The incidence of symptomatic sterile contact lens–associated corneal inflammatory events (CIEs) with extended wear (EW) is well summarized in a recent review article1 and has been estimated to be between 2.5 and 6% per year,2 whereas the rate of EW asymptomatic CIEs is suspected to be 6 to 26% per year.3–5 One prospective study evaluating multiple silicone hydrogel (SH) brands with commercially available contact lens care solutions found a CIE rate of approximately 20% per year for daily wear (DW), although CIE rate varied with care solution.6 A more recent study investigating the rate of CIEs, specifically with lotrafilcon-A lenses worn as DW, found an annualized incidence of 7.2% for all CIEs and 1.9% for symptomatic events.7 The CLAY (Contact Lens Assessment in Youth) Study Group performed a multicenter retrospective chart review on 6117 patients and found a DW CIE rate of 3% per year.8
Noncompliance has been identified as a risk factor for acquiring sterile CIEs as well as microbial keratitis (MK)9 and has been reported to range from 40 to 91% of studied samples.10 One study found that 60% of their sample was noncompliant with four or more care recommendations.11
A lens wear factor that increases CIE risk is EW, which is likely the most significant risk factor for developing both sterile and infectious CIEs.9,12,13 Wearing lenses beyond the manufacturer-recommended replacement frequency (MRRF) has been shown to reduce vision and comfort14 but may also increase the risk of certain contact lens–related adverse events.15
For planned replacement, the lens storage case can harbor microorganisms,16 and poor case hygiene has been found to be a risk factor for MK.17 Proper case hygiene includes emptying used solution, wiping the case with a tissue,18,19 storing face down on a clean tissue, and frequent replacement as recommended by the U.S. Food and Drug Administration (FDA).20 Topping-off,21 defined as not disposing, or augmenting, the existing care solution in the case, reduces the disinfection efficacy of a care solution, which may result in contamination.22
Other risk factors for MK or CIEs are smoking2,4,9,23 and, more specific to sterile CIEs, multipurpose disinfecting solutions (MPDSs).6,8 Nonmodifiable risk factors for CIEs include refractive error (≥5.00D),2 contact lens wear experience, male sex,9,12,23 and age, with risk peaking between 15 and 25 years.8,24
The purpose of this study was to identify contact lens–related modifiable and nonmodifiable factors associated with those individuals presenting with CIEs or MK in a busy university-based optometry setting.
A prospective, cross-sectional, observational study evaluating contact lens care behaviors was performed at The Ohio State University Student Health Center from November 8, 2011, until November 8, 2012. The study was approved by The Ohio State University Institutional Review Board and followed the tenets of the Declaration of Helsinki. Access to care at the Student Health Center is limited to actively enrolled students. In this study, two groups of individuals were targeted. The first group consisted of contact lens wearers seeking problem-focused care and was determined, by an investigator via slitlamp examination, to be presenting with a CIE. The second group consisted of current contact lens wearers entering the clinic for their annual examination without a complication (non-CIE). There were no age or gender restrictions for the participants, and non-CIEs were not age or gender matched with CIE participants, as age11 and sex12,20,25 have been found to be risk factors in previous work. All non-CIE participants were identified from the same clinic, geographic location, and time of the year.
Study eligible participants were interviewed using a survey (see Appendix, available at http://links.lww.com/OPX/A226) regarding their current contact lens care behaviors. Participants were enrolled if the investigator (also the practitioner) had adequate time between patients to consent and interview the participant. If a CIE participant was enrolled, attempts were made to capture one or two non-CIE participants that same day. If a non-CIE participant was not enrolled the same day because of either time limitations or simply no contact lens wearers were seen, attempts were made to capture one the next day. This enrollment strategy was to keep a near 1:1 ratio of CIEs to non-CIEs and to prevent large gaps in seasonal (temporal) enrollment. No participant refused enrollment.
