Contact lens wear is intrinsically inflammatory.

C L I N I C A L A N D E X P E R I M E N TA L

THE H BARRY COLLIN RESEARCH MEDAL LECTURE

Contact lens wear is intrinsically inflammatory Clin Exp Optom 2016 Nathan Efron AC DSc PhD BScOptom Institute of Health and Biomedical Innovation and School of Optometry and Vision Science, Queensland University of Technology, Kelvin Grove, Queensland, Australia E-mail: [email protected]

Submitted: 14 February 2016 Revised: 7 May 2016 Accepted for publication: 9 June 2016

DOI:10.1111/cxo.12487 Eye-care practitioners typically associate ocular inflammation during contact lens wear with serious complications such as microbial keratitis; however, more subtle mechanisms may be at play. This paper tests the notion that contact lens wear is intrinsically inflammatory by exploring whether uncomplicated contact lens wear meets the classical, clinical definition of inflammation – rubor (redness), calor (heat), tumor (swelling), dolor (pain) and functio laesa (loss of function) – as well as the contemporary, sub-clinical definition of inflammation (cellular and biochemical reactions). It is demonstrated that all of these clinical and sub-clinical criteria are met with hydrogel lens wear and most are met with silicone hydrogel lens wear, indicating that uncomplicated contact lens wear is intrinsically inflammatory. Consideration of both traditional and contemporary thinking about the role of inflammation in the human body leads to the perhaps surprising conclusion that the chronic, low grade, sub-clinical inflammatory status of the anterior eye during contact lens wear, which may be termed ‘para-inflammation’, is a positive, protective phenomenon, whereby up-regulation of the immune system, in a non-damaging way, maintains the eye in a state of ‘heightened alert’, ready to ward off any extrinsic noxious challenge. Characterisation of this inflammatory status may lead to the development of lens engineering or pharmacological strategies to modulate contact lens-induced inflammation, so as to render lens wear more safe and comfortable.

Key words: conjunctiva, cornea, contact lens wear, inflammation, para-inflammation The topic that I have chosen to present in this H Barry Collin Research Medal Lecturea is a question that has been niggling away at the back of my mind throughout my career. To illustrate this, I draw your attention to a paper I published in 1985 entitled ‘Is contact lens-induced corneal oedema inflammatory?’1 and a follow-up editorial published over a quarter of a century later entitled ‘Is contact lens wear inflammatory?’2 Although the title of the present paper gives away the conclusion that I have ultimately reached, the thought process that has evolved over the past 30 years, supported by emerging evidence rooted in clinical practice and fundamental vision science, is a story worth telling. The notion that inflammation is an intrinsic component of normal, asymptomatic contact lens wear has emerged in part because it has not been possible to otherwise explain some of the most a Professor Nathan Efron AC was awarded the H Barry Collin Research Medal by Optometry Australia in 2015. This paper is based on his award lecture presented at the Southern Regional Congress (hosted by Optometry Victoria) on 5 March 2016 in Melbourne, Australia.

© 2016 Optometry Australia

fundamental problems relating to contact lens wear – in particular discomfort, which invariably worsens toward the end of the day.3 If it can be established that contact lens wear is inflammatory, this would open up the door for the exploration of a raft of engineering solutions by way of lens material formulations and designs, as well as pharmacological strategies that can modulate the inflammatory response. At the outset, I need to introduce an important point of clarification: I am not referring here to frank, overt inflammatory reactions to contact lens wear, such as papillary conjunctivitis,4 superior limbic keratoconjunctivitis,5 microbial keratitis6 or even the various forms of corneal infiltrative events.7 The proposition I am advancing is that normal, asymptomatic, problem-free contact lens wear (aside from ‘end of day discomfort’, which all lens wearers experience3) is intrinsically inflammatory. My discussion shall be largely confined to the ocular response to soft contact lenses, for three reasons: 1. the vast majority of contact lenses prescribed today are soft lenses;

2. far more fundamental physiological research has been conducted on soft lenses, allowing access to a broader range of scientific literature to test my assumptions; and 3. ease of discussion, in that it would be too cumbersome to recount all of the relevant arguments in respect of rigid lenses, even if all of the supporting evidence I wished to cite were available in the published literature. I shall begin by defining the term ‘inflammation’ and shall proceed to test whether contact lens wear can be considered to be inflammatory, by evaluating various aspects of the ocular response to lens wear against the seven markers that essentially characterise inflammation, as detailed below. I shall then consider the implications of my conclusions and explore possible future research directions. INFLAMMATION DEFINED The Roman writer Aulus Celsus (30 BC – 45 AD) (Figure 1), described four key signs of inflammation as rubor (redness), calor (heat), tumor (swelling) and dolor (pain).8

Clinical and Experimental Optometry 2016

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Contact lens wear is intrinsically inflammatory Efron

We now appreciate that the first three signs are likely attributable to responses of the microvasculature to inflammation. Aelius Galen (129 AD – 200 AD) (Figure 1), the physician and surgeon of Roman emperor Marcus Aurelius, is often credited with introducing a fifth sign of inflammation – functio laesa (loss of function) in the affected tissue. While these early concepts about inflammation were largely derived from intuition rather than careful scientific investigation, they provided the framework for critical experimentation in the later centuries.8 A modern definition of inflammation can be found by consulting a medical dictionary. A search through many of these revealed reasonable consistency, so I have chosen the following definition,9 which seemed to be fairly representative of those I accessed. ‘Inflammation’ is defined as: 1. normal pathological process provoked by actual or threat of imminent physical, chemical or biological injury; 2. characterised by five classic signs – rubor (redness), calor (heat), tumor (swelling), dolor (pain) and functio laesa (loss of function), all or some of which are noted in inflamed tissue; and 3. mediated by a series of cellular and biochemical reactions in affected blood vessels and adjacent tissues.9 This definition identifies three overarching elements. The first element essentially relates to the causative agent that initiates a response. For example, ‘physical injury’ could be caused directly by a

contact lens and ‘chemical injury’ may be attributed to the effects of contact lens care or packaging solutions. ‘Biological injury’ could be lipid or protein mediated or result from infectious agents entering into the ocular tissues during contact lens wear, although the latter scenario would typically result in an overt inflammatory process, which is outside the framework of ‘troublefree’ lens wear being considered here. That a contact lens is being worn is of course the starting assumption of this analysis and does not require further elaboration. The second and third over-arching elements of the above definition constitute the template that I shall use to test whether ‘trouble-free’ contact lens wear is intrinsically inflammatory. The second element stipulates that all or some of the five cardinal signs of inflammation must be observed. It is interesting that these classical descriptors of inflammation, conceived two millennia ago, have stood the test of time and remain firmly embedded in modern definitions of inflammation. The third over-arching element of the definition of inflammation can be described as a contemporary addition. It stipulates that there must be evidence of cellular and biochemical reactions in affected blood vessels and adjacent tissues. It is only through the invention of the microscope in the 17th century and developments in laboratory science over the past half century that it has been possible to demonstrate evidence of cellular and biochemical mediators of inflammation.

Figure 1. Aulus Celcus (30 BC – 45 AD; left) first defined four cardinal signs of inflammation (rubor, calor, tumor and dolor) and a fifth sign (functio laesa) was added about 150 years later by Aelius Galen (129 AD – 200 AD; right). Public domain. Clinical and Experimental Optometry 2016

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In the following analysis, I shall generally begin by drawing upon my own research to test whether the five clinical signs and two sub-clinical markers are evident in troublefree contact lens wear. I shall also refer to evidence published by others, as appropriate. CLINICAL SIGNS (CLASSICAL) If a patient presents with serious microbial keratitis, the five cardinal signs of inflammation are readily apparent: the limbus and conjunctiva are hyperaemic (rubor), patients might report that their eyes feel hot and the tissues around the eye will feel warm (calor); there will be evidence of corneal oedema, conjunctival chemosis and swelling of the eyelids (tumor), the eye will be painful (dolor) and if the central cornea is affected, there will be loss of vision (functio laesa).6 During uncomplicated contact lens wear, perhaps only two of these five clinical signs of inflammation may be apparent – limbal redness (rubor) and end of day discomfort (dolor). More sophisticated clinical techniques would be required to verify calor, tumor and functio laesa. Each of the five cardinal signs of inflammation shall be considered in turn.

