Ozkan, Jerome*; Mandathara, Preeji†; Krishna, Pravin‡; Sankaridurg, Padmaja§; Naduvilath, Thomas¶; Willcox, Mark D. P.**; Holden, Brien††
Silicone hydrogel lenses worn for extended wear (EW) are generally safe; however, compared with daily wear, EW lenses have been associated with an increased incidence of corneal infiltrative events.1,2 Although inflammatory events may not be a marker for increased risk of microbial keratitis,3 the presence of inflammatory cells in the cornea can serve as potential markers of lens/wear modality safety.4,5 Several published studies have examined risk factors related to development of infiltrative events with silicone hydrogel wear.1,6,7 These studies were all conducted in the United States, and the risk factors emerging from these prospective studies include age (<25 and >50 years), refractive error >5 diopters,6 history of ocular inflammatory event, smoking,1 and corneal staining and limbal redness.7 A meta-analysis of the relevant literature by Szczotka-Flynn and Diaz8 to assess the risks of inflammatory events in both silicone hydrogel and low-Dk hydrogel wearers has shown that 30-day EW of silicone hydrogel increases twofold the risk of developing inflammatory events. However, these data are confounded by the difference in the duration of EW between the two lens materials (30 days vs. 7 days, silicone hydrogel vs. low Dk, respectively). Morgan et al. examined, over 12 months, infiltrative event development in the context of contact lens wearers presenting to an eye hospital. In this study, identified risk factors for developing infiltrative events included overnight lens wear, male gender, smoking, compromised ocular or general health, and seasonal effects.2 Cutter et al.9 also concluded that overnight wear and smoking were risk factors for focal corneal infiltrates, as were disposable lenses.
Use of silicone hydrogel lenses, particularly those with relatively higher moduli, has also been implicated in increased occurrence of mechanical events. A review by Dumbleton10 of non-inflammatory complications with silicone hydrogels suggests possible causative factors including greater stiffness of these materials and the correlative greater impact this stiffness would have on the lens edge incurring possible localized areas of adhesion caused by temporary adhesion between the posterior lens surface and the epithelium resulting from overnight wear.
The purpose of this study was, therefore, to further elucidate risk factors for contact lens-related corneal inflammatory and mechanical events in wearers of silicone hydrogel lenses on a EW schedule and to explore differences in the risk factors observed in India compared with studies conducted elsewhere.
Subjects for the study were residents of Hyderabad, Andhra Pradesh, India. The study was conducted at the LV Prasad Eye Institute in Hyderabad. A total of 210 subjects were enrolled in this single-site study, of which 188 who were dispensed with lenses were included in this article. Subject demographics and ocular characteristics of the 188 subjects included in this article are presented in Table 1. Twenty-two subjects did not satisfy the study inclusion/exclusion criteria and were not dispensed with lenses at baseline and discontinued from the trial.
The inclusion criteria were minimum 18 years of age; ametropia within ranges of available lens powers (i.e., −1.00 to −6.00 D); correctable to at least 20/40 or better in each eye with the study contact lens; read, understood, and signed a Statement of Informed Consent; ocular findings considered to be “normal” and which would not prevent a subject from safely wearing contact lenses; willing and able to follow subject instructions and meet the protocol specified schedule for follow-up visits; and able and willing to wear the study lenses on a EW basis. The exclusion criteria were active corneal infection or active ocular disease that would affect wearing of contact lens; clinically significant corneal infiltrates; systemic disease affecting ocular health; use of any systemic or topical medications that will affect ocular physiology or the performance of the lenses; ocular injury or condition of the cornea, conjunctiva, or eyelids that would affect the wearing of contact lenses; corneal refractive surgery or other ocular surgery that could potentially affect contact lens wear; any contraindications to hydrogel contact lens wear; known history of allergy to constituents of study lenses; and currently enrolled in another ophthalmic trial.
Lenses used in this study were of the lotrafilcon A fluorosilicone polymer (CIBA VISION, Atlanta, GA). These lenses were either commercially available or modified commercial lenses of the same base material. Parameters are shown in Table 2.
