learning objectives: 1. understand the incidence of ... contact lenses and corneal infiltrates...

Contact Lenses and Corneal35102-CL - Infiltrates: From Tissue to Treatment

Format: Live Category: Contact Lenses Total CE Hours: 1

Description: Contact lens associated corneal inflammatory events (CIEs) are discussed with incidence rates for extended wear provided. Clinical etiologies are presented which challenge the traditional \"sterile\" keratitis approach. Risk factors and innate immune response leading to these CIEs will be covered, and based on the risk factors, treatment and prevention will be provided.

CEE: No Expires: Course Expires: 07/12/2015

Instructor: Loretta Szczotka-Flynn O.D. Co-instructors: Adjunct/Assistant Instructors: Learning Objectives: 1. Understand the incidence of contact lens induced corneal infiltrates 2. Understand risk factors for contact lens corneal infiltrates 3. Understand the pathophysiology of lens bioburden on corneal infiltrates

http://www.arbo.org/index.php?action=getinstructorinfo&id=519026

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Contact Lens Related Corneal Contact Lens Related Corneal Infiltrates: From Tissue to Infiltrates: From Tissue to

TreatmentTreatment

LORETTA SZCZOTKALORETTA SZCZOTKA--FLYNN OD, PhD, FLYNN OD, PhD, FAAO(FAAO(dipldipl CLCL))

Professor Professor Case Western Reserve UniversityCase Western Reserve University

Department of Ophthalmology & Visual SciencesDepartment of Ophthalmology & Visual SciencesUniversity Hospitals Eye InstituteUniversity Hospitals Eye Institute

Recent Disclosures: Vistakon, Alcon, Bausch & Lomb

The Epidemiological PerspectiveThe Epidemiological Perspective

*cartoons taken from Epidemiology 3rd Edition by Leon Gordis

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Annualized incidence of MK in the Annualized incidence of MK in the prepre--silicone silicone hydrogelhydrogel eraera

Not availableNot available2.7 (1.62.7 (1.6--3.7)3.7)ConventionalConventionalandandDisposableDisposableLow Low DkDk

19991999West ofWest ofScotlandScotland

20.0 (10.320.0 (10.3--35.0)35.0)3.5 (2.73.5 (2.7--4.5)4.5)ConventionalConventionalandand

DisposableDisposableLow Low DkDk

19991999HollandHolland

20.9 (95% CI 15.120.9 (95% CI 15.1--26.7)26.7)4.1 (95 % CI 2.94.1 (95 % CI 2.9--5.2)5.2)ConventionalConventionalLow Low DkDk

19891989NewNewEnglandEngland

Annualized Incidence per Annualized Incidence per 10,000 wearers 10,000 wearers

Extended soft contact lens Extended soft contact lens wearerswearers

Annualized Incidence per Annualized Incidence per 10,000 wearers 10,000 wearers

Daily soft contact lens wearersDaily soft contact lens wearers

Lens TypeLens TypeYearYearStudyStudyLocationLocation

1 in 2500 1 in 500

Annualized incidence of MK in the Annualized incidence of MK in the Silicone Silicone HydrogelHydrogel eraera

Schein et al 2005 Schein et al 2005 OphthalmologyOphthalmology–– 18 per 10,000 18 per 10,000

–– lotrafilconlotrafilcon A 30 day continuous wearA 30 day continuous wear

Stapleton et al 2008Stapleton et al 2008 OphthalmologyOphthalmology–– 11.9 per 10,000 SH daily wear11.9 per 10,000 SH daily wear

–– 25.4 per 10,000 SH extended wear25.4 per 10,000 SH extended wear

Dart Case Control StudyDart Case Control Study

<0.001<0.0010.160.16RGPRGP

0.0090.0091.561.56Daily DisposableDaily Disposable

0.6980.6980.870.87Other softOther soft

0.5250.5251.161.16SiSi--HyHy

Planned REFERENTPlanned REFERENT

Replacement SoftReplacement Soft

P valueP valueRelative RiskRelative RiskRisk Factor Risk Factor

3


<0.001<0.0010.160.16RGPRGP



0.5250.5251.161.16SiSi--HyHy





<0.001<0.0010.160.16RGPRGP



0.5250.5251.161.16SiSi--HyHy





<0.001<0.0010.160.16RGPRGP



0.5250.5251.161.16SiSi--HyHy




4


<0.001<0.0010.160.16RGPRGP



0.5250.5251.161.16SiSi--HyHy




Defining InfiltratesDefining Infiltrates

By EtiologyBy Etiology–– Sweeney et al Sweeney et al –– Infectious (microbial keratitis)Infectious (microbial keratitis)–– NonNon--InfectiousInfectious