The survey evaluated demographics, contact lens brands, lens care products, and modifiable risk factors. Demographic data included age, sex, and level of education, whereas questions pertaining to modifiable risk factors included smoking, EW, and topping-off solution. Participants were asked about the age of their current storage case (in months) and when typical case replacement occurred (in months). Questions were asked about the age of their current pair of lenses, their typical lens replacement frequency, and the replacement schedule prescribed by their eye care practitioner (prescribed). The typical replacement question (and lens rubbing question) was implemented after the start of the study because the question about the age of the current pair was not providing useful information. Many participants changed to a new pair during the active CIE event and then reported that their lenses were only 1 day old.
Participants self-reported, but did not use a visual aid to identify, which brand of soft contact lens they wore. There was no purposeful reason behind the decision to use or not to use a visual aid for lens identification. Based on selected brand, the corresponding FDA-approved MRRF for that brand was assigned as daily disposable (DD), 2-week, or monthly replacement. Compliance with MRRF was then determined as the difference between reported typical lens replacement and the assigned MRRF. If [Typical replacement (weeks) – MRRF (weeks) = 0], then compliance was assigned; if greater than 0, then noncompliance was assigned. This was also done for prescribed replacement compliance.
Recall bias related to medications26 and contact lens care solutions27 prompted use of a visual aid to assist participants in identifying their current contact lens solution because recall accuracy has been shown to improve from 50% without the aid to nearly 90% with the aid.27 Participants did not identify their care solution using Appendix (available at http://links.lww.com/OPX/A226) until they were enrolled.
The CIE definitions used in this study included contact lens peripheral ulcer (CLPU), MK, contact lens acute red eye (CLARE), infiltrative keratitis (IK), asymptomatic infiltrates, and asymptomatic infiltrative keratitis.28 An additional term, contact lens–associated infiltrative keratitis29, is defined as a bilateral, symptomatic, granular infiltrative response. Because of the clinical difficulty to truly differentiate CIEs,30 asymptomatic infiltrates, asymptomatic infiltrative keratitis, CLARE, and contact lens–associated infiltrative keratitis will be collectively referred to as IK for the remainder of the article. The term CLPU will be recorded as such, and the other definition used will be a phlyctenular-like condition defined as limbal edema with adjacent, but localized, corneal edema and infiltrates.
Ideally, every CIE participant would have been captured; however, staffing constraints (two of five clinic days were overseen by noninvestigators), in the presence of an active teaching clinic, prevented the enrollment of every CIE. To investigate the CIE participants not enrolled in the prospective study, a separate retrospective study was performed by generating a search query using the following International Classification of Diseases, Ninth Revision, codes: 370.00, corneal ulcer unspecified; 370.01, marginal corneal ulcer; 370.03, central corneal ulcer; 370.31, phlyctenular keratoconjunctivitis; 370.9, unspecified keratitis; 371.20, corneal edema unspecified; 371.24, corneal edema due to contact lenses; 371.82, corneal disorder due to contact lenses between November 8, 2011, and November 8, 2012. Using unique identification numbers, those enrolled in the prospective study were separated from those not enrolled.
The chart for each patient with one or more of the assigned codes was reviewed. To be included as a participant in the retrospective study, the individual needed to be a contact lens wearer and have recorded evidence of an active CIE (conjunctivitis and viral conditions were excluded) during the period listed above.
All univariate and multivariate analyses were from the prospective data set only and were completed using SAS Version 9.3 (SAS Institute Inc., Cary, NC). Statistical significance was determined using an α = 0.05. An independent-group t-test was used to compare groups (CIEs and non-CIEs) with respect to age. Logistic regression was used to assess the impact of participant characteristics (demographic and behavior) and contact lens factors on the risk of a CIE. The final multivariate logistic regression model was determined using forward selection. The characteristic with the most significant p value was added at step 1 of model building, with additional characteristics added until no candidate p values were less than 0.05. Two-way interactions between the characteristics included in the final model were investigated.
