LESSONS LEARNED:
Contact Lenses, Adverse Events and Bacterial Keratitis

A look at the complex relationships between edema, lens wear patterns and ocular defenses.

By William D. Townsend, OD

Goal Statement:

This course will review many of the changes that have occurred in contact lens-related pathology over the past two decades. These include the epidemiology and pathophysiology of infiltrative and ulcerative conditions caused by contact lens wear.

Faculty/Editorial Board:

Dr. William Townsend, OD, practices in a multi-location setting. He is an adjunct professor at the University of Houston College of Optometry and preceptor for senior externs who rotate through his practice. He conducts research in pharmaceutical agents, contact lens materials and solutions, and ocular surface disease. Dr. Townsend is a fellow of the American Academy of Optometry and president of the Ocular Surface Society of Optometry.

Credit Statement:

This course is COPE approved for 1 hour of CE credit. COPE ID 40892-CL. Check with your local state licensing board to see if this counts toward your CE requirements for relicensure.

Joint-Sponsorship Statement:

This continuing education course is joint-sponsored by the Pennsylvania College of Optometry.

Disclosure Statement:

The author has no financial relationships to disclose.

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LB, a 37-year-old female, presented with recent-onset pain, injection and photophobia in her left eye (figure 1). We had not seen her as a patient in more than a decade. The previous evening she was evaluated at the emergency room, diagnosed with a "corneal ulcer" and obtained a prescription for moxifloxacin 0.5%. She reported overnight wear of her balafilcon A lenses for up to, and sometimes beyond, 30 days of continuous wear.

Examination revealed a 1.5mm staining area with a dense underlying infiltrate located in the inferior nasal left cornea, approximately 2mm from the limbus. In reviewing her records I discovered that, 18 years earlier, LB had presented to our office with essentially the same history, complaints and presentation.

Despite tremendous advances in contact lens materials, solutions and manufacturing techniques, we continue to deal with many of the same contact lens complications that occurred when our patient was a teenager.

In researching historical trends in contact lens-associated infection, I perused the corneal disease section in Mays's Diseases of the Eye 1911. As I read, I was fascinated by how much, as well as how little, we knew over a century ago about bacterial keratitis.¹ But as we look back, it becomes apparent that over the past two decades many accepted and established conceptions about the association between contact lens wear and adverse events such as bacterial keratitis have been revised, or in some cases, totally replaced. Still, many issues remain unresolved.

Developing a better understanding of the epidemiology, pathophysiology and risk factors for contact lens-related complications may allow us to recognize and manage these conditions more efficiently and effectively.

EPIDEMIOLOGY OF BACTERIAL KERATITIS

Contact lens-associated bacterial keratitis (CLBK) is an infrequent complication in contact lens wearers. In 1989, Poggio et al. reported an incidence of 4.0 per 10,000 for rigid gas permeable (RGP) wearers, and 2.0 per 10,000 for hard (PMMA) contact lens wearers.² The researchers estimated the incidence of CLBK in soft lens wearers to be 4.1 per 10,000 for daily wear and 20.9 per 10,000 for extended wear.²

Based on recent reports, it appears that the incidence of contact lens-related bacterial keratitis (CLBK) has remained stable since the publication of Poggio's study, but during that period there have been outbreaks of other, nonbacterial contact lens-related keratitis, notably Acanthamoeba and Fusarium.³

RISK FACTORS

In his 1988 text, Primary Care of the Anterior Segment, Catania listed eight contact lens-related risk factors for infectious keratitis: (1) non-compliance, (2) poor hygiene, (3) tight-fitting lenses, (4) extended wear, (5) old lenses (i.e., over six months old), (6) dirty lens surfaces, (7) recent insertion/ removal and (8) contaminated solutions.⁵ A quarter of a century later, the list of risk factors has not grown substantially.

Additional risk factors consistently associated with increased prevalence of microbial keratitis include smoking, failure to properly air dry contact lens cases and not washing hands prior to handling contact lenses.^3,5 Ocular surface disease, ocular trauma, systemic diseases, adnexal dys function, immunocompromise/ immunosuppression and ocular surgery are also risk factors for microbial keratitis.⁶

Corneal edema has long been recognized as altering the ocular surface and increasing the potential risk of contact lens complications. Researchers have used numerous strategies in an effort to identify the concentration of oxygen required to limit hypoxiainduced corneal edema.^7,8 Predictably, they demonstrated that corneal edema is inversely related to oxygen levels.^7,8

Holden and Mertz determined that a minimum oxygen level of 10% is necessary to prevent unacceptable edema in contact lens wear, and discovered that there are significant variations in oxygen requirements between individual subjects.⁸ This may help to explain why, in individuals wearing the same lens material, some patients tolerate extended wear better than others.