Rubor (redness) By way of subtle changes induced by contact lenses, eye redness and discomfort are the only two of the five cardinal signs of inflammation of which lens wearers may be aware. Indeed, eye redness is of concern to many lens wearers, primarily due to its unsightly cosmetic appearance. Contact lens wearers desire clear, healthy looking ‘white’ eyes; indeed, eye redness was noted by Dumbleton and colleagues10 as the second most common reason (after discomfort) for discontinuing lens wear. Together with Maldonado-Codina and colleagues,11 I investigated short-term changes in eye redness (in addition to other factors) in response to three soft lens materials with different oxygen permeability characteristics. Specifically, 43 participants who had never worn contact lenses previously were randomly prescribed a hydrogel lens (Acuvue 2, Johnson & Johnson Vision Care) or one of two silicone hydrogel lenses – Acuvue Advance (Johnson & Johnson Vision Care) or Focus Night & Day (CIBA Vision) – for four




Calor (heat) Research into changes in the temperature of the eye during contact lens wear have concentrated largely on the thermal perturbations of the cornea. Martin and Fatt15 determined anterior corneal surface temperature beneath a contact lens from

measurements of the average heat flow from the cornea to the atmosphere (efflux) in a group of 13 healthy young subjects. The average heat efflux was 1.1 × 10−2 cal/cm.sec. The mean corneal surface temperature of the same group was 34.5 C for the open eye and 36.2 C for the

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Figure 2. Changes in limbal and bulbar conjunctival redness before and after two weeks of contact lens wear in subjects who had not previously worn lenses. (A) Prior to hydrogel lens wear, (B) two weeks after hydrogel lens wear, (C) prior to silicone hydrogel lens wear, (D) two weeks after silicone hydrogel lens wear. Hydrogel lens wear can be seen to induce greater limbal and bulbar conjunctival redness compared with silicone hydrogel lenses. 1.8 1.6

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weeks on a daily wear basis. A further 19 subjects did not wear lenses (controls). Subjects and controls were examined two and four weeks after dispensing. The redness responses were graded upon inspection of the eyes using a slitlamp biomicroscope in a strictly masked fashion. There was a statistically significant difference in relative change from baseline conjunctival redness at both the two- and fourweek visits (F = 4.0, p = 0.01). Post-hoc assessment indicated that the changes for the Acuvue 2 group were greater than for the Acuvue Advance group (p = 0.008) and the control (p = 0.003) group but not the Focus Night & Day group. Other differences were not statistically significantly different. There was no statistically significant difference in change in conjunctival redness between the two visits (Figure 2). There was a statistically significant difference in relative change from baseline limbal redness score at both the two-week and the four-week visits (F = 5.2, p = 0.003). The Acuvue 2 group demonstrated more change in limbal redness than the Acuvue Advance group (p = 0.003), the Focus Night & Day group (p = 0.01) and the control group (p = 0.003). Other differences were not statistically significant. There was no statistically significant difference in limbal redness between the two visits (Figure 3). Clearly then, among these asymptomatic lens wearers, hydrogel lenses induced significant increases in limbal and conjunctival redness compared to non-lens wearing controls. The finding that higher oxygen transmissibility silicone hydrogel lenses did not induce significant increases in limbal or conjunctival redness compared to non-lens wearing controls is consistent with previous reports12 and represents a distinct benefit of this lens type. Limbal redness during contact lens wear has been demonstrated by Papas13 to be due to lens-induced hypoxia. This raises the question of whether the redness response to lens wear can be taken to be a sign of inflammation. The answer to this is two-fold. First, hypoxia per se can be a direct stimulus to inflammation,14 so hypoxiainduced redness can be considered to be an inflammatory response. Second, the definition discussed earlier merely stipulates that inflammation is indicated by the presence of the five cardinal signs, irrespective of their specific aetiology. That is, the appearance of redness per se satisfies the ‘rubor requirement’ for the eye to be considered as being inflamed.

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Figure 3. Limbal redness before and after two and four weeks of contact lens wear in subjects who had not previously worn lenses. Positive standard deviations are shown for Acuvue 2; standard deviations were similar for the other study groups. From Maldonado-Codina and colleagues.11


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closed eye. The anterior corneal surface temperature beneath a 0.07 mm thick hydrogel contact lens (40 per cent water content) was found to be 34.6 C (rise of 0.1 C) and 34.9 C (rise of 0.4 C) beneath a 0.3 mm thick hydrogel contact lens (40 per cent water content), using the measurement of corneal heat efflux and taking the contact lens to have a slight insulating effect. Contact lenses of higher water content caused a smaller rise in anterior corneal surface temperature than lenses of lower water content. I have had a long-standing interest in the measurement of ocular surface temperature and in my first paper on this topic my colleagues and I demonstrated a temperature profile across the ocular surface in the normal eye using infra-red ocular thermography.16 Specifically, we produced ocular thermograms (surface heat maps), which demonstrated a pattern of ellipsoidal isotherms (major axis horizontal) approximately concentric about a temperature apex (coldest point), which was slightly inferior to the geometric centre of the cornea. We measured a mean temperature of 34.3 0.7 C (range 32.8 C to 35.4 C) at the geometric centre of the cornea,16 in accordance with the previous finding of Martin and Fatt.15 The temperature increased toward the periphery of the cornea, with the limbus being 0.45 C warmer than the geometric centre of the cornea

(p < 0.0001). Following a blink, the geometric centre of the cornea cooled at a mean ( standard deviation) rate of 0.033 0.024 C/sec (p < 0.0001).16 We subsequently identified numerous potential applications of ocular thermography17 but assessment of changes in ocular temperature during contact lens wear was not one of these. Although we could obtain a thermogram demonstrating the temperature profile (attributed to the tear film) on the front surface of a contact lens (Figure 4), it was not possible to directly measure ocular surface temperature beneath a contact lens, as infra-red imaging cannot be performed through a lens. Our attempts to measure ocular surface temperature immediately following contact lens removal were thwarted by our inability to control, or account for, the numerous thermal influences and perturbances entailed in removing the lens and the time delay from lens removal to image capture; however, infra-red imaging technology advanced greatly in the ensuing years and more recently researchers have succeeded in measuring ocular temperature beneath contact lenses, albeit with conflicting results. Purslow, Wolffsohn and SantodomingoRubido18 used a dynamic, non-contact infrared camera (Thermo-Tracer TH7102MX, NEC San-ei) to record the ocular surface temperature in subjects wearing hydrogel (etafilcon A) and silicone

Figure 4. Ocular thermogram of a rigid contact lens on the eye. The colours indicate temperature in C, as per the scale on the right. The classic elliptical isotherms with major horizontal axis are evident. The inferior of the lens is colder than the bare cornea immediately inferior to the lens, probably as a result of tear film evaporation from the lens surface.