Care solutions were compared by disinfectant combinations and not individual brands. The three groups of disinfectant combinations were solutions containing polyquaternium-1 and myristamidopropyl dimethylamine (PQ-1/MAPD), biguanides (polyhexamethylene biguanide or polyaminopropyl biguanide [PHMB]), and peroxide. The post hoc sample size calculations (prospective sample only), using PASS31, allowed for 80% power to detect univariate odds ratios (ORs) of 2.5 or greater when the proportion of participants in the non-CIE group with the given characteristic ranged from 20 to 60% (i.e., overnight wear, rubbing lenses, and silicone hydrogel lens material).
In a 1-year period at this facility, 164 CIE events were identified through two separate studies. The retrospective data were included in the article to display age, sex, EW, and recorded MPDSs for those not enrolled in the prospective study. This was done to demonstrate that CIE enrollment bias did not occur with the prospective sample. The retrospective analysis identified 88 CIEs (mean age, 21.6 ± 3.1 years), whereas 76 CIEs (mean age, 21.7 ± 3.3 years) were enrolled in this prospective study (Table 1). All statistical comparisons below were made using only the prospective data set, which also included 84 non-CIEs (mean age, 25.7 ± 4.2 years) for a total study population of 160 individuals. The 160 participants ranged in age from 18 to 36 years (mean, 23.8 ± 4.3 years), with 53% of the sample being undergraduates and 68% being women.
Sixty participants (38%) reported wearing monthly replacement lenses, whereas 82 (51%) reported wearing 2-week replacement lenses. Seven participants (4.4%) wore DD lenses, one participant wore an annual replacement lens, and 10 (6%) were unaware of their lens brand. Excluding the unknowns, SHs were used by 117 (78%) participants.
In all, 100% of the DD wearers, 92% of the monthly wearers, and 59% of the 2-week wearers correctly identified the MRRF as compared with their prescribed replacement. The mean prescribed replacement was 4.1 ± 1.2 weeks for monthly wearers and 2.9 ± 1.7 weeks for 2-week wearers. For typical lens replacement as compared with the MRRF, the DD lens wearers were 100% compliant, the monthly wearers were 56% compliant (mean replacement, 5.5 ± 2.5 weeks), and the 2-week wearers were 25% compliant (mean replacement, 3.6 ± 1.7 weeks).
For participants for whom data were collected on both (n = 118), the overall mean current lens case age was 5.2 ± 5.5 months, whereas typical lens case replacement occurred every 7.2 ± 6.8 months (p < 0.001). Eleven participants did not know the age of their current contact lens case, and 28 (18%) reported that they typically never replace their storage case. The mean age of the current storage case for non-CIEs was 6.0 ± 7.7 months and 8.5 ± 10.7 months for the CIEs (p = 0.11). In the univariate model (Table 2), participants who typically never replaced their case were at increased risk of a CIE compared with those who replaced their case shorter than 1 to 3 months (OR, 4.4; 95% confidence interval [95% CI], 1.6–12.5) or longer than 4 to 6 months (OR, 2.9; 95% CI, 1.0–7.7). In addition, typical case replacement beyond 7 months was associated with an increased risk of a CIE when compared with case replacements of shorter than 1 to 3 months (OR, 3.4; 95% CI, 1.4–8.4).
Peroxide-using participants replaced their case every 2.3 ± 2.8 months, which was more frequent (analysis of variance, p = 0.043) than those using PQ-1/MAPD (8.1 ± 10.4 months) or PHMB (8.1 ± 9.1 months). There was no difference in case age for CIEs versus non-CIEs for participants using PQ-1/MAPD (p = 0.19), PHMB (p = 0.95), or peroxide (p = 0.90).
In univariate models (Table 2), increasing age (p < 0.001) and replacing the lens case at least every 6 months (compared with never replacing; p = 0.008) were related to decreasing CIE risk. Undergraduate students (p < 0.001), topping-off (p = 0.004), and EW (p < 0.001) increased the risk of a CIE. The use of PQ-1/MAPD compared with peroxide (p < 0.001) and PHMB (p < 0.001) increased CIE risk. Use of toric lenses also increased the risk of a CIE (OR, 2.5; 95% CI, 1.1–5.9; p = 0.033). Not rubbing lenses was not associated with an increased risk of a CIE (p = 0.94).