Recognizing the importance of oxygen levels in contact lens wear, manufacturers developed high water content contact lenses in an attempt to offset the limited oxygen permeability of lower water contact lenses. But after very high water content hydrogel lenses such as PermaLens (71%) were introduced, practitioners noted alterations in water content, oxygen transmissibility, total diameter and base curve radius. These changes may negatively impact the physiologic and optical qualities of these lenses.⁹ In 1980, Manchester reported that approximately one third of aphakic subjects who used PermaLens for overnight wear developed corneal edema that required discontinuation.¹⁰

The introduction of silicone hydrogel (SiHy) lenses was hailed as a promising means of reducing the incidence of CLBK and other complications linked to overnight contact lens wear.¹¹ In a 2003 assessment of overnight contact lens wear, Holden and coworkers evaluated the incidence of CLBK in individuals wearing high-Dk SiHy lenses.¹¹ Their initial findings suggested that patients using these lenses for extended wear had a significantly reduced risk of CLBK compared to those wearing low Dk lenses and when ulceration did occur, none of the subjects with CLBK suffered more than two lines of visual acuity.¹¹

Silicone hydrogel lenses provide oxygen transmissibility levels (Dk/t) four to six times greater than hydrogel materials.¹² Researchers reported that enhanced oxygen levels reduced the incidence of hypoxia-related complications such as corneal striae, folds, microcysts and neovascularization, but the anticipated benefits of high-Dk lenses in reducing CLBK were somewhat disappointing.^12,13 Stapleton et al. reported that the risk of microbial keratitis following 30 nights of extended wear in highly oxygen permeable lenses was equivalent to six nights of hydrogel lens wear.¹³ These are, of course, the FDA approved intervals for extended wear of these respective materials. They also noted that the frequency of vision loss secondary to keratitis was similar between the two modes of extended wear, and determined that the absolute rate of microbial keratitis in their extended wear subjects was one per 500 wearers.¹³

In summary, despite advancements in lens material, surface quality and significantly increased oxygen permeability, extended wear continues to be the single most significant risk factor for developing CLBK and is associated with a fivefold increase in risk of sight-threatening keratitis.¹³

THE DEFENSE SYSTEM

Microbes must overcome a very formidable, multicomponent defense system to infect the cornea.¹⁴ Because the eye is exposed to a broad variety of potentially invasive organisms, this defense system must be capable of reducing or clearing bacteria, viruses, fungi and protozoa.^15,16 In order to infect corneal tissue, pathogens must bind to and breach the ocular surface.

Under normal conditions, the multilayer defenses of the cornea protect very well against invasion. The past decade has produced a large body of research that sheds light on how the eye protects itself from invasion by pathogens.

The initial barrier, the tear film, mechanically removes many invaders by clearance and tear flow.¹⁴ The tear film contains proteins and lipids that can inhibit bacterial replication and/or destroy microbes.¹⁴ Tear components such as lysozyme, lactoferrin, lipocalin and IgA possess bacteriostatic or in some cases bacteriocidal properties that serve to discourage penetration by pathogen.¹²

Glycocalyx, composed of transmembrane mucins (MUCs 1, 4 and 16), acts as a protec- tive layer adhering to the corneal surface (apical) cells. This structure is thought to interact with secreted mucins in tears to inhibit cell-to-cell and cell-to-pathogen adherence.¹⁷ Contact lens wear or pathologic conditions such as dry eye may impair barrier function and increase risk of infection.

Corneal epithelium and anterior basal lamina (Bowman's layer) form the next physical obstruction to invasion.^14,18 Epithelium produces antimicrobial peptides (AMP) including ß-defensins, molecules which can influence epithelial cells to aggressively block transit of Pseudomonas. Down-regulation of AMP inhibits clearing of P. aeruginosa from epithelium. Corneal epithelial basement membrane is also an important barrier to invasion. Some Pseudomonas species are able to traverse epithelium, while others cannot.¹⁸ The findings of Alarcon et al. demonstrate that P. aeruginosa is unable to traverse beneath the basement membrane as long as epithelial basement membrane is intact.¹⁹ These findings help us understand and appreciate the protective value of an intact corneal basement membrane.

