectively; see Table 1 for a listing of lens physical properties), in an attempt to create a pool of participants who did not/did have clinically evident repeated mucin ball presence, respectively. Participants were stratified by clinical site and ability to form mucin balls in phase 1, block randomized to either lens based on ability to form mucin balls in phase 1 (block size of 10), and followed over 12 months of 7-day/6-night extended wear for the development of a corneal infiltrative event. The statistician generated the random allocation sequence in SAS and prepared sequentially numbered opaque envelopes for each site and category of mucin ball former. The site investigators drew each sequential envelope in the correct group for each participant who was ready to be randomized. The repeated presence of mucin balls (defined as one or more mucin balls observed) in phase 2 was the main covariate of interest.

TABLE 1

TABLE 1

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Primary Endpoint

The primary endpoint was presence of any corneal infiltrative event as defined by the “Brien Holden Vision Institute/L.V. Prasad Eye Institute Guide to Corneal Infiltrative Conditions Seen In Contact Lens Practice” and Sweeney et al.43 Briefly, any collection of infiltrative cells in the cornea, whether symptomatic or not, was considered a corneal infiltrative event. A sudden onset painful eye with circumferential redness with no clinically visible infiltrates (and no other confounding diagnosis) was also considered a corneal infiltrative event. An incident, round, well-defined corneal scar with or without symptoms since the last visit was classified as a presumed and resolved corneal infiltrative event. Thus, the corneal infiltrative events could present on a continuous spectrum of severity ranging from no symptoms and minimal signs to severe pain, redness, and photophobia with dense diffuse or focal infiltration. Once a participant experienced a corneal infiltrative event, they were followed to resolution and discontinued from the study.

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Bacterial Bioburden

Contamination of lenses, lid margins, and conjunctivae was assessed with lens and ocular surface aerobic cultures performed in both phases routinely throughout the study period. Methods of lid, conjunctival, and lens cultures used the same techniques as previously reported in the LASH Study.44 Briefly, the lower lid margin and the upper bulbar conjunctivae of each eye were swabbed with calcium alginate swabs directly plated on chocolate agar plates. The lenses were aseptically removed, placed in a vial containing 1.0 ml of sterile saline, and shipped to a central microbiology laboratory where they were aseptically removed and placed concave side down on a chocolate agar plate and covered with 10 ml of molten agar. The lens transport saline was separately plated on another chocolate agar plate. Bacterial bioburden was defined as “substantial” if there was presence of high levels of commensal ocular biota or organisms of low pathogenicity, or any level of pathogenic organisms. Species were grouped and classified as Coagulase-negative Staphylococci (CNS) if they were normal flora expected to be found on skin or periocular tissue; the levels of CNS considered “substantial” varied by location. If the colony-forming unit (CFU) count of CNS cultured from the lens or conjunctiva was ≥10, it was considered substantial. For the lid margin, CNS cultured at 100 CFU or more were considered substantial. Bacillus and Corynebacterium species were considered substantial if CFUs were >10 or >100, respectively. Otherwise, any level of other organisms cultured were considered pathogenic as they were not normal ocular flora.

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Sample Size

Data from the LASH Study were used to determine the required sample size. It was observed that 124 subjects overall were needed to detect a difference in the corneal infiltrative event rate of 9% in mucin ball formers versus 40% in mucin ball non-formers, allowing for a 10% rate of cross-over from mucin ball non-former to mucin ball former (alpha 0.01, power 90%). To obtain a minimum of 62 participants who exhibited mucin balls during the randomized trial, and given an expected differential rate of mucin ball formation between the two lens types, the total sample size was increased to 224. The addition of an expected 28% loss to follow-up yielded a final targeted enrollment of 287 participants across the three sites.