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hydrogel (lotrafilcon A and balafilcon A) contact lenses on daily and extended wear disposable regimens. They found that ocular surface temperature immediately following contact lens wear was significantly greater compared to non-lens wearers versus 35.0 1.1 C; (37.1 1.7 C p < 0.005). Lens surface temperature was highly correlated (r = 0.97) to but lower than ocular surface temperature (by −0.62 0.3 C). There was no difference with modality of wear (daily wear: 37.5 1.6 C; extended wear 37.8 1.9 C; p = 0.63) but significant differences were found between hydrogel and silicone hydrogel lens materials (35.3 1.1 C versus 37.5 1.5 C, respectively; p < 0.0005). Purslow, Wolffsohn and SantodomingoRubido18 reported that ocular surface cooling following a blink was not significantly affected by contact lens wear with (p = 0.07) or without (p = 0.47) lenses in situ. The authors concluded that ocular surface temperature is greater with hydrogel and greater still with silicone hydrogel contact lenses in situ, compared with no lenses, regardless of modality of wear and concluded that the effect is likely to be due to the thermal transmission properties of a contact lens.18 Whereas Purslow, Wolffsohn and Santodomingo-Rubido18 assessed ocular surface temperature immediately following contact lens wear, Ooi and colleagues19 developed a two-dimensional simulation of heat propagation in the human eye, using finite element analysis to estimate ocular surface temperature during lens wear. Three types of contact lens were studied: lotrafilcon A, balafilcon A and etafilcon A. The models were solved for both steady and transient conditions. Corneal surface temperature during contact lens wear was found to decrease by an average of 0.52 0.05 C compared with a bare, nonlens-wearing cornea for all lens types. Higher water contact lenses were found to have a lower steady state temperature than lower water content lenses. The authors suggested that an increase in evaporation rate when a contact lens is worn increases the cooling effect on the ocular surface, resulting in lower corneal surface temperature during lens wear.19 The evidence outlined above on temperature changes of the cornea during contact lens wear is equivocal but putting that aside, changes in corneal temperature may have little to do with inflammation,



Tumor (swelling) Corneal oedema can be verified by careful examination on a slitlamp biomicroscope when a significant amount of swelling is present.22 Striae can be observed as fine, white vertical lines in the posterior stroma, when the level of oedema reaches about five per cent. At around eight per cent oedema, folds and ridges can be observed in the endothelial mosaic, indicating oedema of the most posterior stromal layers. When the level of oedema exceeds


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subjects before and after three hours of afternoon wear of five conventional hydrogel and silicone hydrogel contact lens types, offering a range of oxygen transmissibility values from 2.4 to 115.3 × 10−9 cm2. mlO2/s.ml.mmHg. Curve fitting for plots of change in corneal thickness versus central and peripheral oxygen transmissibility revealed threshold values of 19.8 and 32.6 × 10−9 cm2.mlO2/s.ml.mmHg to avoid corneal swelling during open eye contact lens wear for a typical wearer (Figure 6). Although some conventional hydrogel soft lenses are able to achieve this criterion for either central or peripheral lens areas (depending on lens power), in general, no conventional hydrogel soft lenses meet both the central and peripheral thresholds;

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15 per cent, the stroma starts to loose transparency and becomes hazy in appearance.22 Such high levels of oedema are observed in response to hydrogel lenses, especially when worn on an extended wear basis and are rarely seen today with high oxygen transmissibility silicone hydrogel lenses. Special instrumentation is required to detect levels of oedema in the cornea of less than five per cent. Techniques such as optical or ultrasonic pachymetry, corneal confocal microscopy, optical coherence tomography, optical coherence pachymetry and Scheimpflug imaging can be used for this purpose.23 Together with colleagues in Manchester, UK,24 I measured the amount of corneal swelling during open eye wear in seven

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Figure 5. Average bulbar conjunctival temperature (typical standard error 0.07 C) and redness at baseline and following instillation of hypertonic saline drops. After Efron and colleagues.21 8

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because the cornea is avascular. Thus, any changes in corneal temperature would be modulated by simple heat diffusion through the contact lens and corneal tissue.15,19 The inflammatory response is essentially mediated via tissue microvasculature,20 as stipulated in the third element of the definition of inflammation described earlier. Therefore, of more direct relevance to the issue of contact lens-induced inflammation is the vascular response to contact lens wear, which is apparent in limbal and conjunctival vessels. Soft contact lenses are in contact with both the cornea and an annular one to two millimetre rim of conjunctiva during wear and thus, are capable of inducing an inflammatory response in these tissues. That limbal and conjunctival redness increases during hydrogel contact lens wear, is incontrovertible,11 as outlined above. Evidence of increased ocular surface temperature accompanying contact lensinduced ocular redness would support the hypothesis that the eye is warmer during lens wear, where there is evidence of hyperaemia. My colleagues and I investigated the relationship between bulbar conjunctival hyperaemia and temperature in the following manner.21 Conjunctival redness was induced in 18 volunteers by instilling hypertonic saline into the conjunctival sac. The degree of redness was estimated using a subjective grading scale. Subsequent changes in temperature of the nasal bulbar conjunctiva were monitored over 4.5 hours using an infra-red bolometer. We found conjunctival hyperaemia to be significantly correlated with conjunctival temperature; the maximum response of a three-grade change in redness was accompanied by an increase of 0.5 C in temperature. We noted at the time that these findings confirmed the classic association between inflammation, rubor and calor21 (Figure 5).

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Dk/t Figure 6. Relation between swelling response of the central cornea to four hours daily soft contact lens wear versus lens oxygen transmissibility (Dk/t). After Morgan and colleagues.24


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thus, there will always be some degree of corneal swelling in response to normal, uncomplicated hydrogel lens wear. Silicone hydrogel contact lenses typically meet both the central and peripheral thresholds and therefore, use of these lenses avoids swelling in all regions of the cornea. Corneal swelling during contact lens wear has been demonstrated by Klyce25 to be a hypoxia-driven osmotic phenomenon, attributed to lactate that accumulates in the stroma as the respiratory processes in the cornea shift to an anaerobic state (Figure 7). This raises essentially the same question that I considered previously in relation to lensinduced hyperaemia; that is, whether the corneal swelling response to lens wear can be taken to be a sign of inflammation. The answer also remains the same in this instance. Hypoxia can be a direct stimulus to inflammation,14 so hypoxia-induced osmotic corneal swelling can be considered to be an inflammatory response. Also, as stated previously, the definition of inflammation merely stipulates that inflammation is indicated by the presence of the five cardinal signs, irrespective of their specific aetiology. Thus, the appearance of corneal oedema per se satisfies the ‘tumor requirement’ for the eye to be considered as being inflamed. In 1984, my colleagues and I employed a pharmacological approach to determine whether contact lens-induced corneal swelling has, at least in part, an inflammatory component.26 Previous studies had demonstrated that the prostaglandin inhibitor naproxen could reduce post-surgical corneal oedema,27 which is essentially an inflammatory process caused by the trauma of surgery. To determine whether there was an inflammatory component in the oedematous response of the cornea to contact lens wear, we conducted a randomised, double-masked, placebo-controlled study on the effect of naproxen on contact lensinduced corneal swelling. This drug did not have a significant effect, suggesting that prostaglandins are not involved in the hypoxic oedema response (Figure 8). The discrepancy between the effect of naproxen on surgically and contact lensinduced corneal oedema can be attributed to the different aetiologies of these oedema responses; that is, mechanically induced trauma versus a hypoxia-driven osmotic effect, respectively.26 It should also be recognised that our failure to demonstrate an effect of naproxen


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Figure 7. Schematic illustration of contact lens-induced corneal swelling. (A) The cornea in steady state, with water leaking into the stroma through a semi-permeable endothelium and an active metabolic bicarbonate pump that draws water out of the stroma, thus maintaining constant hydration. (B) When a contact lens is placed on the eye, the epithelium respires anaerobically and releases lactate ions, which diffuse into the stroma and draw water into the cornea across the endothelium at a faster rate than it can be pumped out. (C) As a result of the ingress of water, corneal thickness increases.