CLARECLARECLPUCLPUIKIKAIKAIKAIAI

CONTACT LENS ACUTE CONTACT LENS ACUTE RED EYE (CLARE)RED EYE (CLARE)

Inflammatory reaction of the cornea after Inflammatory reaction of the cornea after overnight wearovernight wearGeneralized redness and pain upon awakeningGeneralized redness and pain upon awakeningUsually unilateralUsually unilateralNo corneal stain overlying infiltratesNo corneal stain overlying infiltratesHas been associated with high levels of Gram Has been associated with high levels of Gram negative bacteria on lensnegative bacteria on lens–– Pseudomonas Pseudomonas aeruginosaaeruginosa–– SerratiaSerratia marcescensmarcescens–– Haemophilus Haemophilus influenzaeinfluenzae

Has also been associated with Gram +Has also been associated with Gram +Streptococcus Streptococcus pneumoniaepneumoniae

5

CLARE

CONTACT LENS CONTACT LENS PERIPHERAL ULCER (CLPU)PERIPHERAL ULCER (CLPU)

Acute inflammatory reaction with PMN Acute inflammatory reaction with PMN infiltrationinfiltrationBiopsies can be sterile or levels Gm +Biopsies can be sterile or levels Gm +Usually located in corneal peripheryUsually located in corneal peripheryMay be asymmptomaticMay be asymmptomaticAlways scarAlways scarUsually adherence of Gram + organisms Usually adherence of Gram + organisms on lenson lens–– Associated with S. Associated with S. aureusaureus bacteriabacteria

6

CLPU CLPU

One active

7

Infiltrative Infiltrative keratitiskeratitis (IK)(IK)Diffuse corneal infiltrationDiffuse corneal infiltration

Associated with Associated with –– Pseudomonas Pseudomonas aeruginosaaeruginosa

–– SerratiaSerratia marcescensmarcescens

–– Haemophilus Haemophilus influenzaeinfluenzaeOften from Often from nasopharynxnasopharynx

Defining InfiltratesDefining Infiltratesas a continuum of disease severityas a continuum of disease severity

EfronEfron & Morgan (2005)& Morgan (2005)–– 10 signs & symptoms (ex. 10 signs & symptoms (ex.

redness, infiltrate size and redness, infiltrate size and shape, haze, discomfort, shape, haze, discomfort, etc.)etc.)

–– Score range 2Score range 2--2222Adapted version 25 maxAdapted version 25 max

–– if > 8: Severe keratitis (MK) if > 8: Severe keratitis (MK)

Schein et al (2005)Schein et al (2005)–– Levels 1 & 2Levels 1 & 2

Probably MKProbably MK

–– Levels 3Levels 3--44Infiltrative keratitisInfiltrative keratitis

–– Level 5Level 5Infiltrates not CL relatedInfiltrates not CL related

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Parameter 0 1 2 3 Point

Total

Symptoms None Mild Moderate Severe

Lid Swelling Absent Present

Conjunctival

Redness

Absent Localized Generalized

Infiltrate Shape Round Irregular

Infiltrate Size

(largest)

<=1.0mm 1.0-2.0mm >=2.0mm

Number of infiltrates 1-4 5-10 >10

Flourescein Staining Absent Present

Surrounding Cornea Clear Slight

haze

Severe haze

Endothelial Debris Absent Present

Hypopyon Absent Present

Effect of Lens

Discontinuation

Resolving No

change

Slight

worsening

Significant

worsening

TOTAL

Risk (Incidence) of CIE Risk (Incidence) of CIE ((““significant CIEsignificant CIE””))

33--4%4%0.6%0.6%Silicone Silicone HydrogelHydrogel

11--2%2%0.14%0.14%Low Low DkDk

Extended WearExtended Wear(eyes)(eyes)

Daily WearDaily Wear(persons)(persons)