If the defense mechanisms of the eye are so formidable, what condition or event allows microbes to enter and colonize the cornea? Some clues to the answers may be gleaned from research directed at contact lens-associated adverse events.

ADVERSE EVENTS AND CLBK

An adverse event is defined as "a harmful and undesired effect resulting from a medication or other intervention."¹⁵ In contact lens studies, this term is frequently used to describe conditions associated with inflammation.¹² The presence of low Dk hydrogel lens materials on the cornea for extended wear may cause noninflammatory events such as striae and folds, mucin balls and epithelial microcysts; these conditions often resolve when patients switch to SiHy materials.¹³ But extended wear of hydrogel and SiHy materials also cause adverse events that are primarily inflammatory in nature.¹² It is very important to differentiate between microbial keratitis and a non-infectious adverse event because the potential loss of vision and appropriate treatment are vastly different.¹²

A contact lens peripheral ulcer (CLPU) is regarded as an immune response, primarily associated with gram-positive bacteria.¹² It is characterized by a focal epithelial excavation overlying necrotic tissue. It invariably involves a subepithelial infiltrate and moderate injection.²¹ These lesions are typically round in shape, and located in the mid-peripheral cornea.¹² The most commonly isolated organism cultured in CPLU is S. aureus. This condition is sometimes misdiagnosed as infectious keratitis.¹² The differential diagnosis is crucial to initiation of appropriate therapy.²⁰

Wu et al. used a rabbit model of CPLU to better understand the underlying pathophysiology of the condition.²¹ The rabbits wore contact lenses for 24 hours; the variables included no bacterial exposure, exposure to live S. aureus, killed S. aureus or live S. epidermidis. A second set of variables included corneas that were scratched within, but not through, the epithelium. The third variable was contact lens wear vs. no lens wear.

Salient findings from this study include the following:

• Lesions very similar to those found in human CLPU were noted only in corneas that were scratched and exposed to live S. aureus.
• Upon removal of the contact lenses and with no antibiotic application, these lesions resolved after 24 hours.
• In all corneas exposed to S. epidermidis, regardless of an intact or scratched surface, no ulceration or reaction was noted. The authors concluded that two important factors that lead to CLPU occurs are exposure to live S. aureus and the presence of a break in corneal epithelium.

Because CLPU can mimic CLBK, it is vital to differentiate between the two.²² Salient differences include shape, degree of pain, anterior chamber reaction and location (Table 1).

TABLE 1. DIFFERENTIAL DIAGNOSIS OF CLPU AND MK Source: Dumbleton K. Contact Lens & Anterior Eye2002(25);137-146.

Given the similarity between CLPU and early CLBK, one might consider the former to be a precursor to the far more serious infectious condition. Sweeny and Naduvilath evaluated this potential relationship and concluded that adverse inflammatory events—i.e., contact lens acute red eye (CLARE) and CLPU—do not progress to increase the risk of CLBK.²³

They proposed several reasons for this disconnect. CPLUs are inflammatory in nature, and biopsies of these lesions consistently fail to show replicating organisms in the tissue. The microorganisms that cause inflammatory vs. infectious conditions are very different. Strains that cause inflammatory events produce low levels of proteinases and are not able to traverse through host tissue, whereas strains that cause infection produce high levels of proteinases and thus can produce epithelial cell cytotoxicity or invade tissues.²³

CONCLUSION

This paper has reviewed many, but certainly not all, issues related to changing concepts and understanding of CLBK and other complications of contact lens wear. Notably absent from this discussion is the role that contact lens solutions and cases play in the development of contact lens-related bacterial, amoebal and fungal keratitis. Years of research have provided us with a new understanding of how contact lens materials, surface treatments and care systems can influence microbial binding to contact lenses surfaces. These and other factors beyond the scope of this article warrant discussion in a subsequent publication.

Writing this review reinforced for me how rapidly the literature in contact lens care is changing and the importance of staying current as we strive to make contact lens wear a safe and enjoyable experience for our patients. SiHy lens use is typically associated with less severe infections than silicone lenses, but the rates and types of organisms found in contact lens-related infections are similar to what was found decades ago.

We must remain vigilant and attuned to the earliest warning signs that something is awry.