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Time (hours) Figure 8. Corneal swelling response to hydrogel contact lens wear following treatment with naproxen (filled squares) and the placebo (filled triangles). The open squares and triangles indicate the response of the contralateral non-lens-wearing eye. The average standard deviation was 1.6 0.4 per cent for the lens wearing eye and 1.0 0.1 per cent for the contralateral eye. Symbols are offset slightly for clarity. After Efron, Holden and Vannas.26 on reducing lens-induced corneal oedema does not rule out this being an inflammatory response. Many different biochemical pathways and inflammatory mediators are known to be involved in the inflammatory response (see below). Therefore, our demonstration that prostaglandins are unlikely to play a role in contact lens-induced oedema does not preclude the involvement of other inflammatory mediators and pathways.

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Dolor (pain) ‘Pain’ is a pejorative term that does not really apply to contact lens wear. If we take this term in its broadest context to include various degrees of pain, then this definition would encompass ‘discomfort’. In 1989, Noel Brennan and I published one of the first reports documenting levels of discomfort experienced with early-generation hydrogel lenses manufactured from

hydroxyethyl methacrylate.28 We noted that 75 per cent of 104 lens wearers surveyed experienced symptoms of discomfort (reported as dryness) on at least some occasions. Little has changed in the ensuing quarter of a century. Discomfort during contact lens wear, especially toward the end of each day, is a general source of displeasure among contact lens wearers and is invariably cited as the main reason for patients discontinuing lens wear. Indeed, this is such a significant issue that in 2013 an entire special issue of the prominent journal Investigative Ophthalmology and Visual Science (Volume 54, No. 11, October 2013) was devoted to the topic of contact lens discomfort. Papas and colleagues29 recently conducted an experiment to establish whether end-of-day discomfort during soft contact lens wear is associated with short-term changes occurring to the lens itself or to the eye. Patients wore hydrogel and silicone hydrogel lenses for 10 hours on multiple occasions. On some occasions, the lenses were worn continuously for 10 hours. During these experiments, a continual decline in comfort was observed with wear of both hydrogel and silicone hydrogel lenses. On other occasions, at the five hour mid-point, lenses were removed and either replaced with the same lens after being rinsed or replaced with a new lens. It was observed that contact lens comfort progressively

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Figure 9. (A) Group mean comfort scores at each study time when hydrogel lenses were either worn continuously for 10 hours or removed after five hours and replaced with the same (old) lens. Error bars indicate 95 per cent confidence intervals. (B) Group mean comfort scores at each study time when hydrogel lenses were either worn continuously for 10 hours or removed after five hours and replaced with a new lens. Error bars indicate 95 per cent confidence intervals. After Papas and colleagues.3



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decreased throughout the day to the same extent in all wearing/interruption scenarios, except for a slight transient increase in comfort at the five hour lens removal midpoint. The same phenomenon was observed for both lens types (Figure 9). The authors concluded that final comfort was not influenced by replacing lenses midway through the wearing period. Comfort decrements experienced by users of these daily-wear contact lenses toward the later part of the wearing period are not caused by changes occurring to the lenses. They cited possible aetiological factors such as a fatigue-like response in one or more ocular tissues or stimulation of ocular surface nociceptors induced by the presence of the contact lens. Somewhat surprisingly, they did not countenance the possibility of a sub-clinical inflammatory response as a cause of the discomfort.

Functio laesa (loss of function) The term ‘loss of function’ was probably intended to infer a loss of function ‘of the affected tissue’. For example, in a serious case of microbial keratitis, where the central cornea is involved, the loss of function would manifest as reduced vision of the affected eye.6 When considering the contact lens-wearing eye as a combined system, two key manifestations of ‘loss of function’ are apparent – a forced reduction in wearing time on a given day and discontinuance of lens wear. Thus, the act of removing a contact lens from the eye toward the end of the day due to discomfort can be construed as a ‘loss of function’. Indeed, recent studies have used ‘comfortable wearing time’ as a measure of successful lens wear.30 The findings of two major surveys of contact lens discontinuation, conducted 14 years apart, reveal a similar rate of contact lens discontinuation, despite being conducted at different phases of the history of contact lens development. In 1999, Pritchard, Fonn and Brazeau31 analysed 1,444 survey forms gathered from patients in 16 clinical practices in Quebec, Canada and found that 34 per cent had discontinued lens wear at least once. At the time of this study, virtually all soft lens wearers surveyed would have been wearing hydrogel contact lenses. A similar study conducted by Dumbleton and colleagues10 in 2013 assessed 4,207 returned survey forms distributed


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Figure 10. Reasons for lapsing from lens wear. After Dumbleton and colleagues.10 D+N: day and night, ECP: eye-care practitioner. via Facebook and reported that 40 per cent had lapsed from lens wear for at least four months. At the time of this study, silicone hydrogel contact lenses had been on the market for over a decade; 45 per cent of those surveyed by Dumbleton and colleagues10 were wearing this lens type and 38 per cent had lapsed from lens wear. It is interesting that the development of high oxygen transmissibility silicone hydrogel contact lenses with supposedly superior biocompatibility, at least in terms of the amelioration of hypoxic problems,12 did not appreciably diminish the rate of contact lens discontinuation.10 In both of these surveys,10,31 discomfort was the major reason for discontinuation (Figure 10). SUB-CLINICAL MARKERS (CONTEMPORARY) The 21st century has been marked by rapid advancements in our understanding of the nature and underlying mechanisms of inflammation. The development of new in vivo models of inflammation, methods to capture and store images of the microcirculation and the application of mathematical and engineering approaches to quantify variables, such as leukocyte adhesion, vasomotor function and vascular permeability, have allowed the field to move forward at a greatly accelerated pace. This period also brought new chemical methods that enabled the discovery of different inflammatory mediators.8 In recent years, important additions to the armamentarium of researchers of

inflammation have come from the fields of molecular biology and immunology. The development of gene-targeted knock-out mice for different inflammatory molecules, such as cytokines, chemokines and their receptors, as well as inflammatory cells, such as leukocytes and Langerhans cells, has been immensely useful in the dissection of molecular mechanisms of inflammation in vivo. Immunological approaches (for example, blocking antibodies, bone marrow chimeras) developed for the mouse, with its exhaustively characterised immune system, have also proven to be powerful tools for the study of inflammation.8 The advances outlined above have led to the extension of the definition of inflammation to encompass cellular and biochemical reactions in affected tissues. These are considered to be ‘sub-clinical’ markers because, unlike the five cardinal signs of rubor, calor, tumor, dolor and functio laesa, upregulation of cellular or biochemical activity cannot be detected in the course of routine clinical examination. Here, I test whether these sub-clinical markers provide evidence of inflammation in the eye during uncomplicated contact lens wear.

Cellular reactions The laser scanning confocal microscope has found considerable utility in assessing the response of the anterior ocular structures to contact lens wear at a cellular level.32 Various studies have used this instrument to observe inflammatory cells – which are presumed to be Langerhans cells



– in both the central and peripheral cornea33 as well as the bulbar34 and palpebral35 conjunctiva. Langerhans cells are observed in the skin, lymph nodes, spleen and mucous membranes, including the ocular surface. Although our understanding of the precise role of Langerhans cells is evolving,36 they are now known to be major histocompatibility complex class II (murine Ia)expressing bone marrow-derived epidermal dendritic cells.37 The cardinal properties of dendritic cells include their ability to migrate selectively through tissues; take up, process and present antigen; and stimulate and direct T-lymphocyte-dependent responses. They are comprised of a heterogeneous group of ‘professional’ bone marrow-derived antigen-presenting cells, which include members of different lineages and states of maturation.37 Immature dendritic cells are characterised by a high capacity for antigen capture and processing but a low T-cell stimulatory capability. The immature dendritic cells have a low-to-negligible amount of major histocompatibility complex class II expression and lack the requisite accessory signals for T-cell activation. Maturation of dendritic cells renders them to be poor in antigen capture but potent in T-cell stimulation.37 Activation of Langerhans cells is an early and sensitive measure of an impending inflammatory process. Because Langerhans cells are a subset of a broad category of cells known as dendritic cells, cells of a dendritic nature observed on the ocular surface with the laser scanning confocal microscope may not all necessarily be Langerhans cells; however, evidence in the literature suggests that there is a direct correlation between laser scanning confocal microscopic and immuno-histochemical observations of dendritic cells in the cornea.38 Furthermore, the expression of Langerhans cellspecific surface markers by dendritic cells in the corneal and limbal epithelia has been reported.39,40 In view of this evidence, there is a strong presumption that dendritic cells observed in the cornea using laser scanning confocal microscopy are indeed Langerhans cells. In the cornea and conjunctiva, Langerhans cells are about 15 μm in diameter and appear in various forms. Immature Langerhans cells either lack dendrites or have small dendritic processes. Mature Langerhans cells develop long