Significant CIESignificant CIE

5.8%5.8%SenofilconSenofilcon AAUS FDA SummaryUS FDA Summary20052005

3.3%3.3%LotrafilconLotrafilcon AAUS FDA SummaryUS FDA Summary20012001

2.9%2.9%BalafilconBalafilcon AAUS FDA SummaryUS FDA Summary20012001

1%1%Various SHVarious SHMorgan, Morgan, EfronEfronBJO 2005BJO 2005

2.5%2.5%(2.4% excluding MK)(2.4% excluding MK)

LotrafilconLotrafilcon AAChalmers, McNally, Chalmers, McNally, Schein Schein OVS 2007OVS 2007

Incidence Incidence (percent)(percent)

Lens Lens StudyStudyThese are all SERIOUS and SIGNIFICANT INFILTRATIVE EVENTS OR THOSE THAT PRESENTED TO A HOSPITAL OR CLINICIAN FOR TREATMENT

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““Asymptomatic InfiltratesAsymptomatic Infiltrates””

Does Definition Matter?Does Definition Matter?

Should we worry about asymptomatic or less Should we worry about asymptomatic or less severe infiltrates?severe infiltrates?–– Are low grade contact lens associated infiltrates Are low grade contact lens associated infiltrates

different from those seen in spectacle wearers?different from those seen in spectacle wearers?–– Are mechanisms different compared to significant Are mechanisms different compared to significant

infiltrates?infiltrates?–– Is the upIs the up--regulation of the host defense system regulation of the host defense system

something we should ignore?something we should ignore?–– Can asymptomatic infiltrates turn symptomatic if not Can asymptomatic infiltrates turn symptomatic if not

treated?treated?

Risk (Incidence) of CIE (all Risk (Incidence) of CIE (all grades)grades)

14%14%33--6%6%Silicone Silicone HydrogelHydrogel

7%7%NANALow Low DkDk

Extended WearExtended Wear(eyes)(eyes)

Daily WearDaily Wear(persons)(persons)

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WHATWHAT’’S THE RELATIVE RISK?S THE RELATIVE RISK?

WHATWHAT’’S THE RELATIVE RISK?S THE RELATIVE RISK?The Silicone The Silicone HydrogelHydrogel EffectEffect

Meta Analysis: Key, randomized studies driving the effect

2.18 (1.52, 3.13)*Vistakon US FDA

2.18 (0.31, 15.27)Fonn et al

1.90 (1.36, 2.65)*Ciba US FDA

2.18 (1.08, 4.42)*Brennan et al

2.16 (1.24, 3.76)*Bausch & Lomb US FDA

2.18 (1.48, 3.19)**Overall

Risk Ratio for SH

*significant at p<0.05**significant at p<0.005

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ConfoundingConfounding

Almost all SH studies used SH lenses Almost all SH studies used SH lenses worn for 30 days CWworn for 30 days CW

Almost all low Almost all low DkDk studies used lenses studies used lenses worn for 7 days EWworn for 7 days EW

Lens material

Length of wear

CIE

Other studies documenting a silicone Other studies documenting a silicone hydrogelhydrogel effect during DW or EWeffect during DW or EW

Radford et al UK Case Control Study Radford et al UK Case Control Study 20092009–– 877 Cases with non877 Cases with non--ulcerative complicationsulcerative complications–– 1069 hospital and 639 population controls1069 hospital and 639 population controls–– SiSi--HyHy increased risk for sterile increased risk for sterile keratitiskeratitis

INDEPENDENT FROM MODE OF WEARINDEPENDENT FROM MODE OF WEAR2.0 X2.0 X

–– SiSi--HyHy also associated with also associated with Mechanical disordersMechanical disorders

–– 1.8X1.8X

Attendance with any nonAttendance with any non--ulcerative complicationulcerative complication–– 1.9X1.9X

Other studies documenting a silicone Other studies documenting a silicone hydrogelhydrogel effect on effect on CIEsCIEs

Chalmers et al OVS 2010Chalmers et al OVS 2010–– 1276 soft lens wearers, retrospective chart 1276 soft lens wearers, retrospective chart

reviewreview

–– Silicone Silicone hydrogelhydrogel lenses increased risk of lenses increased risk of inflammatory eventsinflammatory events

HydrogelHydrogel lenses were protective (0.77 RR)lenses were protective (0.77 RR)

Controlled for mode of wearControlled for mode of wear

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Chalmers et al IOVS 2011Chalmers et al IOVS 2011–– CLAY StudyCLAY Study