References

1. Mays CH. 1911. Diseases of the Eye 7th Edition. William Wood and Company New York p. 113-119.
2. Poggio EC, The incidence of ulcerative keratitis among users of daily-wear and extended-wear soft contact lenses. N Engl J Med. 1989 Sept 21;321(12):779-83
3. Stapleton F, Carnt N. Contact lens-related microbial keratitis: how have epidemiology and genetics helped us with pathogenesis and prophylaxis. Eye (Lond). 2012 Feb;26(2):185-93.
4. Yildiz EH Trends in contact lens-related corneal ulcers at a tertiary referral center. Cornea. 2012 Oct;31(10):1097-102.
5. Catania LJ 1988. Primary Care of the Anterior Segment. Appleton and Lang Norwalk CT. p.118-119
6. Stapleton F, Keay L, Edwards K, Holden B The epidemiology of microbial keratitis with silicone hydrogel contact lenses. Eye Contact Lens. 2013 Jan;39(1):79-85
7. Stapleton F, Carnt N Contact lens-related microbial keratitis: how have epidemiology and genetics helped us with pathogenesis and prophylaxis. Eye (Lond). 2012 Feb;26(2):185-93.
8. Holden BA, Mertz GW. Critical oxygen levels to avoid corneal edema for daily and extended wear contact lenses. Invest Ophthalmol Vis Sci. 1984 Oct;25(10):1161-7.
9. Holden BA, Sweeney DF, Sanderson G. The minimum precorneal oxygen tension to avoid corneal edema. Invest Ophthalmol Vis Sci. 1984 Apr;25(4):476-80.
10. Manchester, PT. Extended wear contact lenses for aphakic correction experiences with the Cooper Permalens: a preliminary report. Trans Am Ophthalmol Soc. 1980; 78: 47–54.
11. Holden BA, Sweeney DF, Sankaridurg PR, Carnt N, Edwards K, Stretton S, Stapleton F. Microbial keratitis and vision loss with contact lenses. Eye Contact Lens. 2003 Jan;29(1 Suppl):S131-4; discussion S143-4, S192-4.
12. Dumbleton K. Adverse events with silicone hydrogel continuous wear. Cont Lens Anterior Eye. 2002 Sep;25(3):137-46.
13. Stapleton F, Keay L, Edwards K, Holden B. The epidemiology of microbial keratitis with silicone hydrogel contact lenses. Eye Contact Lens. 2013 Jan;39(1):79-85.
14. Shovlin JP et al. Ocular surface health with contact lens wear. Cont Lens Anterior Eye. 2013 Jan 15;36 Suppl 1:S14-21.
15. Graham JE, Moore JE, Jiru X, Moore JE, et al. Ocular pathogen or commensal: a PCR-based study of surface bacterial flora in normal and dry eyes. Invest Ophthalmol Vis Sci. 2007 Dec;48(12):5616-23.
16. Narsani AK, Jatoi SM, Khanzada MA, Lohana MK. Etiological diagnosis of microbial keratitis. J Coll Physicians Surg Pak. 2010 Sep;20(9):604-7.
17. Gipson IK, Argüeso P. Role of mucins in the function of the corneal and conjunctival epithelia. Int Rev Cytol. 2003;231:1-49.
18. Augustin DK, et al. Role of defensins in corneal epithelial barrier function against Pseudomonas aeruginosa traversal. Infect Immun. 2011 Feb;79(2):595-605
19. Alarcon I, Kwan L, Yu C, Evans DJ, Fleiszig SM. Role of the corneal epithelial basement membrane in ocular defense against Pseudomonas aeruginosa. Infect Immun. 2009 Aug;77(8):3264-71.
20. Diec J,et al. Prompt diagnosis and treatment of microbial keratitis in a daily wear lens. 19a Optom Vis Sci. 2009 Jul;86(7):E904-7.
21. Wu P, Stapleton F, Willcox MD. The causes of and cures for contact lens-induced peripheral ulcer. Eye Contact Lens. 2003 Jan;29(1 Suppl):S63-6; discussion S83-4, S192-4.
22. Jalbert I, Willcox MD, Sweeney DF. Isolation of Staphylococcus aureus from a contact lens at the time of a contact lens-induced peripheral ulcer: case report. Cornea. 2000 Jan;19(1):116-20.
23. Sweeney DF, Naduvilath TJ. Are inflammatory events a marker for an increased risk of microbial keratitis? Eye Contact Lens. 2007 Nov;33(6 Pt 2):383-7; discussion 399-400.