interdigitating dendrites and can reside alone or form a ‘wire net-like structure’, the latter appearance being especially prevalent in the conjunctiva.33 Cross-sectional studies have found Langerhans cells to be up-regulated in the cornea during contact lens wear.41,42 Zhivov and colleagues42 reported that Langerhans cells could be observed in the cornea of 59 per cent of contact lens wearers and 33 per cent on non-lens wearing controls. In those with Langerhans cells, their density in the central cornea was found to be 78 cells/mm2 in contact lens wearers versus 34 cells/mm2 in non-lens wearing control subjects. Sindt and colleagues41 observed that Langerhans cell density, when compared to non-lens wearing controls (29 23 cells/ mm2), was significantly higher in both hydrogel contact lens wearers (47 44 cells/mm2, p < 0.01) and silicone hydrogel lens wearers (69 77 cells/ mm2, p < 0.01). Together with colleagues at Queensland University of Technology,43 I recently had the opportunity to extend these studies by observing changes in Langerhans cell density in the cornea and bulbar conjunctiva over time in symptomatic and asymptomatic participants who had not previously worn lenses. Twenty-five participants with contact lens-induced dry eye (CLIDE) and 35 without CLIDE (NO-CLIDE), diagnosed

using a range of symptom questionnaires and objective tests (tear film break-up, cotton thread tear test and corneal staining) were enrolled. The central cornea and nasal bulbar conjunctiva were examined using a Heidelberg laser scanning confocal microscope at baseline and following one, four and 24 weeks wear of daily disposable hydrogel contact lenses. Twenty-three noncontact lens-wearing controls were also examined over the same period. Langerhans cell density was determined manually from randomly selected images (Figure 11). In the cornea, mean and standard error of the Langerhans cell density was greater after one week of lens wear in CLIDE (55 7 cells/mm2) versus NO-CLIDE (43 4 cells/mm2) (p = 0.041) and controls (27 4 cells/mm2) (p < 0.001). Langerhans cell density was also greater in NOCLIDE versus controls (p = 0.010). At week four, Langerhans cell density was greater in CLIDE (41 6 cells/mm2) versus controls (27 4 cells/mm2) (p = 0.004). There were no other significant differences between groups at weeks four or 24 (Figure 12). In the conjunctiva, Langerhans cell density was greater after one week of lens wear in CLIDE (17 1 cells/mm2) (p = 0.003) and NO-CLIDE (17 3 cells/ mm2) (p = 0.001) versus controls (7 1 cells/mm2). There were no significant differences between groups at weeks four or 24.43

Figure 11. Laser scanning confocal microscopy images of Langerhans cells. (A) Cornea – the thin arrows indicate the vertically oriented nerve fibres traversing the field. Thick arrows indicate Langerhans cells, typically of the immature type with stunted dendrites. This image was captured at a depth of 59 μm from the corneal epithelial surface. (B) Conjunctiva – arrows indicate Langerhans cells, typically of the mature type with long, thin dendrites in ‘X’ or ‘Y’ formations. This image was captured at a depth of 20 μm from the conjunctival epithelial surface. Clinical and Experimental Optometry 2016

9

Langerhans Cell Density (cells/mm2)


Controls

60

NO-CLIDE CLIDE

50 40 30 20 10 0

0

5

10

15

20

25

Time (weeks)

Figure 12. Langerhans cell density in the cornea of patients with contact lens-induced dry eye (CLIDE) and those without CLIDE (NO-CLIDE) and control participants, over 24 weeks. Error bars indicate mean standard error. After Alzahrani and colleagues.43 My colleagues and I had observed Langerhans cells in the bulbar conjunctiva previously44 but were unable to differentiate Langerhans cell density between those who had been wearing contact lenses for 10 years versus non-lens wearers. That observation is not inconsistent with the findings of our longitudinal study,43 which noted an increase in conjunctival Langerhans cell density after one week of lens wear but no difference after one month of wear. The generally higher values of Langerhans cell density reported by Zhivov and colleagues42 compared with our study43 could be attributed to the assessment of all eyes in our analysis, including those with zero Langerhans cell density. The values of Langerhans cell density reported by Sindt and colleagues41 are generally commensurate with those reported in our study.43 Our observation43 of an initial transient increase in corneal and conjunctival Langerhans cell density in asymptomatic subjects, compared with non-lens-wearing controls, is consistent with the notion that uncomplicated contact lens wear is inflammatory, at least during the first few weeks or months of lens wear. The apparent dampening of this response over time suggests a possible adaptive mechanism, whereby the inflammatory status of the anterior eye is down-regulated as the initial physiological challenge imposed by the insertion of a lens into the eye subsides.


10

Biochemical reactions Tears contain a variety of inflammatory mediators, including histamine,45 46 complement, arachidonic acid metabolites (for example, leukotriene B4 and prostaglandin E2),47 substance P,48 cytokines, such as interferon-c, interleukin-1a, interleukin-1b, interleukin-4, interleukin-6, interleukin-8, interleukin-10 and interleukin-12 and tumour necrosis factor alpha,49–51 leukotriene B4,52 matrix metalloproteinase-953 and epidermal growth factor.54 Up-regulation of the mediators described above during contact lens wear can provide a measure of inflammatory status. My colleagues and I examined subjects who had worn contact lenses on an extended wear basis for one month.55 Eleven subjects wore silicone hydrogel contact lenses and 11 wore high oxygen transmissibility rigid contact lenses. We also examined 11 nonlens-wearing controls. Tear samples were assayed for epidermal growth factor and interleukin-8. We observed statistically significant differences between the samples collected from the three groups for epidermal growth factor (F = 5.8, p = 0.007) and interleukin-8 (F = 4.9, p = 0.015). Post hoc analysis confirmed that epidermal growth factor was significantly greater in the tear samples collected from the silicone hydrogel lens wearers (p = 0.017) and the rigid lens wearers (p = 0.015) compared with those obtained from the control subjects.

Interleukin-8 concentration was significantly higher in the samples collected from the rigid lens wearers compared with those collected from the control subjects (p = 0.012)55 (Figure 13). Our findings confirm previous reports that epidermal growth factor56 and interleukin-851,53 are elevated in uncomplicated contact lens wear. Other inflammatory mediators up-regulated in asymptomatic lens wear include fibronectin,57 secretory immunoglobulin C3 and C4,58 A,58 complements interleukin-6,56,59,60 matrix and tumour metalloproteinase-956,59 necrosis factor alpha.59 Poyraz, Irkec and Mocan60 compared the time course of elevation of interleukin6 and interleukin-8 over a six-month period in 12 participants wearing hydrogel contact lenses and 12 wearing silicone hydrogel lenses. For both of these lens types, both inflammatory markers remained at similar levels to baseline over the first month and then increased steadily over the following five months (Figure 14). HISTORY REPEATING ITSELF Although I may be entitled to lay claim to be one of the first to directly articulate the idea that contact lens wear is intrinsically inflammatory, forensic analysis of the first two publications on contact lenses toward the end of the nineteenth century61,62 might suggest that this thinking, in a more general sense, is not new. In his inaugural dissertation presented to the University of Kiel in Germany in 1887, medical student August Müller (1865 – 1949) (Figure 15) described attempts to correct his own −14.00 D of myopia with ‘cornea lenses’, which were essentially glass scleral lenses.62 This was not a scientific paper published in a learned journal; nevertheless, it is acknowledged as being the first documented account of the correction of myopia with contact lenses. Müller62 was keen to understand how the eye responded to lens wear, so he asked his colleague, Professor Völkers, to examine his eye, while wearing the lenses. Although not referred to directly as such, the five cardinal signs of inflammation were noted, as follows: • rubor: ‘…strong conjunctival, limbal and episcleral injection…’ • calor: ‘…a sensation of…burning appeared…’