–– 3549 soft lens wearers, retrospective chart 3549 soft lens wearers, retrospective chart reviewreview

187 187 CIEsCIEs in 168 patientsin 168 patients

–– Silicone Silicone hydrogelhydrogel lenses increased risk of lenses increased risk of inflammatory eventsinflammatory events

1.85X1.85X

Controlled for mode of wear Controlled for mode of wear


Chalmers et al OVS 2012Chalmers et al OVS 2012–– Case Control StudyCase Control Study

–– 166 patients with symptomatic 166 patients with symptomatic CIEsCIEs

–– Silicone Silicone hydrogelhydrogel increased risk of CIEincreased risk of CIE1.99X1.99X

Daily Wear Daily Wear –– Extended wear did not find SH to increase riskExtended wear did not find SH to increase risk

Morgan & Morgan & EfronEfron StudyStudyAnnualized Incidence of CIE per 10,000 Annualized Incidence of CIE per 10,000

wearerswearers

3.1 (ns)3.1 (ns)7.07.019.819.898.898.8SHSH

15.215.23.4 (ns)3.4 (ns)96.496.448.248.2HydrogelHydrogel

NaNaNaNa0000RGPRGP

EWEW

NaNa4.04.00055.955.9SHSH

1.01.01.01.06.46.414.114.1HydrogelHydrogel

0.80.80.70.74.94.99.19.1DDDD

0.50.50.40.42.92.95.75.7RGPRGP

RR RR SevereSevere

RR NonRR Non--severesevere

SevereSevereNonNon--severesevere

DWDW

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Oxygen Oxygen TransmissionTransmission

1. Epithelial permeability- Lin, Polse, et al

4. Corneal edema- Fonn et al and others

3. Microcysts- Sweeney and others

Absence of chronic tissue changesWITH IMPROVED OXYGEN PERFORMANCE

Absence of chronic tissue changesWITH IMPROVED OXYGEN PERFORMANCE

7. Endothelial polymegathism- Tighe etal Guillon et al

6. Myopic shift- Dumbleton et al

5. Limbal injection- Papas and others

2. Bacterial adherence- Ren, Cavanagh et al

What about Daily Disposables What about Daily Disposables Effect on Effect on CIEsCIEs

Radford 2009Radford 2009–– Overall increased risk of CIE for DDOverall increased risk of CIE for DD

Attributed to one lens typeAttributed to one lens type

Chalmers OVS 2010 and IOVS 2011Chalmers OVS 2010 and IOVS 2011–– Daily disposables had no effect in CIE riskDaily disposables had no effect in CIE risk

They did not reduce the risk either!They did not reduce the risk either!

Chalmers OVS 2012Chalmers OVS 2012–– 4X protective effect for CIE across modes of wear4X protective effect for CIE across modes of wear

–– 12X protective effect for CIE during DW only12X protective effect for CIE during DW only

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What about SH and solution What about SH and solution hypersensitivity?hypersensitivity?

Is it on the rise?Is it on the rise?

Are certain solutions/lenses associated?Are certain solutions/lenses associated?

What good studies are there?What good studies are there?–– Chalmers et al OVS 2012Chalmers et al OVS 2012

81 multiple CIEsinclude: 2 MK, 2 CLPU, 45 IK, 9 CLARE, 13 solution hypersensitivity, 3 viral, 7 AIK

Significant Multivariate Risk FactorsSignificant Multivariate Risk Factors

>45 Combinations of CL & LCPsReflects previously established factors:SiHy, Extended Wear, Lens Reuse, Age

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205 patients in 205 patients in lotrafilconlotrafilcon A 30 day CW A 30 day CW

Primary outcome: CIE Primary outcome: CIE

Main exposure: Main exposure: –– Corneal stainingCorneal staining

Other key/interacting variable: Other key/interacting variable: –– Bacterial contamination of study lensesBacterial contamination of study lenses

–– Indirect assessment of Indirect assessment of mucinmucin layer/layer/mucinmucin balls balls

The Longitudinal Analysis of Silicone The Longitudinal Analysis of Silicone HydrogelHydrogel (LASH) Contact Lens (LASH) Contact Lens

StudyStudy

CONCEPTUAL MODEL FOR CIECONCEPTUAL MODEL FOR CIE

Microbial contamination

+Presence of

Ocular surface Disruption

(staining or disrupted mucins)