This was an interventional, open-labeled study commenced on May 23, 2005. The protocol was reviewed and approved by an independent ethics committee, and this research followed the tenets of the Declaration of Helsinki.
The subjects wore the lenses on a 30-night EW schedule with monthly replacement. At the end of the lens-wear period and after an overnight break from lens wear, lens wear resumed the next morning with new lenses. Subjects were dispensed with lenses at the baseline visit. Follow-up visits were scheduled at 1 night, 1 week, 1 month, 3 months, and 6 months after starting EW. Neophytes to lens wear had an additional visit of 1 week daily wear included before commencing EW.
Lens fitting was required to meet criteria of complete limbal coverage in all directions of gaze, tightness range between 40 to 70 using push-up test (scale, 1–100, where 1 is very loose and 100 denotes an adherent lens), no lens fluting, and fitting acceptance of grade 3 or higher (scale, 0–4, where a rating ≥3 is considered acceptable and <3 is either unacceptable or requires refit).
A full anterior eye examination, using a biomicroscope, was conducted at each visit. At the baseline visit, before lens insertion, an initial history, autorefraction, keratometry, subjective refraction, and spectacle visual acuity were performed along with baseline ocular swabs (upper palpebral and lower lid margin) before lens insertion. Except after 1 week of daily wear for neophytes, worn lenses were collected aseptically for microbiological analysis at all scheduled visits and in the event of an adverse response. Aseptic lens removal was performed using a sterile glove for each lens. Lenses were immediately immersed on removal into 2-mL sterile phosphate buffered saline (PBS) aliquots in glass vials.
Subjects were instructed in aseptic lens removal techniques at the LV Prasad Eye Institute and issued with Adverse Response Kits (containing sterile latex gloves and sterile Bijou bottles containing sterile PBS) at the baseline lens dispensing visit. Subjects were informed of the signs and symptoms associated with adverse events. In the case of any event out of normal hours, subjects were required to remove their lenses aseptically, store them in sterile vials containing 2-mL PBS and report with the lenses to the clinic immediately. If any delay was expected, subjects were advised to store the lenses in a refrigerator until able to reach the clinic.
Adverse events were classified as either inflammatory or mechanical events. An inflammatory event was any event classified as a contact lens-induced acute red eye, contact lens-induced peripheral ulcer, microbial keratitis, or infiltrative keratitis. A mechanical event was any event that was classified as a superior epithelial arcuate lesion, contact lens-induced palpebral conjunctivitis, or corneal erosion. Only first events were considered for the statistical analysis.
All subjects were advised to report/present to the clinic immediately for events not considered normal (e.g., red eye, pain, and persistent irritation). Management of the adverse response depended on the severity and type of condition. If the adverse event were considered serious, the condition was medically treated (at the investigator's discretion). The most common management of adverse responses occurring in the study was to temporarily discontinue lens wear and monitor the subject until resolution of the condition. The subject was then allowed to recommence lens wear if willing to continue in the study. If it was not deemed appropriate for the subject to continue in the study, the subject was discontinued from the study.
The lenses were removed aseptically and placed in sterile vials containing 2 mL of PBS (pH 7.2). The lenses were transported to the microbiology laboratory within 30 minutes of collection. After being vortexed in the transport PBS for 30 seconds, each lens was aseptically transferred into 10 mL of molten nutrient agar (45°C). The nutrient agar containing the lens was gently shaken and poured over a chocolate agar plate. The plate was incubated in 5% of CO2 at 37°C for 2 days. Aliquots of 400 μl of the transport PBS from the lens vial solution were inoculated onto three chocolate agar plates and one Sabouraud's dextrose agar plate. One of the three chocolate agar plates was incubated at 37°C in 5% of CO2 for 2 days, one in aerobic conditions (2 days), and one under anaerobic conditions (4 days). The Sabouraud's dextrose agar plate was incubated at 25°C for 7 days to culture for yeast and fungi. Colony forming units (cfus; cfu/lens) were counted and recorded.
The outcome variable (inflammatory and mechanical events) was analyzed as a binary variable. Controls were subject-eyes that did not experience any adverse event during the course of the study period. Factors that were modeled as covariates included clinical variables, lens performance, and lens culture data. These variables were summarized from all scheduled EW visits for controls. However, for cases, these variables were summarized from all scheduled EW visits before the first event. Data were summarized as average, maximum, or minimum across these visits. Demographic factors were also included for the analysis.