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Statistical Analysis

In each phase, the ability to repeatedly form mucin balls was the main covariate of interest for the risk of corneal infiltrative event development in the 12-month follow-up period. Although mucin balls were determined semiquantitatively using the mucin ball grading scales discussed above, in the main analyses, a participant was qualified as a repeat mucin ball former if any mucin balls, regardless of grade, were detected on a least two visits in the respective phase being analyzed. In modeling the risk of corneal infiltrative event occurrence, covariates were always drawn from the eye experiencing a corneal infiltrative event, whereas in corneal infiltrative event-free participants, covariates were drawn from either eye. Time-to-event analyses were conducted. Kaplan-Meier plots were generated to determine the cumulative unadjusted probability of remaining corneal infiltrative event-free stratified by presence or absence of repeated mucin ball formation and other covariates. Univariate Cox proportional hazards regressions were used to identify candidate variables for inclusion in multivariable models. In addition to repeated mucin ball presence, covariates of interest included age (≤25 or older), sex, lens type, substantial lid, conjunctival, and lens bioburden (yes or no), blepharitis status (grade 2 or higher), conjunctival lissamine green staining (circumlimbal or general grade 2 or higher), corneal fluorescein staining as defined in the LASH Study or the Efron grading scales (grade 2 or higher) and tear break-up time (≤ or >8 seconds). Multivariable Cox proportional hazards regression was then used to model the probability of a corneal infiltrative event as a function of variables found to be significant in the univariate analyses (P < .1) in addition to biologically plausible covariates. An interim analysis was performed when approximately one-half of participants were recruited and followed for 6 months. That analysis was done at a stringent level of significance (alpha = 0.005). The techniques for data analysis were those outlined above. Lastly, to assess if the effect of mucin balls on corneal infiltrative events was dose dependent, we additionally performed Cox proportional hazards regression and logistic regression using the average and maximum mucin ball grades across all visits in phase 2 as continuous covariates in the models, while controlling for lens type.

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RESULTS

Two hundred eighty-nine (289) subjects were enrolled, but 7 were found to be ineligible and not analyzed. Fig. 1 shows the participant flow throughout the study. Mucin ball grades noted through the study ranged from 0 to 4.0. There was an overall corneal infiltrative event incidence of 19.5% (55 corneal infiltrative events in 282 enrolled and eligible participants).

FIGURE 1

FIGURE 1

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Phase 1

Two hundred eighty-two (282) subjects (mean age 34 years, 65% female, 8% neophytes, 72% Caucasian, 9% Asian) entered into phase 1. Sixty-three (63) subjects were either lost to follow-up, discontinued, or had a corneal infiltrative event during phase 1. Throughout phase 1, 74% of participants wearing lotrafilcon A lenses repeatedly produced mucin balls, and throughout the 12-month randomized trial (phase 2), 61 and 79% of participants repeatedly produced mucin balls in balafilcon A and comfilcon A lenses, respectively. Comparing all three silicone hydrogel lens types for mucin ball formation across the first month of wear only, 74% of participants formed mucin balls during wear of lotrafilcon A lenses, followed by 62% of participants while wearing comfilcon A lenses and 38% of participants while wearing lenses made from balafilcon A.

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Phase 2

Two hundred nineteen (219) subjects entered into phase 2 (mean age 34 years, 64% female, 6% neophytes, 70% Caucasian, 8% Asian) and comprised the analysis cohort in which there were 33 corneal infiltrative events. Table 2 gives the characteristics of the analysis cohort overall and stratified by lens type. Throughout phase 2, 61 and 79% of participants repeatedly produced mucin balls in balafilcon A and comfilcon A lenses, respectively. Eighteen percent of the participants forming mucin balls in phase 2 did not form them in phase 1.

TABLE 2

TABLE 2

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Corneal Infiltrative Event Rate by Mucin Ball Formation During Phase 1