A

B 1,000

IL-8 concentration (pg/mL)

EGF concentration (pg/mL)

3,000

2,000

1,000

0

750

500

250

0

Rigid

Control

Si-H

Control

Rigid

Si-H

Group

Group

Figure 13. Epidermal growth factor concentration (A) and interleukin-8 concentration (B) in tear fluid samples collected from subjects wearing high oxygen transmissibility rigid and silicone hydrogel (Si-H) contact lenses and non-contact lens-wearing controls. Shaded box, interquartile range (50 per cent of the values); whiskers, lines that extend from the box to the highest and lowest values; line across the box, median. Epidermal growth factor concentration was significantly greater in the samples collected from the silicone hydrogel lens (p = 0.017) and the rigid lens wearers (p = 0.015) compared with the samples collected from the control subjects. Interleukin-8 concentration was significantly greater in the tears of the rigid lens wearers compared with the tears of the control subjects (p = 0.012). After Kalliniko, Morgan and Efron.55

A

B 600.0

40.0 35.0 30.0 25.0 20.0

SH-CL

15.0

CH-CL

10.0 5.0 0m

1m

3m

6m

Duration of contact lens wear (months)

Tear interleukin-8 level (pg/mL)

Tear interleukin-6 level (pg/mL)

45.0

0.0

• tumor: ‘…the cornea was cloudy with focal illumination…’ • dolor: ‘…upon removal, the violent pain immediately stopped…’ • functio laesa: ‘…the visual acuity decreased to a large extent.’62 Of the five cardinal signs reported by Müller,62 perhaps the weakest evidence is that provided in respect of calor. Müller62 was reporting a subjective burning sensation, which does not necessarily mean that the eye was experiencing an elevation in temperature. As well, Müller62 did not measure eye temperature. Nevertheless, it can be inferred that there was an increase in ocular temperature commensurate with the observed ‘strong conjunctival, limbal and episcleral injection’. The following year, in 1888, Adolf Fick (1852 – 1937) (Figure 15) published the first journal article on contact lenses.61 He described the process of fabricating and fitting scleral contact lenses – first on rabbits, then on himself and finally on a small group of volunteer patients. In the course of his experiments, he observed the following in respect of signs of inflammation: • rubor: ‘…moderate injection.’ (humans) • calor: …no reference to this sign • tumor: ‘…the epithelium of the cornea appears slightly clouded…’ (rabbits) and ‘…any corneal clouding…[will disappear] …in the course of the night’ (rabbits)

500.0 400.0 300.0 SH-CL

200.0

CH-CL

100.0 0.0

0m

1m

3m

6m

Duration of contact lens wear (months)

Figure 14. Changes in ocular tear inflammatory mediator levels (mean standard error) in silicone hydrogel (SH-CL) versus conventional hydrogel contact lens (CH-CL) users over six months. (A) Interleukin-6 – there was no difference between the tear interleukin-6 levels of CH-CL and SH-CL wearers at any time point in the study. A statistically significant increase was observed in tear interleukin-6 levels of both groups over time. (B) Interleukin-8 – there was no difference between the tear interelukin-8 levels of CH-CL and SH-CL wearers at one, three and six months. The baseline tear interleukin-8 levels were significantly different (p = 0.008) between the two lens types. A statistically significant increase was observed in tear interleukin-8 levels of both groups over time. After Poyraz, Irkec and Mocan.60



11


IMPLICATIONS OF LENS-INDUCED INFLAMMATION

Figure 15. Contact lens inventors August Müller (left) and Adolf Fick (right), who both observed cardinal signs of inflammation during contact lens wear. Public domain. • dolor: …‘If symptoms of irritation show themselves, the glass must be removed’ (humans) • functio laesa: the above quotation related to limitation of wearing time, which is a loss of function.62 In the context of observing the cardinal signs of inflammation, neither Müller62 nor Fick61 specifically countenanced the idea that contact lens wear had elicited an inflammatory response. Nevertheless, it is clear from the account provided by Müller,62 in which all five cardinal signs were described, that the contact lens had induced an inflammatory response in his eye. From experiments on rabbits and his own eye, Fick61 described four of the five cardinal signs of inflammation. He made no mention of calor but as in the case of Müller,62 there invariably would have been an increase in ocular temperature as a result of the moderate ‘injection’. Bearing in mind that the classical clinical definition of inflammation discussed earlier stipulates that ‘all or some…are noted in inflamed tissue’,9 then even if it was concluded that there was insufficient evidence of calor, a score of four out of five would still satisfy the definition of inflammation. In what can be construed as advanced thinking at the time, Fick61 attempted to


12

investigate the response of the rabbit eye to contact lens wear by examining the tear film of the rabbits under a light microscope for evidence of a cellular response. Interestingly, Fick61 seemed to dismiss the notion that contact lens wear is inflammatory, noting ‘…in the cornea itself, the well-known inflammatory infiltration with round cells was wholly absent…’. The ocular responses noted by Müller62 and Fick61 represented an overt inflammation as distinct from the subtle inflammatory response to uncomplicated lens wear that is the focus of this paper; nevertheless, it is interesting to observe that the notion of contact lens wear being inflammatory can be traced back almost 130 years to the very first accounts of contact lens wear. Further to my own thoughts on the intrinsically inflammatory basis of contact lens wear – originally published in 1984/51,26 and again in 20122 – others have more recently commented on this issue. Reflecting on their finding of an up-regulation of interleukin-6 and interleukin-8 during contact lens wear, Yuksel Elgin and colleagues63 noted the following: ‘Although contact lens users were asymptomatic, changes in tearfilm levels of several important inflammatory mediators revealed that a chronic inflammatory process occurs during contact lens wear.’

In general parlance, inflammation has a negative connotation, being an entity that is red, hot, swollen and painful and limits function. In a medical context, the extensive tissue destruction that occurs in the process of severe microbial keratitis can only be viewed as a negative occurrence; however, there is a line of thinking that spans back to the first half of the 20th century, suggesting that a sub-clinical or low-grade inflammatory response can be beneficial and perhaps protective. For example, in 1931, Menkin64 published a paper entitled ‘Inflammation: A protective mechanism’. Chronic immune upregulation of the anterior ocular tissues during contact lens wear essentially means that the eye is in a constant state of readiness to suppress any challenge posed by a noxious stimulus, such as an infectious agent, traumatic insult or toxic solution.