CIE

16

Exam Times & ProceduresExam Times & Procedures

128411 week0

CULTURES

SLIT LAMP EXAM, STAINING & CIE

Schirmer

Unadjusted cumulative probability of remaining CIE free in the LASH Study over 1 year of follow-up

Sur

viva

l Dis

trib

utio

n F

unct

ion

0.00

0.25

0.50

0.75

1.00

Days

0 100 200 300 400 500

Legend: Product-Limit Estimate Curve Censored Observations

38 subjects experienced at least one CIE

KM unadjusted cumulative incidence of survival = 73.3% (95% CI 65.0%-79.9%)

KM unadjusted cumulative incidence of CIE = 26.7% (95% CI 20.1%-35.0%)

Unadjusted cumulative probability of remaining CIE free stratified by presence or absence of substantial bioburden on

study lenses

Sur

viva

l Dis

trib

utio

n F

unct

ion

0.00

0.25

0.50

0.75

1.00

Days

0 100 200 300 400 500

STRATA: SubstantialBioburden=0 Censored SubstantialBioburden=0

SubstantialBioburden=1 Censored SubstantialBioburden=1

Univariate Hazard Ratio through 12 months

4.41 (95% CI 2.21-8.79)

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Percentage of subjects with culture positive Percentage of subjects with culture positive lenses stratified by visit and presence of lenses stratified by visit and presence of

infiltrateinfiltrate

*p value compared to asymptomatic events

No Infiltrative Event

During Infiltrative Event

Any event

Asymptomatic Events

Symptomatic Events

Substantial bacterial bioburden

14%

65%

53%

74%

0.1365*

Substantial lens Substantial lens bioburdenbioburden is associated is associated with at least an 8 fold (800%) increased with at least an 8 fold (800%) increased hazard for a CIE regardless if the CIE is hazard for a CIE regardless if the CIE is

symptomatic or notsymptomatic or not

Sur

viva

l Dis

trib

utio

n F

unct

ion

0.00

0.25

0.50

0.75

1.00

Days

0 100 200 300 400 500

STRAT A: ModerateStain=0 Censored ModerateStain=0

ModerateStain=1 Censored ModerateStain=1

Unadjusted cumulative probability of remaining CIE free Unadjusted cumulative probability of remaining CIE free stratified by presence or absence of at least one episode of stratified by presence or absence of at least one episode of

moderate corneal staining or greater moderate corneal staining or greater

18

Surface Area1. 1 – 15%2. 16-30%3. 31-45%4. >45%

Density1. Very Slight 2. Slight 3. Moderate4.Severe

31

4

2

5

MucinMucin Ball DepressionsBall Depressions

Unadjusted cumulative probability of remaining Unadjusted cumulative probability of remaining CIE free stratified by presence or absence of CIE free stratified by presence or absence of

repeated episodes of repeated episodes of mucinmucin ball formationball formation

Sur

viva

l Dis

trib

utio

n F

unct

ion

0.00

0.25

0.50

0.75

1.00

Days

0 100 200 300 400 500

STRATA: RepeatedMucinBalls=0 Censored RepeatedMucinBalls=0

RepeatedMucinBalls=1 Censored RepeatedMucinBalls=1

Univariate Hazard Ratio0.17 (95% CI 0.06-0.43)

Mucins in healthy tearsAt least 4 of 19 At least 4 of 19 mucinmucin genes found genes found on the ocular surfaceon the ocular surface

–– Soluble MUC5AC secreted by Soluble MUC5AC secreted by goblet cells for viscositygoblet cells for viscosity

–– Membrane spanning Membrane spanning mucinsmucinsMUC1 and MUC16 secreted by MUC1 and MUC16 secreted by corneal and corneal and conjuncitvalconjuncitval epitheliumepitheliumMUC4 secreted by MUC4 secreted by conjunctivalconjunctivalepitheliumepithelium

May represent a different May represent a different mucinmucinprofile which renders a subject less profile which renders a subject less likely to likely to upregulateupregulate the immune the immune response against bacterial response against bacterial ligandsligands

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Risk Factor Analysis for CIERisk Factor Analysis for CIE

CORNEAL STAINING

NOT ASSOCIATED

BACTERIAL CONTAMINATION

8OO% INCREASED RISK

SMOKING

400% INCREASED RISK

MUCIN BALLS

84% DECREASED RISK

What is the rate of What is the rate of Lens, Case and Care System Lens, Case and Care System

Contamination?Contamination?