Fig. 2 shows the corneal infiltrative event rate by mucin ball formation in phase 1. Nineteen percent (30/161) of mucin ball formers in phase 1 developed a corneal infiltrative event in phase 2, whereas only 6% (3/53) of non-mucin ball formers in phase 1 experienced a corneal infiltrative event in phase 2. This difference was statistically significant (P = .05). This effect was seen within each lens type: among those randomized to balafilcon A, phase 1 mucin ball formers had a higher corneal infiltrative event incidence rate than non-mucin ball formers (11.7 vs. 3.3%). Among comfilcon A lens users, mucin ball formers also had a higher corneal infiltrative event incidence rate than non-mucin ball formers (25 vs. 8.7%). Table 3 shows the results of the corresponding multivariate survival analysis. It is seen that the use of comfilcon A lenses significantly increased the hazard rate (i.e. rate of development) of a corneal infiltrative event by 2.3-fold whereas repeated mucin ball formation in phase 1 significantly increased the hazard rate 4.7-fold. Fig. 3 presents the univariate Kaplan-Meier plot for mucin ball formation identified in phase 1. As in all the Kaplan-Meier plots, the x-axis represents time in days and the y-axis represents the estimated probability of surviving event-free. In relation to this study, a curve that drops significantly further below the 1.0 cumulative survival compared to the comparison covariate represents a lower probability of remaining corneal infiltrative event-free within that variable over time.

FIGURE 2

FIGURE 2

TABLE 3

TABLE 3

FIGURE 3

FIGURE 3

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Corneal Infiltrative Event Rate by Mucin Ball Formation During Randomized Trial, Phase 2

Another objective of the study was to determine if the physical presence of mucin balls during extended wear (phase 2) of silicone hydrogel lenses conferred protection against corneal infiltrative events during phase 2. Fig. 4 provides the flow of participants by their mucin ball–forming status and corneal infiltrative event rate in phase 2. For phase 2 repeat mucin ball formers, the corneal infiltrative event incidence rate was 10.5% and for non-mucin ball formers the corneal infiltrative event incidence rate was 14.0%. In univariate analyses, it was found that only age ≤25, comfilcon A lenses, and bacterial presence on lid margins were significantly associated with an increased hazard rate of developing corneal infiltrative events (all at p < 0.05). Although, initially, repeated mucin ball formation during phase 2 was not significantly associated with corneal infiltrative event occurrence in univariate analysis, it was included in multivariate modeling because it was the main covariate of interest. Table 4 presents the final multivariate model. It was seen that comfilcon A lenses significantly increased the rate of developing a corneal infiltrative event (hazard rate) by 4.9-fold, whereas repeated mucin ball formation significantly decreased the hazard rate by 0.4-fold. Fig. 5 presents the univariate Kaplan-Meier plots for these same significant covariates.

FIGURE 4

FIGURE 4

TABLE 4

TABLE 4

FIGURE 5

FIGURE 5

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Dose Response Analysis

The survival and logistic regressions for maximum mucin ball grade across phase 2 modeled as a continuous covariate on time to corneal infiltrative event or development of corneal infiltrative event are presented in Tables 5 and 6, respectively. The hazard ratio for maximum mucin ball grade was 0.631 (P = .0199), signifying a statistically significant reduction in risk for time to corneal infiltrative event development for each unit increase in maximum mucin ball grade. The corresponding logistic regression infers that for every unit increase in maximum mucin ball value, the odds for corneal infiltrative event decreases by a factor of 0.32; that is, it decreases by nearly one-third of its value. There was no significant effect noted when the average mucin ball grade was modeled in the same manner (data on file).

TABLE 5

TABLE 5

TABLE 6

TABLE 6

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DISCUSSION

This study provides new insights into corneal infiltrative events and mucin ball development during extended wear with silicone hydrogel lenses. The overall incidence rate of 19.5% corneal infiltrative events is consistent with the literature and our previous studies of silicone hydrogel lens extended wear.10 With regard to mucin ball formation, we documented greater mucin ball presence during EW than during the LASH Study. Using the same definitions of mucin ball formation between the two studies, the LASH Study reported 33% of participants repeatedly formed mucin balls over 12 months of follow-up (in lotrafilcon A lenses) whereas this study found 65% of participants repeatedly formed mucin balls over 12 months of follow-up (in either balafilcon A or comfilcon A). The increased detection of mucin ball production in the current study is not likely driven by lens material because the phase 2 lenses were both of lower modulus compared to lotrafilcon A; therefore, this difference in mucin ball detection was likely caused by trained observers closely looking for the variable of interest.