The multivariate model, using forward selection (see Methods), had a Hosmer-Lemeshow goodness-of-fit test value of p = 0.59. In the multivariate model (Table 3), age (p < 0.001) remained significant. Also significant in the multivariate model was an interaction between solution type and self-report of EW (p = 0.027). As before, the risk of a CIE was higher among younger participants, with each year of age reducing a wearer’s risk by approximately 20% (adjusted OR [aOR], 0.8; p < 0.001). Education level and typical case replacement both correlated with age and failed to reach significance in the multivariate model.
There was a significant interaction between wearing schedule and disinfectant. For DW, when PQ-1/MAPD was compared with peroxide (aOR, 18.4; 95% CI, 1.9–173.9; p = 0.011) and against PHMB (aOR, 15.0; 95% CI, 4.5–50.5; p < 0.0001), there was an increased risk of a CIE. This difference was not observed between DW PHMB and DW peroxide users (p = 0.87). For EW, there was no difference between PQ-1/MAPD (p = 0.74) and PHMB (p = 0.88) when compared with peroxide. When DW PHMB users are compared with EW PHMB users, EW increases CIE risk (aOR, 10.0; 95% CI, 2.0–51.2; p = 0.006). When this comparison is made for peroxide users, there is a trend toward increased risk with EW (p = 0.082). There was no difference between DW and EW PQ-1/MAPD users.
The most common diagnosis for both the prospective and retrospective studies (Table 4) was IK for both unilateral and bilateral presentations. Many of the IK events in both samples were predominantly bilateral, with 42 of the 58 bilateral IK events being associated with a PQ-1/MAPD solution. Contact lens peripheral ulcers were unilateral findings, whereas the other conditions did not display a tendency.
There were no confirmed cases of MK during the 1-year observation period. The most common pharmacologic treatment for the CIEs was a steroid/antibiotic combination (65%), followed by antibiotic only (17%) and steroid only (10%). Five participants were untreated.
This study was designed to evaluate modifiable and nonmodifiable participant factors associated with CIEs among a cohort of contact lens–wearing students at a university health center.
Although the age range was relatively narrow (18 to 36 years) in this sample, the mean age of the CIE participants was 21.7 years, and younger students were at greater risk of CIE compared with older students. Chalmers et al.8 found that CIE events, for an age range of 8 to 33 years, peaked between ages 15 and 25 years, which is similar to the mean CIE age in this sample. The univariate analysis identified that undergraduate students were at increased risk of a CIE; however, education level was closely correlated to age and was not significant in the multivariate model. Although other studies have found that male sex9,12 is a significant risk factor for CIEs or MK, it was not a factor in this sample.
Among differing soft lens modalities, DD lenses have been found to be protective against CIEs,24,32 as compliant use eliminates EW and the need for MPDS with a storage case. Only a small number of DD lens wearers were enrolled in this study (4.4%), which is much lower than the reported use (17%) throughout the United States.33 Two-week lenses were worn by 55% of the sample, whereas nationally, the reported rate is 30%.33
Silicone hydrogels were reportedly used by 79% of the participants, which is higher than the national average (64%).33 Multiple studies have shown that SH lenses are associated with an approximately twofold greater risk of CIEs when compared with hydrogels.5,8,32,34,35 Contrary to those findings, and possibly because of poor patient recall of their lens brand (visual aid not used), or perhaps sample size, there was no difference in CIE risk between hydrogels and SHs. No single lens brand reported was associated with increased CIE risk when compared with other brands (p = 0.38). Toric lenses were found to increase risk of a CIE in the univariate analysis. Although this currently goes unexplained, perhaps the larger lens size is problematic or maybe these participants had a higher refractive error (not recorded), which has been associated with other soft lens adverse events.25
When recalling prescribed replacement frequency, 92% of the participants wearing monthly lenses properly identified the MRRF of their reported lens brand. This is in contrast to 59% of those wearing 2-week lenses. The participants wearing monthly and 2-week lenses reported that they typically replace their lenses 1.4 times MRRF and 1.8 times MRRF, respectively. These findings are consistent with Dumbleton et al.15 for monthly wearers (1.5 times MRRF) but differ for 2-week wearers (2.6 times MRRF). Full compliance was found to be 56% for monthly wearers and 25% for 2-week wearers in this study, whereas Dumbleton et al.36 found full compliance in 34% of monthly wearers and 25% of 2-week wearers. Those wearing monthly lenses seem more knowledgeable of the actual MRRF than 2-week wearers. This may be caused by an eye care practitioner recommendation inconsistent with the MRRF or patient misinterpretation.