Univariate analysis determined the significance of all possible risk factors using χ2/Fisher exact test for categorical risk factors and Student's t-test for those measured on an interval scale. Factors that were significant at p < 0.05 were considered for multivariate testing using logistic regression. The method of model building comprised initially of backward stepwise removal starting from the most non-significant factor until all variables in the model were significant. This was followed by entering back each excluded factor to determine any improved value to the model. Such a factor was retained in the final model if there was a significant improvement in overall χ2 value or if it confounded other existing factors. Interactions were included in the model only if they were significant. Statistical significance was set at 5%. The strength of association for significant factors was summarized using odds ratio and their 95% confidence limits. The goodness-of-fit of the final model was assessed using the Hosmer-Lemeshow test. The discriminatory ability of the model was assessed using the area under the receiver operating characteristic (ROC) curve based on predicted probabilities. All logistic models used the robust estimator of variance11 to adjust for the correlation within a subject because of data from two eyes. SPSS 1212 and STATA 713 were used for statistical analysis.
Among the 66 prior contact lens (CL) experienced wearers, all had prior experience in soft contact lenses, and 12 (18%) wore lenses on an EW schedule. Sixty-five percent of the study sample was students. Of those who commenced lens wear, 18 (9.6%) subjects discontinued before the last study visit, and of these, 10 were due to lens-related reasons. The lens-related reasons for discontinuation included lens fit (three cases) and discomfort (one case). The average follow-up in the study was 5.6 ± 1.4 months with a median of 5.9 months.
Data obtained from 376 eyes of 188 subjects were used for adverse event analysis. Subject-eye years were calculated as the sum of the length of time in years in the study completed by each individual. The total subject-eye years for the study were 83.33 eye years. There were a total of 31 inflammatory and 37 mechanical events during the trial. Only first events were considered for this analysis.
Even though slightly different lens types were used, albeit of the same basic lotrafilcon A material, no significant difference was observed between the two lens types in the first event incidence of corneal inflammatory events (odds ratio = 0.93, p = 1.0) and mechanical events (odds ratio = 1.53, p = 0.30). Both multivariate models were analyzed after adjusting for lens type as a factor in the model though it was not a significant factor.
The results of the inflammatory event model are presented in Table 3. The odds of an inflammatory event increased by 2.78 for every 1 log increase in cfu/mL CL contamination levels. Subjects with an inflammatory event had a mean cfu/lens of 1.97 log compared with a mean cfu/lens of 1.45 log in the group with no inflammatory event. It was also observed that 21% of controls had >2 log cfu/lens on a scheduled visit, whereas among the adverse cases, 52% (p < 0.001) had the same level on visits before and at the time of the inflammatory event. Subjects presenting with corneal vascularization were significantly associated with the development of inflammatory events, with three of six subject-eyes (50.0%) exhibiting vascularization concomitantly experiencing an adverse event. By comparison, 38 of 370 subject-eyes (7.6%) with no vascularization experienced an adverse event. When data were considered before the event, 2% of controls presented with corneal vascularization at a scheduled visit, whereas among adverse event cases, this was 13% (p = 0.008). There was an increased association of inflammatory events for subject-eyes with reduced lens movement, and subjects were more likely to develop inflammatory events compared with those subjects with optimal lens movement. A greater proportion of adverse event cases showed poor lens movement of <0.3 (13% vs. 4.6% for controls, p = 0.072) and lag < 0.2 mm (87.1% vs. 69.6% for controls, p = 0.039).
Subjects working outdoors or in non-ideal environments (exposure to wind, dust, fumes, and water splashes) showed an increased risk of inflammatory events, with 19.2% (5 of 26 eyes) inflammatory events in this group, when compared with 3.3% for the collective study group. Subjects working in a controlled ideal environment (indoors and administrative-type work) had the lowest levels of events (3 events of 92 eyes; 3.3%), and students occupied a position between the two groups (31 events of 364 eyes; 9.3%). Age and gender were not significantly associated with this event. The logistic model goodness of fit (p = 0.823) and area under the ROC curve (79%) were acceptable.