The overarching hypothesis that mucin ball formation was protective against corneal infiltrative events was not supported by this study. Of our two hypotheses, only one was supported by the study results and reflected similar findings to the LASH Study. That is, during extended wear, when mucin balls are repeatedly present over 12 months of follow-up, a small, statistically significant protective effect for mucin ball formers for time to corneal infiltrative event development exists. The protective effect rate is small (65%) and is possibly explained by mucin balls creating a physical barrier or ball bearing effect between lens-associated antigens and the corneal surface. Our dose response analysis in phase 2 corresponds to this philosophy. If the positive effect of mucin ball presence is based solely upon the biological assumption that the mucin balls served as a barrier layer of mucin balls rendering the protective effect, then one would assume that those participants with a greater number of mucin balls would have the least risk for a corneal infiltrative event. Indeed, when mucin ball quantity was assessed as a continuous covariate across all visits in phase 2, the statistically significant protective effect remains. Specifically, for every 1 grade increase in maximum mucin ball quantity across all visits in phase 2, the odds for a corneal infiltrative event during wear of extended wear silicone hydrogel lenses decreases by about one-third of its value. If a mechanical barrier does not exist, then the later mucin ball production may simply signify an adaptive feature of the ocular surface to lens-induced trauma that eliminates the infiltrative risk profile and provides some protection against corneal infiltrative events.

However, our second hypothesis was not supported by the study results. That is, the ability to form mucin balls (as a surrogate of a biomarker for some unknown mucin characteristic which allowed mucin ball formation) was not associated with a decreased risk of a corneal infiltrative event in longer-term follow-up. Of our three lens types, it was assumed that the lotrafilcon A material would form the most mucin balls, and thus phase 1 was designed as a provocative testing period to determine which participants had certain characteristics rendering them the ability to form mucin balls. If the a priori hypothesis was true, then mucin ball–forming participants (in phase 1) should have had a lower rate of corneal infiltrative events (in phase 2) compared to non-mucin ball formers, regardless of their lens randomization. However, the opposite was observed; mucin ball formers in phase 1 had a statistically significantly greater rate (time to event) of eventual corneal infiltrative event formation in phase 2. Furthermore, this effect was seen within each lens type. These results suggest that the early appearance of mucin balls signifies changes to the mucus layer, which can precipitate a corneal infiltrative event through the disruption of an important barrier defense against bacterial antigens. Because mucins that are shed from a cell’s surface can regenerate, there is not necessarily an immediate corneal infiltrative event response under the right conditions; rather, a subclinical inflammatory response may ensue that can prime the immune system for later inflammatory events. In that regard, Grupcheva has shown that dendritic cells accumulate in the anterior corneal stroma beneath mucin balls when imaged on confocal microscopy.45 These dendritic cells can prime the immune response and make it “hypersensitive” to recurrent clinical inflammatory events under the right conditions. Additionally, mucin balls have been shown to activate stromal keratocytes immediately beneath the mucin ball embedded in the epithelial surface.46 Therefore, the risk may be caused by a heightened immune response that primes the immune system for later activation when challenged by an antigen that is simultaneously present. Although our findings of increased corneal infiltrative event risk for phase 1 mucin ball formers is opposite to our original hypothesis, it is consistent with some other literature. Naduvilath, in an unpublished PhD thesis, stated that mucin balls increased the risk of contact lens peripheral ulcers by 1.7-fold.15 Additionally, an unpublished study by Carnt et al. reported that during daily wear with various lens types, mucin balls were associated with an increased risk for corneal infiltrative event.16

Our preliminary study design assumed that mucin ball formation would be predicted by wear of lotrafilcon A lenses and that we could characterize mucin ball producers in the first month of 30-day continuous wear with a minimal cross-over rate. However, the cross-over rate was higher than expected and mucin ball production within the various lens types did not correlate to modulus. That is, the lower modulus comfilcon A material produced more mucin balls than balafilcon A with a higher modulus. The lesson learned from this result is that lens modulus does not necessarily correlate and is not solely responsible for mucin ball formation during silicone hydrogel lens wear. Therefore, other factors such as wettability, surface friction, or ionic properties likely play a role together with lens modulus in mucin ball production.