Wearing lenses beyond the MRRF was not associated with an increased risk of a CIE in this study. Based on the work of Sweeney et al.37 and Gopinathan et al.,38 lens bioburden typically consists of commensal organisms that establish a baseline quantity at day 1, and the raw number of organisms does not typically increase across time. This may explain why wearing lenses beyond the MRRF did not elevate CIE risk in this study. Lens colonization by pathogenic organisms tends to be sporadic and transient,39 and factors other than wearing lenses beyond the MRRF may be responsible for sporadic contamination.
Storage Case, Wearing Schedule, and Care Solution
Studies have shown that between 30 and 80% of lens storage cases are contaminated.21,40 Wu et al.16 cultured lens storage cases and found that 58% of them were contaminated. Cases older than 9 months were more likely to be contaminated. The mean case age for the CIE participants in our study was 8.4 months, and although cultures were not performed, based on the findings of Wu et al.,16 it is possible the CIE storage cases were contaminated. Case replacement has previously been recommended as frequently as every 2 weeks,41,42 and at the time of this study, the FDA-recommended case replacement was 3 to 6 months,20 which was exceeded by those with CIEs.
Extended wear is a well-established risk factor for CIEs and MK,2,9,12,13 which may be caused by tear stagnation, tear compartmentalization, and reduced epithelial turnover.43 In our study, EW was a risk factor in the univariate analysis, but in the multivariate analysis, there was no difference between EW and disinfectant groups when compared with peroxide (Table 3). When comparing EW and DW users for a particular disinfectant, there was an increased risk of CIE for EW with PHMB. For DW peroxide against EW peroxide, there was a trend toward a greater risk with EW. The increased risk of EW against DW was not found with PQ-1/MAPD and may have been caused by the relatively large risk of a CIE with DW.
The greatest CIE risk factor found in this study was PQ-1/MAPD and DW, although no single PQ-1/MAPD solution was associated with a higher CIE risk. In a study by Carnt et al.,6 a specific PQ-1/MAPD solution was associated with a higher incidence of CIEs compared with other MPDSs and peroxide. The association of CIEs and PQ-1/MAPD solutions may be caused by reduced biocidal capabilities against the following gram-negative bacteria: Achromobacter xylosoxidans, Stenotrophomonas maltophilia, and Delftia.44 Recently, Kilvington et al.44 cultured lens storage cases of 18 patients with CIEs who reported using a specific PQ-1/MAPD solution. The presence of A. xylosoxidans was found in 61% of the storage cases, followed by S. maltophilia (22%), Serratia marcescens and Elizabethkingia (both at 17%), and Delftia (11%). Achromobacter xylosoxidans, S. maltophilia, and Delftia were also the most common organisms found by Wiley et al.45 among several patients with contact lens–related keratitis. These microbes have also been found by Willcox et al.46 in the storage cases of non-CIE participants using a SH lens and a specific PQ-1/MAPD solution for 1 month.