Lenses: > 50% harbor micro-organisms; 10% pathogenic

Care Systems: All can be contaminated, including up to 30% of preserved products

Cases: >50% contamination

From Microbial Contamination of Contact Lenses and their Accessories: A Literature Review; Szczotka-Flynn, Pearlman, Ghannoum, ECL, March 2010

LASH STUDY:Lens Microbiology

Pathogical organisms found at at least one visit

68%

32%NOYES

20

0 10 20 30 40Frequency (%) of isolation across

all visits

CNSStaph Aureus

Viridans StrepCorynebacterium

HaemophilusStenotrophomonas

BacillusSerratia

Enterobacter cloacaeProteusE. Coli

Pseudomonas FluorescensLactobacillus

Lens Organisms: Frequency (%) of isolation in LASH Study

L Lens

R Lens

Lens ContaminationLens Contamination

The presence of ocular pathogens is typically The presence of ocular pathogens is typically sporadic and unpredictable sporadic and unpredictable Variable opinions on whether silicone Variable opinions on whether silicone hydrogelhydrogellenses differ from traditional lenses differ from traditional pHEMApHEMA lenses in lenses in terms of levels or frequency of bacterial terms of levels or frequency of bacterial colonization colonization in vivoin vivoLens handling greatly increases the incidence of Lens handling greatly increases the incidence of lens contaminationlens contaminationThe ocular surface has a tremendous ability to The ocular surface has a tremendous ability to destroy organismsdestroy organisms

21

The Ocular Immune ResponseThe Ocular Immune Response

Two types of immune response:Two types of immune response:–– InnateInnate

First line of defenseFirst line of defenseRapid onset (minutes)Rapid onset (minutes)Lacks memoryLacks memoryLacks more aggressive response following subsequent exposureLacks more aggressive response following subsequent exposure

–– AdaptiveAdaptiveHumoralHumoral (antibody) and cell mediated pathways(antibody) and cell mediated pathwaysLonger time frame (hours or days)Longer time frame (hours or days)Three phases:Three phases:

–– Antigen recognition and presentation to host T cellsAntigen recognition and presentation to host T cells–– Antigen processing and activation of T and B cells and Antigen processing and activation of T and B cells and effectoreffector

lymphocyteslymphocytes–– Mature cells interact with target antigenMature cells interact with target antigen

Memory! Subsequent exposure generates a more aggressive Memory! Subsequent exposure generates a more aggressive responseresponse

The Innate ResponseThe Innate Response

In the eyes: bony orbit, blink reflex, tear film with In the eyes: bony orbit, blink reflex, tear film with antianti--inflammatory and antiinflammatory and anti--microbial proteins, microbial proteins, commensalcommensal bacteria, tight junctions of corneal bacteria, tight junctions of corneal epithelium, Bepithelium, B--defensinsdefensins, alternate pathway of , alternate pathway of complement, pattern recognition receptorscomplement, pattern recognition receptors

If microbes are present at If microbes are present at the site of an inflammatory the site of an inflammatory

response, how are they response, how are they recognized as recognized as ““foreignforeign””??

22

Innate immunity: activationInnate immunity: activation

Some components of innate host Some components of innate host responses are constitutive and fully or responses are constitutive and fully or partially active at all timespartially active at all times::

––Barrier functions of skin and Barrier functions of skin and mucous membranes (mechanical)mucous membranes (mechanical)

––LysozymesLysozymes , , proteolyticproteolytic enzymes, enzymes, acid, etc which exist in tears, and acid, etc which exist in tears, and other body fluids such as in the other body fluids such as in the stomach (chemical)stomach (chemical)

Other innate defense mechanisms require Other innate defense mechanisms require short term activationshort term activation…………....

How can bacterial initiate the How can bacterial initiate the immune response?immune response?

We live in a virtual sea of bacteria with We live in a virtual sea of bacteria with which we peacefully cowhich we peacefully co--existexist………….most of .most of the time. the time.