Although we performed extensive microbiological analyses as part of this study, in our final person-based multivariate models, the bacterial bioburden variables were not found to be significant covariates. This was surprising to us because bacterial biodurden is a well-known risk factor for corneal infiltrative event development as previously explained. In this study, we had a strict protocol for screening the microbiology specimens to rule out contaminated samples that may have occurred from patient handling during lens removal, or shipping delays leading to potential overgrowth before laboratory analyses. In fact, almost one-third of the presumed contaminated lens samples that were not used in the analyses were from the corneal infiltrative event participants. Although participants were provided gloves to wear and sterile vials to transport lenses in case emergent lens removal for red or painful eyes was required, many of them did not utilize these supplies properly during an adverse event. If proper aseptic techniques were not followed, then the microbiology data from these specimens were not used in the analyses, which may have limited our ability to detect an effect of bacterial bioburden. Furthermore, viable organisms are not required to initiate an immune response. Pearlman has shown that microbial breakdown products, such a lipopolysaccharide found on Gram-negative bacteria, can activate Toll-like receptors in the corneal epithelium and stimulate an inflammatory response in the absence of live organisms.27 Therefore, it is possible that nonviable organisms were present on the lens surfaces preventing isolation via traditional culture techniques. Additional studies are required to determine if lens contamination with bacteria or their by-products is a necessary risk factor corneal infiltrative event development.

In summary, early mucin ball formation likely signifies a disrupted mucus layer, which can increase subsequent risk for corneal infiltrative event during extended wear with silicone hydrogel lenses. Eye care providers can easily observe this clinical marker and adjust continued extended wear appropriately. The risk may be a result of a heightened immune response that primes the immune system for later activation when challenged by an antigen, such as bacteria on lids or lenses that are simultaneously present. However, a later concurrent presence of mucin balls can also serve a protective role and the protective effect increases when the maximum grade increases, perhaps acting as a physical barrier between the lens and ocular surface once successful extended wear has been established. Rapid onset mucin ball formation not only negates the protective effect seen over time but increases the risk of corneal infiltrative event from presumed disruption of the ocular surface mucins, which can overwhelm the protective response. Clinically, we can infer that early mucin ball production is disruptive to the ocular surface and, when observed during follow-up in extended wear neophytes, is a marker for risk, and continued extended wear should be discouraged. These findings are important for clinicians as they place and monitor their patients in extended wear.

Loretta B. Szczotka-Flynn

University Hospitals Eye Institute

11100 Euclid Ave., Lakeside 4126C

Cleveland, OH 44106

e-mail: loretta.szczotka@uhhospitals.org

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ACKNOWLEDGMENTS

This work was supported by Johnson & Johnson Vision Care, Inc. with indirect support for laboratories and coordination from the Ohio Lions Eye Research Foundation and Research to Prevent Blindness. The clinicaltrials.gov identifier is NCT01437319.

The Mucin Ball Investigator Study Group

Members: Loretta Szczotka-Flynn, OD, PhD; Thomas Stokkermans, OD, PhD; Mary Jo Stiegemeier, OD; Alicia Palmer, OD; Haily Unkefer, OD; Jessica Simon, OD; Donald Mutti, OD, PhD; Jeffrey Walline, OD, PhD; Kathleen Reuter, OD; Greg Hopkins, OD; Matthew Garvey; Roger Bielefeld, PhD.

Steering Committee: Loretta Szczotka-Flynn, OD, PhD; Mary Jo Stiegemeier, OD; Donald O. Mutti, OD, PhD; Jeffrey Walline, OD, PhD; Sara Debanne, PhD; Jason Nichols, OD, PhD; Carol Lakkis, OD, PhD; and Tawnya Wilson, OD.

The authors also thank their External Advisory Committee: Joseph Shovlin, OD, and Jennifer Smythe Coyle, OD, MS; and our Microbiology Data Review Committee: Michael Jacobs, MD, PhD; Carol Lakkis, OD, PhD; Loretta Szczotka-Flynn, OD, PhD; Sara Debanne, PhD; and Tawnya Wilson, OD.

Received May 25, 2016; accepted November 8, 2016.

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Keywords:

corneal infiltrative event; silicone hydrogel contact lens; mucin balls

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