In the Kilvington article, four MPDSs were tested against A. xylosoxidans, S. maltophilia, and Delftia. They found that two of the PQ-1/MAPD solutions had significantly less disinfection capabilities at recommended soaking times compared with two other MPDSs.44 Specific to S. maltophilia, Watanabe et al.47 have found that some MPDSs require a higher biocidal concentration compared with other MPDSs. Possible explanations for reduced biocidal capabilities could include different ingredients in the formulations6,48 or disinfectant uptake by contact lenses.49
The most common CIE presentation in this study was IK, with the infiltrates appearing superficial, granular, scattered on the cornea, and many times were bilateral. These IK events appeared like CLARE events, which are thought to be a corneal hypersensitivity to gram-negative lipopolysaccharides or endotoxins from species such as Haemophilus influenzae, 50 Pseudomonas, or Serratia. 51,52 If a solution is less effective at disinfecting specific gram-negative microbes, as suggested by two studies,44,47 then the corneas of patients storing contact lenses in that solution may be exposed to significant levels of these organisms, or endotoxins, which could trigger this granular infiltrative response.
Although the evidence in this study suggest that DW with PQ-1/MAPD care solutions increases the risk of a CIE, a retrospective study by Chalmers et al.32 found no evidence of increased CIE risk with specific lenses or lens care products. Katz and Schein,53 however, challenge the results because of an insufficient sample size to detect a signal for increased risk with a care solution. The only truly unbiased method to detect whether a lens, MPDS, or lens-MPDS interaction increased the risk of a CIE would be through a double-masked randomized study. This type of study would yield the highest level of evidence,54 but this type of study would require multiple soft lens and MPDS combinations, necessitating thousands of participants, and substantial funding.
The observational nature of this study lends itself to potential bias. The control participants were not age or sex matched, and this could confound the data; however, all controls were identified from the same population at risk as the CIE participants (i.e., college students). Another limitation was the inability to capture all CIE participants and to enroll a greater number of control participants, although the retrospective analysis shows very similar sample characteristics. Participants were identified on a first-come basis as time allowed, and we do not believe that any systematic bias was introduced. Product market share may also bias the results because PQ-1/MAPD-containing products compose the largest share of the MPDS market.33 A larger representation of all current solutions would have also added strength to the study.
This study suggests that younger college students are at greater risk of acquiring a CIE. The greatest risk factor found in this study was an interaction between DW and use of solutions containing the disinfectant combination of PQ-1/MAPD. Extended wear increased the risk of a CIE compared with DW for PHMB users, but there was equal CIE risk between EW and DW PQ-1/MAPD users.
Contact lens–related CIEs are an economic burden,55 and minimizing risk factors is essential to preventing these events.56 If planned replacement lenses are prescribed, the practitioner must educate the patient on the risks associated with EW and topping-off, emphasize regular case replacement, and recommend peroxide or an MPDS with a disinfection profile similar to a peroxide for lens storage. The most prudent option may be DD lenses because they eliminate solutions, the storage case, and minimize lens handling.56
Aaron B. Zimmerman
The Ohio State University College of Optometry
338 W 10Th Ave
Columbus, OH 43210
A.B. Zimmerman has served on an advisory panel for gas-permeable lens solutions for Bausch+Lomb. He was a panelist for Bioscience Communications in 2013 on the topic of infiltrative events. He is a member of the Contact Lens Assessment in Youth (CLAY) Study Group (Alcon). G.L. Nixon is on the Alcon Glaucoma Advisory Board, Alcon Speakers Bureau, Bausch+Lomb Advisory Board, and Allergan Academic Advisory Board. The remaining authors have no disclosures. A.J. Emch was an assistant professor at Ohio State during the study period and was involved in the study design, data collection, and writing.
A portion of the data from this study was presented at the 2012 American Academy of Optometry meeting in Phoenix, Arizona (October 2012). Complete data acquisition had not been completed at that time.
Received October 02, 2014; accepted August 11, 2015.
The Appendix, a survey of behaviors associated with contact lens–related inflammatory or infectious conditions, is available at http://links.lww.com/OPX/A226.
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