The results of the mechanical event model are presented in Table 4. Higher levels of palpebral roughness (per unit increase in grade) increased the risk of developing mechanical events (p = 0.001, odds ratio 6.86). It was also observed from scheduled visits that 9.1% of control eyes had a palpebral roughness grade of >2, whereas among the adverse event cases, this was 35.1% (p < 0.001) of visits before the mechanical event. Similarly with palpebral redness, the adverse event cases had grades >2.5 at 18.9% of visits, whereas the controls had that level for 2.4% of visits (p < 0.001). Corneal staining, in terms of the worse case of the depth of staining (per unit increase in grade) was also associated with mechanical events (p = 0.005, odds ratio 2.48). From scheduled visits, the adverse event cases had a worst-case depth of staining greater than grade 1 on 21.6% of visits, whereas for controls this was 1.8% (p < 0.001). Higher surface wetting was associated with lower incidence of mechanical events, which implied that reduced wetting of the lens surface was associated with mechanical events. Lenses of subject-eyes with front surface wetting grade <1.5 was 27% among adverse event cases and 14.2% among the controls (p = 0.053). Age and gender were not significantly associated with this event. The logistic model goodness of fit (p = 0.49) and area under the ROC curve (81%) were acceptable.
The study has identified several factors associated with inflammatory events and mechanically driven events using a multivariate model from a sample of CL wearers in India. In summary, the multivariate model had acceptable fit and discriminatory ability based on the goodness of fit and area under the ROC curve. This implies that confidence can be placed on the associated factors identified from the model. As the study population consisted predominantly of young males and neophytes, the ability to generalize the results to other populations may be limited to lens wear, making it different to the broader international contact lens wearing population.14 The study population instead reflects the groups adopting lens wear in the growing contact lens market of India.
Multiple factors were associated with inflammatory events in this trial including increased microbial contamination of lenses, corneal vascularization, reduced lens movement, and subject's working environment. Stapleton et al.4 also found a multiplicity of risk factors associated with sterile infiltrates because of EW of silicone hydrogel lenses namely history of lens-related inflammation, initial period of adaptation, limbal redness, corneal staining, younger (≤25 years) and older (>50 years), smoking, high ametropia, shorter duration of EW, and bacterial contamination of the storage case. This study found that lens contamination conferred increased risk of inflammatory events. Contamination of lenses with gram-positive bacteria, in particular Staphylococcus aureus, has been implicated with contact lens-induced peripheral ulcer.15,16 Contamination of lenses with gram-negative bacteria and Staphylococcus pneumoniae has been implicated with contact lens-induced acute red eye and some events of infiltrative keratitis.17–20 It has been proposed that endotoxin released from these bacteria was a primary cause of the cellular response.17 Trauma to the cornea, leading to epithelial compromise, has been suggested to induce infiltrative responses.19 In vitro work by Kodjikian et al.21 have demonstrated increased bacterial adhesion on some silicone hydrogel lenses compared with conventional low-Dk hydrogel lenses. A limitation of this study was that the adverse response kits provided to subjects have not been validated. This technique, however, has been used previously, and a significant correlation was found between adverse events and isolation of pathogenic microorganisms from contact lenses.18,22
Compared with subjects working in an ideal environment (administrative or other work indoors), those working outdoors or in non-ideal environments showed an increased risk of inflammatory events. The professions in the latter group had varying degrees of exposure to ocular irritants within their work environment, including dust, fumes, and repeated water splashes to face. Admittedly, the sample size of the non-ideal subgroup was relatively small, but the large disparity between the inflammatory event rate for the entire study group of the ideal and the non-ideal group (3.3% vs. 19.2%) serves as an indication of the increased risk. The non-ideal environment may be confounded by subject's smoking habits; however, this data were not collected. Moreover, it is known that the prevalence of smoking in India is higher in men and lower socioeconomic groups.23 The non-ideal environmental factor identified in this study may, therefore, suggest the influence of more than one socioeconomic and environmental condition.