Lessons from the Manchester Keratitis Study My own observations stemming from a major study that I directed with Philip Morgan in the mid-2000s – the Manchester Keratitis Study65–67 – seem to support the idea that a sub-clinical inflammatory response can be protective. In this study, all presenting patients who habitually wore contact lenses completed a patient survey questionnaire, which gathered information about whether they slept in lenses (wearing modality), the type of lenses they wore (rigid, hydrogel daily disposable, all other hydrogels or silicone hydrogels) and other personal, health and lifestyle factors. If a corneal infiltrative event was noted on ocular examination, the attending clinician completed a survey form that detailed clinical information relevant to this study and the severity of the event was assessed using a ‘clinical severity matrix’. A total of 118 corneal infiltrative events were observed during the survey period.67 Logistic regression analyses were performed to investigate the association between a range of risk factors and the occurrence of corneal infiltrative events.66 Of particular interest in the context of this paper was the finding that lens wearers have approximately a two times lower risk of developing a corneal infiltrative event in



Non severe keratitis

Severe keratitis

Other problems

Reports of flu 50

45

40 80% 35

30 60% 25

20

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Consultations for influenza-like illness to the NHS Helpline per 100,000 persons in England aged 15 - 64

Proportion of contact lens patients attending hospital

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Feb

Mar

Apr

May

Jun

Jul

Aug

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Figure 16. Proportion of contact lens-wearing patients attending the acute service of the Royal Eye Hospital, Manchester, over a 12-month period, with severe keratitis, non-severe keratitis and other problems. Also shown is the number of consultations for influenza-like illness to the telephone Helpline of the UK National Health Service (NHS) per 100,000 persons in England aged 15 to 64 years, over the same period. The peak in telephone consultations for influenza corresponded to a drop in the proportion of patients seen with keratitis. After Morgan and colleagues.66

the presence of compromised ocular and general health. At first glance, this finding would appear to be counter-intuitive; it might be expected that a contact lens wearer who is ill has a transiently compromised immune system commensurate with the debilitated state, which in turn could compromise the ability of the eye to ward off any noxious challenge, resulting in a greater risk of an adverse ocular reaction to contact lenses and an exacerbated reaction should one occur. Furthermore, this finding of the Manchester Keratitis Study directly contradicts the findings of other studies that contact lens-related microbial keratitis is associated with self-reported poor health.68 Nevertheless, the ‘protective’ effect of compromised ocular health in lowering the risk of contact lens-associated corneal infiltrative events may be explained in a number of ways. For example, a contact


lens wearer who is feeling ill, might adopt a precautionary attitude; if also suffering from an eye problem, such a person might cease lens wear, reduce wearing time or use self-prescribed systemic or topical ocular medications in an attempt to alleviate the condition. Such strategies might have the secondary effect of precluding the development of a corneal infiltrative event. An alternative but equally compelling explanation is that compromised ocular health may be associated with a general upregulation of the innate defensive status of the eye, so that there is an ever-present resistance to extraneous challenges to the ocular surface, which could result in a corneal infiltrative event. These principles can be extended to explain why compromised general health also serves to protect the eye from developing a corneal infiltrative event.

The notion that adverse ocular conditions related to contact lens wear can be influenced by the time of year (‘seasonal effect’) is well established; for example, Begley, Riggle and Tuel69 reported that the onset of contact lens-associated papillary conjunctivitis was seasonal, in that the incidence of this condition peaked during the ‘allergy seasons’ in mid-western USA. It may be supposed that, in the Manchester Keratitis Study, the incidence of corneal infiltrative events was related to such seasonal variations in ocular or general health. In that study, a two to four times increased risk of developing corneal infiltrative events was noted in late winter (January to March in the northern hemisphere) compared with the risk in mid-summer (July in the northern hemisphere).66 We accessed the number of consultations for influenza-like illness to the United Kingdom National Health Service helpline70 by people aged


13


15 to 64 years in England during the same period as the Manchester Keratitis Study and found that this number peaked around October and November 2003, which is in discordance with the peak incidence of corneal infiltrative events in our study from January to March 200366 (Figure 16). Interestingly, this observation is consistent with the finding described above of a lower incidence of corneal infiltrative events in association with compromised general health.66

Para-inflammation Medzhitov71 introduced the concept of ‘para-inflammation’ to reinforce the notion that inflammation can have an important adaptive and protective function. He begins by proposing a severity spectrum comprised of three modes of adaptation and maintenance of tissues: homeostasis, para-inflammation and inflammation. Medzhitov71 proposes that cell states are discrete rather than graded and that

transitions between these states occur in an all-or-none manner. By contrast, tissue states are graded: tissues can contain different numbers of dead cells, for example, or they can malfunction to different degrees. Accordingly, the adaptive response elicited by tissues can take different forms depending on the degree of the problem that is experienced. Thus, in basal conditions (the least severe end of the spectrum), tissues are maintained in a homeostatic state, in many cases with the help of tissue-resident macrophages and in some instances by various types of leukocytes. In noxious conditions (the most severe end of the spectrum), tissues undergo stress and can malfunction. If the changes are considerable, then adaptation to the conditions requires the help of tissue-resident or recruited macrophages and might require small-scale delivery of additional leukocytes and plasma proteins, depending on the extent of the problem. This extreme response is termed ‘inflammation’, which follows infection or tissue damage.

Medzhitov71 proposes an adaptive response that has characteristics that are intermediate between basal and inflammatory states, which he refers to as para-inflammation (Figure 17). Para-inflammatory responses are graded: at one extreme, they are close to the basal state, whereas at the other, they start to transition into inflammation. The induction of a para-inflammatory response does not require overt tissue injury or infection, instead, it is switched on by tissue malfunction to restore tissue functionality and homeostasis. If tissue malfunction is present for a sustained period, parainflammation can become chronic. According to this model, contact lens wear probably results in the eye residing in a state of para-inflammation that is close to the basal state, whereby the subtle tissue perturbances caused by the contact lenses result in a sub-clinical tissue reaction to restore functionality and homeostasis in the affected ocular tissues. Medzhitov71 also suggests that sustained malfunction can result from environmental factors. He proposes that many chronic inflammatory diseases that are not caused by infection or injury seem to be associated with conditions that were not present during the early evolution of humans, including the continuous availability of highcalorie nutrients, a low level of physical activity, exposure to toxic compounds and old age. The wearing of contact lenses could be added to this list.

Novel management strategies

Figure 17. Three modes of adaptation and maintenance of tissue homeostasis. The state of a tissue can range from basal, to stressed or malfunctioning, to damaged or infected and each state is graded (as indicated by shading). The state affects the mode of maintenance of tissue homeostasis or adaptive response that is engaged by tissueresident macrophages and, in some tissues, by various types of leukocytes. Blue arrows indicate signals that report the tissue state to macrophages; red arrows indicate macrophage-derived signals that control tissue adaptation. At one extreme of the range of responses is inflammation, which follows infection or tissue damage. By contrast, tissue stress or malfunction induces para-inflammation, which helps a tissue to adapt to the noxious conditions and restore tissue functionality. After Medzhitov.71


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While the cause of contact lens discomfort is likely to be multifactorial,72 inflammation is a likely candidate. For example, Masoudi and colleagues73 have recently demonstrated that the inflammatory mediator leukotriene B4 increases in concentration during the day and during the wearing of lenses that progressively become less comfortable. Therefore, modulation of the intrinsic inflammatory response to contact lens wear is one possible strategy for enhancing contact lens comfort. At a fundamental level, such approaches are already in place, albeit inadvertently. Some contact lens materials, most notably etafilcon A, have a propensity for attracting proteins, in particular lysozyme.74 As long as this lysozyme can remain on the lens surface in an active form, it can serve as a potent anti-bacterial and anti-inflammatory