Bacteria can cause disease by:Bacteria can cause disease by:–– ““invadinginvading”” a space where they are not a space where they are not

““normallynormally”” foundfound

–– Producing toxinsProducing toxins

–– ImmunopathologyImmunopathology–– sometimes the immune sometimes the immune response response is the diseaseis the disease

Toll Like Receptors (TLRToll Like Receptors (TLR’’s) are s) are A Class of PRRA Class of PRR’’ss

Signaling through various combinations of Signaling through various combinations of TLRTLR’’s activates the epithelial cells to s activates the epithelial cells to produce inflammatory cytokines and produce inflammatory cytokines and chemokineschemokines

The cytokines/The cytokines/chemokineschemokines recruit white recruit white blood cells (mostly blood cells (mostly PMNsPMNs) to the site of ) to the site of insult so they can insult so they can phagocytosephagocytose and kill the and kill the microbemicrobe

23

HypoHypo--methylatedmethylated CpGCpG((bacterial) DNA

TLR9TLR9

Bacterial flagellinTLR5TLR5

LPS, , TaxolTaxol, HSP60, , HSP60, fibronectinfibronectin extra domain A, extra domain A, respiratory respiratory syncytialsyncytial virus F virus F proteinprotein

TLR4TLR4

Double stranded (viral) RNADouble stranded (viral) RNATLR3TLR3

Bacterial LipoproteinsBacterial Lipoproteins, , PeptidoglycanPeptidoglycan, , ZymosanZymosan(Yeast), GPI anchor of T (Yeast), GPI anchor of T cruzicruzi, , some bacterial LPSsome bacterial LPS, , LipoarabinomannanLipoarabinomannan and and phosphotidylinositolphosphotidylinositoldimanosidedimanoside (MTB) (MTB)

TLR2 + TLR6 TLR2 + TLR6

Underhill & Ozinsky, Current Opinion Immunol,14: 103-110, 2002

Bacterial plasma membranes are surrounded by a cell wall composed of a repeating polymer of peptides and sugars (peptidylglycan). The cell wall is relatively thin in Gram negative bacteria and thicker in Gram positive Bacteria

(CpG DNA)

Several Bacterial components such Peptidlyglycan, LPS, and bacterial DNA serve as TLR ligands which can initiate innate inflammatory responses

Gram - Gram +

Underhill & Ozinsky, Current Opinion Immunol,14: 103-110, 2002

24

Mouse model of Contact lens Mouse model of Contact lens associated corneal inflammationassociated corneal inflammation

Epithelial abrasionEpithelial abrasion2 2 µµl LPS or other microbial l LPS or other microbial product added to corneal product added to corneal surfacesurface

–– 2mm diameter punch from 2mm diameter punch from contact lens placed on ocular contact lens placed on ocular surface 2h surface 2h

–– Or soak CL in LPSOr soak CL in LPSLens removed, mice wake upLens removed, mice wake upMeasure CXC Measure CXC chemokineschemokines at 6 at 6 hourshours

–– Dissect and ELISADissect and ELISANeutrophilNeutrophil infiltration to corneal infiltration to corneal stroma, corneal thickness and stroma, corneal thickness and haze at 24 hourshaze at 24 hours

–– ConfocalConfocal microscopy to microscopy to measure infiltratemeasure infiltrate

–– ImmunohistochemistryImmunohistochemistry for for neutrophilsneutrophils

25

Normal C57Bl/6 LPS treated C57BL/6

Central corneal stroma 24h Central corneal stroma 24h after topical exposure to LPSafter topical exposure to LPS

Infiltrates evident, highly refractile cells

TreatmentTreatment

AntibioticsAntibiotics

SteroidsSteroids

Removal of antigen/removal of CLRemoval of antigen/removal of CL

Prevention, Prevention, Prevention, Prevention, PreventionPrevention

26

PreventionPrevention

Lid Hygiene?Lid Hygiene?

Antibacterial coated lenses?Antibacterial coated lenses?

Antibacterial coated cases?Antibacterial coated cases?

Antimicrobial CasesAntimicrobial CasesDecreased microbial contamination of Decreased microbial contamination of lenses stored in silver ion caselenses stored in silver ion case

Etafilcon A Lens Recovery Plates. Clockwise from Top Left: AQuify MPS-Soaked Lenses in PRO-GUARD Silver Case, ReNu with Moisture Loc-Soaked Lenses in ReNu Case, Opti-Free Express-Soaked Lenses in Opti-Free Case, AQuify MPS-Soaked Lenses in Standard AQuify MPS Case.

Thank youThank you

learning objectives: 1. understand the incidence of ... contact lenses and corneal infiltrates...

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