The high oxygen permeability of the silicone hydrogel lenses used in this study has previously been demonstrated to produce negligible hypoxic physiological changes to the cornea.24–26 With this in mind, six subjects with mild to moderate corneal vascularization, because of previous prolonged wear of low oxygen permeable lenses, and otherwise acceptable ocular findings for silicone hydrogel wear, were enrolled into the study. The results showed that the presence of previous vascularization was significantly associated with the development of inflammatory events, with three of the six (50%) subjects with vascularization experiencing an adverse event compared with only 7.6% of subjects with no corneal vascularization. Because of the limited sample size and low incidence, it is not possible to make any broad statements as to the significance of this finding. Other studies have also highlighted the detrimental effects of corneal vascularization including loss of immune privilege in the anterior chamber27 and an increase in the risk of rejection in corneal grafts.28
This study found that for each 0.1 mm increase in on-eye lens movement (to an upper limit considered acceptable), there was an associated decrease in the risk of an inflammatory event, further evidence that tight fitting of hydrogel lenses, particularly in an EW scenario, should be robustly avoided. Suboptimal lens fit potentially affects ocular physiology and the efficiency of tear exchange under the contact lens. In general, contact lens wear seems to reduce tear exchange, as the mean elimination rate in eyes wearing conventional hydrogel lenses is about half of that observed in normal non-lens wearers.29 However, compared with conventional hydrogel lenses, eyes wearing silicone hydrogel lenses have significantly higher levels of tear exchange.29 More importantly, an unacceptable lens fit, which directly affects lens movement, can affect tear film stability and tear exchange or clearance of the postlens tear film.30,31 This is because key factors responsible for tear exchange are the extent of contact lens movement during a blink and the force applied by the upper lid.31
Mechanical events were defined as any presenting clinical event related to mechanical disturbances, i.e., all non-inflammatory complications. Factors associated with mechanical events included higher palpebral roughness, reduced surface wetting, and corneal staining. Both silicone hydrogel lens material and an EW regimen have previously been implicated in causing increased incidence of palpebral changes.32,33 Dumbleton10 attributes this to the edge effects from the stiffer material and possibly also because of differences in surface wettability of the silicone hydrogel material. Improved surface wetting was associated with a decrease in mechanical events. According to Cheng et al.,34 a distinction needs to be drawn between protein and lipid deposition, which can be harmful to successful lens wear, and protein adsorption into the lens matrix, which improves wetting performance of silicone and low-Dk hydrogel lenses. Corneal staining, representative of compromised tissue integrity, is an obvious risk factor for increased incidence of mechanical events. The presence of chronic staining may be indicative of excessive mechanical pressure, poor fit or general incompatibility with the lens or wear schedule, or a combination of these factors. As mentioned previously, the higher levels of airborne dust and other atmospheric contaminants in the south Indian region may also have had a contributory role.22 Although mechanical complications, by themselves, resolve relatively easily with modifications to wear schedule, lens design, or material, the larger concern is that insults to the ocular tissue provide a vector for bacterial entry increasing the risks of developing inflammatory or infective events.35
This study indicates that a multitude of factors, including patient ocular characteristics, lens fit, and environmental influences, contributed to the development of inflammatory or mechanical events, information that is of clinical relevance to practitioners worldwide. The significant finding of this study is the multiplicity of factors associated with these types of CL events. The implication of this multiplicity is that there needs to be better understanding of the interaction between the contact lens device, lens wearer, and environment factors influencing the occurrence of these events. Occupational environment was also a contributory factor, confirming that a duty of clinicians is to ascertain the nature of the work environment of lens wearers (and potential wearers), educate CL wearers about contact lens wear in the work place, and to balance the needs of the wearer with the potential risks.
We thank all the staff and patients at the LV Prasad Eye Institute, Hyderabad, India, for their assistance with this study.
This work at the LV Prasad Eye Institute was partly supported by CIBA VISION and the Australian Federal Government through the Cooperative Research Centres Program Industry Scheme.
This paper was presented at the British Contact Lens Association meeting in Manchester, England, May 2007, and at the Association for Research in Vision and Ophthalmology meeting, Hyderabad, India, January 2009.
Brien Holden Vision Institute
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