Characteristic

Meaning

Evidence

Confirmation of inflammation Hydrogel Silicone hydrogel

Clinical markers (classical) Rubor

Redness

Limbal and conjunctival hyperaemia

Yes

No

Calor

Heat

Limbal and conjunctival warming

Yes

No

Tumor

Swelling

Corneal oedema

Yes

No

Dolor

Pain

End of day discomfort

Yes

Yes

Functio laesa

Loss of function

Discontinuation from lens wear

Yes

Yes

Sub-clinical markers (contemporary) Cellular reactions

–

Increase in Langerhans cell density

Yes

Yes

Biochemical reactions

–

Up-regulation of inflammatory mediators

Yes

Yes

Table 1. Summary of evidence of inflammation during uncomplicated contact lens wear ‘shield’.74 Protein deposition was considered to be a problem in the early days of contact lenses75 but realisation of the potential benefits of non-denatured lysozyme deposition on lenses has directed efforts to promote this form of deposition.76 Such a strategy could lead to a lower risk of inflammation and greater lens comfort. An alternative strategy, at least in theory, might be to modulate the sub-clinical inflammatory response by incorporating non-steroidal anti-inflammatory agents into contact lens materials using novel engineering strategies, such as molecular imprinting.77 A slow, even release of low doses of such drugs over a 10- to 15-hour period from daily disposable lenses would ensure a constant release into the eye while such lenses are worn;78 however, current generation non-steroidal anti-inflammatory agents can result in delayed corneal wound healing and stromal ulceration and as such, are at present not encouraged in contact lens wearers. Accordingly, long-term ophthalmic use of non-steroidal antiinflammatory agents is generally discouraged. Such a strategy may have to wait until such drugs are developed that are safe for long-term ocular use. Both omega-3 fatty acids79 and omega-6 fatty acids80 have known anti-inflammatory properties81 and have been demonstrated to alleviate symptoms of discomfort and dryness associated with contact lens wear over a six-month period. Kokke, Morris and Lawrenson80 suggested that these supplements might be useful as a therapeutic adjunct for contact lens dry eye. For example, long-chain omega-3 fatty acids are found in high concentration in fish oil.


Dietary supplementation with omega-3 fatty acids may alleviate symptoms of discomfort during lens wear.

CONCLUSIONS By drawing upon research I have conducted with colleagues throughout my career in the contact lens field, supported by other published research, I have been able to provide evidence to support the notion that contact lens wear is intrinsically inflammatory in nature. Specifically, I have demonstrated that all eight requisites of inflammation – the stimulating agent (contact lens), the five clinical cardinal signs (rubor, calor, tumor, dolor and functio laesa) and the two subclinical markers (cellular and biochemical up-regulation) – are evident during normal, uncomplicated lens wear. The extent to which the above conclusion applies to all contact lens types is open to question. With respect to clinical markers, hydrogel contact lenses meet all five requisites outlined in the definition of inflammation. The situation is less clear with silicone hydrogel lenses, which induce very little, if any, limbal or conjunctival redness (rubor).11 This means there will also be no increase in temperature (calor). Furthermore, silicone hydrogel lenses do not induce any corneal swelling (tumor) during open-eye, daily lens wear;24 however, like hydrogel lenses, silicone hydrogel lenses can become uncomfortable toward the end of the day (dolor)29 and a significant proportion of people wearing this lens type discontinue from lens wear (functio laesa) due to problems of discomfort.10

With respect to sub-clinical markers, Langerhans cell density is elevated41 and inflammatory mediators are up-regulated60 in wearers of both hydrogel and silicone hydrogel lenses. Taking clinical signs and sub-clinical markers together, hydrogels meet all seven requisites according to the definition of inflammation, whereas silicone hydrogels meet only four out of the seven criteria. However, given that the clinical element of the definition of inflammation stipulates that all or some of the signs are present in inflamed tissue9 and considering that both cellular and biochemical changes accompany silicone hydrogel lens wear (meeting the sub-clinical definition), it is concluded that silicone hydrogel lens wear is also intrinsically inflammatory. This analysis is summarised in Table 1. The state of chronic low-grade inflammation accompanying contact lens wear, which may be termed para-inflammation, serves an important protective function and ought to be viewed as a positive attribute. With the anterior ocular tissues in a constant up-regulated immune status during lens wear, any noxious stimulus that may be present, such as virulent microorganisms or toxic contact lens solutions, can be dealt with more rapidly compared with an eye in which the immune system is dormant. Evidence for this notion comes from the Manchester Keratitis Study,65–67 which found that contact lens wearers have approximately a two times lower risk of developing a corneal infiltrative event in the presence of compromised ocular and general health. The development of a more comprehensive understanding of the intrinsically


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inflammatory nature of the eye during contact lens wear may reveal strategies that can be applied to alleviate some of the associated disbenefits, such as discomfort. Such strategies might involve promoting absorption of non-denatured protein into the lens matrix, molecular imprinting of antiinflammatory agents into daily disposable lenses for slow release back into the eye and dietary supplementation with omega-3 and omega-6 fatty acids. ACKNOWLEDGEMENTS

I wish to acknowledge and thank a number of mentors and colleagues who have been of great assistance during my career. Barry Cole and Leo Carney have been magnificent ‘career mentors’. I have published works with a total of 385 co-authors and I thank all of these colleagues. It is obviously not possible to acknowledge them all; however, I do wish to single out a few who have been with me for the long haul. I have had the good fortune and very great pleasure to have worked with Noel Brennan since 1984, Phil Morgan since 1990, Rayaz Malik since 2000 and Nicola Pritchard since 2006. I thank the four of you for enriching my life in research. Suzi Fleiszig and I have enjoyed mentoring each other (if that is possible) for over 30 years. Thanks Suzi for your unfailing friendship. On a personal level, I thank my wife, Suzanne and children, Zoe and Bruce, for their wonderful support, encouragement, love and devotion. I also thank my mother, Elaine and late father Jack, who sacrificed much to provide me with my early educational opportunities. REFRENCES 1. Efron N. Is contact lens induced corneal oedema inflammatory? Aust J Optom 1985; 68: 167–172. 2. Efron N. Is contact lens wear inflammatory? Br J Ophthalmol 2012; 96: 1447–1448. 3. Papas E, Tilia D, McNally J et al. Ocular discomfort responses after short periods of contact lens wear. Optom Vis Sci 2015; 92: 665–670. 4. Efron N. Papillary conjunctivitis. In: Efron N, ed. Contact Lens Complications, 3rd edn. Edinburgh: Elsevier, 2012. p 122–132. 5. Efron N. Superior Limbic keratoconjunctivitis. In: Efron N, ed. Contact Lens Complications, 3rd edn. Edinburgh: Elsevier, 2012. p 146–154. 6. Efron N. Microbial keratitis. In: Efron N, ed. Contact Lens Complications, 3rd edn. Edinburgh: Elsevier, 2012. p 245–258. 7. Efron N. Corneal infiltrative events. In: Efron N, ed. Contact Lens Complications, 3rd edn. Edinburgh: Elsevier, 2012. p 225–244. 8. Granger DN, Senchenkova E. Inflammation and the Microcirculation. San Rafael, CA: Morgan & Claypool Life Sciences, 2010.


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Infection with contact lens wear.

Biochmical aspects of contact lens wear.

Tear calcium levels and contact lens wear.

Keratoconus keratoplasty curvatures and contact lens wear.

Tear plasmin activity with contact lens wear.

Meibomian therapy in problematic contact lens wear.

Lid Margin Sensitivity and Staining in Contact Lens Wear Versus No Lens Wear.

Risk factors for contact lens-induced papillary conjunctivitis associated with silicone hydrogel contact lens wear.

Polymicrobial Infection of the Cornea Due to Contact Lens Wear.

The microbial flora in extended-wear soft contact-lens wearers.

Perspectives on the future of contact lens wear: summary.

Corneal epithelial alterations induced by disposable contact lens wear.

Ocular discomfort responses after short periods of contact lens wear.

Corneal Biomechanical Changes Following Toric Soft Contact Lens Wear.

Clinical manifestations secondary to soft contact lens wear.

Blepharoptosis induced by prolonged hard contact lens wear.

Acute eye disease secondary to contact-lens wear.

Some clinically observed phenomena in extended contact lens wear.

Corneal endothelial irregularity with long-term contact lens wear.

The significance of oxygen during contact lens wear.

Reducing dropout of contact lens wear with Biotrue multipurpose solution.

Development of keratoconus after contact lens wear. Patient characteristics.

Nonulcerative complications of contact lens wear. Relative risks for different lens types.

Improved Vision and Contact Lens Wear Time With Piggy-Back Contact Lens Systems in Children After Penetrating Corneal Trauma.